CN117136052A

CN117136052A - CDK inhibitors and methods of use thereof

Info

Publication number: CN117136052A
Application number: CN202280027277.6A
Authority: CN
Inventors: A·M·泰勒; T·F·布里格斯; N·A·帕邦; J·何; A·莱斯卡姆; A·贝齐奥; C·A·埃万斯; C·G·弗里德里希; B·P·凯利; E·B·克鲁格; R·库鲁库拉苏利亚; T·H·麦克林
Original assignee: Communication Therapy Ltd
Current assignee: Communication Therapy Ltd
Priority date: 2021-02-12
Filing date: 2022-02-11
Publication date: 2023-11-28

Abstract

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods of inhibiting CDK enzyme activity using the compounds and compositions of the present disclosure. The present disclosure also relates to, but is not limited to, methods of treating disorders associated with CDK signaling with the compounds and compositions of the present disclosure.

Description

CDK inhibitors and methods of use thereof

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional application No. 63/149,095 filed on month 2 of 2021, U.S. provisional application No. 63/166,638 filed on month 3 of 2021, U.S. provisional application No. 63/192,627 filed on month 5 of 2021, U.S. provisional application No. 63/250,473 filed on month 9 of 2021, and U.S. provisional application No. 63/292,337 filed on month 21 of 2021, each of which is incorporated herein by reference in its entirety.

Background

Cyclin Dependent Kinases (CDKs) are a family of serine/threonine kinases that are regulated by direct binding to cyclin. CDKs (CDK 1, CDK2, CDK4, CDK 6) were initially discovered to bind to homologous cyclin during specific cell cycle phases, thereby activating their kinase activity and promoting cell cycle progression (Malumbres m.genome Biology 2014). Members of the CDK family (CDK 7, CDK8, CDK9, CDK12, CDK 13) are involved in other biological functions, such as transcriptional control (Chou J. Et al, cancer Discovery 2020).

The cell cycle is initiated following mitogenic stimulation that signals cyclin D expression, binding to CDK4/6, and kinase activation. The active CDK 4/6-cyclin D complex mono-phosphorylates retinoblastoma protein (RB) (tumor suppressor) to initiate cyclin E expression and formation of the active CDK 2-cyclin E complex. Activated CDK 2-cyclin E hyperphosphorylates RB, triggering DNA replication, which is further promoted by CDK 2-cyclin A. Finally, CDK 1-cyclin B and CDK 1-cyclin A coordinate the isolation of replication DNA within the parent cell to complete cell division and form two new daughter cells (Otto, T. And Sicinski, P.Nat Rev Cancer 2017).

Since sustained cell proliferation is a hallmark of cancer, alterations in the pathways that control cell cycle progression are often associated with cancer. In fact, CCNE1 (a gene encoding cyclin E1 protein) is one of the most frequently amplified genes among various cancers including ovarian Cancer, endometrial Cancer, gastric Cancer, cervical Cancer, bladder Cancer, esophageal Cancer, lung Cancer, and breast Cancer (Sanchez-Vega F. Et al, cell 2018; cerami E. Et al, cancer discover 2012). The amplified CCNE1 gene, which leads to overexpression of cyclin E1 protein, is considered an oncogenic driver in those tumors due to the increased CDK 2-cyclin E activity. Notably, CCNE1 amplified or overexpressed tumor cells are dependent on CDK2 activity and thus provide a theoretical basis for targeting CDK2 in this genetically defined patient population (McDonald e.r. et al, cell 2017; au-Yeung g et al, clin Cancer Research 2016). Furthermore, CDK2 activation via cyclin E1 amplification and overexpression is a common resistance mechanism to several approved targeted therapies (e.g., CDK4/6 and HER2 modulators), and thus supports combined targeting of CDK2 with other validated Cancer drivers (Turner N.C. et al, J Clin Oncology 2019; herrera-Abreu M.T. et al, cancer Research 2016; scalteri M. Et al, PNAS 2011).

A variety of pan CDK inhibitors with activity against CDK2 and other CDKs have shown evidence of clinical activity, but they have also shown significant hematopoietic and gastrointestinal toxicity, possibly due to their inhibition of CDK1 (Otto, t. And sibinski, p., nat. Review Cancer 2017; kumar, k.s. et al, blood 2015; shapiro g.i. et al, clin Cancer Research 2001). Although CDK2 activity may not be important for normal cellular function, CDK1 activity is critical in all cells, particularly in the highly proliferating cells of the intestinal and hematopoietic systems (Berchet C. Et al, current Biology 2003; jayapal S.R. et al, haemallogic 2015;Santamaria D. Et al, nature 2007; luS. Et al, tox Sciences 2020).

Disclosure of Invention

In some embodiments, the disclosure encompasses recognizing that CDK selective inhibitor compounds, e.g., CDK2 selective inhibitor compounds, are needed, as well as methods of treating cancer and other disorders with these compounds.

In some embodiments, the present disclosure provides compounds of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein Cy ^A 、Cy ^B Each of Q, W and Z is as defined in the implementations herein as well as in the classes and subclasses.

In some embodiments, the present disclosure provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein Cy ^A 、Cy ^B 、Cy ^C Each of Q and P are as defined in the implementations herein as well as in the categories and subclasses.

In some embodiments, the present disclosure provides compounds of formula II, III, IV, V, VI, VII, VIII or IX:

or a pharmaceutically acceptable salt thereof, wherein Cy ^A 、Cy ^B 、Cy ^C 、Q、P、W、X、Y、R ^Z 、R ^B And n are each as defined in embodiments herein, as well as in classes and subclasses.

In some embodiments, the present disclosure provides compounds of formula X-a, X-b, X-c, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-a, XIII-b, XII-c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, XVIII-c, XIX-a, XIX-b, XIX-c, XX-a, XX-b, XXI-c, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-b, XXV-c, or XXV-c:

or a pharmaceutically acceptable salt thereof, wherein Cy ^A 、Cy ^C Q, Z, W, X, Y and R ^Z As defined in the implementations herein, as well as in the categories and subclasses.

In some embodiments, the present disclosure provides compounds of formula XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII-a, XXVIII-b or XXVIII-c:

Or a pharmaceutically acceptable salt thereof, wherein Cy ^C X, Y and R ^Z As defined in the implementations herein, as well as in the categories and subclasses.

In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent. In some embodiments, the present disclosure provides pharmaceutical compositions comprising compounds of the present disclosure (e.g., formulas II, III, IV, V, VI, VII, VIII, IX, X-a, X-b, X-c, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-b, XIII-c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, XVIII-c, XIX-a, XIX-b, XIX-c, XX-a, XXI-b, XXI-c, XXII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIII-c, XXIV-b, XXIV-c, XXII-a, XXII-b, XXIII-c, XXII-a, XXIII-b, XXIII-c, XXI-c, XXIV-c, XXII-b, XXI-c, XXII-b) or a pharmaceutical compositions of the present disclosure, or pharmaceutical compositions of the present disclosure. In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure (e.g., a compound of formula I-a), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

In some embodiments, the present disclosure provides a method of treating a CDK2 mediated disorder comprising administering to a patient in need thereof a compound of formula I or a composition comprising the same. In some embodiments, the disclosure provides methods of treating a CDK2 mediated disorder, the methods comprise administering to a patient in need thereof a compound of the disclosure (e.g., formula II, III, IV, V, VI, VII, VIII, IX, X-a, X-b, X-c, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-a, XIII-b, XIII-c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, XVIII-c, XIX-a XIX-b, XIX-c, XX-a, XX-b, XX-c, XXI-a, XXI-b, XXI-c, XXII-a, XXII-b, XXII-c, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-a, XXV-b, XXV-c, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII-a, XXVIII-b or XXVIII-c) or a composition comprising said compound. In some embodiments, the present disclosure provides methods of treating a CDK 2-mediated disorder comprising administering to a patient in need thereof a compound of the present disclosure (e.g., a compound of formula I-a) or a composition comprising the compound.

In some embodiments, the present disclosure provides methods for providing a compound of formula I or a synthetic intermediate thereof. In some embodiments, the present disclosure provides methods for providing compounds of the present disclosure (e.g., compounds of formula II, III, IV, V, VI, VII, VIII, IX, X-a, X-b, X-c, XI-a, XI-b, XI-c, XII-a, XII-b, XIII-c, XII-a, XIII-b, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, XVIII-c, XIX-a, XIX-b, XIX-c, XX-a, XX-b, XXI-c, XXII-a, XXII-b, XXIII-c, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXII-b, XXIV-c, XXV-a, XXII-b, XXIII-a, XXIII-c, XXIV-b, XXIV-a, XXII-b, XXIII-c, or a, VI-b) or a combination thereof, of the above. In some embodiments, the present disclosure provides methods for providing a compound of the present disclosure (e.g., a compound of formula I-a) or a synthetic intermediate thereof.

In some embodiments, the present disclosure provides methods for providing pharmaceutical compositions comprising compounds of formula I. In some embodiments of the present invention, in some embodiments, the present disclosure provides methods for providing compositions comprising the present disclosure (e.g., formulas II, III, IV, V, VI, VII, VIII, IX, X-a, X-b, X-c, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-a, XIII-b, XIII-c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, XVIII-c, XIX-a) a compound of XIX-b, XIX-c, XX-a, XX-b, XX-c, XXI-a, XXI-b, XXI-c, XXII-a, XXII-b, XXII-c, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-a, XXV-b, XXV-c, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII-a, XXVIII-b or XXVIII-c). In some embodiments, the present disclosure provides methods for providing pharmaceutical compositions comprising compounds of the present disclosure (e.g., compounds of formula I-a).

Detailed Description

1. General description of certain embodiments

The compounds and pharmaceutical compositions provided herein are useful as inhibitors of CDK 2. In some embodiments, the present disclosure provides compounds of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein:

q is L ¹ ；

Cy ^A Is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^A Except for Q and Cy ^B In addition to being R ^A M example substitutions of (a);

Cy ^B is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a phenylene group; or a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^B Removing Cy ^A And Z is also covered by R ^B N example substitutions of (a);

z is hydrogen or L ² -R ^Z ；

R ^Z Is hydrogen or an optionally substituted group selected from the group consisting of: c (C) _1-8 Aliphatic, saturated or partially unsaturated 3-to 14-membered carbocyclic ring, phenyl, 3-to 10-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-to 14-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

w is hydrogen or Cy ^C ；

Cy ^C Is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a phenyl group; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^C Is also denoted by R in addition to Q ^C P example substitutions of (a);

R ^A 、R ^B and R is ^C Each instance of (2) is independently R ¹ Or R is ² Wherein R is ^A Quilt R ³ Q of (2) ^A Example substitution, R ^B Quilt R ³ Q of (2) ^B Substituted by examples, and R ^C Quilt R ³ Q of (2) ^C Example substitution; or (b)

R ^A Is shown in (1), R ^B Is shown in (1), R ^C Is shown in (1), R ^A And R ^L Or R ^C And R ^L Together with intervening atoms, form a 4-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic ring is R ³ R example substitutions of (a);

L ¹ and L ² Each of which is independently a covalent bond, or C _1-5 Saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently replaced by: -CH (R) ^L )-、-C(R ^L ) ₂ -、C _3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N (R) ^L )-、-NHC(O)-、-N(R ^L )C(O)-、-C(O)NH-、-C(O)N(R ^L )-、-NHS(O) ₂ -、-N(R ^L )S(O) ₂ -、-S(O) ₂ NH-、-S(O) ₂ N(R ^L ) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -S (O) -or-S (O) ₂ -; wherein said C _3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with R ¹ Or C _1-6 Aliphatic group substitution;

R ^L each instance of (2) is independently R ¹ Or R is ² And is R ³ T example substitutions of (a);

R ¹ Is independently oxo, halogen, -CN, -NO ₂ 、-OR、-SR、-NR ₂ 、-S(O) ₂ R、-S(O) ₂ NR ₂ 、-S(O)R、-S(O)NR ₂ 、-C(O)R、-C(O)OR、-C(O)NR ₂ 、-C(NR)NR ₂ 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR ₂ 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(NR)R、-N(R)C(O)NR ₂ 、-N(R)C(NR)NR ₂ 、-N(R)S(O) ₂ NR ₂ -N (R) S (O) R or-N (R) S (O) ₂ R；

R ² Each instance of (2) is independently C _1-7 An aliphatic group; a phenyl group; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ³ is independently oxo, halogen, -CN, -NO ₂ 、-OR、-SR、-NR ₂ 、-S(O) ₂ R、-S(O) ₂ NR ₂ 、-S(O)R、-S(O)NR ₂ 、-S(O) ₂ F、-OS(O) ₂ F、-C(O)R、-C(O)OR、-C(O)NR ₂ 、-C(NR)NR ₂ 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR ₂ 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(NR)R、-N(R)C(O)NR ₂ 、-N(R)C(NR)NR ₂ 、-N(R)S(O) ₂ NR ₂ 、-N(R)S(O)R、-N(R)S(O) ₂ R or an optionally substituted group selected from: c (C) _1-6 Aliphatic, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

each R is independently hydrogen or an optionally substituted group selected from: c (C) _1-6 Aliphatic, saturated or partially unsaturated 3-to 7-membered carbocyclic ring, phenyl, 3-to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen together with the intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and is also provided with

m、n、p、q ^A 、q ^B 、q ^C Each of r and t is independently 0, 1, 2, 3 or 4.

In some embodiments, the present disclosure provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

q is L ¹ ；

Cy ^B is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a phenylene group; or a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^B Removing Cy ^A And P is also covered by R ^B N example substitutions of (a);

p is hydrogen or-L ² -R ^P ；

R ^P Is R;

R ^A Is shown in (1), R ^B Is shown in (1), R ^C Is shown in (1), R ^A And R ^L Or R ^C And R ^L One example of (2) andthe intervening atoms together form a 4-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic ring is R ³ R example substitutions of (a);

R ² Each instance of (2) is independently C _1-7 An aliphatic group; a phenyl group; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocycle; with 1-2 independent choices3-7 membered saturated or partially unsaturated monocyclic heterocycles from heteroatoms of nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Two R groups on the same nitrogen together with the intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

or a pharmaceutically acceptable salt thereof, wherein:

q is L ¹ ；

Cy ^B is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a phenylene group; or a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^B Removing Cy ^A And P or X are also covered by R ^B N example substitutions of (a);

x is selected from O, NR ^X And S;

y is selected from O, NR ^Y And S;

R ^X and R is ^Y Independently R;

P is hydrogen or-L ² -R ^P ；

R ^P Is R;

w is hydrogen or Cy ^C ；

Cy ^C Is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl, or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^C Is also covered by other than QR ^C P example substitutions of (a);

2. Compounds and definitions

The compounds described herein include those generally set forth herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of this disclosure, chemical elements are identified according to the periodic table of the elements (CAS version), handbook of Chemistry and Physics, 75 th edition. Furthermore, the general principles of organic chemistry are described in the following documents: "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999 and "March's Advanced Organic Chemistry", 5 th edition, smith, m.b. and March, j. Editions, john Wiley & Sons, new york:2001, the entire contents of which are hereby incorporated by reference. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If both chemical structure and chemical name are used to refer to a compound, and there is ambiguity between the structure and name, the structure is subject to control.

The term "aliphatic" or "aliphatic group" as used herein means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a mono-or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" or "alicyclic") having a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms. In the case of a further embodiment of the present invention,the aliphatic group contains 1 to 4 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle") refers to a monocyclic C that is fully saturated or contains one or more unsaturated units ₃ -C ₆ Hydrocarbons, but not aromatic, have a single point attached to the remainder of the molecule. In some cases, the carbocycle may be a bridged bicyclic or fused ring, such as an ortho-fused carbocycle, a spiro-fused carbocycle, and the like. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.

The term "alkyl" as used herein, unless otherwise indicated, refers to a monovalent aliphatic hydrocarbon radical having a straight chain, branched chain, monocyclic or polycyclic moiety or combination thereof, wherein said radical is optionally substituted on each carbon by one or more substituents on one or more carbons of said straight chain, branched chain, monocyclic or polycyclic moiety or combination thereof, wherein said one or more substituents are independently C ₁ -C ₁₀ An alkyl group. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and the like.

The term "lower alkyl" refers to C _1-4 Linear or branched alkyl. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

The term "lower haloalkyl" refers to C substituted with one or more halogen atoms _1-4 Linear or branched alkyl.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternary ammonium forms of any basic nitrogen; or heterocyclic substitutable nitrogen, such as N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (e.g. in N-fetch)Substituted pyrrolidinyl)).

The term "unsaturated" as used herein means that the moiety has one or more unsaturated units.

The term "alkylene" refers to a divalent alkyl group. "alkylene chain" is polymethylene, i.e., - (CH) ₂ ) _n -wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those set forth below for substituted aliphatic groups.

The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those set forth below for substituted aliphatic groups.

The term "halogen" means F, cl, br or I.

The term "aryl" used alone or as part of a larger moiety refers to a mono-or bi-cyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the compounds described herein, "aryl" refers to an aromatic ring system that may bear one or more substituents, including, but not limited to, phenyl, naphthyl, anthracenyl, and the like. It should be appreciated that an "aryl" group may comprise carbon and heteroatom ring members.

The term "heteroaryl" or "heteroaromatic" as used herein, unless otherwise defined, refers to a monocyclic aromatic 5-6 membered ring containing one or more heteroatoms (e.g., 1 to 4 heteroatoms such as nitrogen, oxygen, and sulfur), or an 8-10 membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring in the polycyclic ring system is aromatic and the point of attachment of the polycyclic ring system is through a ring atom on the aromatic ring. The heteroaryl ring may be attached to the adjacent group through carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, and the like. For example, unless otherwise defined, if the point of attachment of a 1,2,3, 4-tetrahydroquinoline is through a benzo ring, it is a heteroaryl ring, for example:

unless otherwise defined, the term "heterocyclyl" or "heterocyclic group" refers to a saturated or partially unsaturated 3-10 membered monocyclic or 7-14 membered polycyclic ring system including bridged or fused rings (e.g., ortho-fused bicyclic or spiro-fused bicyclic) and whose ring system includes 1 to 4 heteroatoms, such as nitrogen, oxygen, and sulfur. The heterocyclyl ring may be attached to the adjacent group through carbon or nitrogen.

The term "partially unsaturated" in the context of a ring refers to a constituent ring within a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the constituent ring contains at least one unsaturation other than that provided by the ring itself, but which is not aromatic, unless otherwise defined. Examples of partially unsaturated rings include, but are not limited to, 3, 4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, and the like. Where the partially unsaturated ring is part of a polycyclic ring system, the other constituent rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on the partially unsaturated constituent ring. For example, unless otherwise defined, if the point of attachment of 1,2,3, 4-tetrahydroquinoline is through piperidinyl, it is a partially unsaturated ring, for example:

the term "saturated" in the context of a ring refers to a 3-10 membered monocyclic or 7-14 membered polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the monocyclic or constituent ring, which is the point of attachment for the polycyclic system, contains no additional unsaturation beyond that provided by the ring itself, unless otherwise defined. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, and the like. Where the saturated ring is part of a polycyclic ring system, the other constituent rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on the saturated constituent ring. For example, unless otherwise defined, if the point of attachment of 2-azaspiro [3.4] oct-6-ene is through an azetidinyl ring, it is a saturated ring, such as:

The terms "alkylene", "arylene", "cycloalkylene", "heteroarylene", "heterocycloalkylene" and other similar terms having the suffix "-subunit" as used herein refer to the divalent bonding form of the suffix-modified group. For example, "alkylene" is a divalent alkyl group that connects the groups to which it is attached.

As used herein, the term "bridged bicyclic" refers to any bicyclic system having at least one bridge, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or a bond connecting two bridgeheads, wherein a "bridgehead" is any backbone atom (excluding hydrogen) in a ring system bonded to three or more backbone atoms. In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those described below, wherein each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents as described for the aliphatic group. Additionally or alternatively, any substitutable nitrogen bridging the bicyclic group is optionally substituted. An exemplary bridged bicyclic ring includes:

As described herein, the compounds described herein may contain an "optionally substituted" moiety. In general, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and where more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents at each position may be the same or different. Combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to the following compounds: without substantial change when subjected to conditions that permit its production, detection, and in certain embodiments its recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on the substitutable carbon atom of an "optionally substituted" group are independently halogen; - (CH) ₂ ) _0-4 R ^o ；-(CH ₂ ) _0-4 OR ^o ；-O(CH ₂ ) _0-4 R ^o 、-O-(CH ₂ ) _0-4 C(O)OR ^o ；-(CH ₂ ) _0-4 CH(OR ^o ) ₂ ；-(CH ₂ ) _0- ₄ SR ^o ；-(CH ₂ ) _0-4 Ph, which may be R ^o Substitution; - (CH) ₂ ) _0-4 O(CH ₂ ) _0-1 Ph, which may be R ^o Substitution; -ch=chph, which may be R ^o Substitution; - (CH) ₂ ) _0-4 O(CH ₂ ) _0-1 -pyridinyl, which may be substituted by R ^o Substitution; -NO ₂ ；-CN；-N ₃ ；-(CH ₂ ) _0-4 N(R ^o ) ₂ ；-(CH ₂ ) _0-4 N(R ^o )C(O)R ^o ；-N(R ^o )C(S)R ^o ；-(CH ₂ ) _0-4 N(R ^o )C(O)NR ^o ₂ ；-N(R ^o )C(S)NR ^o ₂ ；-(CH ₂ ) _0-4 N(R ^o )C(O)OR ^o ；-N(R ^o )N(R ^o )C(O)R ^o ；-N(R ^o )N(R ^o )C(O)NR ^o ₂ ；-N(R ^o )N(R ^o )C(O)OR ^o ；-(CH ₂ ) _0-4 C(O)R ^o ；-C(S)R ^o ；-(CH ₂ ) _0-4 C(O)OR ^o ；-(CH ₂ ) _0-4 C(O)SR ^o ；-(CH ₂ ) _0-4 C(O)OSiR ^o ₃ ；-(CH ₂ ) _0-4 OC(O)R ^o ；-OC(O)(CH ₂ ) _0-4 SR ^o ；-SC(S)SR ^o ；-(CH ₂ ) _0-4 SC(O)R ^o ；-(CH ₂ ) _0-4 C(O)NR ^o ₂ ；-C(S)NR ^o ₂ ；-C(S)SR ^o ；-SC(S)SR ^o 、-(CH ₂ ) _0-4 OC(O)NR ^o ₂ ；-C(O)N(OR ^o )R ^o ；-C(O)C(O)R ^o ；-C(O)CH ₂ C(O)R ^o ；-C(NOR ^o )R ^o ；-(CH ₂ ) _0-4 SSR ^o ；-(CH ₂ ) _0-4 S(O) ₂ R ^o ；-(CH ₂ ) _0-4 S(O) ₂ OR ^o ；-(CH ₂ ) _0-4 OS(O) ₂ R ^o ；-S(O) ₂ NR ^o ₂ ；-(CH ₂ ) _0-4 S(O)R ^o ；-N(R ^o )S(O) ₂ NR ^o ₂ ；-N(R ^o )S(O) ₂ R ^o ；-N(OR ^o )R ^o ；-C(NH)NR ^o ₂ ；-P(O)(OR ^o )R ^o ；-P(O)R ^o ₂ ；-OP(O)R ^o ₂ ；-OP(O)(OR ^o ) ₂ ；-SiR ^o ₃ ；-(C _1-4 Linear or branched alkylene) O-N (R) ^o ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or- (C) _1-4 Straight or branched chain alkylene) C (O) O-N (R) ^o ) ₂ Wherein each R is ^o May be substituted as defined below and independently hydrogen, C _1-6 Aliphatic radical, -CH ₂ Ph、-O(CH ₂ ) _0-1 Ph、-CH ₂ - (5-6 membered heteroaryl ring), or 3-6 membered saturated, partially unsaturated, or having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfurAryl ring, or R, although defined above, two independently occurring ^o Together with intervening atoms, form a 3-to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

R ^o (or by two independently-occurring R' s ^o Ring formed with intervening atoms) is independently halogen, - (CH) ₂ ) _0-2 R ^· - (halo R) ^· )、-(CH ₂ ) _0-2 OH、-(CH ₂ ) _0-2 OR ^· 、-(CH ₂ ) _0-2 CH(OR ^· ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the -O (halo R) ^· )、-CN、-N ₃ 、-(CH ₂ ) _0-2 C(O)R ^· 、-(CH ₂ ) _0-2 C(O)OH、-(CH ₂ ) _0-2 C(O)OR ^· 、-(CH ₂ ) _0-2 SR ^· 、-(CH ₂ ) _0- ₂ SH、-(CH ₂ ) _0-2 NH ₂ 、-(CH ₂ ) _0-2 NHR ^· 、-(CH ₂ ) _0-2 NR ^· ₂ 、-NO ₂ 、-SiR ^· ₃ 、-OSiR ^· ₃ 、-C(O)SR ^· 、-(C _1-4 Straight-chain OR branched alkylene) C (O) OR ^· or-SSR ^· Wherein each R is ^· Unsubstituted or substituted with one or more halogens only when preceded by a "halo" group, and is independently selected from C _1-4 Aliphatic radical, -CH ₂ Ph、-O(CH ₂ ) _0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. R is R ^o Suitable divalent substituents on saturated carbon atoms of (c) include =o and =s.

Suitable divalent substituents on the saturated carbon atoms of an "optionally substituted" group include the following: =o, =s, =nnr ^* ₂ 、＝NNHC(O)R ^* 、＝NNHC(O)OR ^* 、＝NNHS(O) ₂ R ^* 、＝NR ^* 、＝NOR ^* 、-O(C(R ^* ₂ )) _2-3 O-or-S (C (R) ^* ₂ )) _2-3 S-, wherein each independently occurs R ^* Selected from hydrogen, C which may be substituted as defined below _1-6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to ortho-substitutable carbons of an "optionally substituted" group include: -O (CR) ^* ₂ ) _2-3 O-, wherein each independently occurs R ^* Selected from hydrogen, C which may be substituted as defined below _1-6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

R ^* Suitable substituents on the aliphatic group of (C) include halogen, -R ^· - (halo R) ^· )、-OH、-OR ^· (halo R) ^· )、-CN、-C(O)OH、-C(O)OR ^· 、-NH ₂ 、-NHR ^· 、-NR ^· ₂ or-NO ₂ Wherein each R is ^· Unsubstituted or substituted with one or more halogen groups only when preceded by a "halo" group, and is independently C _1-4 Aliphatic radical, -CH ₂ Ph、-O(CH ₂ ) _0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the substitutable nitrogen of an "optionally substituted" group include Or->Each of which is->C independently is hydrogen, which may be substituted as defined below _1-6 Aliphatic, unsubstituted-OPh or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occurring in spite of the above definition>Together with one or more intervening atoms thereof form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic groups of (2) are independently halogen, -R ^· - (halo R) ^· )、-OH、-OR ^· (halo R) ^· )、-CN、-C(O)OH、-C(O)OR ^· 、-NH ₂ 、-NHR ^· 、-NR ^· ₂ or-NO ₂ Wherein each R is ^· Unsubstituted or substituted with one or more halogen groups only when preceded by a "halo" group, and is independently C _1-4 Aliphatic radical, -CH ₂ Ph、-O(CH ₂ ) _0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

The term "isomer" as used herein refers to compounds of the same chemical formula but differing in structure or optical configuration. The term "stereoisomer" as used herein refers to and includes heterogeneous molecules having the same molecular formula but where atoms and/or functional groups are spatially located differently. All stereoisomers (e.g., those that may exist due to asymmetric carbons on various substituents) of the compounds of the invention, including enantiomeric and diastereomeric forms, are contemplated within the scope of the disclosure. Thus, unless otherwise indicated, single stereochemical isomers as well as mixtures of enantiomers, diastereomers and geometric (or conformational) isomers of the compounds of the invention are within the scope of the present disclosure.

The term "tautomer" as used herein refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as proton transfer tautomers). Valence tautomers include the interconversion of some bonded electrons by recombination. Proton tautomers include interconversions via proton transfer, such as keto-enol and imine-enamine isomerisation. Unless otherwise indicated, all tautomers of the compounds described herein are within the scope of the disclosure.

The term "isotopically substituted" as used herein means that an atom is replaced by its isotope. The term "isotope" as used herein refers to an atom having the same atomic number as the atomic number of an atom dominant in nature but having a mass number (neutron number) different from the mass number of an atom dominant in nature. It is understood that a compound having isotopic substitution refers to a compound in which at least one of the atoms contained is replaced by its isotope. Atoms that may be isotopically substituted include, but are not limited to, hydrogen, carbon, and oxygen. Examples of isotopes of hydrogen atoms include ² H (also denoted as D) and ³ H. examples of isotopes of carbon atoms include ¹³ C and C ¹⁴ C. Examples of isotopes of oxygen atoms include ¹⁸ O. Unless otherwise indicated, all isotopic substitutions of the compounds described herein are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, probes in bioassays, or therapeutic agents according to the present disclosure.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Exemplary pharmaceutically acceptable salts are found, for example, in Berge et al, j.pharm.sci.1977,66 (1), 1; and Gould, P.L., int.J.Pharmaceutics 1986,33,201-217 (each hereby incorporated by reference in its entirety).

Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with: inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid; or an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; or salts formed by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartate, benzenesulfonates, benzoates, bisulphates, borates, butyrates, camphorinates, camphorsulphonates, citrates, cyclopentanepropionates, digluconates, dodecylsulphates, ethanesulphonates, formates, fumarates, glucoheptonates, glycerophosphate, gluconate, hemisulphates, heptanonates, caprates, hydroiodinates, 2-hydroxy-ethanesulphonates, lactonates, lactates, laurates, lauryl sulphates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulphonates, nicotinates, nitrates, oleates, oxalates, palmates, pamonates, pectinates, persulphates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulphates, tartrates, thiocyanates, p-toluene sulphonates, undecanoates, valerates and the like.

Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N ⁺ (C _1-4 Alkyl group ₄ And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include nontoxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate, as appropriate.

Pharmaceutically acceptable salts are also intended to cover half salts, wherein the ratio of compound to acid is 2:1, respectively. Exemplary half salts are those derived from acids containing two carboxylic acid groups (e.g., malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid). Other exemplary hemi-salts are those derived from a di-protic mineral acid (e.g., sulfuric acid). Exemplary preferred hemi-salts include, but are not limited to, hemi-maleate, hemi-fumarate, and hemi-succinate.

As used herein, the term "about" is used herein to refer to about, approximately, about, or near. When the term "about" is used in connection with a range of values, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value to vary above and below (either higher or lower) 20% of the stated value.

An "effective amount," "sufficient amount," or "therapeutically effective amount" as used herein is an amount of a compound that is sufficient to treat (e.g., achieve a beneficial or desired result, including a clinical result) a disease, disorder, and/or condition when administered to a subject or population suffering from or susceptible to the disease, disorder, and/or condition according to a therapeutic dosing regimen. Thus, an effective amount may be sufficient, for example, to reduce or ameliorate the severity and/or duration of an affliction or one or more symptoms thereof associated with CDK2 signaling, prevent progression of a condition or symptom associated with an affliction associated with CDK2 signaling, or enhance or otherwise improve one or more prophylactic or therapeutic effects of another therapy. An effective amount also includes an amount of a compound that avoids or substantially reduces undesirable side effects.

As used herein and as fully understood in the art, "treatment" is a method for achieving a beneficial or desired result, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease or illness, stabilized (i.e., not worsening) state of disease or illness, preventing spread of disease or illness, delaying or slowing of disease or illness progression, amelioration or palliation of the disease or illness state, and remission (whether partial or total), whether detectable or undetectable. "treatment" may also mean prolonged survival compared to the expected survival when not receiving treatment. In some embodiments, the treatment may be administered after one or more symptoms have occurred. In other embodiments, the treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to onset of symptoms (e.g., in view of a history of symptoms and/or in view of genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, for example, to prevent or delay recurrence thereof.

The phrase "in need thereof" refers to a need for symptomatic or asymptomatic relief from a condition associated with CDK2 signaling activity or that can be alleviated by the compounds and/or compositions of the present disclosure.

3. Description of exemplary embodiments

In some embodiments, the present disclosure provides compounds of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein:

q is L ¹ ；

z is hydrogen or L ² -R ^Z ；

R ^Z Is hydrogen or an optionally substituted group selected from the group consisting of: c (C) _1-8 Aliphatic, saturated or partially unsaturated 3-to 14-membered carbocyclic ring, phenyl, 3-to 10-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur A 5-14 membered heteroaryl ring;

w is hydrogen or Cy ^C ；

m、n、p、q ^A 、q ^B 、q ^C 、q ^Z Each of r and t is independently 0, 1, 2, 3 or 4.

As described above, in some embodiments, the present disclosure provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

q is L ¹ ；

p is hydrogen or-L ² -R ^P ；

R ^P Is R;

Cy ^C is a saturated or partially unsaturated 3-14 membered carbocyclic ring; having 1 to 4 groups independently selected from nitrogen, oxygen andsaturated or partially unsaturated 3-14 membered heterocyclic ring of sulfur heteroatom; a phenyl group; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^C Is also denoted by R in addition to Q ^C P example substitutions of (a);

Each R is independently hydrogen or an optionally substituted group selected from: c (C) _1-6 Aliphatic, saturated or partially unsaturated 3-to 7-membered carbocyclic ring, phenyl, having 1 to 2 groups independently selected from nitrogen, oxygen anda 3-7 membered saturated or partially unsaturated heterocycle of a heteroatom of sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

As described above, in some embodiments, the present disclosure provides compounds of formula II, III, IV, V, VI or VII:

or a pharmaceutically acceptable salt thereof, wherein:

q is L ¹ ；

x is selected from O, NR ^X And S;

y is selected from O, NR ^Y And S;

R ^X and R is ^Y Independently R;

p is hydrogen or-L ² -R ^P ；

R ^P Is R;

w is hydrogen or Cy ^C ；

Cy ^C Is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl, or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^C Is also denoted by R in addition to Q ^C P example substitutions of (a);

In some embodiments of formulas VIII, IX, X-a, X-b, X-c, XII-a, XII-b, XII-c, XIV-a, XIV-b, XIV-c, XVI-a, XVI-b, XVI-c, XIX-a, XIX-b, XIX-c, XXI-a, XXI-b, or XXI-c, W is Cy ^C 。

In some embodiments of formulas X-a, X-b, X-c, XI-a, XI-b, XI-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, or XVIII-c, wherein Z is L ² -R ^Z Wherein:

R ^Z is hydrogen or an optionally substituted group selected from the group consisting of: c (C) _1-6 Aliphatic, saturated or partially unsaturated 3-to 7-membered carbocyclic ring, phenyl, 3-to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and is also provided with

L ² As defined in the embodiments and classes and subclasses herein.

In some embodiments of formulas XII-a, XII-b, XII-c, XIII-a, XIII-b, XIII-c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XIX-a, XIX-b, XIX-c, XX-a, XX-b, XX-c, XXI-a, XXI-b, XXI-c, XXII-a, XXII-b, XXII-c, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-a, XXV-b or XXV-c In the scheme, R ^Z Is hydrogen or an optionally substituted group selected from the group consisting of: c (C) _1-6 Aliphatic, saturated or partially unsaturated 3-to 7-membered carbocyclic ring, phenyl, 3-to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

Cy, as generally defined above ^A Is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^A Except for Q and Cy ^B In addition to being R ^A M example substitutions of (a). In some embodiments, cy ^A Is that Wherein->Represents a covalent bond with Q and->Representation and Cy ^B Is a covalent bond of (c). In some embodiments, cy ^A Is->In some embodiments, cy ^A Is->In some embodiments, cy ^A Is->In some embodiments, cy ^A Is->In some embodiments, cy ^A Is- >In some embodiments, cy ^A Is->In some embodiments, cy ^A Is thatIn some embodiments, cy ^A Is->In some embodiments, cy ^A Is thatIn some embodiments, cy ^A Is->In some embodiments, cy ^A Is->In some embodiments, cy ^A Is->In some embodiments, cy ^A Is->In some embodiments, cy ^A Selected from the groups depicted in the compounds in table 1.

Cy, as generally defined above ^B Is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a phenylene group; or a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^B Removing Cy ^A And P is also covered by R ^B N example substitutions of (a). In some embodiments of any of formulas II, III, IV, V, VI and VII, cy ^B Is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a phenylene group; or a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^B Removing Cy ^A And P or X are also covered by R ^B N example substitutions of (a). In some embodiments of formula I-A, cy ^B Is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a phenylene group; or a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^B Removing Cy ^A And Z is also covered by R ^B N example substitutions of (a).

In some embodiments, cy ^B Is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, cy ^B Is a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^B Is phenylene. In some embodiments, cy ^B Is a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, cy ^B Is a 3-7 membered saturated carbocyclic ring. In some embodiments, cy ^B Is a cyclopropylene ring. In some embodiments, cy ^B A cyclobutylidene ring. In some embodiments, cy ^B Is a cyclopentylene ring. In some embodiments, cy ^B Is a cyclohexylidene ring. In some embodiments, cy ^B Is a cycloheptylene ring.

In some embodiments, cy ^B Is that Wherein->Representation and Cy ^A Covalent bond of >Representing a covalent bond with P, X or Z. In some embodiments, cy ^B Is->In some embodiments, cy ^B Is->In some embodiments, cy ^B Is thatIn some embodiments, cy ^B Is->In some embodiments, cy ^B Is->In some embodiments, cy ^B Is->In some embodiments, cy ^B Is->In some embodiments, cy ^B Is->In some embodiments, cy ^B Is->

At Cy ^B In some embodiments of (2), cy ^A And P, X or Z are in trans relationship. At Cy ^B In some embodiments of (2), cy ^A And P, X or Z are in cis relationship. See, e.g., cy depicted in the compounds in table 1 ^B A group.

In some embodiments, cy ^B Is a 5-8 membered saturated or partially unsaturated bridged bicyclic or fused carbocyclic ring. In some embodiments, cy ^B Is a 5-8 membered saturated bridged bicyclic or fused carbocyclic ring. In some embodiments, cy ^B Is a 6-7 membered saturated bridged bicyclic or fused carbocyclic ring. In some embodiments, cy ^B Is thatWherein->Representation and Cy ^A Covalent bond of>Representing a covalent bond with P, X or Z. In some embodiments, cy ^B Is->In some embodiments, cy ^B Is that

In some embodiments, cy ^B Is a 3-7 membered partially unsaturated carbocyclic ring. In some embodiments, cy ^B Is a 5-6 membered partially unsaturated carbocyclic ring. In some embodiments, cy ^B Is thatIn some embodiments, cy ^B Is->

In some embodiments, cy ^B Is a saturated or partially unsaturated 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^B Is a saturated 3-7 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^B Is a saturated 4-7 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, cy ^B Is that Wherein->Representation and Cy ^A Covalent bond of>Representing a covalent bond with P, X or Z.

In some embodiments, cy ^B Is thatIn some embodiments, cy ^B Is->In some embodiments, cy ^B Is->In some embodiments, cy ^B Is->In some embodiments, cy ^B Is->In some embodiments, cy ^B Is->In some embodiments, cy ^B Is->In some embodiments, cy ^B Is->

In some embodiments, cy ^B Is a 5-14 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^B Is a 9-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^B Selected from the group consisting of

In some embodiments, cy ^B Is a saturated 6-10 membered bridged bicyclic or fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^B Is a saturated 6-10 membered bridged bicyclic or fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^B Is a saturated 6-10 membered bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^B Is a saturated 7-8 membered bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, cy ^B Is a saturated or partially unsaturated 6-10 membered spiro-fused heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^B Is a saturated or partially unsaturated 6-9 membered spiro-fused heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, cy ^B Is that Wherein->Representation and Cy ^A Covalent bond of>Representing a covalent bond with P, X or Z. In some embodiments, cy ^B Is thatIn some embodiments, cy ^B Is->In some embodiments, cy ^B Is thatIn some embodiments, cy ^B Is->In some embodiments, cy ^B Is thatIn some embodiments, cy ^B Is->

In some embodiments, cy ^B Selected from the groups depicted in the compounds in table 1.

P is hydrogen or-L, as defined generally above ² -R ^P Wherein L is ² And R is ^P As defined in the implementations herein, as well as in the categories and subclasses. In some embodiments, P is hydrogen. In some embodiments, P is-L ² -R ^P . In some embodiments, P is-OR ^P 、-NHR ^P 、-SR ^P 、-NHC(O)NHR ^P 、-OC(O)NHR ^P and-NHC (O) OR ^P 。

In some embodiments, P is-XC (O) YR ^P Wherein X, Y and R ^P As defined in the implementations herein, as well as in the categories and subclasses. In some embodiments, each P is selected from the groups depicted in the compounds in table 1.

Z is hydrogen or-L, as defined generally above ² -R ^Z Wherein L is ² And R is ^Z As defined in the implementations herein, as well as in the categories and subclasses. In some embodiments, Z is hydrogen. In some embodiments, Z is-L ² -R ^Z . In some embodiments, Z is-OR ^Z 、-NHR ^Z 、-SR ^Z 、-NHC(O)NHR ^Z 、-OC(O)NHR ^Z and-NHC (O) OR ^Z . In some embodiments, each Z is selected from the groups depicted in the compounds in table 1.

R is as defined generally above ^P Is R, wherein R is as defined in embodiments and classes and subclasses herein. In some embodiments, R ^P Is hydrogen or an optionally substituted group selected from the group consisting of: c (C) _1-6 Aliphatic, saturated or partially unsaturated 3-to 7-membered carbonA ring, a phenyl group, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^P Is hydrogen. In some embodiments, R ^P Is optionally substituted C _1-6 Aliphatic groups. In some such embodiments, R ^P Is optionally substituted C _1-4 Aliphatic groups. In some embodiments, R ^P is-CH ₃ 、-CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ or-CH ₂ CH(CH ₃ ) ₂ 、-C(CH ₃ ) ₃ 、 In some embodiments, R ^P Is optionally covered by-R ^o OR-OR ^o Substituted C _1-6 Aliphatic groups. In some embodiments, R ^P Is->In some embodiments, R ^P Is->Wherein R is ^o is-OR ^o or-N (R) ^o ) ₂ . In some embodiments, R ^P Is->In some embodiments, R ^P Is->In some embodiments, R ^P Is->

In some embodiments, R ^P Is an optionally substituted saturated or partially unsaturated 3-7 membered carbocyclic ring. In some embodiments, R ^P Is an optionally substituted saturated 3-membered carbocyclic ring. In some such embodiments, R ^P Is thatIn some such embodiments, R ^o Optionally substituted with halogen.

In some embodiments, R ^P Is an optionally substituted phenyl ring. In some embodiments, R ^P Is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^P Is an optionally substituted 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some such embodiments, R ^P Is thatIn some such embodiments, R ^P Is->

In some embodiments, R ^P Is an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^P Is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some such embodiments, R ^P Is thatIn some such embodiments, R ^P Is->

In some embodiments, R ^P Is an optionally substituted 6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some such embodiments, R ^P Is that

In some embodiments, R ^P Is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^P Is an optionally substituted 5 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^P Is an optionally substituted 6 membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R ^P Selected from optionally substituted isothiazolyl, pyridinyl or pyridazinyl. In some such embodiments, R ^P Is that

In some embodiments, R ^P Selected from the groups depicted in the compounds in table 1.

R is as defined generally above ^Z Is hydrogen or an optionally substituted group selected from the group consisting of: c (C) _1-8 Aliphatic, saturated or partially unsaturated 3-to 14-membered carbocyclic ring, phenyl, 3-to 10-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-to 14-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, R ^Z Is hydrogen or an optionally substituted group selected from the group consisting of: c (C) _1-6 Aliphatic, saturated or partially unsaturated 3-to 7-membered carbocyclic ring, phenyl, having 1 to 2 groups independently selected from nitrogen, oxygen and sulfur 3-7 membered saturated or partially unsaturated heterocyclic ring of heteroatoms, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^Z Is hydrogen. In some embodiments, R ^Z Is optionally substituted C _1-6 Aliphatic groups. In some such embodiments, R ^Z Is optionally substituted C _1-4 Aliphatic groups. In some embodiments, R ^Z is-CH ₃ 、-CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ or-CH ₂ CH(CH ₃ ) ₂ 、-C(CH ₃ ) ₃ 、In some embodiments, R ^Z Is optionally covered by-R ^o OR-OR ^o Substituted C _1-6 Aliphatic groups. In some embodiments, R ^Z Is->In some embodiments, R ^Z Is->Wherein R is ^o is-OR ^o or-N (R) ^o ) ₂ . In some embodiments, R ^Z Is thatIn some embodiments, R ^Z Is->In some embodiments, R ^Z Is->

In some embodiments, R ^Z Is an optionally substituted saturated or partially unsaturated 3-7 membered carbocyclic ring. In some embodiments, R ^Z Is optionally covered bySubstituted saturated 3-membered carbocycles. In some such embodiments, R ^Z Is thatIn some such embodiments, R ^o Optionally substituted with halogen.

In some embodiments, R ^Z Is an optionally substituted phenyl ring. In some embodiments, R ^Z Is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^Z Is an optionally substituted 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some such embodiments, R ^Z Is thatIn some such embodiments, R ^Z Is->

In some embodiments, R ^Z Is an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^Z Is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some such embodiments, R ^Z Is thatIn some such embodiments, R ^Z Is->

In some embodiments, R ^Z Is an optionally substituted 6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some such embodiments, R ^Z Is that

In some embodiments, R ^Z Is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^Z Is an optionally substituted 5 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^Z Is an optionally substituted 6 membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R ^Z Selected from optionally substituted isothiazolyl, pyridinyl or pyridazinyl. In some such embodiments, R ^Z Is that

In some embodiments, R ^Z Is an optionally substituted group selected from: c (C) _1-8 Aliphatic, saturated or partially unsaturated 3-to 14-membered carbocyclic ring, phenyl, 3-to 10-membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-to 14-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, R ^Z Is optionally substituted C _1-8 Aliphatic groups. In some embodiments, R ^Z Is an optionally substituted saturated or partially unsaturated 3-14 membered carbocyclic ring. In some embodiments, R ^Z Is an optionally substituted 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^Z Is an optionally substituted 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^Z Is an optionally substituted 10 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^Z Is an optionally substituted 10 membered heteroaryl ring having 1-4 nitrogen heteroatoms. In some embodiments, R ^Z Is an optionally substituted 10 membered heteroaryl ring having 3 nitrogen heteroatoms. In some embodiments, R ^Z Is pyrido [3,4-d ]]Pyridazine.

In some embodiments, R ^Z Selected from the groups depicted in the compounds in table 1.

L as defined generally above ² Is a covalent bond, or C _1-4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or both methylene units of the chain are optionally and independently replaced by: -CH (R) ^L )-、-C(R ^L ) ₂ -、C _3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N (R) ^L )-、-NHC(O)-、-N(R ^L )C(O)-、-C(O)NH-、-C(O)N(R ^L )-、-NHS(O) ₂ -、-N(R ^L )S(O) ₂ -、-S(O) ₂ NH-、-S(O) ₂ N(R ^L ) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -S (O) -or-S (O) ₂ -; wherein said C _3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with R ¹ Or C _1-6 Aliphatic group substitution.

In some embodiments, L ² Is a covalent bond. In some embodiments, L ² Is C _1-4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or both methylene units of the chain are optionally and independently replaced by: -CH (R) ^L )-、-C(R ^L ) ₂ -、C _3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N (R) ^L )-、-NHC(O)-、-N(R ^L )C(O)-、-C(O)NH-、-C(O)N(R ^L )-、-NHS(O) ₂ -、-N(R ^L )S(O) ₂ -、-S(O) ₂ NH-、-S(O) ₂ N(R ^L ) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -S (O) -or-S (O) ₂ -; wherein said C _3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with R ¹ Or C _1-6 Aliphatic group substitution. In some embodiments, L ² is-CH ₂ -. In some embodiments, L ² is-CH ₂ O-。

In some embodiments, L ² is-O-, -NH-, -S-, NHC (O) NH-, -N (CH) ₃ )C(O)NH-、-OC(O)NH-、-OC(O)N(CH ₃ )-、-NHC(O)O-、-CH ₂ C(O)NH-、-CH ₂ OC (O) NH-, -C (O) NH-, and-C (O) O-. In some embodiments, L ² is-O-, -NH-, -S-, NHC (O) NH-, -N (CH) ₃ )C(O)NH-、-OC(O)NH-、-OC(O)N(CH ₃ )-、-NHC(O)O-、-CH ₂ C(O)NH-、-NHC(O)CH ₂ -、-CH ₂ OC(O)NH-、-C(O)NH-、-NHC(O)-、-C(O)O-、-OC(O)-、-NHS(O) ₂ -、-NHS(O) ₂ NH-and-OC (O) N% ⁱ Pr) -. In some embodiments, L ² is-O-. In some embodiments, L ² is-NH-. In some embodiments, L ² is-S-. In some embodiments, L ² is-NHC (O) NH-. In some embodiments, L ² is-N (CH) ₃ ) C (O) NH-. In some embodiments, L ² is-OC (O) NH-. In some embodiments, L ² is-NHC (O) O-. In some embodiments, L ² is-CH ₂ C (O) NH-. In some embodiments, L ² is-CH ₂ OC (O) NH-. In some embodiments, L ² is-C (O) NH-. In some embodiments, L ² is-NHC (O) -. In some embodiments, L ² is-C (O) O-. In some embodiments, L ² is-OC (O) -. In some embodiments, L ² is-NHC (O) CH ₂ -. In some embodiments, L ² is-NHS (O) ₂ -. In some embodiments, L ² is-NHS (O) ₂ NH-. In some embodiments, L ² is-OC (O) N% ⁱ Pr) -. In some embodiments, L ² Is a covalent bond, -CH ₂ -、-NH-、-O-、-NHC(O)NH-、 Wherein->Representation and Cy ^B Covalent bond of>Representing and R ^P Or R is ^Z Is a covalent bond of (c). In some embodiments, L ² Is->Wherein->Representation and Cy ^B Covalent bond of>Representing and R ^P Or R is ^Z Is a covalent bond of (c). In some embodiments, L ² Is->Wherein->Representation and Cy ^B Covalent bond of>Representing and R ^P Or R is ^Z Is a covalent bond of (c).

In some embodiments, L ² is-XC (O) Y-, wherein each of X and Y is as defined in embodiments and classes and subclasses herein. In some embodiments, X is-O-. In some embodiments, X is-NR ^X -. In some embodiments, X is-NH-. In some casesIn embodiments, X is-N (CH) ₃ ) -. In some embodiments, X is-S-. In some embodiments, Y is-O-. In some embodiments, Y is-NR ^Y -. In some embodiments, Y is-NH-. In some embodiments, Y is-N (CH ₃ ) -. In some embodiments, Y is-S-.

In some embodiments, each L ² Selected from the groups depicted in the compounds in table 1.

Q is L, as defined generally above ¹ Wherein L is ¹ As defined in the embodiments and classes and subclasses herein. In some embodiments, Q is-NH- Wherein->Representation and Cy ^A Covalent bond of>Representation and Cy ^C Or a covalent bond of W. In some embodiments, Q is-NH-. In some embodiments, Q is-O-. In some embodiments, Q is +.>In some embodiments, Q is +.>In some embodiments, Q is +.>In some embodiments, Q is-NHC (O) NH-. In some embodiments, Q is

In some embodiments, Q is selected from the groups depicted in the compounds in table 1.

L as defined generally above ¹ Is a covalent bond, or C _1-4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or both methylene units of the chain are optionally and independently replaced by: -CH (R) ^L )-、-C(R ^L ) ₂ -、C _3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N (R) ^L )-、-NHC(O)-、-N(R ^L )C(O)-、-C(O)NH-、-C(O)N(R ^L )-、-NHS(O) ₂ -、-N(R ^L )S(O) ₂ -、-S(O) ₂ NH-、-S(O) ₂ N(R ^L ) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -S (O) -or-S (O) ₂ -; wherein said C _3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with R ¹ Or C _1-6 Aliphatic group substitution.

In some embodiments, L ¹ Is a covalent bond. In some embodiments, L ¹ Is C _1-4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or both methylene units of the chain are optionally and independently replaced by: -CH (R) ^L )-、-C(R ^L ) ₂ -、C _3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N (R) ^L )-、-NHC(O)-、-N(R ^L )C(O)-、-C(O)NH-、-C(O)N(R ^L )-、-NHS(O) ₂ -、-N(R ^L )S(O) ₂ -、-S(O) ₂ NH-、-S(O) ₂ N(R ^L ) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -S (O) -or-S (O) ₂ -; wherein said C _3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with R ¹ Or C _1-6 Aliphatic group substitution.

In some embodiments, L ¹ is-NH-, Wherein->Representation and Cy ^A Covalent bond of>Representation and Cy ^C Or a covalent bond of W. In some embodiments, L ¹ is-NH-. In some embodiments, L ¹ is-O-. In some embodiments, L ¹ Is->In some embodiments, L ¹ Is->In some embodiments, L ¹ Is thatIn some embodiments, L ¹ Is->In some embodiments, L ¹ Is thatIn some embodiments, L ¹ Is->

In some embodiments, L ¹ Selected from the groups depicted in the compounds in table 1.

R is as defined generally above ^L Each instance of (2) is independently R ¹ Or R is ² And is R ³ T example substitutions of (c). In some embodiments, R ^L Is R ¹ . In some embodiments, R ^L Is R ² 。

R is as defined generally above ^A 、R ^B And R is ^C Each instance of (2) is independently R ¹ Or R is ² Wherein R is ^A Quilt R ³ Q of (2) ^A Example substitution, R ^B Quilt R ³ Q of (2) ^B Substituted by examples, and R ^C Quilt R ³ Q of (2) ^C Example substitutions. In some embodiments, R ^A Is R ¹ . In some embodiments, R ^B Is R ¹ . In some embodiments, R ^C Is R ¹ . In some embodiments, R ^A Is R ² . In some embodiments, R ^B Is R ² . In some embodiments, R ^C Is R ² 。

R is as defined generally above ¹ Is (e.g., R ^A R of (2) ¹ Radicals, R ^B R of (2) ¹ Radicals or R ^C R of (2) ¹ Groups) are independently oxo, halogen, -CN, -NO ₂ 、-OR、-SR、-NR ₂ 、-S(O) ₂ R、-S(O) ₂ NR ₂ 、-S(O)R、-S(O)NR ₂ 、-C(O)R、-C(O)OR、-C(O)NR ₂ 、-C(NR)NR ₂ 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR ₂ 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(NR)R、-N(R)C(O)NR ₂ 、-N(R)C(NR)NR ₂ 、-N(R)S(O) ₂ NR ₂ -N (R) S (O) R or-N (R) S (O) ₂ R is defined as the formula. In some embodiments, R ¹ Is oxo. In some embodiments, each R ¹ Independently halogen, -CN, -NO ₂ 、-OR、-SR、-NR ₂ 、-S(O) ₂ R、-S(O) ₂ NR ₂ 、-S(O)R、-S(O)NR ₂ 、-C(O)R、-C(O)OR、-C(O)NR ₂ 、-C(NR)NR ₂ 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR ₂ 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(NR)R、-N(R)C(O)NR ₂ 、-N(R)C(NR)NR ₂ 、-N(R)S(O) ₂ NR ₂ -N (R) S (O) R or-N (R) S (O) ₂ R。

In some embodiments，R ¹ Is halogen, -CN or-NO ₂ . In some embodiments, R ¹ is-OR, -SR OR-NR ₂ . In some embodiments, R ¹ is-S (O) ₂ R、-S(O) ₂ NR ₂ 、-S(O)R、-S(O)NR ₂ 、-C(O)R、-C(O)OR、-C(O)NR ₂ 、-C(NR)NR ₂ OR-C (O) N (R) OR. In some embodiments, R ¹ is-S (O) ₂ R、-S(O) ₂ N (H) R, -S (O) N (H) R, -C (O) OR, -C (O) N (H) R, -C (NH) N (H) R OR-C (O) N (H) OR. In some embodiments, R ¹ is-OC (O) R, -OC (O) NR ₂ 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(NR)R、-N(R)C(O)NR ₂ 、-N(R)C(NR)NR ₂ 、-N(R)S(O) ₂ NR ₂ -N (R) S (O) R or-N (R) S (O) ₂ R is defined as the formula. In some embodiments, R ¹ is-OC (O) R, -OC (O) N (H) R, -N (H) C (O) OR' -N (H) C (O) R, -N (H) C (NH) R, -N (H) C (O) NR ₂ 、-N(H)C(NH)NR ₂ 、-N(H)S(O) ₂ NR ₂ -N (H) S (O) R or-N (H) S (O) ₂ R is defined as the formula. In some embodiments, R ^A Is halogen. In some embodiments, R ^B Is halogen. In some embodiments, R ^B is-C.ident.N. In some embodiments, R ^C is-S (O) ₂ R is defined as the formula. In some embodiments, R ^C is-S (O) ₂ CH ₃ . In some embodiments, R ^C is-OR. In some embodiments, R ^C is-OCH ₃ . In some embodiments, R ^C Is oxo. In some embodiments, R ^C is-N (R) C (O) R. In some such embodiments, R ^C is-N (H) C (O) R. In some embodiments, R ^C is-C.ident.N.

R is as defined generally above ² Is (e.g., R ^A R of (2) ² Radicals, R ^B R of (2) ² Radicals or R ^C R of (2) ² Groups) are independently C _1-7 An aliphatic group; a phenyl group; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3- A 7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ² Is C _1-7 Aliphatic groups. In some embodiments, R ² Is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ² Is phenyl. In some embodiments, R ² Is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ² Is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ² Is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R ² Is a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ² Is a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, R ^A Is C _1-7 Aliphatic groups. In some such embodiments, R ^A is-CH ₃ . In some embodiments, R ^A is-C (CH) ₃ ) ₃ 。

In some embodiments, R ^B Is C _1-7 Aliphatic groups. In some such embodiments, R ^B is-CH ₃ . In some embodiments, R ^B Is selected from-CH ₃ 、-CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ 、In some embodiments, R ^B Is covered by R ³ Substituted C _1-7 Aliphatic groups. In some embodiments, R ^B Is covered by R ³ Substituted C _1-7 Aliphatic group, wherein R ³ is-OR. In some embodiments, R ^B Is covered by R ³ Substituted C _1-2 Aliphatic group, wherein R ³ is-OR. In some embodiments, R ^B is-CH ₂ OH. In some embodiments, R ^B Is oxo. In some embodiments, R ^B is-OR, wherein R is C _1-6 Aliphatic groups. In some embodiments, R ^B is-OCH ₃ 。

In some embodiments, R ^C Is C _1-7 Aliphatic groups. In some such embodiments, R ^C is-CH ₃ or-C (CH) ₃ ) ₃ . In some embodiments, R ^C is-CH ₂ C(CH ₃ ) ₃ . In some embodiments, R ^C Is covered by R ³ Substituted C _1-7 Aliphatic groups. In some embodiments, R ^C Is covered by R ³ Substituted C _1-7 Aliphatic group, wherein R ³ is-OR. In some embodiments, R ^C Is covered by R ³ Substituted C _1-2 Aliphatic group, wherein R ³ is-OR. In some embodiments, R ^C is-CH ₂ OCH ₃ . In some embodiments, R ^C Is thatIn some embodiments, R ^C is-N (H) C (O) CH ₃ . In some embodiments, R ^C is-C (O) OR. In some embodiments, R ^C is-C (O) OR, wherein R is C _1-6 Aliphatic groups. In some embodiments, R ^C is-C (O) OCH ₂ CH ₃ . In some embodiments, R ^C Is covered by R ³ Substituted C _1-7 Aliphatic group, wherein R ³ Is halogen. In some embodiments, R ^C Is covered by R ³ Substituted C _1-7 Aliphatic group, wherein R ³ Is fluorine. In some embodiments, R ^C is-CF ₃ . In some embodiments, R ^C Is oxo. In some embodiments, R ^C Is covered by R ³ substituted-OR. In some embodiments, R ^C Is covered by R ³ substituted-OR wherein R is C _1-6 Aliphatic group and R ³ is-OR. In some embodiments, R ^C is-OCH ₂ CH ₂ OH. In some embodiments, R ^C Is covered by R ³ Substituted C _1-7 Aliphatic group, wherein R ³ is-OR. In some embodiments, R ^C Is covered by R ³ Substituted C _1-7 Aliphatic group, wherein R ³ is-OR. In some embodiments, R ^C Is covered by R ³ Substituted C _1-7 Aliphatic group, wherein R ³ is-OR and R is C optionally substituted by halogen _1-6 Aliphatic groups.

R is as defined generally above ³ Is independently oxo, halogen, -CN, -NO ₂ 、-OR、-SR、-NR ₂ 、-S(O) ₂ R、-S(O) ₂ NR ₂ 、-S(O)R、-S(O)NR ₂ 、-S(O) ₂ F、-OS(O) ₂ F、-C(O)R、-C(O)OR、-C(O)NR ₂ 、-C(NR)NR ₂ 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR ₂ 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(NR)R、-N(R)C(O)NR ₂ 、-N(R)C(NR)NR ₂ 、-N(R)S(O) ₂ NR ₂ 、-N(R)S(O)R、-N(R)S(O) ₂ R or an optionally substituted group selected from: c (C) _1-6 Aliphatic groups, phenyl groups, 3-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ³ Is oxo. In some embodiments, R ³ Is halogen, -CN, -NO ₂ 、-OR、-SR、-NR ₂ 、-S(O) ₂ R、-S(O) ₂ NR ₂ 、-S(O)R、-S(O)NR ₂ 、-S(O) ₂ F、-OS(O) ₂ F、-C(O)R、-C(O)OR、-C(O)NR ₂ 、-C(NR)NR ₂ 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR ₂ 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(NR)R、-N(R)C(O)NR ₂ 、-N(R)C(NR)NR ₂ 、-N(R)S(O) ₂ NR ₂ 、-N(R)S(O)R、-N(R)S(O) ₂ R or an optionally substituted group selected from: c (C) _1-6 Aliphatic groups, phenyl groups, 3-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ³ Is halogen, -CN or-NO ₂ . In some embodiments, R ³ is-OR, -SR OR-NR ₂ . In some embodiments, R ³ is-S (O) ₂ R、-S(O) ₂ NR ₂ 、-S(O)R、-S(O)NR ₂ 、-S(O) ₂ F、-OS(O) ₂ F、-C(O)R、-C(O)OR、-C(O)NR ₂ 、-C(NR)NR ₂ OR-C (O) N (R) OR. In some embodiments, R ³ is-S (O) ₂ R、-S(O) ₂ N(H)R、-S(O)R、-S(O)N(H)R、-S(O) ₂ F、-OS(O) ₂ F、-C(O)R、-C(O)OR、-C(O)N(H)R、-C(NH)NR ₂ OR-C (O) N (H) OR. In some embodiments, R ³ Is OC (O) R, -OC (O) NR ₂ 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(NR)R、-N(R)C(O)NR ₂ 、-N(R)C(NR)NR ₂ 、-N(R)S(O) ₂ NR ₂ -N (R) S (O) R or-N (R) S (O) ₂ R is defined as the formula. In some embodiments, R ³ is-OC (O) R, -OC (O) N (H) R, -N (H) C (O) OR' -N (H) C (O) R, -N (H) C (NH) R, -N (H) C (O) NR ₂ 、-N(H)C(NH)NR ₂ 、-N(H)S(O) ₂ NR ₂ -N (H) S (O) R or-N (H) S (O) ₂ R is defined as the formula. In some embodiments, R ³ Is an optionally substituted group selected from: c (C) _1-6 Aliphatic groups, phenyl groups, 3-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ³ Is optionally substituted C _1-6 Aliphatic groups. In some embodiments, R ³ Is optionally substituted phenyl. In some embodiments, R ³ Is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ³ Is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

W is hydrogen or Cy, as defined generally above ^C . In some embodiments, W is hydrogen. In some embodiments, W is Cy ^C 。

Cy, as generally defined above ^C Is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a phenyl group; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^C Is also denoted by R in addition to Q ^C P example substitutions of (a). In some embodiments, cy ^C Is a saturated or partially unsaturated 3-14 membered carbocyclic ring. In some embodiments, cy ^C Is a saturated or partially unsaturated 3-7 membered monocyclic carbocyclic ring. In some embodiments, cy ^C Is cyclopropyl.

In some embodiments, cy ^C Is a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^C Is phenyl. In some embodiments, cy ^C Is a 5-14 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, cy ^C Is a 5-6 membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^C Is a 5 membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^C Is a 5 membered heteroaryl ring having 1-2 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^C Is thatIn some embodiments, cy ^C Is->In some embodiments, cy ^C Is->In some embodiments, cy ^C Is->In some embodiments, cy ^C Is->In some embodiments, cy ^C Is->

In some embodiments, cy ^C Is a 6 membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, cy ^C Is a pyridyl group. In some embodiments, cy ^C Is pyrimidinyl. In some embodiments, cy ^C Is a pyridazinyl group. In some embodiments, cy ^C Is thatIn some embodiments, cy ^C Is->In some embodiments, cy ^C Is->In some embodiments, cy ^C Is->In some embodiments, cy ^C Is->In some embodiments, cy ^C Is->

In some embodiments, cy ^C Is a 9-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^C Is a 9-10 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, cy ^C Is a 9-10 membered heteroaryl group having 2-4 nitrogen atoms. In some embodiments, cy ^C Is that In some embodiments, cy ^C Is->In some embodiments, cy ^C Is thatIn some embodiments, cy ^C Is->In some embodiments, cy ^C Is->In some embodiments, cy ^C Is->In some embodiments, cy ^C Is thatIn some embodiments, cy ^C Is->In some embodiments, cy ^C Is thatIn some embodiments, cy ^C Is->In some embodiments, cy ^C Is thatIn some embodiments, cy ^C Is->In some embodiments, cy ^C Is thatIn some embodiments, cy ^C Is->In some embodiments, cy ^C Is thatIn some embodiments, cy ^C Is->

As generally defined above, each R is independently hydrogen or an optionally substituted group selected from: c (C) _1-6 Aliphatic, saturated or partially unsaturated 3-to 7-membered carbocyclic ring, phenyl, 3-to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen together with intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen. In some embodiments In the scheme, R is hydrogen. In some embodiments, R is an optionally substituted group selected from: c (C) _1-6 Aliphatic, saturated or partially unsaturated 3-to 7-membered carbocyclic ring, phenyl, 3-to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen together with intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen. In some embodiments, R is optionally substituted C _1-6 Aliphatic groups. In some embodiments, R is an optionally substituted saturated or partially unsaturated 3-7 membered carbocyclic ring. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

As generally defined above, m is 0, 1, 2, 3 or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0 or 1. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 2 or 3. In some embodiments, m is 2, 3, or 4. In some embodiments, m is 3 or 4. In some embodiments, m is selected from the values represented in the compounds in table 1.

As generally defined above, n is 0, 1, 2, 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 2 or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 3 or 4. In some embodiments, n is selected from the values represented in the compounds in table 1.

As generally defined above, p is 0, 1, 2, 3 or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 0 or 1. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. In some embodiments, p is 2, 3, or 4. In some embodiments, p is 3 or 4. In some embodiments, p is selected from the values represented in the compounds in table 1.

Q, as defined generally above ^A Is 0, 1, 2, 3 or 4. In some embodiments, q ^A Is 0. In some embodiments, q ^A Is 1. In some embodiments, q ^A Is 2. In some embodiments, q ^A Is 3. In some embodiments, q ^A Is 4. In some embodiments, q ^A Is 0 or 1. In some embodiments, q ^A Is 0, 1 or 2. In some embodiments, q ^A Is 0, 1, 2 or 3. In some embodiments, q ^A Is 1 or 2. In some embodiments, q ^A Is 1, 2 or 3. In some embodiments, q ^A Is 1, 2, 3 or 4. In some embodiments, q ^A Is 2 or 3. In some embodiments, q ^A Is 2, 3 or 4. In some embodiments, q ^A Is 3 or 4. In some embodiments, q ^A Selected from the values indicated in the compounds in table 1.

Q, as defined generally above ^B Is 0, 1, 2, 3 or 4. In some embodiments, q ^B Is 0. In some embodiments, q ^B Is 1. In some embodiments, q ^B Is 2. In some embodiments, q ^B Is 3. In some embodiments, q ^B Is 4. In some embodiments, q ^B Is 0 or 1. In some embodiments, q ^B Is 0, 1 or 2. In some embodiments, q ^B Is 0, 1, 2 or 3. In some embodiments, q ^B Is 1 or 2. In some embodiments, q ^B Is 1, 2 or 3. In some embodiments, q ^B Is 1, 2, 3 or 4. In some embodiments, q ^B Is 2 or 3. In some embodiments, q ^B Is 2, 3 or 4. In some embodiments, q ^B Is 3 or 4. In some embodiments, q ^B Selected from the values indicated in the compounds in table 1.

Q, as defined generally above ^C Is 0, 1, 2, 3 or 4. In some embodiments, q ^C Is 0. In some embodiments, q ^C Is 1. In some embodiments, q ^C Is 2. In some embodiments, q ^C Is 3. In some embodiments, q ^C Is 4. In some embodiments, q ^C Is 0 or 1. In some embodiments, q ^C Is 0, 1 or 2. In some embodiments, q ^C Is 0, 1, 2 or 3. In some embodiments, q ^C Is 1 or 2. In some embodiments, q ^C Is 1, 2 or 3. In some embodiments, q ^C Is 1, 2, 3 or 4. In some embodiments, q ^C Is 2 or 3. In some embodiments, q ^C Is 2, 3 or 4. In some embodiments, q ^C Is 3 or 4. In some embodiments, q ^C Selected from the values indicated in the compounds in table 1.

R is 0, 1, 2, 3 or 4, as generally defined above. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0 or 1. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 1 or 2. In some embodiments, r is 1, 2, or 3. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, r is 2 or 3. In some embodiments, r is 2, 3, or 4. In some embodiments, r is 3 or 4. In some embodiments, r is selected from the values represented in the compounds in table 1.

As generally defined above, t is 0, 1, 2, 3 or 4. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 0 or 1. In some embodiments, t is 0, 1, or 2. In some embodiments, t is 0, 1, 2, or 3. In some embodiments, t is 1 or 2. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1, 2, 3, or 4. In some embodiments, t is 2 or 3. In some embodiments, t is 2, 3, or 4. In some embodiments, t is 3 or 4. In some embodiments, t is selected from the values represented in the compounds in table 1.

Examples of compounds described herein include those listed in the tables and examples herein, or pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers thereof. In some embodiments, the present disclosure comprises a compound selected from those depicted in table 1 below, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments

In the present disclosure, compounds listed in table 1 below, or pharmaceutically acceptable salts thereof, are provided. In some embodiments, the present disclosure provides the compounds listed in table 1 below.

Table 1. Representative compounds and bioactivity data.

In the chemical structures in table 1 above, when the stereocenters are depicted with a dashed or wedge-shaped bond and labeled as "abs" (or unlabeled), the compounds are essentially single isomers (rather than equimolar mixtures) at the stereocenters, and the absolute stereochemistry is as shown in the chemical structures. (see, e.g., structure of example 5.) when the stereocenter is depicted with a dashed or wedge-shaped bond and is also labeled "or1" or2", the compound is a single isomer at the stereocenter, but the absolute stereochemistry at the stereocenter has not yet been determined. (see, e.g., structure of example 27.) when the stereocenter is depicted with a dashed or wedge-shaped bond and is also labeled "and1" or "&1", the compound is a mixture of two isomers at the stereocenter: the structure as depicted, as well as isomers with opposite configuration of the stereocenter. (see, e.g., example 3. Structure.)

Some of the compounds depicted in table 1 above exist in solution as non-reciprocal atropisomers across biaryl linkages at room temperature. When one atom of the biaryl linkage is labeled "or1", this means that the compound is present in solution as a non-reciprocal atropisomer at room temperature and that the compound is essentially a single atropisomer (rather than an equimolar mixture).

In some embodiments, the present disclosure provides a compound of table 1 above, wherein the compound is represented as a biochemical CDK2 Caliper IC having "a" ₅₀ . In some embodiments, the present disclosure provides the compounds in table 1 above, wherein the compounds are represented as biochemical CDK2 Caliper IC having "a" or "B ₅₀ . In some embodiments, the present disclosure provides the compounds in table 1 above, wherein the compounds are represented as biochemical CDK2 Caliper IC having "a", "B" or "C ₅₀ 。

In some embodiments, the present disclosure provides compounds in table 1 above, wherein the compounds are represented as Cell nanoBRET IC with "a ₅₀ . In some embodiments, the present disclosure provides compounds in table 1 above, wherein the compounds are represented as Cell nanoBRET IC with "a" or "B ₅₀ . In some embodiments, the present disclosure provides compounds in table 1 above, wherein the compounds are represented as Cell nanoBRET ICs with "a", "B" or "C ₅₀ 。

4. General methods for providing the Compounds of the invention

The compounds described herein may generally be prepared or isolated by synthetic and/or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods set forth in detail in the examples herein.

5. Use, formulation and administration

Pharmaceutically acceptable compositions

According to another embodiment, the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable carrier. The amount of the compound in the compositions described herein is such that CDK2 protein kinase or a mutant thereof in the biological sample or patient is effectively measurably inhibited. In certain embodiments, the amount of the compound in the compositions described herein is such that it is effective to measurably inhibit a CDK2 protein kinase or mutant thereof in a biological sample or patient. In certain embodiments, the compositions described herein are formulated for administration to a patient in need of such compositions. In some embodiments, the compositions described herein are formulated for oral administration to a patient.

The terms "subject" and "patient" as used herein mean an animal (i.e., a member of the kingdom animalia), preferably a mammal, and most preferably a human. In some embodiments, the subject is a human, mouse, rat, cat, monkey, dog, horse, or pig. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, rat, cat, monkey, dog, horse, or pig.

The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

By "pharmaceutically acceptable derivative" is meant any non-toxic salt, ester, salt of an ester or other derivative of a compound described herein that is capable of providing the compound described herein, or inhibiting an active metabolite or residue thereof, directly or indirectly upon administration to a recipient.

As used herein, the term "inhibiting an active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of CDK2 protein kinase or a mutant thereof.

The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.

The sterile injectable form of the compositions described herein may be an aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be employed include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids (e.g. oleic acid and its glyceride derivatives) find use in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants (e.g., tween, span, and other emulsifying agents or bioavailability enhancers) commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

The pharmaceutically acceptable compositions described herein may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. A lubricant, such as magnesium stearate, is also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. Certain sweeteners, flavoring agents or coloring agents may also be added if desired.

Alternatively, the pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal or vaginal administration. These compositions can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions described herein may also be administered topically, especially when the therapeutic target comprises a site or organ (including diseases of the eye, skin or lower intestinal tract) readily accessible by topical administration. Suitable topical formulations are readily prepared for each of these sites or organs.

Topical application for the lower intestinal tract may be effected in the form of rectal suppository formulations (see above) or in the form of a suitable enema formulation. Topical transdermal patches may also be used.

For topical application, the provided pharmaceutically acceptable compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetostearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably as solutions in isotonic, pH adjusted sterile saline, with or without a preservative such as benzalkonium chloride (benzylalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment, such as petrolatum.

The pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Preferably, the pharmaceutically acceptable compositions described herein are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions described herein are not administered with food. In other embodiments, the pharmaceutically acceptable compositions described herein are administered with food.

The amount of the compounds described herein that can be combined with a carrier material to produce a composition in a single dosage form will vary depending upon the patient being treated, the particular mode of administration. Preferably, the compositions provided should be formulated such that an inhibitor in a dose of between 0.01 and 100mg/kg body weight/day can be administered to a patient receiving these compositions.

It will also be appreciated that the specific dosage and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the particular compound employed, the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the judgment of the treating physician and the severity of the particular disease undergoing therapy. The amount of a compound described herein in a composition will also depend on the particular compound in the composition.

The precise dosage to be used for the composition will also depend on the route of administration and should be determined according to the judgment of the practitioner and the circumstances of each subject. In particular embodiments of the present disclosure, suitable dosage ranges for oral administration of the compounds of the present disclosure are generally from about 1 mg/day to about 1000 mg/day. In some embodiments, the oral dosage is from about 1 mg/day to about 800 mg/day. In some embodiments, the oral dosage is from about 1 mg/day to about 500 mg/day. In some embodiments, the oral dosage is from about 1 mg/day to about 250 mg/day. In some embodiments, the oral dosage is from about 1 mg/day to about 100 mg/day. In some embodiments, the oral dosage is from about 5 mg/day to about 50 mg/day. In some embodiments, the oral dose is about 5 mg/day. In some embodiments, the oral dose is about 10 mg/day. In some embodiments, the oral dose is about 20 mg/day. In some embodiments, the oral dose is about 30 mg/day. In some embodiments, the oral dose is about 40 mg/day. In some embodiments, the oral dose is about 50 mg/day. In some embodiments, the oral dose is about 60 mg/day. In some embodiments, the oral dose is about 70 mg/day. In some embodiments, the oral dose is about 100 mg/day. It will be appreciated that any of the doses listed herein may constitute an upper or lower dose range limit, and may be combined with any other dose to constitute a dose range that includes both the upper and lower limit.

In some embodiments, the pharmaceutically acceptable composition contains the provided compounds and/or pharmaceutically acceptable salts thereof at concentrations within the following ranges: about 0.01wt% to about 90wt%, about 0.01wt% to about 80wt%, about 0.01wt% to about 70wt%, about 0.01wt% to about 60wt%, about 0.01wt% to about 50wt%, about 0.01wt% to about 40wt%, about 0.01wt% to about 30wt%, about 0.01wt% to about 20wt%, about 0.01wt% to about 2.0wt%, about 0.01wt% to about 1wt%, about 0.05wt% to about 0.5wt%, about 1wt% to about 30wt%, or about 1wt% to about 20wt%. The composition may be formulated as a solution, suspension, ointment, capsule, or the like. The pharmaceutical composition may be prepared as an aqueous solution and may contain additional components such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity adjusting components and the like.

Pharmaceutically acceptable carriers are well known to those skilled in the art and include, for example, adjuvants, diluents, excipients, fillers, lubricants and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient.

Examples of pharmaceutically acceptable carriers may include, for example, water or saline solutions, polymers (e.g., polyethylene glycol), carbohydrates and derivatives thereof, oils, fatty acids, or alcohols. Non-limiting examples of oils as pharmaceutical carriers include oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carrier may also be saline, acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants can be used. Other examples of suitable pharmaceutical carriers are set forth, for example, in the following documents: remington's The Science and Practice of Pharmacy, 22 nd edition (Allen, loyd v., jr edit, pharmaceutical Press (2012)); modern Pharmaceutics, 5 th edition (Alexander t. Florence, jergen Siepmann, CRC Press (2009)); handbook of Pharmaceutical Excipients, 7 th edition (Rowe, raymond C.; shreskey, paul J.; cook, walter G.; fenton, marian E. Edit, pharmaceutical Press (2012)) (each of which is hereby incorporated by reference in its entirety).

The pharmaceutically acceptable carrier employed herein may be selected from a variety of organic or inorganic materials that are used as materials for pharmaceutical formulations and incorporated as analgesics, buffers, binders, disintegrants, diluents, emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and viscosity enhancing agents. Pharmaceutical additives such as antioxidants, fragrances, colorants, flavor modifiers, preservatives and sweeteners may also be added. Examples of acceptable pharmaceutical carriers include, inter alia, carboxymethylcellulose, crystalline cellulose, glycerol, acacia (gum arabic), lactose, magnesium stearate, methylcellulose, powders, saline, sodium alginate, sucrose, starch, talc and water. In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

Surfactants (e.g., detergents) are also suitable for use in the formulation. Specific examples of surfactantsIncluding polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylated esters of sorbitan; lecithin or sodium carboxymethyl cellulose; or acrylic derivatives such as methacrylates and others; anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecyl benzene sulfonate or dioctyl sodium sulfosuccinate; or fatty acids, particularly those derived from coconut oil; cationic surfactants, e.g. of formula N ⁺ R'R”R”'R””Y ^- Wherein R groups are the same or different optionally hydroxylated hydrocarbon radicals and Y ^- Anions of strong acids such as halide, sulfate, and sulfonate anions; cetyl trimethylammonium bromide is one of the cationic surfactants that can be used, formula N ⁺ Amine salts of R' wherein the R groups are the same or different optionally hydroxylated hydrocarbyl groups; octadecylamine hydrochloride is one of the cationic surfactants that can be used, nonionic surfactants such as optionally polyoxyethylated esters of sorbitan, in particular polysorbate 80, or polyoxyethylated alkyl ethers; polyethylene glycol stearates, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids or copolymers of ethylene oxide and propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaines.

Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20 and the like. The compositions of the present invention may also contain wetting or emulsifying agents or pH buffering agents, if desired.

The tablet and capsule formulations may also contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers or lubricants, each of which is known in the art. Examples of such include carbohydrates such as lactose or sucrose, anhydrous calcium hydrogen phosphate, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silica, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffers, disintegrants and coloring agents. Compositions for oral administration may contain one or more optional agents, for example sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen or cherry; a colorant; and a preservative to provide a pharmaceutically palatable preparation.

Use of compounds and pharmaceutically acceptable compositions

The compounds and compositions described herein are generally useful for inhibiting kinases or mutants thereof. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a Cyclin Dependent Kinase (CDK). In some embodiments, the kinase inhibited by the compounds and compositions described herein is one or more of CDK1, CDK2, CDK4, and CDK 6. In some embodiments, the kinase inhibited by the compounds and compositions described herein is CDK2.

The compounds or compositions of the present disclosure may be used in applications benefiting from the inhibition of CDK2 enzymes. For example, the CDK2 inhibitors described herein are generally useful in the treatment of proliferative disorders.

CDK2 is known to be a factor in the formation and proliferation of tumors of many cancer types, including lung, liver, colon and breast cancers (Opyrchal, int J Oncol 2014;Shi,PLoS One2015;Lim,Cancer Prev Res 2014). There is evidence that CDK2 is functionally associated with the hyperproliferative of a variety of cancer cells and is a potential therapeutic target for cancer therapies (Chohan, curr Med Chem 2015).

CDK2 plays a role in malignant transformation of mammary epithelial cells. Inhibition of CDK2 activity is effective in inhibiting proliferation of human breast Cancer cells (Ali, cancer Res 2009). Active CDK2 in the form of a cyclin D1/CDK2 fusion protein induces tumors containing invasive components that exhibit a variety of characteristics common to human basal-like tumors and tumor-derived cell lines (Corsino, neplasia 2008). Cyclin D1/CDK2 complexes were detected in human breast cancer cell lines (Sweeney, oncogene 1998), and the levels of these complexes were closely related to the extent of cyclin D1 overexpression.

The role of cyclin E and its related kinase CDK2 in ovarian cancer has been studied by screening for primary, metastatic, recurrent and benign ovarian tumors. Using gene amplification, cyclin E has been shown to amplify in 21% of the cases analyzed and CDK2 in 6.4% of the cases analyzed. Furthermore, cyclin E RNA was overexpressed in 29.5% of ovarian tumors tested, and CDK2 was overexpressed in 6.5% of ovarian tumors tested. Cyclin E and CDK2 are predominantly overexpressed in primary ovarian Cancer (32% and 10%, respectively) compared to metastatic disease and recurrent disease (Marone, int J Cancer 1998).

CDK2 expression has been found to be significantly elevated in glioma tumors, particularly in glioblastoma multiforme (GBM), and is functionally required for GBM cell proliferation and tumor formation (Wang, trans l Oncol 2016). CDK2 expression was identified to be significantly enriched in GBM tumors and required for tumor proliferation both in vitro and in vivo. Furthermore, high CDK2 expression is associated with a poor prognosis for GBM patients. Radioactivity resistance is a major factor in poor clinical prognosis and tumor recurrence in GBM patients. CDK2 was found to be one of the uppermost kinase-encoding genes in GBM following radiation therapy. CDK 2-dependent resistance to radiation is essential for GBM neoplasia and recurrence following therapeutic treatment (supra).

Elevated levels of CDK2 expression have been observed in human cholangiocarcinoma tissue, with apoptosis-related protein 1-dependent repression of CDK2 inducing cell cycle arrest and inhibiting tumor growth (Zheng, oncol Rep 2016).

CDK2 overexpression in oral Squamous Cell Carcinoma (SCC) can increase pRB phosphorylation and allow cancer cells to enter S phase more rapidly. In clinical pathology studies of oral SCC, the incidence of CDK2 expression is high in poorly differentiated lesions and is associated with tumor invasion patterns, lymph node involvement and survival, suggesting that changes in CDK2 expression are associated with oral Cancer progression (Mihara, jpn J Cancer Res 2001). CDK2 expression is significantly associated with lymph node involvement, tumor differentiation, tumor invasion pattern and shorter survival. Thus, increased expression of CDK2 is a factor in oral cancer progression and a negative predictive marker for patient prognosis (supra).

CDK2 has been found to play a role in cell proliferation of non-small cell lung cancer (Kawana, am J Pathol 1998). CDK2 has also been found to play a role in cell proliferation of prostate cancer (Flores, endocrinology 2010).

The activity of a compound described herein as an inhibitor of a CDK kinase (e.g., CDK2 or a mutant thereof) may be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine the phosphorylation activity and/or subsequent functional consequences or inhibition of atpase activity of activated CDK2 or a mutant thereof. Alternative in vitro assays quantify the ability of inhibitors to bind to CDK 2. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/CDK 2 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment in which the novel inhibitor is incubated with CDK2 bound to a known radioligand. Representative in vitro and in vivo assays useful for assaying CDK2 inhibitors include those set forth and disclosed in the patent and scientific publications described herein. Detailed conditions for determining the compounds described herein as inhibitors of CDK2 or mutants thereof are set out in the examples below.

Treatment of disorders

The compounds provided are inhibitors of CDK2 and are therefore useful in the treatment of one or more disorders associated with the activity of CDK2 or mutants thereof. Thus, in certain embodiments, the present disclosure provides a method of treating a CDK 2-mediated disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of any of the foregoing. In certain embodiments, the present disclosure provides a method of treating a CDK 2-mediated disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable composition thereof.

As used herein, the term "CDK2 mediated" disorder, disease and/or condition means any disease or other detrimental condition in which CDK2 or a mutant thereof is known to play a role. Thus, another embodiment of the present disclosure relates to the treatment or lessening the severity of a disease in which one or more CDK2 or mutants thereof are known to function. Such CDK2 mediated disorders include, but are not limited to, proliferative disorders (e.g., cancer).

In some embodiments, the present disclosure provides methods for treating one or more disorders, wherein the disorder is selected from the group consisting of a proliferative disorder and craniosynostosis premature closure syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of any of the foregoing. In some embodiments, the present disclosure provides methods for treating one or more disorders, wherein the disorder is selected from the group consisting of proliferative disorders and craniosynostosis syndromes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable composition thereof.

In some embodiments, the disorder is associated with CDK2 signaling. CDK2 is known to have a variety of upstream and downstream signaling pathways, and inhibition of CDK2 may be useful in the treatment of disorders associated with aberrant signaling within those pathways. In some embodiments, the disorder is associated with cyclin E, cyclin E1, or retinoblastoma protein (RB) signaling.

In some embodiments, the method of treatment comprises the steps of: i) Identifying a subject in need of such treatment; (ii) Providing a disclosed compound or a pharmaceutically acceptable salt thereof; and (iii) administering the provided compounds in a therapeutically effective amount to treat, suppress and/or prevent a disease state or condition in a subject in need of such treatment.

In some embodiments, the method of treatment comprises the steps of: i) Identifying a subject in need of such treatment; (ii) Providing a composition comprising the disclosed compounds or pharmaceutically acceptable salts thereof; and (iii) administering the composition in a therapeutically effective amount to treat, suppress and/or prevent a disease state or condition in a subject in need of such treatment.

Another aspect of the present disclosure provides a pharmaceutical composition according to a compound as defined herein, or a pharmaceutically acceptable salt thereof, or any of the foregoing, for use in the treatment of a disorder described herein. Another aspect of the present disclosure provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing, for the treatment of a disorder described herein. Similarly, the present disclosure provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder described herein.

Proliferative disorders

In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the proliferative disorder is ovarian cancer, breast cancer, lung cancer, colorectal cancer, or a combination thereof. In some embodiments, the proliferative disorder is leukemia. In some embodiments, the proliferative disorder is breast cancer. In some embodiments, the proliferative disorder is lung cancer. In some embodiments, the proliferative disorder is colorectal cancer.

In some embodiments, the proliferative disorder is breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, or bladder cancer. In some embodiments, the proliferative disorder is intrahepatic cholangiocarcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, or ovarian cancer. In some embodiments, the proliferative disorder is gastric cancer, breast cancer, triple negative breast cancer, or rectal cancer. In some embodiments, the proliferative disorder is endometrial cancer, non-small cell lung cancer, lung squamous cell carcinoma, gastric cancer, breast cancer, or urothelial cancer.

In some embodiments, the disorder is ovarian cancer, endometrial cancer, gastric cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, stomach cancer, sarcoma cancer, liver cancer, esophageal cancer, laryngeal cancer, multiple myeloma, colorectal cancer, rectal cancer, skin cancer, or pancreatic cancer. In some embodiments, the bladder cancer is urothelial cancer. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the lung cancer is lung squamous cell carcinoma or non-small cell lung cancer. In some embodiments, the laryngeal carcinoma is a laryngeal squamous cell carcinoma. In some embodiments, the skin cancer is melanoma.

In some embodiments, the proliferative disorder is associated with a deregulation of CDK2 or cyclin E. In some embodiments, the deregulation of CDK2 is overexpression of CDK2 or cyclin E. In some embodiments, the deregulation of cyclin E is overexpression of CDK2 or cyclin E. In some embodiments, the proliferative disorder is associated with a deregulation of CDK2 and cyclin E. In some embodiments, the deregulation of CDK2 and cyclin E is overexpression of CDK2 and cyclin E.

In some embodiments, the proliferative disorder is associated with one or more activating mutations in CDK 2. In some embodiments, the activating mutation in CDK2 is a mutation in one or more of the intracellular kinase domain and the extracellular domain. In some embodiments, the activating mutation in CDK2 is a mutation in an intracellular kinase domain.

Route of administration and dosage form

According to the methods described herein, the compounds and compositions can be administered using any amount and any route of administration effective to treat or reduce the severity of a disorder (e.g., a proliferative disorder or a craniosynostic syndrome). The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject; the severity of the infection, the particular agent, its mode of administration, etc. For ease of administration and dose uniformity, the compounds described herein are preferably formulated in unit dosage forms. The expression "unit dosage form" as used herein refers to physically discrete units of an agent suitable for the patient to be treated. However, it will be appreciated that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the particular compound employed; the specific composition used; age, weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular compound being used; duration of treatment; drugs used in combination or simultaneously with the particular compound employed, and similar factors well known in the medical arts.

The pharmaceutically acceptable compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., by powders, ointments or drops), bucally, as an oral or nasal spray, and the like. In certain embodiments, the compounds described herein may be administered orally or parenterally at a dosage level of from about 0.01mg/kg to about 50mg/kg, and preferably from about 1mg/kg to about 25mg/kg of subject body weight/day, one or more times per day, to achieve the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable formulations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be employed include water, ringer's solution U.S. P. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulation may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or another sterile injectable medium prior to use.

In order to prolong the effect of the compounds described herein, it is often desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of a compound then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of the compound form for parenteral administration is achieved by dissolving or suspending the compound in an oil vehicle. The injectable depot forms are prepared by forming a microencapsulated matrix of the compound in a biodegradable polymer (e.g., polylactic acid-polyglycolide). Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and polyanhydrides. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and/or the following: a) Fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) Binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) Humectants, such as glycerol; d) Disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) Slow solvents such as paraffin; f) Absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Similar types of solid compositions can also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. It may optionally contain opacifying agents, and may also have a composition such that it releases one or more active ingredients, optionally in a delayed manner, only (or preferentially) in a certain portion of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols and the like.

The active compound may also be in microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be admixed with at least one inert diluent (e.g., sucrose, lactose or starch). Such dosage forms may also contain, in accordance with common practice, additional substances other than inert diluents, such as tabletting lubricants and other tabletting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. It may optionally contain opacifying agents, and may also have a composition such that it releases one or more active ingredients, optionally in a delayed manner, only (or preferentially) in a certain portion of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers which may be required. Ophthalmic formulations, ear drops, and eye drops are also within the scope of the present disclosure. Furthermore, the present disclosure encompasses the use of transdermal patches that have the additional advantage of controlled delivery of compounds to the body. Such dosage forms may be prepared by dissolving or partitioning the compound in an appropriate medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate may be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Dosage and regimen

According to the methods of the present disclosure, a compound of the present disclosure is administered to a subject in a therapeutically effective amount, e.g., to alleviate or ameliorate symptoms of a disorder in the subject. This amount is readily determined by one of skill in the art based on known procedures, including analysis of titration curves established in vivo, as well as the methods and assays disclosed herein.

In some embodiments, the methods comprise administering a therapeutically effective dose of a compound of the present disclosure. In some embodiments of the present invention, in some embodiments, the therapeutically effective dose is at least about 0.0001mg/kg body weight, at least about 0.001mg/kg body weight, at least about 0.01mg/kg body weight, at least about 0.05mg/kg body weight, at least about 0.1mg/kg body weight, at least about 0.25mg/kg body weight, at least about 0.3mg/kg body weight, at least about 0.5mg/kg body weight, at least about 0.75mg/kg body weight, at least about 1mg/kg body weight, at least about 2mg/kg body weight, at least about 3mg/kg body weight, at least about 4mg/kg body weight, at least about 5mg/kg body weight, at least about 6mg/kg body weight, at least about 7mg/kg body weight, at least about 8mg/kg body weight, at least about 9mg/kg body weight, at least about 10mg/kg body weight, at least about 15mg/kg body weight, at least about 20mg/kg body weight at least about 25mg/kg body weight, at least about 30mg/kg body weight, at least about 40mg/kg body weight, at least about 50mg/kg body weight, at least about 75mg/kg body weight, at least about 100mg/kg body weight, at least about 200mg/kg body weight, at least about 250mg/kg body weight, at least about 300mg/kg body weight, at least about 350mg/kg body weight, at least about 400mg/kg body weight, at least about 450mg/kg body weight, at least about 500mg/kg body weight, at least about 550mg/kg body weight, at least about 600mg/kg body weight, at least about 650mg/kg body weight, at least about 700mg/kg body weight, at least about 750mg/kg body weight, at least about 800mg/kg body weight, at least about 900mg/kg body weight, or at least about 1000mg/kg body weight. It will be appreciated that any of the doses listed herein may constitute an upper or lower dose range limit, and may be combined with any other dose to constitute a dose range that includes both the upper and lower limit.

In some embodiments, the therapeutically effective dose is in the range of about 0.1mg to about 10mg/kg body weight, about 0.1mg to about 6mg/kg body weight, about 0.1mg to about 4mg/kg body weight, or about 0.1mg to about 2mg/kg body weight.

In some embodiments, the therapeutically effective dose is in the range of about 1 to 500mg, about 2 to 150mg, about 2 to 120mg, about 2 to 80mg, about 2 to 40mg, about 5 to 150mg, about 5 to 120mg, about 5 to 80mg, about 10 to 150mg, about 10 to 120mg, about 10 to 80mg, about 10 to 40mg, about 20 to 150mg, about 20 to 120mg, about 20 to 80mg, about 20 to 40mg, about 40 to 150mg, about 40 to 120mg, or about 40 to 80 mg.

In some embodiments, the method comprises a single administration or administration (e.g., as a single injection or deposition). Alternatively, in some embodiments, the method comprises administering to a subject in need thereof once a day, twice a day, three times a day, or four times a day for a period of about 2 to about 28 days, or about 7 to about 10 days, or about 7 to about 15 days, or longer. In some embodiments, the method comprises chronic administration. In other embodiments, the method comprises administration over the course of weeks, months, years or decades. In other embodiments, the method comprises administration over a period of weeks. In other embodiments, the method comprises administration over a period of months. In other embodiments, the method comprises administration over the course of years. In other embodiments, the method comprises administration over the course of decades.

The dosage administered may vary depending upon known factors, such as the pharmacodynamic characteristics of the active ingredient, as well as its mode and route of administration; the time of application of the active ingredient; age, sex, health condition and weight of the recipient; the nature and extent of the symptoms; the type of treatment, the frequency of treatment, and the desired effect; and rate of excretion. These factors can be readily determined and can be used by those skilled in the art to adjust or titrate the dosage and/or dosing regimen.

Inhibition of protein kinase

According to one embodiment, the present disclosure relates to a method of inhibiting protein kinase activity in a biological sample, the method comprising the step of contacting the biological sample with a compound described herein or a composition comprising the compound.

According to another embodiment, the present disclosure relates to a method of inhibiting the activity of CDK2 or a mutant thereof in a biological sample, said method comprising the step of contacting said biological sample with a compound described herein or a composition comprising said compound. In certain embodiments, the present disclosure relates to a method of reversibly inhibiting the activity of CDK2 or a mutant thereof in a biological sample, comprising the step of contacting said biological sample with a compound described herein or a composition comprising said compound.

In another embodiment, the present disclosure provides a method of selectively inhibiting CDK2 relative to one or more of CDK1, CDK4, CDK5, CDK6, and CDK 9. In some embodiments, the compounds described herein are more than 5-fold selective for CDK2 than for CDK1, CDK4, CDK5, CDK6, and CDK 9. In some embodiments, the compounds described herein are more than 10-fold selective for CDK2 over CDK1, CDK4, CDK5, CDK6, and CDK 9. In some embodiments, the compounds described herein are more than 50-fold selective for CDK2 over CDK1, CDK4, CDK5, CDK6, and CDK 9. In some embodiments, the compounds described herein are more than 100-fold selective for CDK2 over CDK1, CDK4, CDK5, CDK6, and CDK 9. In some embodiments, the compounds described herein are more than 200-fold selective for CDK2 over CDK1, CDK4, CDK5, CDK6, and CDK 9.

The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; a biopsy material or extract thereof obtained from a mammal; and blood, saliva, urine, stool, semen, tears, or other bodily fluids or extracts thereof.

Inhibition of the activity of CDK2 (or a mutant thereof) in a biological sample may be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and bioassays.

Another embodiment of the present disclosure relates to a method of inhibiting protein kinase activity in a patient, the method comprising the step of administering to the patient a compound described herein or a composition comprising the compound.

According to another embodiment, the present disclosure relates to a method of inhibiting the activity of CDK2 or a mutant thereof in a subject, said method comprising the step of administering to said subject a compound described herein or a composition comprising said compound. According to certain embodiments, the present disclosure relates to a method of reversibly inhibiting the activity of one or more CDK2 or mutants thereof in a patient, said method comprising the step of administering to said patient a compound described herein or a composition comprising said compound.

According to another embodiment, the present disclosure provides a method for treating a disorder mediated by CDK2 or a mutant thereof in a subject in need thereof, comprising the step of administering to said subject a compound described herein or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein. In some embodiments, the present disclosure provides a method for treating a disorder mediated by CDK2 or a mutant thereof in a subject in need thereof, the method comprising the step of administering to the subject a compound described herein or a pharmaceutically acceptable composition thereof, wherein the compound reversibly inhibits CDK2 or a mutant thereof.

According to another embodiment, the present disclosure provides a method of inhibiting the signaling activity of CDK2 or a mutant thereof in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable composition thereof. In some embodiments, the present disclosure provides a method of inhibiting CDK2 signaling activity in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable composition thereof.

In some embodiments, the present disclosure provides a method for treating a disorder mediated by CDK2 or a mutant thereof in a subject in need thereof, the method comprising the step of administering to the subject a compound described herein or a pharmaceutically acceptable composition thereof, wherein the compound reversibly inhibits CDK2 or a mutant thereof.

The compounds described herein may also inhibit CDK2 function by incorporating into agents that catalyze the disruption of CDK 2. For example, the compounds may be incorporated into proteolytically targeted chimeras (PROTAC). Protoc is a bifunctional molecule, one part of which is capable of binding to the E3 ubiquitin ligase and the other part has the ability to bind to a target protein intended for degradation by cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase will cause it to be labeled as disrupted (i.e. ubiquitinated) and subsequently degraded by the proteasome. Any E3 ligase may be used. The E3 ligase-binding portion of PROTAC is linked to the target protein-binding portion of PROTAC via a linker consisting of a variable atom chain. Thus, recruitment of CDK2 to the E3 ligase will result in disruption of CDK2 protein. The variable atom chain may comprise, for example, rings, heteroatoms, and/or repeating polymer units. It may be rigid or flexible. Which can be connected to the two parts using standard techniques in the field of organic synthesis.

Combination therapy

Depending on the particular disorder, condition, or disease to be treated, additional therapeutic agents that are typically administered to treat the condition may be administered in combination with the compounds and compositions described herein. As used herein, additional therapeutic agents that are typically administered to treat a particular disease or disorder are referred to as "appropriate for the disease or disorder being treated.

Thus, in certain embodiments, the methods of treatment comprise administering a compound or composition described herein in combination with one or more additional therapeutic agents. In certain other embodiments, the method of treatment comprises administering a compound or composition described herein as the sole therapeutic agent.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulators, and histone deacetylase inhibitors. In some embodiments, the one or more additional therapeutic agents are selected from the following agents or pharmaceutically acceptable salts thereof: BCR-ABL inhibitors: such as imatinib (imatinib), nilotinib (nilotinib), dasatinib (dasatinib), bosutinib (bosutinib), panatinib (ponatinib), bafitinib (bafetinib), danasetinib (danusertib), secatinib (saracatinib), PF03814735; ALK inhibitors (see Dardaei et al, 2018, nat Med.;24 (4): 512-517): such as crizotinib (crizotinib), NVP-TAE 684, ceritinib (ceritinib), ai Leti ni (aletinib), bragg inib (brinatinib), emtrictinib (entrecinib), and loratinib (loretinib); BRAF inhibitors (see Prahallad et al, 2015,Cell Rep.12,1978-1985): such as vemurafenib (vemurafenib), dabrafenib (dabrafenib); FGFR inhibitors: such as infliximab (infigr atinib), doratinib (dovitinib), erdasatinib (erdafitinib), BLU-554, AZD 4547; FLT3 inhibitor: such as sunitinib, midostaurin, tandutinib, sorafenib, lestaninib, quetiatinib, quezatinib and clenbuterinib; MEK inhibitors (see Fedel et al 2018,BioRxiv 307876;Torres-Ayuso et al 2018,Cancer Discov.8,1210-1212; and Wong et al 2016, oncostarget.2) 10 months and 4 days 016; 7 (40):65676-65695): such as trametinib (trametinib), cobimetinib (cobimetinib), metinib (binimeinib), semetinib (selumetinib); ERK inhibitors: such as ulitinib (ulixertiinib), MK-8353, LY-3214996; VEGF receptor inhibitors: such as bevacizumab, axitinib, aflibercept, brivanib, motesanib, pasireotide, sorafenib; tyrosine kinase inhibitors: such as erlotinib (erlotinib), li Nifa ni (liniflanib), sunitinib, pazopanib (pazopanib); epidermal Growth Factor Receptor (EGFR) inhibitors: gefitinib (gefitnib), octreotide (osimerinib), cetuximab (cetuximab), panitumumab (panitumumab); HER2 receptor inhibitors: such as trastuzumab, lenatinib (nepatinib), lapatinib (lapatinib), lapatinib; MET inhibitors: such as crizotinib, cabozantinib (cabozantinib); CD20 antibody: such as rituximab (rituximab), tositumomab (tositumomab), ofatumumab (ofatumumab); DNA synthesis inhibitor: such as capecitabine (capecitabine), gemcitabine (gemcitabine), nelarabine (nilarabine), hydroxyurea; antitumor agent: such as oxaliplatin (oxaliplatin), cisplatin; HER dimerization inhibitors: such as pertuzumab (pertuzumab); human granulocyte colony-stimulating factor (G-CSF) modulator: such as filgrastim; immunomodulators: such as alfuzumab, lenalidomide, thalidomide, pomalidomide; CD40 inhibitors: such as daclizumab (dactuzumab); pro-apoptotic receptor agonists (PARA): for example Du Lale min (dulnermin); heat Shock Protein (HSP) inhibitors: such as tanspiramycin (17-allylamino-17-desmethoxygeldanamycin); hedgehog antagonists: such as vmodegin (vismodegib); proteasome inhibitors: such as bortezomib (bortezomib); PI3K inhibitors: such as pitilist (picilisib), dacrilst (dactylisib), bupirib (buseliib), talellist (taseliib), idolarisib (idelalisib), dulirise (duvelisib), wu-Lini Palivist (umbralisib); phospholipase A2 inhibitors: such as anagrelide; BCL-2 inhibitors: such as vinatoclax (vennetoclax); aromatase inhibitors: exemestane (exemestane), letrozole (letrozole), anastrozole (anastrozole), falodex (faslodex), tamoxifen (tamoxifen); topoisomerase I inhibitors: such as irinotecan (irinotecan), topotecan (topotecan); topoisomerase II inhibitors: such as etoposide (etoposide), teniposide (teniposide); mTOR inhibitors: such as temsirolimus (temsirolimus), geothermal limus (ridaforolimus), everolimus (everolimus), sirolimus (sirolimus); osteoclast bone resorption inhibitors: such as zoledronic acid (zoledronic acid); CD33 antibody drug conjugate: such as gemtuzumab (gemtu zumab ozogamicin); CD22 antibody drug conjugate: such as oorituximab (inot uzumab ozogamicin); CD20 antibody drug conjugate: such as ibritumomab (ibritu momab tiuxetan); somatostatin (somatostatin) analogs: such as octreotide (octreotide); interleukin-11 (IL-11): such as the opregnileukin (oprelvekin); synthesis of erythropoietin: such as dapoxetine alpha (darbepoetin alfa); nuclear factor κb Receptor Activator (RANK) inhibitor: such as denosumab (denosumab); thrombopoietin mimetic peptide: such as romidepsin (romiplostim); cell growth stimulants: such as palifermin (palifermin); anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies: such as phenytoin (figitumumab); anti-CSl antibody: such as erlotinib (elotuzumab); CD 52 antibody: such as alemtuzumab (alemtuzumab); CTLA-4 inhibitors: such as tiximumab (tremelimumab), ipilimab (ipilimumab); PD1 inhibitors: such as nivolumab (nivolumab), pembrolizumab (pembrolizumab); immunoadhesin; such as pilizumab (pidirizumab), AMP-224; PDL1 inhibitor: such as MSB0010718C; yw243.55.s70, MPDL3280A; MEDI-4736, MSB-0010718C or MDX-1105; LAG-3 inhibitors: such as BMS-986016; GITR agonists; GITR fusion proteins and anti-GITR antibodies; histone Deacetylase Inhibitor (HDI): such as vorinostat (voninostat); anti-CTLA 4 antibodies: for example, tiximumab (tremelimumab), ipilimumaab (ipilimumaab) ) The method comprises the steps of carrying out a first treatment on the surface of the Alkylating agent: such as temozolomide, dacarbazine, melphalan, altretamine, mechlorethamine, and bis (chloroethyl) methylamine, streptozolomide, thiotepa; biological response modifier: such as BCG (bacillus calmette-guerin), diniinterleukin (denileukin diftitox); antitumor antibiotics: such as doxorubicin (doxorubicin), bleomycin (bleomycin), daunorubicin (daunorubicin), daunorubicin liposome, mitoxantrone (mitoxantrone), pan Ai Meisu (epiubicin), idarubicin (idarubicin), mitomycin C (mitomycin C); anti-microtubule agents: such as estramustine; cathepsin K inhibitors: such as obcurrent (odanacatib); epothilone (Epothilone) analogs: such as ixabepilone (ixabepilone); tpoR agonists: such as eltrombopag (eltrombopag); antimitotic agents: such as docetaxel; adrenal steroid inhibitors: such as aminoglutethimide (aminoglutethimide); antiandrogens: such as nilutamide (nilutamide); androgen receptor inhibitors: such as enzalutamide (enzalutamide), abiraterone acetate (abiraterone acetate), ortronine (ortronil), galterone (galterone), and sevelocin (sevitronine), bicalutamide (bicalutamide), flutamide (flutamide); androgens: such as fluoromethylolmesterone (fluorooxyesterone); CDK1 inhibitors: such as alvocidib (alvocidib), palbociclib (palbociclib), rebabociclib (ribocilib), qu Laxi b (trilciclib), abbe's cilib (abemaciclib); gonadotropin releasing hormone (GnRH) receptor agonists: such as Liu Peilin (leuprolide) or acetic acid Liu Peilin (leuprolide acetat e); taxane antitumor agent: such as cabazitaxel (cabazitaxel), lotxel (larotaxel); 5-HTla receptor agonists: such as zaleproden (xaliproden); HPV vaccine: for example sold by GlaxoSmithKline Sold by Merck->Iron chelator: such as deferasirox (deferasirox); antimetabolites: such as cladribine (clarithromycin), 5-fluorouracil, 6-thioguanine, pemetrexed (pemetrexed), cytarabine liposome, decitabine (dectabine), hydroxyurea, fludarabine (fludarabine), fluorouridine, cladribine (claritubine), methotrexate (methotrexa), pentostatin (pentastatin); bisphosphonates: such as pamidronate (pamidronate); demethylating agent: such as 5-azacitidine (5-azacitidine), decitabine; antitumor plant alkaloids: such as protein-bound paclitaxel (paclitaxel protein-bound); vinblastine (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), paclitaxel (paclitaxel); retinoids: such as alisretinin (alitretinoin), tretinoin (tretinoin), isotretinoin (isotretinoin), bexarotene (bexarotene); glucocorticosteroids: such as hydrocortisone (hydrocortisone), dexamethasone (dexamethasone), prednisolone (prednisolone), prednisone (prednisone), methylprednisolone (methylpr ednisolone); cytokines: such as interleukin-2, interleukin-11 (oprevelkin), interferon alpha alfa (IFN-alpha); estrogen receptor down-regulation: fulvestrant (fulvestrant); antiestrogens: such as tamoxifen, toremifene (toremifene); selective Estrogen Receptor Modulator (SERM): such as raloxifene (raloxifene); luteinizing Hormone Releasing Hormone (LHRH) agonists: such as goserelin (goserelin); progesterone: such as megestrol (megestrol); cytotoxic agent: arsenic trioxide, asparaginase (also known as L-asparaginase, irwinia (Erwinia) L-asparaginase; antiemetics such as NK-1 receptor antagonists (e.g., casapitan)), cytoprotective agents such as amifostine (amifosine), leucovorin, and immune checkpoint inhibitors the term "immune assay" Checkpoint "refers to a set of molecules on the cell surface of CD4 and CD 8T cells. Immune checkpoint molecules include, but are not limited to, programmed death 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD 137, CD40, and LAG3. Immunotherapeutic agents useful as immune checkpoint inhibitors useful in the methods of the present disclosure include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR, CD 160, 2B4, and/or TGFR beta.

In some embodiments, the one or more additional therapeutic agents are selected from the following agents: an anti-CDK 2 antibody; a cytotoxic agent; estrogen receptor targeting or other endocrine therapies, immune checkpoint inhibitors, other CDK inhibitors, receptor tyrosine kinase inhibitors, BRAF inhibitors, MEK inhibitors, PI3K inhibitors, SHP2 inhibitors, and SRC inhibitors. ( See M.Katoh, nat.Rev.Clin.Oncol.2019,16:105-122; K.Chae et al, oncostarget 2017,8:16052-16074; formisano et al, nat.Comm.2019,10:1373-1386; and references cited therein. )

The structure of an active compound identified by code, common name or trade name can be obtained from The current version of The standard schema "The Merck Index" or from a database, such as Patents International (e.g., IMS World Publications).

The compounds described herein may also be used in combination with known methods of treatment (e.g., administration of hormones or radiation). In certain embodiments, the provided compounds are useful as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

The compounds described herein may be administered alone or in combination with one or more other therapeutic compounds, with possible combination therapies taking the form: a fixed combination, or a compound described herein and one or more other therapeutic compounds are administered either in a staggered manner or independently of each other, or a fixed combination and one or more other therapeutic compounds are administered in combination. The compounds described herein may be administered in addition or in combination with chemotherapy, radiation therapy, immunotherapy, phototherapy, surgical intervention, or a combination of these, particularly for oncological therapy. With other treatment strategies as described above, long-term therapy is equally possible as adjuvant therapy. Other possible treatments are therapies that maintain the patient in a state after tumor regression, or even chemopreventive therapies, for example in patients at risk.

Those additional agents may be administered separately from the compositions containing the provided compounds as part of a multi-dose regimen. Alternatively, those agents may be part of a single dosage form that is mixed with the compounds described herein in a single composition. If administered as part of a multi-dose regimen, the two active agents may be administered simultaneously, sequentially or within a period of time of each other, typically within five hours of each other.

As used herein, the terms "combination", "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the compounds described herein may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form comprising a compound described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of both the compound described herein and the additional therapeutic agent (in those compositions comprising additional therapeutic agents as described above) that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions described herein should be formulated such that a dose of between 0.01 and 100mg/kg body weight/day of the compounds described herein can be administered.

In those compositions comprising additional therapeutic agents, the additional therapeutic agents and the compounds described herein may act synergistically. Thus, the amount of additional therapeutic agent in such compositions will be less than would be required in monotherapy utilizing the therapeutic agent alone. In such compositions, additional therapeutic agents may be administered at a dose of between 0.01 and 1,000 μg/kg body weight/day.

The amount of additional therapeutic agent present in the compositions described herein will not exceed the amount typically administered in compositions comprising the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will be in the range of about 50% to 100% of the amount typically present in compositions comprising the agent as the sole therapeutically active agent.

The compounds described herein, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating implantable medical devices, such as prosthetic limbs, prosthetic valves, vascular grafts, stents, and catheters. Vascular stents have been used, for example, to overcome restenosis (restenosis of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or alleviated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. The present disclosure also encompasses implantable devices coated with the compounds described herein.

Any of the compounds and/or compositions of the present disclosure may be provided in a kit comprising the compounds and/or compositions. Thus, in some embodiments, the compounds and/or compositions of the present disclosure are provided in a kit.

The disclosure is further illustrated by the following non-limiting examples.

Examples

Examples are provided herein to facilitate a more complete understanding of the present disclosure. The following examples are presented to illustrate exemplary modes of making and practicing the presently disclosed subject matter. However, the scope of the present disclosure should not be construed as being limited to the particular embodiments disclosed in these examples, which are illustrative only.

As depicted in the examples below, in certain exemplary embodiments, compounds were prepared according to the following general procedure. It should be appreciated that while the general methods depict the synthesis of certain compounds described herein, the following general methods and other methods known to those of ordinary skill in the art may be applicable to other classes and subclasses and species of each of these compounds as described herein. The additional compounds described herein are prepared by methods substantially similar to those described in the examples herein and known to those skilled in the art.

In the description of the synthetic methods described below, unless otherwise indicated, all reaction conditions (e.g., reaction solvents, atmospheres, temperatures, durations, and treatment procedures) are understood to be selected from standard conditions for the reactions, unless otherwise indicated. In a general scheme, one skilled in the art of organic synthesis will understand that the functional groups present on different parts of the molecule should be compatible with the reagents and reactions presented. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art and thus indicate alternative methods (e.g., use of protecting groups or alternative reactions). The starting materials for the examples are commercially available or can be readily prepared from known materials by standard methods.

It is contemplated that at least some of the compounds identified herein as "intermediates" are compounds of the present disclosure.

Example 1

N- (1-methylcyclopropyl) -2- ((1R, 3S) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) acetamide

(Z) -3- (2- (tert-butoxy) -2-oxoethylene) cyclopentane-1-carboxylic acid methyl ester

Step 1: to a mixture of tert-butyl 2- (diethoxyphosphoryl) acetate (35 g,0.14 mol) in THF (100 mL) was added LiHMDS (140 mL,0.14 mol) dropwise at 0deg.C under nitrogen. The mixture was stirred at 0deg.C for 1h, followed by the addition of methyl 3-oxocyclopentane-1-carboxylate (10 g,70 mmol). The mixture was stirred at 25℃for 2h. The reaction mixture was treated with saturated NH ₄ Cl (50 mL) was quenched and the aqueous phase was extracted three times with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by chromatography on silica gel (20 g column; elution with PE/EA; 8/1). Concentrating in vacuum(Z) -3- (2- (tert-butoxy) -2-oxoethylene) cyclopentane-1-carboxylic acid methyl ester (4.8 g, 28%) was produced as a colorless oil. m/z (ES) ⁺ )[M+H] ⁺ ＝241.10；HPLC tR＝1.227min。

3- (2- (tert-butoxy) -2-oxoethyl) cyclopentane-1-carboxylic acid methyl ester

Step 2: a stirred mixture of (Z) -3- (2- (tert-butoxy) -2-oxoethylene) cyclopentane-1-carboxylic acid methyl ester (4.8 g,20 mmol) and Pd/C (0.43 g,4.0 mmol) in MeOH (50 mL) at 25℃was treated with H ₂ And (5) treating for 2 hours. The mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo. Concentration in vacuo afforded methyl 3- (2- (tert-butoxy) -2-oxoethyl) cyclopentane-1-carboxylate (4.1 g, 85%) as a colorless oil. m/z (ES) ⁺ )[M+Na] ⁺ ＝265.15；HPLC tR＝1.243min。

2- (3- (2-cyanoacetyl) cyclopentyl) acetic acid tert-butyl ester

Step 3: at-78deg.C under nitrogen atmosphere to CH ₃ To a mixture of CN (1.4 g,34 mmol) and methyl 3- (2- (tert-butoxy) -2-oxoethyl) cyclopentane-1-carboxylate (4.1 g,17 mmol) in THF (40 mL) was added LiHMDS (25 mL,25 mmol) dropwise. The mixture was slowly warmed to room temperature and stirred at room temperature for an additional 2h. The reaction mixture was treated with H ₂ O (50 mL) was quenched and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Tert-butyl 2- (3- (2-cyanoacetyl) cyclopentyl) acetate (1.6 g, 38%) was isolated as a colorless oil. m/z (ES) ⁺ )[M+H] ⁺ ＝252.10；HPLC tR＝0.982min。

2- (3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl) acetic acid tert-butyl ester

Step 4: to a mixture of t-butylhydrazine (0.88 g,9.9 mmol) in EtOH (5 mL) at 25deg.C under nitrogen was added NaOH (0.40 g,9.9 mmol) in portions. The mixture was stirred at 25℃for 1h, followed by the addition of tert-butyl 2- (3- (2-cyanoacetyl) cyclopentyl) acetate (2.5 g,9.9 mmol). The mixture was stirred at 50℃for 3h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 15 min; detector, UV 220nm. Concentration in vacuo afforded tert-butyl 2- (3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl) acetate (2 g, 60%) as a colorless oil. m/z (ES) ⁺ )[M+H] ⁺ ＝322.30；HPLC tR＝0.985min.。

2- (3- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) cyclopentyl) acetic acid tert-butyl ester

Step 5: a round bottom flask was charged with tert-butyl 2- (3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl) acetate (2 g,6 mmol), 2- (3-methylisoxazol-5-yl) acetic acid (1 g,7 mmol), HATU (4 g,9 mmol), DIEA (2 g,0.02 mol) and DCM (20 mL). The solution was stirred at 25℃for 1h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by silica gel chromatography (eluting with DCM/meoh=20/1). Concentration in vacuo afforded tert-butyl 2- (3- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) cyclopentyl) acetate (800 mg, 30%) as a colorless oil. m/z (ES) ⁺ )[M+H] ⁺ ＝445.35；HPLC tR＝1.243min。

2- (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) acetic acid

Step 6: a stirred mixture of tert-butyl 2- (3- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) cyclopentyl) acetate (844 mg,1.90 mmol) in FA (8 mL) was treated with N at 75deg.C ₂ And (5) treating for 12h. The crude material obtained was purified by C18 (acetonitrile/water). Lyophilization afforded 2- (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) acetic acid (600 mg, 95.1%) as a yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝333.20；HPLC tR＝0.302min。

N- (1-methylcyclopropyl) -2- (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) acetamide

Step 7: the resealable reaction vial was charged with 2- (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) acetic acid (600 mg,1.81 mmol), 1-methylcyclopropan-1-amine (640 mg,9.03 mmol), HOBt (415 mg,2.71 mmol), EDC (692 mg,3.61 mmol) and stir bar, followed by evacuation and purging with nitrogen three times. DCM (10 mL) was added and the mixture was stirred at 25℃for 1h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (1 g column; elution with DCM/MeOH; 20/1). Concentration in vacuo afforded N- (1-methylcyclopropyl) -2- (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) acetamide (187 mg, 26.9%) as a colorless oil. m/z (ES) ⁺ )[M+H] ⁺ ＝386.35；HPLC tR＝0.778min。

Step 8: n- (1-methylcyclopropyl) -2- (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) acetamide (400 mg,1.04 mmol) was purified by chiral preparative HPLC (column: CHIRALPAK IG, 2X 25cm,5 μm; mobile phase A: mtBE (0.1% TEA) - -, mobile phase B: IPA: DCM=1:1; flow: 20mL/min; gradient: 40% B to 40% B in 19 min; wavelength: 220/254nm; RT1 (min): 11.69; RT2 (min): 15.11; sample solvent: IPA: DCM=1:1; injection volume: 0.3mL; run number: 10). Lyophilization afforded N- (1-methylcyclopropyl) -2- ((1 r,3 s) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) acetamide (44 mg, 11%) as a white amorphous solid. m/z (ES) ⁺ )[M+H] ⁺ ＝386.25；HPLC tR＝0.800min。 ¹ H NMR(400MHz,DMSO-d ₆ )δ12.07(s,1H),10.61(s,1H),7.99(s,1H),6.24(d,J＝14.6Hz,2H),3.83(s,2H),3.02(dq,J＝10.7,8.4Hz,1H),2.20(s,4H),2.10(dt,J＝13.5,7.0Hz,1H),2.06-1.92(m,3H),1.77(dq,J＝14.8,7.7Hz,1H),1.59(dtd,J＝12.5,9.3,6.5Hz,1H),1.31(dtd,J＝12.9,9.1,5.9Hz,1H),1.25(s,3H),1.18(dt,J＝12.3,10.5Hz,1H),0.59-0.52(m,2H),0.52-0.44(m,2H)。

Additional compounds prepared according to the method of example 1 are depicted in table 2 below.

TABLE 2 additional exemplary Compounds

Example 2

(1-methylcyclopropyl) carbamic acid rel- (1R, 4S) -4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cycloheptyl ester

4- ((tert-Butyldiphenylsilyl) oxy) cycloheptane-1-carboxylic acid methyl ester

Step 1: to a mixture of methyl 4-hydroxycycloheptane-1-carboxylate (1 g,6 mmol) and 1H-imidazole (1 g,0.02 mol) in DMF (10 mL) was added dropwise t-butylchlorodiphenylsilane (2 g,7 mmol) at 0deg.C under nitrogen. The mixture was stirred at 25℃for 12 hours. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluting with PE/EA (ratio: 10/1)). Concentration in vacuo afforded methyl 4- ((tert-butyldiphenylsilyl) oxy) cycloheptane-1-carboxylate (2 g,5mmol, 80%) as a yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝411.20；HPLC tR＝1.527min。

3- (4- ((tert-butyldiphenylsilyl) oxy) cycloheptyl) -3-oxopropionitrile

Step 2: lithium bis (trimethylsilyl) amide (0.81 g,4.8 mmol) was added dropwise to a solution of methyl 4- ((tert-butyldiphenylsilyl) oxy) cycloheptane-1-carboxylate (1.8 g,4.4 mmol) and acetonitrile (0.36 g,8.8 mmol) in THF (20 mL) at-78deg.C under nitrogen. The mixture was warmed to 25 ℃ and stirred for 1h. The mixture was treated with saturated NH ₄ And (5) quenching Cl. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluting with PE/EA (ratio: 30/1)). Concentration in vacuo afforded 3- (4- ((tert-butyldiphenylsilyl) oxy) cycloheptyl) -3-oxopropanenitrile (1.7 g,4.1mmol, 92%) as a yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝420.10；HPLC tR＝1.280min。

1- (tert-butyl) -3- (4- ((tert-butyldiphenylsilyl) oxy) cycloheptyl) -1H-pyrazol-5-amine

Step 3: a round bottom flask was charged with tert-butylhydrazine hydrochloride (0.76 g,6.1 mmol), sodium hydroxide (0.24 g,6.1 mmol), etOH (18 mL) and stir bar. The solution was stirred at 25℃for 1 hour. 3- (4- ((tert-butyldiphenylsilyl) oxy) cycloheptyl) -3-oxopropionitrile (1.7 g,4.1 mmol) was added and the solution stirred at 50℃for 6 hours. The mixture was quenched with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; flow ofA phase, meCN in water, gradient 40% to 70% in 12 min; the detector, UV 254nm, gave 1- (tert-butyl) -3- (4- ((tert-butyldiphenylsilyl) oxy) cycloheptyl) -1H-pyrazol-5-amine (1.9 g,3.9mmol, 96%) as a yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝490.50；HPLC tR＝1.305min。

N- (1- (tert-butyl) -3- (4- ((tert-butyldiphenylsilyl) oxy) cycloheptyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 4: a round bottom flask was charged with 1- (tert-butyl) -3- (4- ((tert-butyldiphenylsilyl) oxy) cycloheptyl) -1H-pyrazol-5-amine (1 g,2 mmol), 2- (3-methylisoxazol-5-yl) acetic acid (0.3 g,2 mmol), N-ethyl-N-isopropyl-2-amine (0.8 g,6 mmol), EA (12 mL), and a stir bar. T added to EA ₃ P (2 g,50% Wt,3 mmol) and the solution was stirred at 25℃for 3 hours. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 80% to 100% in 10 min; the detector, UV 254nm, gave N- (1- (tert-butyl) -3- (4- ((tert-butyldiphenylsilyl) oxy) cycloheptyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (1.1 g,1.8mmol, 90%) as a yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝613.25；HPLC tR＝1.543min。

N- (1- (tert-butyl) -3- (4-hydroxycycloheptyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 5: a round bottom flask was charged with N- (1- (tert-butyl) -3- (4- ((tert-butyldiphenylsilyl) oxy)) Cycloheptyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (1.1 g,1.8 mmol) and stir bar. A1N solution of TBAF in THF (12 mL) was added and the solution was stirred at 75deg.C for 16 hours. The mixture was quenched with water (20 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 20% to 70% in 15 min; the detector, UV 254nm, gave N- (1- (tert-butyl) -3- (4-hydroxycycloheptyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (450 mg,1.20mmol, 67%) as a yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝375.15；HPLC tR＝0.860min。

(1-methylcyclopropyl) carbamic acid 4- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) cycloheptyl ester

Step 6: a round bottom flask was charged with N- (1- (tert-butyl) -3- (4-hydroxycycloheptyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (79mg, 2.11 mmol), 1-isocyanato-1-methylcyclopropane (6.8 mL,0.62M in toluene, 4.22 mmol), N-ethyl-N-isopropylpropan-2-amine (812 mg,6.33 mmol), toluene (10 mL) and a stirring bar. The solution was stirred at 110℃for 20 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 20% to 60% in 10 min; the detector, UV 220nm, gave 4- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) cycloheptyl (800 mg,1.70mmol, 80.4%) carbamate as a yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝472.15；HPLC tR＝1.098min。

(1-methylcyclopropyl) carbamic acid 4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cycloheptyl ester

Step 7: a round bottom flask was charged with 4- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) cycloheptyl (870 mg,1.84 mmol) of (1-methylcyclopropyl) carbamate and a stirring bar. HCOOH (8 mL) was added and the solution was stirred at 75 ℃ for 8 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 20% to 70% in 15 min; the detector, UV 220nm, gave (1-methylcyclopropyl) carbamic acid 4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cycloheptyl ester (650 mg,1.56mmol, 84.8%) as a yellow amorphous solid. m/z (ES) ⁺ )[M+H] ⁺ ＝416.40；HPLC tR＝0.926min。

Step 8: (1-methylcyclopropyl) carbamic acid 4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cycloheptyl ester (650 mg,1.56 mmol) was purified by chiral preparative HPLC (column: CHIRALPAK IF,2 x 25cm,5 μm; mobile phase A: hex (0.2% TEA) - -, mobile phase B: meOH: DCM=1:1; flow: 20mL/min; gradient: 60% B to 60% B in 21 min; wavelength: 220/254nm; RT1 (min): 7.33; RT2 (min): 13.51; sample solvent: meOH: DCM=1:1; injection volume: 0.3mL; run number: 9). Lyophilization gives rel- (1R, 4S) -4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cycloheptyl (31.1 mg, 74.9. Mu. Mol, 4.78%) carbamate as a white amorphous solid. m/z (ES) ⁺ )[M+H] ⁺ ＝416.35；HPLC tR＝0.909min。 ¹ H NMR(400MHz,DMSO-d ₆ )δ12.06(s,1H),10.62(s,1H),7.32(s,1H),6.27(s,1H),6.22(s,1H),4.74(s,1H),3.83(s,2H),2.97-2.66(m,1H),2.21(s,3H),1.94(d,J＝7.4Hz,2H),1.77(s,5H),1.58(d,J＝11.2Hz,2H),1.39(s,1H),1.24(s,3H),0.59(s,2H),0.47(s,2H)。

Additional compounds prepared according to the method of example 2 are depicted in table 3 below.

TABLE 3 additional exemplary Compounds

Example 3

(1R, 3S) -3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl (1-methylcyclopropyl) carbamate

3- ((tert-Butyldiphenylsilyl) oxy) cyclopentane-1-carboxylic acid methyl ester

Step 1: to 3-hydroxycyclopentane-1-carboxylic acid methyl ester (3.5 g,24 mmol) and Et ₃ To an ice-cold solution of N (7.4 g,10mL,73 mmol) in DMF (40 mL) was added TBDPS-Cl (10 g,36 mmol), and the resulting mixture was then stirred at room temperature overnight. The obtained mixture is usedEA (100 mL) was diluted and washed with brine (3 x 80 mL). The organic layer was purified by Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 0 to 15% EA in petroleum ether) to give methyl 3- ((tert-butyldiphenylsilyl) oxy) cyclopentane-1-carboxylate (8.8 g,23mmol, 95%) as a pale solid. m/z (ES) ⁺ )[M+H] ⁺ ＝383.15；HPLC tR＝1.425min。

3- ((tert-Butyldiphenylsilyl) oxy) -1-methylcyclopentane-1-carboxylic acid methyl ester

Step 2: to a solution of methyl 3- ((tert-butyldiphenylsilyl) oxy) cyclopentane-1-carboxylate (8.8 g,23 mmol) in THF (100 mL) at-78deg.C was added a solution of LDA (13.7 mL,2M in THF, 27.6 mmol). The resulting mixture was stirred at-78 ℃ for 0.5h, then MeI (16 g,0.12 mol) was added to the above mixture at-78 ℃. After stirring for an additional 1 hour, the reaction mixture was allowed to warm to room temperature. Subjecting the resulting mixture to NH ₄ Cl (saturated aqueous, 150 mL) was quenched and extracted with EA (3X 150 mL). The combined organic layers were washed with brine (2 x 100 ml), dried over Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 0 to 15% EA in petroleum ether) to give methyl 3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentane-1-carboxylate (8.5 g,21mmol, 93%) as a pale oil. m/z (ES) ⁺ )[M+H] ⁺ ＝397.20；HPLC tR＝1.507min。

3- (3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentyl) -3-oxopropanenitrile

Step 3: to a solution of 3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentane-1-carboxylic acid methyl ester (8.5 g 21 mmol) and MeCN (1.1 g 26 mmol) in THF (80 mL)LiHMDS (21 mL,1M in THF, 21 mmol) was slowly added dropwise to maintain the internal temperature below-60 ℃. After stirring at-70℃for 1 hour, the reaction was taken up with saturated NH ₄ Cl (100 mL) was quenched and extracted with EA (3X 100 mL). The combined organic layers were washed with brine (2 x 100 ml), dried over Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give 3- (3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentyl) -3-oxopropanenitrile (8 g,0.02mol, 90%) as a pale oil. m/z (ES) ⁺ )[M+H] ⁺ ＝406；HPLC tR＝1.507min。

1- (tert-butyl) -3- (3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentyl) -1H-pyrazol-5-amine

Step 4: sodium hydroxide (0.2 g,5 mmol) was added in portions to a suspension of tert-butylhydrazine hydrochloride (0.8 g,6 mmol) in EtOH (0.5 mL) at room temperature and stirred at room temperature for 1 hour. A solution of 3- (3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentyl) -3-oxopropanenitrile (2 g,5 mmol) in ethanol was added at room temperature, and the mixture was then heated to 50℃and stirred overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 15 min; the detector, UV 220nm, gave 1- (tert-butyl) -3- (3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentyl) -1H-pyrazol-5-amine (0.95 g,2.0mmol, 40%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝476.40；HPLC tR＝1.287min。

N- (1- (tert-butyl) -3- (3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 5: to a cooled mixture of 1- (tert-butyl) -3- (3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentyl) -1H-pyrazol-5-amine (0.95 g,2.0 mmol), 2- (3-methylisoxazol-5-yl) acetic acid (0.34 g,2.4 mmol) and DIEA (0.77 g,6.0 mmol) in DCM (10 mL) was added 2,4, 6-tripropyl-1,3,5,2,4,6-trioxatriphosphohexane 2,4, 6-trioxide (3.8 g,50% Wt in ethyl acetate, 6.0 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was taken up in saturated Na ₂ CO ₃ Aqueous solution (10 mL) was quenched and extracted with DCM (2 x 10 mL). The organic layer was taken up with Na ₂ CO ₃ (2 x 10 mL), brine (30 mL) and concentrated. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 15 min; detector, UV 220nm. This gave N- (1- (tert-butyl) -3- (3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (1.05 g,1.75mmol, 88%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝599.50；HPLC tR＝1.608min。

N- (1- (tert-butyl) -3- (3-hydroxy-1-methylcyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 6: a mixture of N- (1- (tert-butyl) -3- (3- ((tert-butyldiphenylsilyl) oxy) -1-methylcyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (1.05 g,1.75 mmol) and TBAF (15 mL,1M in THF, 15 mmol) was stirred at 75deg.C for 6 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (2 x 100 ml), dried over Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 40 min; the detector, UV 220nm, gave N- (1- (tert-butyl) -3- (3-hydroxy-1-) -as a white solidMethylcyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (450 mg,1.25mmol, 71.2%). m/z (ES) ⁺ )[M+H] ⁺ ＝361.25；HPLC tR＝0.817min。

(1-methylcyclopropyl) carbamic acid 3- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) -3-methylcyclopentyl ester

Step 7: to a stirred mixture of N- (1- (tert-butyl) -3- (3-hydroxy-1-methylcyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (450 mg,1.25 mmol) and 1-isocyanato-1-methylcyclopropane (0.6M in toluene) (6 ml,4 mmol) was added DIEA (254 mg,3.75 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 ℃ under nitrogen atmosphere for 16 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 3- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) -3-methylcyclopentyl (480 mg,1.05mmol, 84.0%) carbamate as a pale yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝458.40；HPLC tR＝1.170min。

(1-methylcyclopropyl) carbamic acid 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl ester

Step 8: a solution of 3- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) -3-methylcyclopentyl (480 mg,1.05 mmol) of (1-methylcyclopropyl) carbamate in FA (3 mL) was stirred at 70℃for 4 hours. The resulting mixture was concentrated to dryness and purified by reverse phase flash chromatography to give (1-methylcyclopropyl) carbamic acid 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) ring as a white solidAmyl ester (360 mg, 897. Mu. Mol, 85.5%). m/z (ES) ⁺ )[M+H] ⁺ ＝402.20；HPLC tR＝0.880min。

Cis- (1-methylcyclopropyl) carbamic acid 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl ester and trans- (1-methylcyclopropyl) carbamic acid 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl ester

Step 9: 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl (360 mg,897 μmol) carbamate was isolated by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ +0.1％ NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 60mL/min; gradient: 20% B to 42% B,42% B within 8 min; wavelength: 220nm; RT1 (min): 6.97/7.93; number of runs: 3, cis- (1-methylcyclopropyl) carbamic acid 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl ester (60 mg,0.15mmol, 17%) and trans- (1-methylcyclopropyl) carbamic acid 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl ester (220 mg, 548. Mu. Mol, 61.1%) as a white solid were obtained.

Cis form: m/z (ES) ⁺ )[M+H] ⁺ ＝402.35；HPLC tR＝0.854min。

Trans: m/z (ES) ⁺ )[M+H] ⁺ ＝402.40；HPLC tR＝0.894min。

Step 10: cis- (1-methylcyclopropyl) carbamic acid 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl ester (100 mg,249 μmol) was purified by preparative chiral-HPLC using the following conditions: column: CHIRALPAK IG,2×25cm,5 μm; mobile phase a: hex (0.2% TEA) -HPLC, mobile phase B: etOH, dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 70% B to 70% B within 15 min; wavelength: 220/254nm; RT1 (min): 5.33; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 0.9mL; number of runs: 3. this gave (1 r,3 s) -3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl (34 mg,85 μmol, 34%) carbamate as a white amorphous solid. m/z (ES) ⁺ )[M+H] ⁺ ＝402.35；HPLC tR＝0.861min。 ¹ H NMR(400MHz,DMSO-d ₆ )δ12.08(s,1H),10.61(s,1H),7.16(d,J＝103.7Hz,1H),6.26(d,J＝28.0Hz,2H),5.05(s,1H),3.83(s,2H),2.20(s,3H),2.18-2.04(m,2H),1.99(s,1H),1.85(d,J＝14.0Hz,1H),1.69(s,2H),1.23(d,J＝8.9Hz,6H),0.58(s,2H),0.45(s,2H)。

(1R, 3R) -3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl (1-methylcyclopropyl) carbamate

Trans- (1-methylcyclopropyl) carbamic acid 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl ester (220 mg,548 μmol) was purified by preparative chiral-HPLC using the following conditions: column: CHIRALPAK IH,2×25cm,5 μm; mobile phase a: hex (0.2% TEA) -HPLC, mobile phase B: etOH: dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 30% B to 30% B within 8 min; wavelength: 220/254nm; RT1 (min): 5.03; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 0.4mL; number of runs: 6. this gave (1 r,3 r) -3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl (81.3 mg,203 μmol, 37.0%) carbamate as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝402.35；HPLC tR＝0.900min。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.12(s,1H),10.63(s,1H),7.23(d,J＝88.4Hz,1H),6.26(d,J＝27.4Hz,2H),5.02(d,J＝41.5Hz,1H),3.83(s,2H),2.39-2.25(m,1H),2.21(s,3H),2.10-1.97(m,1H),1.91(d,J＝6.5Hz,1H),1.72(d,J＝44.1Hz,3H),1.35(s,3H),1.24(s,3H),0.61(d,J＝6.1Hz,2H),0.48(d,J＝5.2Hz,2H)。

(1S, 3R) -3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl (1-methylcyclopropyl) carbamate

Cis- (1-methylcyclopropyl) carbamic acid 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl ester (100 mg,249 μmol) was purified by preparative chiral-HPLC using the following conditions: column: CHIRALPAK IG,2×25cm,5 μm; mobile phase a: hex (0.2% TEA) -HPLC, mobile phase B: etOH, dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 70% B to 70% B within 15 min; wavelength: 220/254nm; RT2 (min): 10.65; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 0.9mL; number of runs: 3. this gave (1 s,3 r) -3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl (34 mg,85 μmol, 34%) carbamate as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝402.35；HPLC tR＝0.865min。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.08(s,1H),10.62(s,1H),7.29(s,1H),6.26(d,J＝26.7Hz,2H),5.05(s,1H),3.83(s,2H),2.20(s,3H),2.16-2.03(m,2H),1.98(s,1H),1.86(s,1H),1.73-1.59(m,2H),1.23(d,J＝8.7Hz,6H),0.51(d,J＝49.6Hz,4H)。

(1S, 3S) -3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl (1-methylcyclopropyl) carbamate

Trans- (1-methylcyclopropyl) carbamic acid 3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl ester (220 mg,548 μmol) was purified by preparative chiral-HPLC using the following conditions: column: CHIRALPAK IH,2×25cm,5 μm; mobile phase a: hex (0.2% TEA) -HPLC, mobile phase B: etOH, dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 30% B to 30% B within 8 min; wavelength: 220/254nm; RT2 (min): 7.26; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 0.4mL; number of runs: 6. this gave (1S, 3S) -3-methyl-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl (86.8 mg, 216. Mu. Mol, 39.5%) carbamate as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝402.35；HPLC tR＝0.898min。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.12(s,1H),10.63(s,1H),7.34(s,1H),6.26(d,J＝27.2Hz,2H),5.02(d,J＝42.9Hz,1H),3.83(s,2H),2.42-2.25(m,1H),2.21(s,3H),2.01(s,1H),1.92(t,J＝9.4Hz,1H),1.72(d,J＝46.0Hz,3H),1.35(s,3H),1.24(s,3H),0.60(s,2H),0.48(s,2H)。

Additional compounds prepared according to the method of example 3 are depicted in table 4 below.

Example 4

3-fluoro-4-isopropylpyridazine

4- (prop-1-en-2-yl) pyridazin-3 (2H) -one

Step 1: a round bottom flask was charged with 6-chloropyridazin-3 (2H) -one (10 g,1Eq,77 mmol), 4, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (23 g,1.8Eq,0.14 mol), potassium carbonate (32 g,3Eq,0.23 mol), dioxane/H ₂ O (20 mL) and stirring bar, then evacuated and purged three times with nitrogen, pd (dppf) Cl was added ₂ (2.8 g,0.05Eq,3.8 mmol). The mixture was stirred at 100℃for 2 hours. The solution was concentrated. The crude material obtained was purified by flash chromatography (acetonitrile/water). Lyophilization afforded 4- (prop-1-en-2-yl) pyridazin-3-ol (4.0 g, 31%) as a white amorphous solid.

4-isopropyl-pyridazin-3 (2H) -one

Step 2: a round bottom flask was charged with 4- (prop-1-en-2-yl) pyridazin-3-ol (4 g,1eq,0.03 mol), pd/C (0.5 g), meOH (20 mL) and a stirring bar followed by evacuation and purging three times with hydrogen. The mixture was stirred at 25℃for 2 hours. The mixture was filtered, and the filtrate was concentrated to give 4-isopropylpyridazin-3 (2H) -one (3.7 g, 91%) as a yellow oil.

3-chloro-4-isopropylpyridazine

Step 3: a round bottom flask was charged with 4-isopropylpyridazin-3-ol (3.7 g,1eq,27 mmol), POCl ₃ (15 mL) and stirringStick, and stir the solution at 85 ℃ for 4 hours. The reaction mixture was poured into ice water. The solution was extracted three times with EA. The organics were combined and concentrated. The crude material obtained was purified by flash chromatography (acetonitrile/water). Lyophilization afforded 3-chloro-4-isopropylpyridazine (3.8 g,24mmol, 91%) as a black oil.

3-fluoro-4-isopropylpyridazine

Step 4: a solution of 3-chloro-4-isopropylpyridazine (1.9 g,12.1mmol,1 eq), csF (12.8 g,84.7mmol,7 eq) and 4A molecular sieve (1 g) in DMSO (25 mL) was stirred at 100deg.C for 16h. The solution was filtered. The solution was purified by flash chromatography (MeCN/H ₂ O) purification gave 3-fluoro-4-isopropylpyridazine (410 mg, 24%) as a black oil.

Example 5

4-cyclopropyl-isothiazol-3-ol

3- (benzyloxy) isothiazoles

Step 1: to a mixture of isothiazol-3 (2H) -one (5 g,0.05 mol) in DMF (50 mL) was added potassium carbonate (13.66 g,0.1 mol) and (bromomethyl) benzene (10.09 g,0.06 mol) in portions at 0deg.C under nitrogen atmosphere. The mixture was stirred at 25℃for 4 hours. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed three times with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (10 g column; elution with PE/EA (ratio: 30/1)). Concentration in vacuo afforded 3- (benzyloxy) isothiazole (5.5 g,29mmol, 60%) as a clear oil.

3- (benzyloxy) -4-bromoisothiazole

Step 2: a round bottom flask was charged with 3- (benzyloxy) isothiazole (5.5 g,29 mmol), 1-bromopyrrolidine-2, 5-dione (5.6 g,32 mmol), meCN (60 mL) and stirring bar. The solution was stirred at 25℃for 2 days. The mixture was quenched with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (15 g column; elution with PE/EA (ratio: 50/1)). Concentration in vacuo afforded 3- (benzyloxy) -4-bromoisothiazole (6 g,0.02mol, 80%) as a clear oil.

3- (benzyloxy) -4-cyclopropyl isothiazole

Step 3: the resealable reaction vial was charged with 3- (benzyloxy) -4-bromoisothiazole (200 mg, 740. Mu. Mol), cyclopropylboronic acid (636 mg,7.40 mmol), pdCl ₂ (dppf)(54.2mg,74.0μmol)、Cs ₂ CO ₃ (480 mg,1.48 mmol), 1, 4-dioxane/H ₂ O (4 mL, 4/1) and stir bar, followed by evacuation and purging with nitrogen three times. The mixture was stirred at 100℃for 12 hours. The mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 20% to 100% in 20 min; the detector, UV 254nm, gave 3- (benzyloxy) -4-cyclopropylisothiazole (130 mg, 562. Mu. Mol, 75.9%) as a brown oil.

4-cyclopropyl-isothiazol-3-ol

Step 4: a round bottom flask was charged with 3- (benzyloxy) -4-cyclopropylisothiazole (600 mg,2.59 mmol) and a stir bar. Concentrated HCl (6 mL) was added and the solution was stirred at 50 ℃ for 5 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 30% in 10 min; the detector, UV 254nm, gave 4-cyclopropylisothiazol-3-ol (280 mg,1.98mmol, 76.5%) as a yellow amorphous solid.

Example 6

(1R, 3S) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-1,2, 4-triazol-1-yl) cyclopentyl (1-methylcyclopropyl) carbamate and (1-methylcyclopropyl) carbamic acid

(1S, 3R) -3- (3- (2- (3-methyl isoxazol-5-yl) acetamido) -1H-1,2, 4-triazol-1-yl) cyclopentyl ester

Trans- (1R, 3R) -3- ((tert-butyldiphenylsilyl) oxy) cyclopenta-1-ol

Step 1: TBDPSCl (2 g,9 mmol) was added in portions to a mixture of cyclopentane-1, 3-diol (1 g,0.01 mol) and imidazole (0.8 g,0.01 mol) in DMF (50 mL) at 0deg.C under nitrogen. The mixture was stirred at 25℃for 12h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by chromatography on silica gel (1 g column; eluting with PE/ea=4/1). Concentration in vacuo afforded trans-3- ((tert-butyldiphenylsilyl) oxy) cyclopenta-1-ol (262 mg, 8%) as a white solid.

m/z(ES ⁺ )[M+Na] ⁺ ＝364.05；HPLC tR＝1.373min。

Trans-methanesulfonic acid (1R, 3R) -3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl ester

Step 2: trans-3- ((tert-butyldiphenylsilyl) oxy) cyclopenta-1-ol (120 mg, 352. Mu. Mol) and Et at 0deg.C under nitrogen atmosphere ₃ N (107 mg,1.06 mmol) in DCM (3 mL) MsCl (63.4 mg, 423. Mu. Mol) was added dropwise. The mixture was stirred at 25℃for 1h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product, 3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl ester (130 mg, 88.1%) was isolated as a colorless oil.

m/z(ES ⁺ )[M+H] ⁺ ＝419.05；HPLC tR＝1.332min。

1- ((1S, 3R) -3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl) -3-nitro-1H-1, 2, 4-triazole

Step 3: cs was added in portions to a mixture of 3-nitro-1H-1, 2, 4-triazole (88 mg,0.77 mmol) and trans-3- ((tert-butyldiphenylsilyl) oxy) cyclopenta-1-ol (0.22 g,0.64 mmol) in DMF (5 mL) at 25 ℃ under nitrogen atmosphere ₂ CO ₃ (0.63 g,1.9 mmol). The mixture was stirred at 80℃for 3h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by chromatography on silica gel (1 g column; eluting with PE/ea=4/1). Concentration in vacuo afforded 1- (cis-3- ((tert-butyldiphenylsilyl) oxy) as a colorless oil ) Cyclopentyl) -3-nitro-1H-1, 2, 4-triazole (16 mg, 5.7%).

m/z(ES ⁺ )[M+H] ⁺ ＝437.30；HPLC tR＝1.468min。

1- ((1S, 3R) -3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl) -1H-1,2, 4-triazol-3-amine

Step 4: a stirred mixture of 1- (cis-3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl) -3-nitro-1H-1, 2, 4-triazole (745 mg,1.71 mmol) and Pd/C (182 mg) in THF (1 mL) at 25℃was treated with H ₂ And (5) treating for 2 hours. The solid was filtered off. The filtrate was concentrated in vacuo. Concentration in vacuo afforded 1- (cis-3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl) -1H-1,2, 4-triazol-3-amine (625 mg, 90.1%) as a colorless oil.

m/z(ES ⁺ )[M+H] ⁺ ＝407.35；HPLC tR＝1.348min。

N- (1- ((1S, 3R) -3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl) -1H-1,2, 4-triazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 5: to a mixture of 1- (cis-3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl) -1H-1,2, 4-triazol-3-amine (780 mg,1.92 mmol), DIEA (744 mg,5.75 mmol) and 2- (3-methylisoxazol-5-yl) acetic acid (325 mg,2.30 mmol) in EA (10 mL) was added dropwise T at 0deg.C under a nitrogen atmosphere ₃ P (1.83 g,5.75 mmol). The mixture was stirred at 25℃for 30min. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (3 g column; elution with DCM/MeOH (ratio: 20/1)). Concentration in vacuo afforded N- (1- (cis-3- ((tert-butyl) as a yellowish solid Phenylsilyl) oxy) cyclopentyl) -1H-1,2, 4-triazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (900 mg, 88.6%).

m/z(ES ⁺ )[M+H] ⁺ ＝530.04；HPLC tR＝1.436min。

N- (1- ((1S, 3R) -3-hydroxycyclopentyl) -1H-1,2, 4-triazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 6: the resealable reaction vial was charged with N- (1- (cis-3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl) -1H-1,2, 4-triazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (460 mg, 868. Mu. Mol), TBAF (454 mg,1.74 mmol), THF (5 mL) and stirring bars, followed by evacuation and purging with nitrogen three times, and the mixture was stirred at 70℃for 2H. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 10 min; detector, UV 254nm. Concentration in vacuo afforded N- (1- ((cis-3-hydroxycyclopentyl) -1H-1,2, 4-triazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (80 mg, 32%) as a colorless oil.

m/z(ES ⁺ )[M+H] ⁺ ＝292.15；HPLC tR＝0.743min。

(1R, 3S) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-1,2, 4-triazol-1-yl) cyclopentyl (1-methylcyclopropyl) carbamate

Step 7: the resealable reaction vial was charged with N- (1- (cis-3-hydroxycyclopentyl) -1H-1,2, 4-triazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (400 mg,1.37 mmol), 1-isocyanato-1-methylcyclopropane (53 mg,5.49 mmol), DIEA (710 mg,5.49 mmol), toluene (10 mL) and a stirring bar, which was then evacuated and purged three times with nitrogen and the mixture stirred at 110 ℃ for 12H. Will be H for the reaction mixture ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by preparative HPLC (column XBridge Prep OBD C, column 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 10% B to 35% B,35% B within 8 min; wavelength: 220nm; RT1 (min): 7.32 And (3) purifying. Lyophilization afforded 3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-1,2, 4-triazol-1-yl) cyclopentyl carbamate (100 mg, 18.7%) as a white solid.

(1R, 3S) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-1,2, 4-triazol-1-yl) cyclopentyl (1-methylcyclopropyl) carbamate and (1S, 3R) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-1,2, 4-triazol-1-yl) cyclopentyl (1S, 3R) -carbamate

Step 8: cis- (1-methylcyclopropyl) carbamic acid 3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-1,2, 4-triazol-1-yl) cyclopentyl ester (150 mg,386 μmol) was purified by chiral preparative HPLC (column: DZ-CHIRALPAK IG-3,4.6 x 50mm,3.0 μm; mobile phase a: hex (0.2% IPAmine): etOH: dcm=1:1) =60:40; flow: 1mL/min; injection volume: 5ul mL). Lyophilization afforded (1 r,3 s) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-1,2, 4-triazol-1-yl) cyclopentyl (38.8 mg, 25.9%) carbamate as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝389.15；HPLC tR＝1.082min。

¹ H NMR(400MHz,DMSO-d ₆ )δ10.68(s,1H),8.41(s,1H),7.41(s,1H),6.24(s,1H),4.99(s,1H),4.76-4.68(m,1H),3.87(s,2H),2.60-2.52(m,1H),2.08(d,J＝24.8Hz,3H),2.03-1.89(m,4H),1.81(s,1H),1.23(s,2H),0.59(s,2H),0.47(s,2H)。

Cis- (1-methylcyclopropyl) carbamic acid 3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-1,2, 4-triazol-1-yl) cyclopentyl ester (150 mg,386 μmol) was purified by chiral preparative HPLC (column: DZ-CHIRALPAK IG-3,4.6 x 50mm,3.0 μm; mobile phase a: hex (0.2% IPAmine): etOH: dcm=1:1) =60:40; flow: 1mL/min; injection volume: 5ul mL). Lyophilization afforded (1 s,3 r) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-1,2, 4-triazol-1-yl) cyclopentyl (35.1 mg,90.4 μmol, 23.4%) carbamate as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝389.15；HPLC tR＝1.082min。

¹ H NMR(400MHz,DMSO-d ₆ )δ10.69(s,1H),8.41(s,1H),7.41(s,1H),6.24(s,1H),4.99(s,1H),4.71(q,J＝7.6Hz,1H),3.87(s,2H),2.60-2.52(m,1H),2.21(s,3H),2.11(s,1H),1.95(s,2H),1.80(s,1H),1.23(s,3H),0.59(s,2H),0.47(s,2H)。

Example 7

(1 s,4 s) -N-isopropyl-4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexane-1-carboxamide and (1 r,4 r) -N-isopropyl-4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexane-1-carboxamide

(1 s,4 s) -4- (isopropylcarbamoyl) cyclohexane-1-carboxylic acid methyl ester

Step 1: to a stirred solution of (1 s,4 s) -4- (methoxycarbonyl) cyclohexane-1-carboxylic acid (3 g,0.02 mol) and propan-2-amine (1 g,0.02 mol) in ethyl acetate (20 mL) was added DIEA (6 g,0.05 mol) and T ₃ P (12 g,50% Wt in ethyl acetate, 0.02 mmol). The reaction was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The mixture was concentrated and recrystallized from PE/ea=1:8. This gives rise to a white solid (1 s,4 s) -4- (isopropylcarbamoyl) cyclohexane-1-carboxylic acid methyl ester (3.24 g,14.3mmol, 90%).

m/z(ES ⁺ )[M+H] ⁺ ＝228.20；HPLC tR＝0.918min。

(1 s,4 s) -4- (2-cyanoacetyl) -N-isopropylcyclohexane-1-carboxamide

Step 2: liHMDS (21 mL,1M in THF, 21 mmol) was added dropwise to a solution of methyl (1 s,4 s) -4- (isopropylcarbamoyl) cyclohexane-1-carboxylate (2.2 g,9.7 mmol) and acetonitrile (0.60 g,15 mmol) in THF (20 mL) at-78deg.C under nitrogen. The mixture was warmed to 25 ℃ and stirred for 4 hours. The mixture was treated with saturated NH ₄ And (5) quenching Cl. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 70% in 15 min; detector UV 254nm gave (1 s,4 s) -4- (2-cyanoacetyl) -N-isopropylcyclohexane-1-carboxamide (1.75 g,7.41mmol, 77%) as an off-white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝237.20；HPLC tR＝0.739min。

(1 s,4 s) -4- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) -N-isopropylcyclohexane-1-carboxamide

Step 3: sodium hydroxide (439 mg,11.0 mmol) was added in portions to a suspension of tert-butylhydrazine hydrochloride (1.37 g,11.0 mmol) in EtOH (14 mL) at room temperature and stirred at room temperature for 1 hour. A solution of (1 s,4 s) -4- (2-cyanoacetyl) -N-isopropylcyclohexane-1-carboxamide (1.73 g,7.32 mmol) in ethanol was added at room temperature, and the mixture was then heated to an internal temperature of 50℃and stirred overnight. The mixture was quenched with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 60% in 15 min; the detector, UV 254nm, gave (1 s,4 s) -4- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) -N-isopropylcyclohexane-1-carboxamide (1.3 g,4.2mmol, 58%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝307.25；HPLC tR＝0.788min。

(1 s,4 s) -4- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) -N-isopropylcyclohexane-1-carboxamide

Step 4: to a mixture of (1 s,4 s) -4- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) -N-isopropylcyclohexane-1-carboxamide (1.4 g,4.6 mmol), 2- (3-methylisoxazol-5-yl) acetic acid (0.97 g,6.9 mmol) and DIEA (1.8 g,2.4mL,14 mmol) in EA (15 mL) was added dropwise under nitrogen at 0 ℃ phosphine-t 3 (4.4 g,50% wt in EA, 6.9 mmol) in EA. The mixture was stirred at 25℃for 2 hours. The mixture was quenched with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 20% to 80% in 20 min; the detector, UV 220nm, gave (1 s,4 s) -4- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) -N-isopropylcyclohexane-1-carboxamide (1.8 g,4.2mmol, 92%) as a yellow amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝430.45；HPLC tR＝0.955min。

(1 s,4 s) -N-isopropyl-4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexane-1-carboxamide

Step 5: a round bottom flask was charged with (1 s,4 s) -4- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) -N-isopropylcyclohexane-1-carboxamide (200 mg, 466. Mu. Mol) and a stirring bar. HCOOH (3 mL) was added and the solution was stirred at 75 ℃ for 12 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 60% in 15 min; the detector, UV 254nm, gave (1 s,4 s) -N-isopropyl-4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexane-1-carboxamide (120 mg, 321. Mu. Mol, 69.0%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝374.10；HPLC tR＝0.646min。

(1 s,4 s) -N-isopropyl-4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexane-1-carboxamide (120 mg, 321. Mu. Mol) was purified by chiral preparative HPLC (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: mtBE (0.1% DEA) -HPLC; mobile phase B: etOH- -HPLC; flow: 20mL/min; gradient: 50% B to 50% B in 21 min; wavelength: 220/254nm; RT1 (min): 5.48; sample solvent: etOH- -HPLC; injection volume: 1mL; number of runs: 4). Lyophilization afforded (1 s,4 s) -N-isopropyl-4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexane-1-carboxamide (64.3 mg,172 μmol, 53.6%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝374.10；HPLC tR＝0.658min。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.05(s,1H),10.63(s,1H),7.48(d,J＝7.8Hz,1H),6.30(s,1H),6.23(s,1H),3.91-3.72(m,3H),2.82(s,1H),2.20(s,4H),1.93(d,J＝15.1Hz,2H),1.65(t,J＝9.0Hz,4H),1.49(q,J＝6.4,4.2Hz,2H),1.01(d,J＝6.6Hz,6H)。

(1 r,4 r) -N-isopropyl-4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexane-1-carboxamide (120 mg, 321. Mu. Mol) was purified by chiral preparative HPLC (column: CHIRAL ART Amylose-SA, 2X 25cm,5 μm; mobile phase A: mtBE (0.1% DEA) -HPLC; mobile phase B: etOH- -HPLC; flow: 20mL/min; gradient: 50% B to 50% B within 21 min; wavelength: 220/254nm; RT2 (min): 11.01; sample solvent: etOH- -HPLC; injection volume: 1mL; number of runs: 4). Lyophilization afforded (1 r,4 r) -N-isopropyl-4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexane-1-carboxamide (19.9 mg,53.3 μmol, 16.6%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝374.15；HPLC tR＝0.647min。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.08(s,1H),10.61(s,1H),7.58(d,J＝7.7Hz,1H),6.24(d,J＝11.9Hz,2H),3.90-3.70(m,3H),2.61-2.52(m,1H),2.20(s,3H),2.07(tt,J＝11.7,3.4Hz,1H),1.96(dd,J＝13.2,3.5Hz,2H),1.76(dd,J＝13.5,3.5Hz,2H),1.46(qd,J＝12.7,2.9Hz,2H),1.38-1.22(m,2H),1.03(d,J＝6.6Hz,6H)。

Example 8

1s,4 s) -4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexyl isopropyl carbamate

(1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexane-1-carboxylic acid methyl ester

Step 1: to a stirred solution of methyl (1 s,4 s) -4-hydroxycyclohexane-1-carboxylate (5 g,0.03 mol) in DMF (25 mL) was added imidazole (6 g,0.09 mol) and TBDPS-Cl (0.01 kg,0.04 mol) at 0deg.C. The reaction was stirred at room temperature overnight. The resulting solution was diluted with 30mL of water, followed by extraction with 3X 40mL of ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography using petroleum ether to give methyl (1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexane-1-carboxylate (10.59 g,26.70mmol, 80%) as a colorless oil.

m/z(ES ⁺ )[M+H] ⁺ ＝397.30；HPLC tR＝1.595min。

3- ((1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexyl) -3-oxopropanenitrile

Step 2: to a stirred solution of methyl (1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexane-1-carboxylate (5 g,0.01 mol) in tetrahydrofuran (15 mL) was added acetonitrile (1.0 g,25 mmol). At-70 ℃ under N ₂ LiHMDS (25 mL,1M in THF, 0.03 mol) was added dropwise to the mixture. The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with 3×40mL ethyl acetate. The organic layers were combined, washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate/(5/1) to give 3- ((1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexyl) -3-oxopropanenitrile (4.6 g,11mmol, 90%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝406.10；HPLC tR＝1.386min。

1- (tert-butyl) -3- ((1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexyl) -1H-pyrazol-5-amine

Step 3: a solution of tert-butylhydrazine hydrochloride (2.1 g,17 mmol) and NaOH (0.67 g,17 mmol) in ethanol (25 mL) was stirred for 1h followed by the addition of 3- ((1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexyl) -3-oxopropanenitrile (4.5 g,11 mmol). The reaction was stirred at 50 ℃ overnight. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 95% gradient over 10 min; the detector, UV 220nm, gave 1- (tert-butyl) -5- ((1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexyl) -1H-pyrazol-3-amine (2.5 g,5.3mmol, 47%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝476.35；HPLC tR＝1.234min。

N- (1- (tert-butyl) -3- ((1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 4: to a stirred solution of 1- (tert-butyl) -5- ((1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexyl) -1H-pyrazol-3-amine (1.9 g,1eq,4.0 mmol) and 2- (3-methylisoxazol-5-yl) acetic acid (0.85 g,1.5eq,6.0 mmol) in ethyl acetate (15 mL) was added DIEA (1.5 g,2.1mL,3eq,12 mmol) and propane phosphonic acid cyclic anhydride/EA (3.8 g,50% wt,6.0 mmol). The reaction was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The mixture was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; a mobile phase, ACN in water, gradient from 95% to 100% in 10 min; detector, UV 220nm. This gave N- (1- (tert-butyl) -5- ((1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (2.043 g,3.411mmol, 85%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝599.55；HPLC tR＝1.596min。

N- (1- (tert-butyl) -3- ((1 s,4 s) -4-hydroxycyclohexyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 5: to a stirred solution of N- (1- (tert-butyl) -5- ((1 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) cyclohexyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (1.9 g,3.2 mmol) in THF (15 mL) was added 1M TBAF in THF (19 mL). The reaction was stirred at 75℃for 18h. The resulting mixture was washed with water and extracted with ethyl acetate. The organic layers were combined, dried and concentrated in vacuo. The mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 19% gradient over 10 min; the detector, UV 220nm, gave N- (1- (tert-butyl) -5- ((1 s,4 s) -4-hydroxycyclohexyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (660 mg,2.44mmol, 77%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝361.10；HPLC tR＝0.858min。

(1 s,4 s) -4- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) cyclohexyl isopropyl carbamate

Step 6: to a stirred solution of N- (1- (tert-butyl) -5- ((1 s,4 s) -4-hydroxycyclohexyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (650 mg,1.80 mmol) in toluene (6 mL) was added DIEA (699 mg,5.41 mmol) and 2-isocyanatopropane (460 mg,5.41 mmol). The reaction was stirred at 85 ℃ overnight. The resulting mixture was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 19% gradient over 10 min; the detector, UV 220nm, gives (1 s,4 s) -cyclohexyl 4- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) carbamate (268 mg, 826. Mu. Mol, 45.8%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝446.15；HPLC tR＝1.059min。

Step 7: (1 s,4 s) -4- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexyl isopropyl carbamate (350 mg, 786. Mu. Mol) was dissolved in formic acid (6 mL). The reaction was stirred at 75 ℃ overnight. The mixture was concentrated and purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; a mobile phase, ACN in water, 46% gradient over 10 min; the detector, UV 220nm, gave (1 s,4 s) -4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexyl carbamate (210 mg, 539. Mu. Mol, 68.6%) as a white solid. The solid was purified by preparative HPLC (column: xselect CSH OBD column 30X 150mm,5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow: 60mL/min; gradient: 30% B to 31% B,31% B over 7 min; wavelength: 220 nm). Lyophilization afforded (1 s,4 s) -4- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclohexyl carbamate (139.2 mg,357.4 μmol, 69.6%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝390.15；HPLC tR＝0.726min。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.11(s,1H),10.65(s,1H),6.94(d,J＝7.6Hz,1H),6.29(s,1H),6.22(s,1H),4.75(s,1H),3.83(s,2H),3.61-3.55(m,1H),2.67(s,1H),2.20(s,3H),1.78-1.71(m,5H),1.64(t,J＝14.2Hz,3H),1.04(d,J＝6.5Hz,6H)。

Example 9

N- (5- ((1S, 3R) -3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide and N- (5- ((1R, 3S) -3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

(1- (tert-butyl) -3- ((1R, 3R) -3- (4, 4-dimethyl-2, 5-dioxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-5-yl) carbamic acid benzyl ester

Step 1: to an ice-cold solution of benzyl (1- (tert-butyl) -5- (trans-3-hydroxycyclopentyl) -1H-pyrazol-3-yl) carbamate (1 g,3 mmol), 5-dimethylimidazolidine-2, 4-dione (0.4 g,3 mmol) and triphenylphosphine (1 g,4 mmol) in THF (10 mL) was added DIAD (0.8 g,4 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with EA (100 mL) and washed with brine (2 x 80 mL), dried over Na ₂ SO ₄ And (5) drying. The organic layer was concentrated under vacuum. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 40 min; the detector, UV 220nm, gave benzyl (1- (tert-butyl) -5- (cis-3- (4, 4-dimethyl-2, 5-dioxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) carbamate (1.03 g,2.20mmol, 80%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝468.25；HPLC tR＝1.106min。

(1- (tert-butyl) -3- ((1R, 3R) -3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-5-yl) carbamic acid benzyl ester

Step 2: to a solution of benzyl (1- (tert-butyl) -5- (cis-3- (4, 4-dimethyl-2, 5-dioxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) carbamate (100 mg,1.07 mmol) in toluene (5 mL) at 0 ℃ was added dropwise Red-Al solution (3.09 g,70% wt in toluene) slowly enough to maintain an internal temperature below 5 ℃. After stirring for a further 5 hours at room temperature, the resulting mixture was treated with NH ₄ Cl (saturated aqueous, 150 mL) was quenched and extracted with EA (3X 150 mL). The combined organic layers were washed with brine (2 x 100 ml), dried over Na ₂ SO ₄ Dried and concentrated under vacuum. This product was combined with another 5 identically prepared batches (each starting at 100 mg) and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 15 min; the detector, UV 220nm, gave benzyl (1- (tert-butyl) -5- (cis-3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) carbamate (250 mg, 551. Mu. Mol, 51.5%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝454.15；HPLC tR＝1.103min。

1- ((1 r,3 r) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl) -4, 4-dimethylimidazolidin-2-one

Step 3: a suspension of Pd/C (50%, 77 mg) and benzyl (1- (tert-butyl) -5- (cis-3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) carbamate (330 mg, 728. Mu. Mol) in 2-propanol (10 mL) was degassed and purged with hydrogen (3 cycles) at room temperature, followed by stirring under a hydrogen balloon for 0.5 hours. The suspension was filtered. The filtrate was concentrated in vacuo and the residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 20 min; the detector, UV 220nm, gave 1- (cis-3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) -4, 4-dimethylimidazolidin-2-one (180 mg, 563. Mu. Mol, 77.4%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝320.25；HPLC tR＝1.093min。

N- (1- (tert-butyl) -3- ((1S, 3R) -3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 4: to a mixture of 1- (cis-3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) -4, 4-dimethylimidazolidin-2-one (200 mg, 626. Mu. Mol), 2- (3-methylisoxazol-5-yl) acetic acid (97.2 mg, 689. Mu. Mol) and DIEA (243 mg,1.88 mmol) in EA (5 mL) was added dropwise 2,4, 6-tripropyl-1,3,5,2,4,6-trioxatriphosphohexane 2,4, 6-trioxide (328 mg,50% Wt, in EA) at 0 ℃ under nitrogen. The mixture was stirred at 25℃for 1 hour. The reaction was taken up in saturated Na ₂ CO ₃ (10 mL) quenched and extracted with DCM (2X 10 mL). The organic layer was treated with more Na ₂ CO ₃ (2 x 10 mL) and brine (30 mL) and concentrated. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 20% to 80% in 20 min; the detector, UV 220nm, gave N- (1- (tert-butyl) -5- (cis-3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (230 mg, 520. Mu. Mol, 83.0%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝443.20；HPLC tR＝0.955min。

N- (5- ((1S, 3R) -3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 5: n- (1- (tert-butyl) -5- (cis-3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (50 mg, 9.02. Mu. Mol) was reacted with TFA/H ₂ The solution in O (5 mL, 20:1) was stirred at 90℃for 0.5 h. The resulting mixture was concentrated to dryness. This product was combined with another 5 identically prepared batches (each starting with 50 mg) and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 15 min; the detector, UV 220nm, gave N- (5- (cis-3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (128 mg,331 μmol, 73.3%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝387.30；HPLC tR＝0.804min。

Step 6: cis-N- (5- (3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (128 mg,331 μmol) was purified by preparative chiral-HPLC using the following conditions: column: CHIRALPAK IG,2×25cm,5 μm; mobile phase a: hex (0.2% TEA) -HPLC, mobile phase B: etOH: dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 90% B to 90% B within 18 min; wavelength: 220/254nm; RT1 (min): 5.46; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 2.2mL; number of runs: 2, cis-N- (5- (-3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (50.5 mg,131 μmol, 39.5%) was obtained as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝387.15；HPLC tR＝0.653min。

¹ H NMR(400MHz,DMSO)δ1.17(d,J＝2.7Hz,6H),1.63(dt,J＝18.7,11.4,11.4Hz,3H),1.76(d,J＝9.9Hz,1H),1.91-2.13(m,2H),2.20(d,J＝1.4Hz,3H),3.05(d,J＝9.6Hz,3H),3.83(s,2H),4.22(q,J＝8.3,8.3,8.3Hz,1H),5.97-6.51(m,3H),10.65(s,1H),12.14(s,1H)。

N- (5- ((1R, 3S) -3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 7: cis-N- (5- (3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (128 mg,331 μmol) was purified by preparative chiral-HPLC using the following conditions: column: CHIRALPAK IG,2×25cm,5 μm; mobile phase a: hex (0.2% TEA) -HPLC, mobile phase B: etOH: dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 90% B to 90% B within 18 min; wavelength: 220/254nm; RT2 (min): 8.40; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 2.2mL; number of runs: 2, N- (5- ((1 r,3 s) -3- (4, 4-dimethyl-2-oxoimidazolidin-1-yl) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (48.2 mg,125 μmol, 37.7%) was obtained as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝387.15；HPLC tR＝0.662min。

¹ H NMR(400MHz,DMSO-d ₆ )δ1.17(d,J＝2.7Hz,6H),1.41-1.68(m,3H),1.76(d,J＝9.7Hz,1H),2.02(dd,J＝18.5,7.6Hz,2H),2.20(s,3H),3.05(d,J＝8.9Hz,3H),3.83(s,2H),4.22(q,J＝8.4,8.3,8.3Hz,1H),6.11-6.58(m,3H),10.65(s,1H),12.14(s,1H)。

Example 10

2- (3-methylisoxazol-5-yl) -N- (5- ((1 s,3 r) -3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) acetamide and 2- (3-methylisoxazol-5-

Phenyl) -N- (5- ((1 r,3 s) -3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) acetamide

Methanesulfonic acid (1S, 3S) -3- (5- (((benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl ester

Step 1: benzyl (1- (tert-butyl) -5- (trans-3-hydroxycyclopentyl) -1H-pyrazol-3-yl) carbamate (250 mg, 699. Mu. Mol) and Et were reacted under nitrogen at 0deg.C ₃ N (84.9 mg, 839. Mu. Mol) to a mixture of DCM (10 mL) was added MsCl (303 mg,2.10 mmol) dropwise. The mixture was stirred at 25℃for 1h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give trans-methanesulfonic acid 3- (3- (((benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl ester (300 mg, 98.5%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝436.25；HPLC tR＝1.202min。

3- ((1S, 3R) -3- ((4-bromopyridin-3-yl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-5-amine

Step 2: the resealable reaction vials were charged with trans-methanesulfonic acid 3- (3- (((benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl ester (300 mg, 689. Mu. Mol), 4-bromopyridin-3-ol (144 mg, 827. Mu. Mol), K ₂ CO ₃ (284 mg,2.07 mmol), DMF (10 mL) and a stirring bar, followed by evacuation and purging with nitrogen three times and stirring the mixture at 80℃for 3h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). Will beThe combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (PE/EA; ratio: 4/1) to give 5- (cis-3- ((4-bromopyridin-3-yl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-3-amine (120 mg, 45.5%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝379.20；HPLC tR＝0.810min。

N- (3- ((1S, 3R) -3- ((4-bromopyridin-3-yl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 3: to a resealable reaction vial was charged 5- (cis-3- ((4-bromopyridin-3-yl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-3-amine (256 mg, 675. Mu. Mol), DIEA (349 mg,2.70 mmol), 2- (3-methylisoxazol-5-yl) acetamide (114 mg, 810. Mu. Mol) in EA (5 mL), and T was added dropwise under nitrogen at 0deg.C ₃ P (640 mg,2.02 mmol). The mixture was stirred at 25℃for 1h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH; ratio: 20/1) to give N- (5- (cis-3- ((4-bromopyridin-3-yl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (240 mg, 70.8%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝502.10；HPLC tR＝0.747min。

N- (1- (tert-butyl) -3- ((1S, 3R) -3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 4: to resealableThe reaction vial was charged with N- (5- ((1S, 3R) -3- ((4-bromopyridin-3-yl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (60 mg,0.12 mmol), prop-1-en-2-ylboronic acid (12 mg,0.14 mmol), pd (dppf) Cl ₂ (8.7mg,12μmol)、K ₂ CO ₃ (46 mg,0.36 mmol), dioxane/H ₂ O (1 mL) and stir bar, then evacuated and purged three times with nitrogen, and the mixture stirred at 60℃for 1h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH; ratio: 20/1) to give N- (1- (tert-butyl) -5- ((1S, 3R) -3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (40 mg, 72%) as an orange oil.

m/z(ES ⁺ )[M+H] ⁺ ＝464.25；HPLC tR＝1.100min。

2- (3-methylisoxazol-5-yl) -N- (5- ((1 s,3 r) -3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) acetamide

Step 5: the resealable reaction vial was charged with N- (1- (tert-butyl) -5- (cis-3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (200 mg,431 μmol), FA (5 mL) and a stirring bar, which was then evacuated and purged three times with nitrogen, and the mixture was stirred at 75 ℃ for 12H. The crude material obtained was purified by C18 flash chromatography (acetonitrile/water/0.1% formic acid). Concentration in vacuo afforded 2- (3-methylisoxazol-5-yl) -N- (5- (cis-3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) acetamide (70 mg, 39.8%) as a colorless oil.

m/z(ES ⁺ )[M+H] ⁺ ＝408.30；HPLC tR＝0.790min。

2- (3-methylisoxazol-5-yl) -N- (5- (cis-3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) acetamide (70 mg,0.17 mmol) was purified by chiral preparative HPLC (column CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex (0.2% dea) -HPLC, mobile phase B: etOH: dcm=1:1-HPLC; flow: 20mL/min; gradient: 50% B to 50% B; wavelength: 220/254nm; rt1 (min): 15.69; rt2 (min): 25.34; sample solvent: etOH: dcm=1:1-HPLC; injection volume: 0.8mL; run number: 4). Lyophilization afforded 2- (3-methylisoxazol-5-yl) -N- (5- ((1 s,3 r) -3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) acetamide (28.9 mg, 41%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝408.35；HPLC tR＝0.962min。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.16(s,1H),10.62(s,1H),8.31(s,1H),8.15(d,J＝4.8Hz,1H),7.17(d,J＝4.8Hz,1H),6.29(s,1H),6.22(s,1H),5.27-5.20(m,2H),5.05(s,1H),3.83(s,2H),3.18-3.07(m,1H),2.66(dt,J＝14.4,7.3Hz,1H),2.20(s,3H),2.10-1.97(m,5H),1.89(d,J＝13.4Hz,1H),1.76(td,J＝14.0,12.3,5.3Hz,2H)。

2- (3-methylisoxazol-5-yl) -N- (5- ((1 r,3 s) -3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) acetamide

2- (3-methylisoxazol-5-yl) -N- (5- (cis-3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) acetamide (70 mg,0.17 mmol) was purified by chiral preparative HPLC (column CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex (0.2% dea) -HPLC, mobile phase B: etOH: dcm=1:1-HPLC; flow: 20mL/min; gradient: 50% B to 50% B; wavelength: 220/254nm; rt1 (min): 15.69; rt2 (min): 25.34; sample solvent: etOH: dcm=1:1-HPLC; injection volume: 0.8mL; run number: 4). Lyophilization afforded 2- (3-methylisoxazol-5-yl) -N- (5- ((1 r,3 s) -3- ((4- (prop-1-en-2-yl) pyridin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) acetamide (25.9 mg, 37%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝408.35；HPLC tR＝0.928min。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.16(s,1H),10.63(s,1H),8.31(s,1H),8.15(d,J＝4.8Hz,1H),7.17(d,J＝4.8Hz,1H),6.29(s,1H),6.22(s,1H),5.23(qd,J＝2.7,2.0,1.3Hz,2H),5.06(d,J＝4.4Hz,1H),3.83(s,2H),3.13(p,J＝9.2Hz,1H),2.67(tt,J＝14.3,7.3Hz,1H),2.20(s,3H),2.10-1.97(m,5H),1.89(d,J＝13.0Hz,1H),1.85-1.69(m,2H)。

Additional compounds prepared according to the methods of example 9 or example 10 are depicted in table 6 below.

Example 11

(1R, 3S) -3- (3- ((2- (methoxymethyl) thiazolo [5,4-c ] pyridin-6-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropyl carbamate and (1S, 3R) -3- (3- ((2- (methoxymethyl) thiazolo [5,4-c ] pyridin-6-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropyl carbamate

N- (5-bromo-2-chloropyridin-4-yl) -2-methoxyacetamide

Step 1: to an ice-cold solution of 5-bromo-2-chloropyridin-4-amine (5 g,1eq,24 mmol) in DCM (50 mL) was added TEA (3.6 g,1.5eq,36 mmol) and 2-methoxyacetyl chloride (3.9 g,1.5eq,36 mmol). The mixture was stirred at 20℃for 16h. The solvent was removed under reduced pressure, and the residue was dissolved in water (70 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 45% B to 55% B) purification within 7 min; the solvent was evaporated to give N- (2, 5-dichloropyridin-4-yl) -2-methoxyacetamide (1.51 g,5.4mmol, 22%) as a pale yellow solid.

m/z(ES ⁺ )[M+H] ⁺ ＝278.85；HPLC tR＝0.997min。

N- (5-bromo-2-chloropyridin-4-yl) -2-methoxyethylsulfanamide

Step 2: to a solution of N- (5-bromo-2-chloropyridin-4-yl) -2-methoxyacetamide (1.33 g,1eq,4.76 mmol) in toluene (20 mL) was added 2, 4-bis (4-methoxyphenyl) -1,3,2, 4-dithio-diphosphobutane 2, 4-disulfide (1.44 g,0.75eq,3.57 mmol). The mixture was heated to 110℃under N ₂ Heating for 4h. The reaction mixture was filtered to remove the filter cake and the filtrate was concentrated in vacuo. The crude material obtained was purified by silica gel chromatography (eluting with a mixture of petroleum ether/ethyl acetate 20:1) to give 2- (1-benzothien-2-yl) -N- (1- {5- [ (3S) -1-methylpiperidin-3-yl) as a yellow amorphous solid ]Pyrimidin-2-yl } -1H-pyrazol-4-yl) acetamide (1.1 g,4.76mmol, 78%).

m/z(ES ⁺ )[M+H] ⁺ ＝294.90；HPLC tR＝0.727min。

6-chloro-2- (methoxymethyl) thiazolo [5,4-c ] pyridine

Step 3: to a solution of N- (5-bromo-2-chloropyridin-4-yl) -2-methoxyethylsulfamide (490 mg,1eq,1.66 mmol) in NMP (5 mL) was added NaH (59.7 mg,0.9eq,1.49 mmol). The mixture was heated at 160℃for 1 hour. The reaction mixture was brought to room temperature and poured into ice-cold water, followed by extraction with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (mobile phase A: water, mobile phase B: ACN; flow: 60mL/min; gradient: 40B to 50B in 8 min); the solvent was evaporated to give 6-chloro-2- (methoxymethyl) thiazolo [5,4-c ] as a brown solid]Pyridine (240 mg,1.12mmol, 67.4%).

m/z(ES ⁺ )[M+H] ⁺ ＝215.00；HPLC tR＝0.594min。

Cis-isopropylcarbamic acid 3- (5- (((benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl ester

Step 4: to a solution of benzyl (1- (tert-butyl) -5- (cis-3-hydroxycyclopentyl) -1H-pyrazol-3-yl) carbamate (5 g,1eq,0.01 mol) in toluene (20 mL) was added 2-isocyanatopropane (6 g,5eq,0.07 mol), DIEA (5 g,3eq,0.04 mol). The mixture was stirred at 85 ℃ for 16 hours. The mixture was diluted with water and the aqueous phase was extracted with EA (3×40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by flash chromatography (mobile phase A: water/0.1% formic acid, mobile phase B: ACN; flow: 60mL/min; gradient: 40B to 50B in 8 min); after evaporation of the solvent, cis-isopropylcarbamic acid 3- (3- (((benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl ester (4.2 g,8.9mmol, 60%) was obtained as a brown amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝443.10；HPLC tR＝0.889min。

Cis-isopropylcarbamic acid 3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl ester

Step 5: a solution of cis-isopropylcarbamic acid 3- (3- (((benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl ester (4.2 g,1eq,9.5 mmol) in MeOH (15 mL) was bubbled nitrogen through the reaction mixture 3 times. Pd/C (0.50 g,0.5eq,4.7 mmol) was then added. In the process of H ₂ After bubbling through the reaction mixture 3 times, the mixture was admixed with H ₂ Stir at room temperature for 2 hours. The reaction mixture was filtered to remove the filter cake and the filtrate was concentrated in vacuo. The crude material obtained was purified by flash chromatography (mobile phase A: water/0.1% formic acid, mobile phase B: ACN; flow: 60mL/min; gradient: 45B to 55B in 6 min); after evaporation of the solvent, cis-isopropylcarbamic acid 3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl ester (2.3 g,7.5mmol, 79%) was obtained as a brown amorphous oil.

m/z(ES ⁺ )[M+H] ⁺ ＝309.15；HPLC tR＝0.691min。

Cis-isopropylcarbamic acid 3- (1- (tert-butyl) -5- ((2- (methoxymethyl) thiazolo [5,4-c ] pyridin-6-yl) amino) -1H-pyrazol-3-yl) cyclopentyl ester

Step 6: 6-chloro-2- (methoxymethyl) thiazolo [5,4-c]Pyridine (234 mg,1.2eq,1.09 mmol), cs ₂ CO ₃ (1.18 g,4eq,3.63 mmol) and Xphos (86.4 mg,0.2eq, 182. Mu. Mol) were added to a solution of cis-isopropylcarbamic acid 3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl ester (280 mg,1eq, 908. Mu. Mol) in DME (4 mL). In the process of making After nitrogen bubbling through the reaction mixture for 5 minutes, pd was added ₂ dba ₃ (166 mg,0.2eq, 182. Mu. Mol). The reaction mixture was heated at 90 ℃ with vigorous stirring for 3 hours. After cooling to room temperature, the mixture was evaporated and extracted with ethyl acetate (3×50 mL), taken up in Na ₂ SO ₄ Dried and evaporated in vacuo. The crude residue was purified by flash chromatography (mobile phase A: water, mobile phase B: ACN; flow: 60mL/min; gradient: 45% B to 55% B over 6 min); the solvent evaporated to give cis-isopropylcarbamic acid 3- (1- (tert-butyl) -3- ((2- (methoxymethyl) thiazolo [5, 4-c) as a brown oil]Pyridin-6-yl) amino) -1H-pyrazol-5-yl cyclopentyl ester (120 mg,247 μmol, 27.2%).

m/z(ES ⁺ )[M+H] ⁺ ＝487.10；HPLC tR＝1.029min。

(1R, 3S) -3- (3- ((2- (methoxymethyl) thiazolo [5,4-c ] pyridin-6-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropyl carbamate

Step 7: a solution of cis-isopropylcarbamic acid 3- (1- (tert-butyl) -3- ((2- (methoxymethyl) thiazolo [5,4-c ] pyridin-6-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester (101 mg,1Eq, 208. Mu. Mol) in FA (2 mL) was heated at 70℃for 45min. After cooling to room temperature, the mixture was evaporated. The crude residue was purified by preparative HPLC (column: sunfire preparative C18 column, 30 x 150mm,5 μm; mobile phase a: water (0.05% TFA), mobile phase B: ACN; flow: 60mL/min; gradient: 10% B to 45% B over 7 min); after evaporation of the solvent, 3- (3- ((2- (methoxymethyl) thiazolo [5,4-c ] pyridin-6-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester (27 mg, 63. Mu. Mol, 30%) of cis-isopropylcarbamic acid was obtained as a yellow solid

Step 8: cis-isopropylcarbamic acid 3- (3- ((2- (methoxymethyl) thiazolo [5,4-c ] pyridin-6-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester (27 mg,1eq,63 μmol) was purified by chiral-HPLC (column CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex (0.2% DEA) -HPLC; mobile phase B: etOH: dcm=1:1-HPLC; flow: 20mL/min; gradient: 80% B to 80% B in 14.5 min; wavelength: 220/254nm; rt1 (min): 9.73; rt2 (min): 12.26; sample solvent: etOH: dcm=1:1-HPLC; injection volume: 0.9 mL); lyophilization afforded (1 r,3 s) -3- (3- ((2- (methoxymethyl) thiazolo [5,4-c ] pyridin-6-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester (6 mg,0.01mmol, 40%) as a pale yellow amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝431.15；HPLC tR＝0.731min。

¹ H NMR (400 MHz, chloroform-d) δ8.77 (s, 1H), 7.77 (s, 1H), 7.28 (s, 1H), 6.02 (s, 1H), 5.24 (s, 1H), 4.86 (s, 2H), 4.70 (s, 1H), 3.83 (s, 1H), 3.60 (s, 3H), 3.22 (t, j=8.3 hz, 1H), 2.53 (s, 1H), 2.16 (d, j=5.5 hz, 1H), 1.97 (s, 2H), 1.90 (d, j=10.1 hz, 2H), 1.28 (s, 1H), 1.18 (dd, j=6.7, 2.5hz, 6H).

Lyophilization afforded (1 s,3 r) -3- (3- ((2- (methoxymethyl) thiazolo [5,4-c ] pyridin-6-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester (8.4 mg,20 μmol, 62%) as a pale yellow amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝431.10；HPLC tR＝0.724min。

¹ H NMR (400 MHz, chloroform-d) δ8.78 (s, 1H), 7.76 (s, 1H), 7.35 (s, 1H), 6.03 (s, 1H), 5.24 (s, 1H), 4.86 (s, 2H), 4.71 (s, 1H), 3.83 (s, 1H), 3.60 (s, 3H), 3.26-3.18 (m, 1H), 2.54 (s, 1H), 2.18-2.12 (m, 1H), 1.96 (s, 2H), 1.90 (d, j=9.5 hz, 2H), 1.28 (s, 1H), 1.18 (dd, j=6.8, 2.9hz, 6H).

Additional compounds prepared according to the method of example 11 are depicted in table 7 below.

Example 12

(1R, 3S) -3- (3- (isothiazol-3-ylamino) -1H-pyrazol-5-yl) cyclopentyl and (1S, 3R) -3- (3- (isothiazol-3-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropyl carbamate

Cis-isopropylcarbamic acid 3- (1- (tert-butyl) -5- (isothiazol-3-ylamino) -1H-pyrazol-3-yl) cyclopentyl ester

Step 1: 3-Bromoisothiazole (223 mg,2eq,1.36 mmol), cesium carbonate (887 mg,4eq,2.72 mmol) and (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) (39.4 mg,0.1eq, 68.1. Mu. Mol) were added to a solution of cis-isopropylcarbamic acid 3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl ester (210 mg,1Eq, 681. Mu. Mol) in dioxane (4 mL). After bubbling nitrogen through the reaction mixture for 5 minutes, pd was added ₂ (dba) ₃ (62.3 mg,0.1Eq, 68.1. Mu. Mol). The reaction mixture was heated at 110 ℃ with vigorous stirring for 16 hours. After cooling to room temperature, the mixture was evaporated and extracted with ethyl acetate (3×40 mL), taken up in Na ₂ SO ₄ Dried and evaporated in vacuo. The crude residue was purified by flash chromatography (mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 45% B to 55% B) purification within 6 min; after evaporation of the solvent, cis-isopropylcarbamic acid 3- (1- (tert-butyl) -3- (isothiazol-3-ylamino) -1H-pyrazol-5-yl) cyclopentyl ester (102 mg,261 μmol, 38.3%) was obtained as a pale yellow solid.

m/z(ES ⁺ )[M+H] ⁺ ＝392.50；HPLC tR＝0.854min。

Cis-isopropylcarbamic acid 3- (3- (isothiazol-3-ylamino) -1H-pyrazol-5-yl) cyclopentyl ester

Step 2: a solution of cis-isopropylcarbamic acid 3- (1- (tert-butyl) -3- (isothiazol-3-ylamino) -1H-pyrazol-5-yl) cyclopentyl ester (115 mg,1Eq, 294. Mu. Mol) in FA (2 mL) was heated at 70℃for 16H. After cooling to room temperature, the mixture was evaporated. The residue was purified by flash chromatography (mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 55mL/min; gradient: 7mi45% B to 55% B) purification within n; after evaporation of the solvent, cis-isopropylcarbamic acid 3- (3- (isothiazol-3-ylamino) -1H-pyrazol-5-yl) cyclopentyl ester (60 mg,0.18mmol, 61%) was obtained as a colorless amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝336.25；HPLC tR＝0.921min。

Step 3: cis-isopropylcarbamic acid 3- (3- (isothiazol-3-ylamino) -1H-pyrazol-5-yl) cyclopentyl ester (60 mg,1eq,0.18 mmol) was purified by chiral-HPLC (column: CHIRALPAK IE,2 x 25cm,5 μm; mobile phase A: hex (0.2% DEA) -HPLC; mobile phase B: etOH: DCM=1:1- -HPLC; flow: 20mL/min; gradient: 40% B to 40% B within 15 min; wavelength: 220/254nm; RT1 (min): 8.13; RT2 (min): 11.87; sample solvent: etOH: DCM=1:1- -HPLC; injection volume: 0.6 mL). Lyophilization afforded (1 r,3 s) -3- (3- (isothiazol-3-ylamino) -1H-pyrazol-5-yl) cyclopentyl carbamate (18.6 mg,55.5 μmol, 62%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝336.05；HPLC tR＝0.676min。

¹ H NMR (400 MHz, chloroform-d) δ8.49 (d, j=4.7 hz, 1H), 7.51 (s, 1H), 6.87 (d, j=4.7 hz, 1H), 6.27 (s, 1H), 5.22 (s, 1H), 4.69 (s, 1H), 3.83 (s, 1H), 3.22 (q, j=8.1 hz, 1H), 2.50 (s, 1H), 2.14 (s, 1H), 1.93 (d, j=22.8 hz, 4H), 1.17 (t, j=5.5 hz, 6H).

Lyophilization afforded (1S, 3R) -3- (3- (isothiazol-3-ylamino) -1H-pyrazol-5-yl) cyclopentyl carbamate (14.9 mg, 44.4. Mu. Mol, 50%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝336.05；HPLC tR＝0.675min。

¹ H NMR (400 MHz, chlorine)Imitation-d) δ8.49 (d, j=4.8 hz, 1H), 7.58 (s, 1H), 6.88 (d, j=4.8 hz, 1H), 6.29 (s, 1H), 5.22 (s, 1H), 4.71 (s, 1H), 3.83 (s, 1H), 3.21 (t, j=8.2 hz, 1H), 2.50 (s, 1H), 2.15 (d, j=8.6 hz, 1H), 1.91 (s, 4H), 1.17 (t, j=5.7 hz, 6H).

Example 13

1-isopropyl-3- ((1 r,3 s) -3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) urea and 1-isopropyl-3- ((1 s,3 r) -3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) urea

Cis- (1- (tert-butyl) -3- (3- (1, 3-dioxoisoindolin-2-yl) cyclopentyl) -1H-pyrazol-5-yl) carbamic acid benzyl ester

Step 1: cis- (1- (tert-butyl) -5- (3-hydroxycyclopentyl) -1H-pyrazol-3-yl) carbamic acid benzyl ester (780 mg,2.18 mmol), PPh under nitrogen atmosphere at 0 ℃ ₃ To a mixture of (743 mg,2.84 mmol) and isoindoline-1, 3-dione (385 mg,2.62 mmol) in THF (10 mL) was added DIAD (514 mg,2.84 mmol) dropwise. The mixture was stirred at 0℃for 1h. The mixture was then stirred at 25℃for 12h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (2 g column; elution with PE/EA (ratio: 8/1)). Concentration in vacuo afforded benzyl cis- (1- (tert-butyl) -5- (3- (1, 3-dioxoisoindolin-2-yl) cyclopentyl) -1H-pyrazol-3-yl) carbamate (1 g, 90%) as a colorless oil.

m/z(ES ⁺ )[M+H] ⁺ ＝487.35；HPLC tR＝1.285min。

Cis-2- (3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl) isoindoline-1, 3-dione

Step 2: a stirred mixture of cis- (1- (tert-butyl) -5- (3- (1, 3-dioxoisoindolin-2-yl) cyclopentyl) -1H-pyrazol-3-yl) carbamic acid benzyl ester (1 g,2 mmol) and Pd/C (0.2 g) in THF (10 mL) was reacted with H at 25 ℃ ₂ And (5) treating for 2 hours. The reaction mixture was filtered (through a celite pad), the pad was washed with EA, and the filtrate was concentrated in vacuo. Concentration in vacuo afforded cis-2- (3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) isoindoline-1, 3-dione (640 mg, 90%) as a colorless oil.

m/z(ES ⁺ )[M+H] ⁺ ＝0.868；HPLC tR＝353.25min。

Cis-2- (3- (1- (tert-butyl) -5- (pyrimidin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl) isoindoline-1, 3-dione

Step 3: the resealable reaction vial was charged with cis-2- (3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) isoindoline-1, 3-dione (1.5 g,4.3 mmol), 2-bromopyrimidine (0.81 g,5.1 mmol), cs ₂ CO ₃ (4.2g,13mmol)、Pd ₂ (dba) ₃ (0.39 g,0.43 mmol), xantphos (0.49 g,0.85 mmol), dioxane (20 mL) and stirring bar, followed by evacuation and purging with nitrogen three times and stirring the mixture at 110℃for 1h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (10 g column; elution with PE/EA (ratio: 2/1)). Concentration in vacuo afforded cis-2- (3- (1- (tert-butyl) -3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) isoindoline-1, 3-dione (1 g, 50%) as an orange solid.

m/z(ES ⁺ )[M+H] ⁺ ＝431.25；HPLC tR＝1.127min。

cis-N- (3- (3-aminocyclopentyl) -1- (tert-butyl) -1H-pyrazol-5-yl) pyrimidin-2-amine

Step 4: the resealable reaction vial was charged with cis-2- (3- (1- (tert-butyl) -3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) isoindoline-1, 3-dione (1 g,2 mmol), NH ₂ NH ₂ .H ₂ O/MeOH (3:1) (4 mL) and stir bar, then evacuated and purged three times with nitrogen, and the mixture was stirred at 50℃for 1h. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 20 min; the detector, UV 250nm. Concentration in vacuo afforded cis-N- (5- (3-aminocyclopentyl) -1- (tert-butyl) -1H-pyrazol-3-yl) pyrimidin-2-amine (500 mg, 70%) as a colorless solid.

m/z(ES ⁺ )[M+H] ⁺ ＝301.30；HPLC tR＝0.718min。

Cis-1- (3- (1- (tert-butyl) -5- (pyrimidin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl) -3-isopropylurea

Step 5: to a mixture of cis-N- (5- (3-aminocyclopentyl) -1- (tert-butyl) -1H-pyrazol-3-yl) pyrimidin-2-amine (560 mg,1.86 mmol) and DIEA (723 mg,5.59 mmol) in DCM (5 mL) was added dropwise 2-isocyanatopropane (190 mg,2.24 mmol) at 25 ℃ under nitrogen. The mixture was stirred at 25℃for 2h. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 15 min; detector, UV 220nm. Concentration in vacuo afforded cis-1- (3- (1- (tert-butyl) -3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) -3-isopropylurea (360 mg, 50.1%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝386.40；HPLC tR＝0.902min。

Cis-1-isopropyl-3- (3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) urea

Step 6: the resealable reaction vial was charged with cis-1- (3- (1- (tert-butyl) -3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) -3-isopropylurea (340 mg,882 μmol), FA (10 mL) and a stirring bar, followed by evacuation and purging with nitrogen three times, and the mixture was stirred at 75 ℃ for 12H. The reaction was concentrated under vacuum. The reaction mixture was poured into 10mL of MeOH. The isolated solid was collected to give cis-1-isopropyl-3- (3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) urea (220 mg, 75.7%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝330.30；HPLC tR＝0.735min。

1-isopropyl-3- ((1 r,3 s) -3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) urea

Step 7: cis-1-isopropyl-3- (3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) urea (220 mg, 668. Mu. Mol) material was purified by chiral preparative HPLC (column: CHIRALPAK IE, 2X 25cm, 5. Mu.m; mobile phase A: hex (0.2% CH) ₃ COOH) - —hplc, mobile phase B: etOH, dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 40% B to 40% B within 31 min; wavelength: 220/254nm; RT1 (min): 19.81; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 1.2mL; number of runs: 14 And (3) purifying. Lyophilization yielded 1-isopropyl-3- ((1 r,3 s) -3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) urea (64 mg,0.19mmol, 29%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝330.20；HPLC tR＝0.615min。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.93(s,1H),9.55(s,1H),8.42(d,J＝4.8Hz,2H),6.76(t,J＝4.8Hz,1H),6.32(s,1H),5.82(d,J＝7.6Hz,1H),5.54(d,J＝7.7Hz,1H),3.96(p,J＝7.4Hz,1H),3.65(dp,J＝7.7,6.4Hz,1H),3.08-2.95(m,1H),2.31(dt,J＝13.6,7.3Hz,1H),1.94(dddd,J＝33.7,15.2,12.3,7.4Hz,2H),1.68(dtd,J＝10.8,8.8,8.2,6.4Hz,1H),1.51-1.32(m,2H),1.02(dd,J＝6.5,1.0Hz,6H)。

1-isopropyl-3- ((1 s,3 r) -3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) urea

Cis-1-isopropyl-3- (3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) urea (220 mg, 668. Mu. Mol) material was purified by chiral preparative HPLC (column: CHIRALPAK IE, 2X 25cm, 5. Mu.m; mobile phase A: hex (0.2% CH) ₃ COOH) - —hplc, mobile phase B: etOH, dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 40% B to 40% B within 31 min; wavelength: 220/254nm; RT2 (min): 25.25; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 1.2mL; number of runs: 14 And (3) purifying. Lyophilization yielded 1-isopropyl-3- ((1 s,3 r) -3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) urea (65.7 mg, 29.9%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝330.15；HPLC tR＝0.615min。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.92(s,1H),9.55(s,1H),8.42(d,J＝4.7Hz,2H),6.76(t,J＝4.8Hz,1H),6.32(s,1H),5.82(d,J＝7.5Hz,1H),5.54(d,J＝7.7Hz,1H),3.96(h,J＝7.4Hz,1H),3.72-3.59(m,1H),3.00(h,J＝8.6Hz,1H),2.31(dt,J＝13.4,7.1Hz,1H),2.04-1.83(m,2H),1.68(dtd,J＝10.9,8.8,8.1,6.4Hz,1H),1.51-1.32(m,2H),1.02(dd,J＝6.5,1.0Hz,6H)。

Additional compounds prepared according to the method of example 13 are depicted in table 8 below.

Example 14

N- ((1R, 3S) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide and N- ((1S, 3R) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide

cis-N- (3- (1- (tert-butyl) -5- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-3-yl) cyclopentyl) benzamide

Step 1: a round bottom flask was charged with N- (5- (cis-3-aminocyclopentyl) -1- (tert-butyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (180 mg,1Eq, 374. Mu. Mol), DCM (6 mL), TEA (120 mg,3Eq,1.12 mmol) and a stirring bar. Benzoyl chloride (63.1 mg,1.2Eq, 449. Mu. Mol) was added at 0deg.C, and the solution was stirred at 25deg.C for 1 hour. The crude material was purified by TLC (DCM/meoh=10:1). Concentration in vacuo afforded N- (cis-3- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide (130 mg,289 μmol, 77.3%) as a yellow amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝450.15；HPLC tR＝0.942min。

cis-N- (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide

Step 2: a round bottom flask was charged with N- (cis-3- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide (130 mg,1Eq, 289. Mu. Mol), FA (3 mL) was added, and the solution was stirred at 75℃for 16 hours. The crude material obtained was purified by flash chromatography (acetonitrile/water). Lyophilization afforded cis-N- (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide (90 mg,0.23mmol, 79%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝394.10；HPLC tR＝0.517min。

Step 3: n- (cis-3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide (90 mg,1Eq,0.23 mmol) was purified by chiral-HPLC (column CHIRALPAK IG, 2X 25cm,5 μm; mobile phase A: hex (0.2% DEA) -HPLC; mobile phase B: etOH: DCM=1:1- -HPLC; flow: 20mL/min; gradient: 60% B to 60% B in 11 min; wavelength: 220/254nm; RT1 (min): 6.97; RT2 (min): 8.65; sample solvent: etOH: DCM=1:1- -HPLC; injection volume: 0.3mL; number of runs: 6). Lyophilization afforded N- ((1 r,3 s) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide (27.5 mg,0.070mmol, 30.5%) as a white amorphous solid and N- ((1 s,3 r) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide (29.6 mg,0.075mmol, 32.9%) as a white amorphous solid.

N- ((1 r,3 s) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide:

m/z(ES ⁺ )[M+H] ⁺ ＝394.15；HPLC tR＝1.128min。

¹ H NMR(400MHz,DMSO-d ₆ )12.13(s,1H),10.64(s,1H),8.42(d,J＝7.6Hz,1H),7.88-7.81(m,2H),7.56-7.48(m,1H),7.48-7.41(m,2H),6.35(s,1H),6.22(s,1H),4.37(q,J＝7.6Hz,1H),3.83(s,2H),3.13-3.02(m,1H),2.39(dd,J＝12.9,7.0Hz,1H),2.20(s,3H),2.02(t,J＝7.9Hz,2H),1.78-1.69(m,2H),1.69-1.61(m,1H)。

N- ((1 s,3 r) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclopentyl) benzamide:

m/z(ES ⁺ )[M+H] ⁺ ＝394.20；HPLC tR＝1.112min。

¹ H NMR(400MHz,DMSO-d ₆ )12.13(s,1H),10.64(s,1H),8.42(d,J＝7.4Hz,1H),7.87-7.81(m,2H),7.56-7.49(m,1H),7.49-7.41(m,2H),6.35(s,1H),6.22(s,1H),4.42-4.34(m,1H),3.83(s,2H),3.11-3.02(m,1H),2.39(dd,J＝13.1,7.1Hz,2H),2.20(s,3H),2.02(t,J＝8.0Hz,2H),1.81-1.61(m,4H),1.08(t,J＝7.2Hz,1H)。

example 15

2- (3-methylisoxazol-5-yl) -N- (5- (thieno [3,2-d ] pyrimidin-7-yl) -1H-pyrazol-3-yl) acetamide

2- (5-bromo-1H-pyrazol-3-yl) isoindoline-1, 3-dione

Step 1: to a solution of 5-bromo-1H-pyrazol-3-amine (2.5 g,1eq,15 mmol) and isobenzofuran-1, 3-dione (2.7 g,1.2eq,19 mmol) in AcOH (25 mL) under nitrogen at room temperature. The reaction mixture was stirred at 125℃for 16h. The mixture was cooled to room temperature. The mixture was concentrated and the residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 2- (5-bromo-1H-pyrazol-3-yl) isoindoline-1, 3-dione (4.4 g,15mmol, 98%) as a yellow solid.

m/z(ES ⁺ )[M+H] ⁺ ＝291.85；HPLC tR＝0.773min。

2- (5-bromo-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) isoindoline-1, 3-dione

Step 2: to 2- (5-bromo-1H-pyrazol-3-yl) isoindoline-1, 3-dione (4 g,0.01 mol) and K at room temperature under nitrogen atmosphere ₂ CO ₃ To a solution of (6 g,0.04 mol) in MeCN (30 mL) was added 1- (chloromethyl) -4-methoxybenzene (3 g,0.02 mol). The reaction mixture was stirred at 80℃for 16h. The mixture was cooled to room temperature, the resulting mixture was filtered, and the filter cake was washed with EA (3×250 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE/EA (2/1)) to give 2- (5-bromo-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) isoindoline-1, 3-dione (5 g,0.01mol, 90%) as an off-white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝411.95；HPLC tR＝0.939min。

2- (1- (4-methoxybenzyl) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-3-yl) isoindoline-1, 3-dione

Step 3: to a solution of 2- (5-bromo-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) isoindoline-1, 3-dione (5 g,0.01 mol) and 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (6 g,0.02 mol) in 1, 4-dioxane (20 mL) was added potassium acetate (4 g,0.04 mol) and PdCl2 (dppf) -CH2Cl2 adduct (1 g,1 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100℃for 16h. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EA (3X 250 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE/EA (1/1)) to give 2- (1- (4-methoxybenzyl) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-3-yl) isoindoline-1, 3-dione (2.6 g,4.5mmol,40%,80% purity) as an off-white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝460.05；HPLC tR＝1.225min。

2- (1- (4-methoxybenzyl) -5- (thieno [3,2-d ] pyrimidin-7-yl) -1H-pyrazol-3-yl) isoindoline-1, 3-dione

Step 4: to 2- (1- (4-methoxybenzyl) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-3-yl) isoindoline-1, 3-dione (600 mg,1.31 mmol) and 7-bromothieno [3,2-d ] ]To a solution of pyrimidine (281mg, 1.31 mmol) in THF (10 mL) was added K3PO4 (381 mg,3.92 mmol) and Pd XantPhos G3 (111 mg, 131. Mu. Mol). The resulting mixture was subjected to N at 50 ℃ ₂ Stirring for 1.5h under an atmosphere. The desired product can be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; a mobile phase, ACN in water, gradient 0% to 100% in 20 min; detector, UV 254nm. This gives 2- (1- (4-methoxybenzyl) -5- (thieno [3, 2-d) as a yellow solid]Pyrimidin-7-yl) -1H-pyrazol-3-yl-isoindoline-1, 3-dione (190 mg, 406. Mu. Mol, 31.1%).

m/z(ES ⁺ )[M+H] ⁺ ＝468.00；HPLC tR＝1.052min。

1- (4-methoxybenzyl) -5- (thieno [3,2-d ] pyrimidin-7-yl) -1H-pyrazol-3-amine

Step 5: 2- (1- (4-methoxybenzyl)Radical) -5- (thieno [3, 2-d)]A solution of pyrimidin-7-yl) -1H-pyrazol-3-yl-isoindoline-1, 3-dione (190 mg, 406. Mu. Mol) was dissolved in MeOH (2 mL) and N ₂ H ₄ .H ₂ O (6 mL). The resulting mixture was stirred at 50 ℃ under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under vacuum. The desired product can be detected by LCMS. The residue was purified by reverse phase flash chromatography using the following conditions: column: XBIdge-prepared OBD C18 column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 30% B to 50% B in 8min, detector, UV 254nm. This gives 1- (4-methoxybenzyl) -5- (thieno [3, 2-d) as an orange solid]Pyrimidin-7-yl) -1H-pyrazol-3-amine (100 mg, 296. Mu. Mol, 72.9%).

m/z(ES ⁺ )[M+H] ⁺ ＝338.00；HPLC tR＝0.734min。

N- (1- (4-methoxybenzyl) -5- (thieno [3,2-d ] pyrimidin-7-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 6: to 1- (4-methoxybenzyl) -5- (thieno [3, 2-d) at room temperature]Pyrimidin-7-yl) -1H-pyrazol-3-amine (100 mg, 296. Mu. Mol), 2- (3-methylisoxazol-5-yl) acetic acid (62.7 mg, 445. Mu. Mol) and DIEA (115 mg, 889. Mu. Mol) were added dropwise T to a stirred solution of DCM (3 mL) ₃ P (283 mg, 889. Mu. Mol). The resulting mixture was stirred at 25 ℃ under nitrogen atmosphere for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The mixture was concentrated to give N- (1- (4-methoxybenzyl) -5- (thieno [3, 2-d) as a yellow solid]Pyrimidin-7-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (120 mg,261 μmol, 87.9%).

m/z(ES ⁺ )[M+H] ⁺ ＝461.00；HPLC tR＝0.911min。

Step 7: n- (1- (4-methoxybenzyl) -5- (thieno [3, 2-d) was added to the vial at room temperature]Pyrimidin-7-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (110 mg,239 μmol) and TFA (2 mL). The resulting mixture was stirred at 80℃for a further 1 hour. The resulting mixture was concentrated under vacuum. The crude residue was purified by preparative HPLC (column XBridge Prep OBD C, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 10% B to 35% B,35% B within 8 min; wavelength: 220 nm) was purified. This gives 2- (3-methylisoxazol-5-yl) -N- (5- (thieno [3, 2-d) as a white solid]Pyrimidin-7-yl) -1H-pyrazol-3-yl) acetamide (42.6 mg,125 μmol, 52.4%).

m/z(ES ⁺ )[M+H] ⁺ ＝341.05；HPLC tR＝0.975min。

¹ H NMR(400MHz,DMSO-d6)13.03(s,1H),10.89(s,1H),9.63(s,1H),9.31(s,1H),8.77(s,1H),7.48(s,1H),6.28(s,1H),3.91(s,2H),2.22(s,3H)。

Example 16

N- (5- (bicyclo [2.2.1] hept-1-yl) -1H-pyrazol-3-yl) pyrimidin-2-amine

Bicyclo [2.2.1] heptane-1-carboxylic acid methyl ester

Step 1: sulfur dichloride (1.31 g,2.2eq,11.0 mmol) was added dropwise to a solution of bicyclo [2.2.1] heptane-1-carboxylic acid (700 mg,1eq,4.99 mmol) in MeOH (16 mL) under nitrogen atmosphere at 0deg.C. The mixture was stirred at 60℃for 3h. The solvent was removed at room temperature under reduced pressure to give methyl bicyclo [2.2.1] heptane-1-carboxylate (720 mg,4.67mmol, 93.5%) as a white solid. The crude product was used in the next step without further purification.

m/z(ES ⁺ )[M+H] ⁺ ＝155.10；HPLC tR＝1.035min。

3- (bicyclo [2.2.1] hept-1-yl) -3-oxopropionitrile

Step 2: liHMDS (1.17 g,7.00mL,1 molar, 1.5eq,7.00 mmol) was added to the bicyclo [2.2.1] at-78deg.C]Methyl heptane-1-carboxylate (720 mg,1eq,4.67 mmol) and acetonitrile (383 mg,2eq,9.34 mmol) in THF (16 mL). The reaction mixture was stirred at-78 ℃ for 1 hour. LCMS showed no SM. The reaction mixture was treated with saturated NH ₄ Cl (15 mL) was quenched and the aqueous phase was extracted three times with DCM (60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 3- (bicyclo [ 2.2.1)]Hept-1-yl) -3-oxopropionitrile (730 mg,4.47mmol, 95.8%) was used in the next step without further purification.

m/z(ES ⁺ )[M+H] ⁺ =no quality signal; HPLC tr=0.976 min.

3- (bicyclo [2.2.1] hept-1-yl) -1- (tert-butyl) -1H-pyrazol-5-amine

Step 3: tert-butylhydrazine hydrochloride (836 mg,1.5eq,6.71 mmol) and sodium hydroxide (178 mg,1eq,4.47 mmol) were stirred in EtOH (5 mL) for 1h. The solution was added dropwise to 3- (bicyclo [ 2.2.1)]Hept-1-yl) -3-oxopropionitrile (730 mg,1Eq,4.47 mmol) in EtOH (8 mL). The solution was stirred at 50℃for 2 hours. The reaction mixture was treated with saturated NH ₄ Cl (20 mL) was diluted and the aqueous phase was extracted three times with DCM (40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Passing the crude material obtained through Flash chromatography (acetonitrile/water/0.1% formic acid). Concentration in vacuo afforded 5- (bicyclo [ 2.2.1) as a brown solid]Hept-1-yl) -1- (tert-butyl) -1H-pyrazol-3-amine (600 mg,2.57mmol, 57.5%).

m/z(ES ⁺ )[M+H] ⁺ ＝234.10；HPLC tR＝0.824min。

N- (3- (bicyclo [2.2.1] hept-1-yl) -1- (tert-butyl) -1H-pyrazol-5-yl) pyrimidin-2-amine

Step 4: at N ₂ Pd is put down ₂ (dba) ₃ (31 mg,0.1eq, 34. Mu. Mol) to Xantphos (40 mg,0.2eq, 69. Mu. Mol), 5- (bicyclo [ 2.2.1)]Hept-1-yl) -1- (tert-butyl) -1H-pyrazol-3-amine (80 mg,1eq,0.34 mmol) and 2-chloropyrimidine (35 mg,0.9Eq,0.31 mmol) in 1, 4-dioxane (2 mL). The reaction mixture was taken up in N at 80 ℃ ₂ Stirring is carried out for 16 hours under an atmosphere. The reaction mixture was used in the next step without any work-up.

m/z(ES ⁺ )[M+H] ⁺ ＝312.10；HPLC tR＝1.114min。

N- (5- (bicyclo [2.2.1] hept-1-yl) -1H-pyrazol-3-yl) pyrimidin-2-amine

Step 5: formic acid (975 mg,60eq,21.2 mmol) was added to the reaction mixture from the previous step and then the reaction was heated to 80 ℃ for 16 hours. The reaction was concentrated to remove excess formic acid and purified directly by flash chromatography (acetonitrile/water/0.1% formic acid). Concentration in vacuo afforded the crude product as a red oil. The crude product was further purified by preparative HPLC using the following conditions: column: XBridge Shield RP 18O BD column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 60mL/min; gradient: 30% B to 50% B,50% in 8minB, a step of preparing a composite material; wavelength: 254nm; RT1 (min): 7.32. after evaporation of the solvent, N- (5- (bicyclo [ 2.2.1) is obtained as a white solid]Hept-1-yl) -1H-pyrazol-3-yl) pyrimidin-2-amine (36.5 mg, 143. Mu. Mol, 40.5%).

m/z(ES ⁺ )[M+H] ⁺ ＝256.15；HPLC tR＝1.361min。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.92(s,1H),9.49(s,1H),8.41(d,J＝4.8Hz,2H),6.75(t,J＝4.8Hz,1H),6.38(s,1H),2.37-2.22(m,1H),1.83-1.65(m,4H),1.64-1.47(m,4H),1.41-1.26(m,2H)。

Additional compounds prepared according to the method of example 18 are set forth below:

n- (5- (bicyclo [2.2.1] hept-1-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

¹ H NMR(400MHz,DMSO-d ₆ )12.13(s,1H),10.63(s,1H),6.29(d,J＝2.1Hz,1H),6.22(s,1H),3.83(s,2H),2.30(s,1H),2.20(s,3H),1.77¨C 1.63(m,4H),1.61¨C 1.47(m,4H),1.40¨C 1.28(m,2H)。

m/z(ES ⁺ )[M+H] ⁺ ＝301.0。

Example 17

N- (3- ((1 s,3 s) -3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide and N- (5- ((1 r,3 r) -3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

N- (1- (tert-butyl) -3- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 1: a round bottom flask was charged with 1- (tert-butyl) -5- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-amine (1.98 g,1eq,4.29 mmol), EA (10 mL) and stirring bar, and 2- (3-methylisoxazol-5-yl) acetic acid (328 mg,1.5eq,6.43 mmol), DIEA (1.66 g,3eq,12.9 mmol), T was added ₃ P (5.45 g,50% wt,2eq,8.58 mmol) and the solution was stirred at 25℃for 2 hours. The solution was quenched with water and the organic phase was collected. The aqueous phase was extracted three times with EA. The organic phases were combined and concentrated. The crude material obtained was purified by flash chromatography (acetonitrile/water). Concentrated in vacuo to give N- (1- (tert-butyl) -5- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (2.50 g,4.27mmol, 99.7%) as a brown amorphous solid.

N- (1- (tert-butyl) -3- (3- (hydroxymethyl) cyclobutyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 2: a round bottom flask was charged with N- (1- (tert-butyl) -5- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (2.5 g,1eq,4.3 mmol), THF (15 mL) and stir bar. TBAF (8.5 mL,1 molar, 2eq,8.5mmol in 2.2 g) was added and the solution was stirred at 25℃for 2 days. The mixture was diluted with water and the aqueous phase was extracted three times with EA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by flash chromatography (NH ₃ ·H ₂ O/water) purification. Concentrated in vacuo to give N- (1- (tert-butyl) -5- (3- (hydroxymethyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (900 mg,2.60mmol, 61%) as a brown amorphous solid.

N- (1- (tert-butyl) -3- (3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 3: to a solution of N- (1- (tert-butyl) -5- (3- (hydroxymethyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (150 mg,1eq, 433. Mu. Mol) in toluene (5 mL) was added 4-cyclopropylisothiazol-3-ol (91.7 mg,1.5eq, 649. Mu. Mol) and triphenylphosphine (170 mg,1.5eq, 649. Mu. Mol). After bubbling nitrogen through the reaction mixture for 1 minute, di-tert-butyl (E) -diazene-1, 2-dicarboxylate (150 mg,1.5Eq, 649. Mu. Mol) was added dropwise under nitrogen atmosphere at 0 ℃. The mixture was stirred at 40℃for 2 hours. The resulting solution was purified using C18 flash chromatography using the following conditions (mobile phase A: water, mobile phase B: ACN; flow: 60mL/min; gradient: 0% B to 100% B, within 40 min; 254/220 nm). This gave N- (1- (tert-butyl) -5- (3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (150 mg,0.27mmol,62%,84% purity).

N- (3- (3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 4: a solution of N- (1- (tert-butyl) -5- (3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (133 mg,1eq, 283. Mu. Mol) in FA (3 mL) was heated at 80℃for 3 hours. The solvent was evaporated. The residue was purified by preparative HPLC (column XBridge Prep OBD C18, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 30% B to 55% B,55% B within 8 min; wavelength: 220nm; RT1 (min): 7.62 And (3) purifying. This gives N- (5- (3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) as a white amorphous solid) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (100 mg,242 μmol, 85.4%).

N- (3- ((1 s,3 s) -3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 5: n- (3- ((1 s,3 s) -3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide was purified by chiral-HPLC.

¹ H NMR(400MHz,CDCl ₃ )0.6-0.73(m,2H),0.86-1(m,2H),1.82(tt,J＝8.4,5.1Hz,1H),2.18(qd,J＝9.5,2.7Hz,2H),2.32(s,3H),2.51-2.63(m,2H),3.49(p,J＝9.0Hz,1H),3.89(s,2H),4.40(d,J＝5.7Hz,2H),6.18(s,1H),6.56(s,1H),7.84(d,J＝0.7Hz,1H),8.82(s,1H)。

m/z(ES ⁺ )[M+H] ⁺ ＝414.15。

N- (5- ((1 r,3 r) -3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

N- (3- ((1 r,3 r) -3- (((4-cyclopropylisothiazol-3-yl) oxy) methyl) cyclobutyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide was purified by chiral-HPLC.

Example 18

Additional compounds listed in table 9 were synthesized according to the procedure described herein.

Example 19

(1-methylcyclopropyl) carbamic acid rel- (3S, 5R) -5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

Rel- (3R, 5R) -5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl 2- (1-methylcyclopropyl) acetate

(1-methylcyclopropyl) carbamic acid (3S, 5R) -5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

(1-methylcyclopropyl) carbamic acid (3R, 5S) -5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

4, 4-Dimethoxytetrahydrofuran-2-carboxylic acid methyl ester

Step 1: a round bottom flask was charged with methyl 4-oxotetrahydrofuran-2-carboxylate (2 g,0.01 mol), trimethoxymethane (9 g,0.08 mol), tsOH (0.05 g,0.3 mmol), meOH (20 mL) and a stirring bar. The solution was stirred at 24℃for 16 hours. The product was detected by TLC. Will be The mixture was saturated with NaHCO ₃ (aqueous solution) quench followed by concentration under vacuum to remove most of the methanol. The reaction mixture was diluted with water (50 mL) and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give methyl 4, 4-dimethoxytetrahydrofuran-2-carboxylate (1.5 g,7.9mmol, 60%) as a yellow oil.

m/z(ES ⁺ ): no MS signal.

3- (4, 4-Dimethoxytetrahydrofuran-2-yl) -3-oxopropionitrile

Step 2: to 4, 4-Dimethoxytetrahydrofuran-2-carboxylic acid methyl ester (1.4 g,7.4 mmol) and CH under nitrogen at-78deg.C ₃ CN (0.91 g,22 mmol) in THF (15 mL) was added dropwise lithium bis (trimethylsilyl) amide (15 mL,1M in THF, 15 mmol). The mixture was stirred at-78 ℃ for 1.5 hours. The reaction mixture was checked by TLC. The reactant is treated with NH ₄ Cl (saturated aqueous, 15 mL) was quenched and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2×10 ml), dried over Na ₂ SO ₄ Dried, filtered, and concentrated under vacuum. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 20 min; the detector, UV 220nm, gave 3- (4, 4-dimethoxytetrahydrofuran-2-yl) -3-oxopropanenitrile (970 mg,4.87mmol, 66.4%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ No signal.

1- (tert-butyl) -5- (4, 4-dimethoxy tetrahydrofuran-2-yl) -1H-pyrazol-3-amine

Step 3: sodium hydroxide (1.03 g,25.7 mmol) was added in portions to a suspension of tert-butylhydrazine hydrochloride (3.23 g,25.8 mmol) in EtOH (40 mL) at room temperature and stirred at room temperature for 1 hour. A solution of 3- (4, 4-dimethoxytetrahydrofuran-2-yl) -3-oxopropionitrile (4.25 g,21.3 mmol) in ethanol was added at room temperature, and the mixture was then heated to an internal temperature of 50℃and stirred overnight. The mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 30% to 60% in 20 min; detector, UV 254nm. Concentration in vacuo afforded 1- (tert-butyl) -5- (4, 4-dimethoxytetrahydrofuran-2-yl) -1H-pyrazol-3-amine (1.2 g,4.5mmol, 21%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝270.20；HPLC tR＝0.892min。

N- (1- (tert-butyl) -5- (4, 4-dimethoxy tetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -2- (3-methyl isoxazol-5-yl) acetamide

Step 4: to a mixture of 2- (3-methylisoxazol-5-yl) acetic acid (635 mg,4.50 mmol), 1- (tert-butyl) -5- (4, 4-dimethoxytetrahydrofuran-2-yl) -1H-pyrazol-3-amine (1.21 g,4.50 mmol) and DIEA (1.74 g,13.5 mmol) in EA (15 mL) was added dropwise 2,4, 6-tripropyl-1,3,5,2,4,6-trioxatriphosphohexane 2,4, 6-trioxide (4.29 g,50% Wt in ethyl acetate, 6.75 mmol) under nitrogen atmosphere at 0 ℃. The mixture was stirred at 25℃for 2 hours. The reaction was taken up in saturated Na ₂ CO ₃ Aqueous solution (10 mL) was quenched and extracted with EA (2 x 10 mL). The organic layer was treated with more Na ₂ CO ₃ Aqueous (2 x 10 mL) and brine (30 mL) were washed and concentrated. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 15 min; the detector, UV 220nm, gave N- (1- (tert-butyl) -5- (4, 4-dimethoxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (920 mg, 52%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝393.25；HPLC tR＝0.945min

N- (1- (tert-butyl) -5- (4-oxotetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 5: a round bottom flask was charged with N- (1- (tert-butyl) -5- (4, 4-dimethoxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (910 mg,2.32 mmol) and a stirring bar. HCl (3 mol/L)/THF (10 mL) was added and the solution was stirred at 24℃for 2 hours. The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted three times with DCM (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 15 min; the detector, UV 254nm, gave N- (1- (tert-butyl) -5- (4-oxotetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (803 mg,2.32mmol, 100%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝347.30；HPLC tR＝0.813min。

N- (1- (tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 6: a round bottom flask was charged with N- (1- (tert-butyl) -5- (4-oxotetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (270 mg, 779. Mu. Mol), meOH (5 mL) and a stirring bar. Adding NaBH to the above mixture ₄ (88.5 mg,2.34 mmol). The resulting solution was stirred at 24℃for 2h. The mixture was quenched with water and concentrated in vacuo to remove most of the MeOH. The reaction mixture was diluted with water (30 mL) and the aqueous phase was taken up with DCM (20 mL) was extracted three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 40% in 15 min; the detector, UV 254nm, gave N- (1- (tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (180 mg, 517. Mu. Mol, 66.3%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝349.30；HPLC tR＝0.772min。

(1-methylcyclopropyl) carbamic acid 5- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

Step 7: to a stirred mixture of N- (1- (tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (160 mg, 459. Mu. Mol) and 1-isocyanato-1-methylcyclopropane (0.6M in toluene) (2.3 mL,1.38 mmol) was added dropwise DIEA (178 mg, 240. Mu.L, 1.38 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 100 ℃ under nitrogen atmosphere for 2 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give (1-methylcyclopropyl) carbamic acid 5- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester (145 mg,325 μmol, 70.9%) as a pale yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝446.30；HPLC tR＝0.952min

(1-methylcyclopropyl) carbamic acid 5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

Step 8: a round bottom flask was charged with 5- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (170 mg, 382. Mu. Mol) carbamate and a stir bar. HCOOH (5 mL) was added and the solution was stirred at 70 ℃ for 3 hours and concentrated under vacuum to remove HCOOH. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 10 min; the detector, UV 254nm, gave (1-methylcyclopropyl) carbamic acid 5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester (100 mg, 257. Mu. Mol, 67.3%).

m/z(ES ⁺ )[M+H] ⁺ ＝390.15；HPLC tR＝0.887,0.961min。

(cis) (1-methylcyclopropyl) carbamic acid (3 s,5 s) -5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester and trans (1-methylcyclopropyl) carbamic acid (3 s,5 r) -5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

Step 9: (1-methylcyclopropyl) carbamic acid 5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester (100 mg, 57. Mu. Mol) was purified by preparative HPLC (column: XB ridge preparative OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 10% B to 32% B,32% B within 8 min; wavelength: 220nm; RT1 (min): 7.55/8.27) purification. Lyophilization afforded 5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl carbamate (50 mg,0.13mmol, 50%) as a white amorphous solid and 5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl carbamate (10 mg,26 μmol, 10%) as a white amorphous solid.

(cis) m/z (ES ⁺ )[M+H] ⁺ ＝390.30；HPLC tR＝0.746min。

(trans) m/z (ES ⁺ )[M+H] ⁺ ＝390.30；HPLC tR＝0.780min。

Step 10: the compound cis- (1-methylcyclopropyl) carbamic acid 5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester (50 mg,0.13 mmol) was purified by preparative-chiral-HPLC (column CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex (0.2% DEA) -HPLC, mobile phase B: etOH: dcm=1:1-HPLC; flow: 20mL/min; gradient: 80% B to 80% B over 11.5 min; wavelength: 220/254nm; rt1 (min): 4.02; sample solvent EtOH: dcm=1:1-HPLC; injection volume: 1.7mL; number of runs: 1). Lyophilization afforded rel- (3 s,5 r) -5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester (13 mg,33 μmol, 52%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝390.15；HPLC tR＝0.954min。

¹ H NMR (400 MHz, chloroform-d) 8.89 (s, 1H), 6.62 (s, 1H), 6.18 (s, 1H), 5.36 (s, 2H), 5.13 (s, 1H), 4.12 (d, j=10.7 hz, 1H), 3.98 (s, 1H), 3.90 (s, 2H), 2.67 (s, 1H), 2.33 (s, 3H), 2.20 (d, j=14.1 hz, 1H), 1.34 (s, 3H), 0.74 (s, 2H), 0.60 (s, 2H).

The compound cis- (1-methylcyclopropyl) carbamic acid 5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester (50 mg,0.13 mmol) was purified by preparative-chiral-HPLC (column CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex (0.2% DEA) -HPLC, mobile phase B: etOH: dcm=1:1-HPLC; flow rate: 20mL/min; gradient: 80% B to 80% B in 11.5 min; wavelength: 220/254nm; rt2 (min): 8.23; sample solvent EtOH: dcm=1:1-HPLC; injection volume: 1.7mL; number of runs: 1). Lyophilization afforded rel- (3 r,5 r) -5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester (12.3 mg,31.7 μmol, 49%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝390.20；HPLC tR＝0.961min。

¹ H NMR (400 MHz, chloroform-d) 9.01 (s, 1H), 6.62 (s, 1H), 6.18 (s, 1H), 5.40 (s, 1H), 5.35 (s, 1H), 5.13 (s, 1H), 4.12 (d, j=10.8 hz, 1H), 3.97 (d, j=11.0 hz, 1H), 3.90 (s, 2H), 2.68 (s, 1H), 2.33 (s, 3H), 2.20 (d, j=13.9 hz, 1H), 1.34 (s, 3H), 0.73 (s, 2H), 0.59 (s, 2H).

The compound trans- (1-methylcyclopropyl) carbamic acid 5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester (10 mg,26 μmol) was purified by preparative-chiral-HPLC (column: CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex (0.2% DEA) -HPLC, mobile phase B: etOH: dcm=1:1-HPLC; flow: 20mL/min; gradient: 80% B to 80% B in 13.5 min; wavelength: 220/254nm; rt1 (min): 5.27; sample solvent: etOH: dcm=1:1-HPLC; injection volume: 1.65mL; number of runs: 1). Lyophilization afforded (3 s,5 r) -5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4.2 mg,11 μmol, 80%) carbamate as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝390.15；HPLC tR＝1.016min。

¹ H NMR (400 MHz, chloroform-d) 8.85 (s, 1H), 6.58 (s, 1H), 6.19 (s, 1H), 5.38 (s, 1H), 5.20 (d, j=12.7 hz, 2H), 4.12 (s, 1H), 3.99 (d, j=10.6 hz, 1H), 3.89 (s, 2H), 2.50 (s, 1H), 2.32 (s, 3H), 2.30-2.22 (m, 1H), 1.39 (s, 3H), 0.79 (s, 2H), 0.68-0.63 (m, 2H).

The compound trans- (1-methylcyclopropyl) carbamic acid 5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester (10 mg,26 μmol) was purified by preparative-chiral-HPLC (column: CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex (0.2% DEA) -HPLC, mobile phase B: etOH: dcm=1:1-HPLC; flow: 20mL/min; gradient: 80% B to 80% B in 13.5 min; wavelength: 220/254nm; rt2 (min): 10.63; sample solvent: etOH: dcm=1:1-HPLC; injection volume: 1.65mL; number of runs: 1). Lyophilization afforded (3 r,5 s) -5- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (3.6 mg,9.2 μmol, 70%) carbamate as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝390.15；HPLC tR＝1.012min。

¹ H NMR (400 MHz, chloroform-d) 8.93 (s, 1H), 6.57 (s, 1H), 6.18 (s, 1H), 5.38 (s, 1H), 5.20 (s, 2H), 4.15 (s, 1H), 3.98 (d, J=10.5 Hz, 1H), 3.91 (s, 2H), 2.50 (s, 1H), 2.32 (s, 3H), 2.28-2.24 (m, 1H), 1.39 (s, 3H), 0.80 (s, 2H), 0.73-0.62 (m, 2H).

Additional compounds prepared according to the method of example 19 are depicted in table 10 below.

Example 20

Rel- (1R, 3S) -3- (2- (2- (3-methylisoxazol-5-yl) acetamido) thiazol-5-yl) cyclopentyl ester of isopropyl carbamate and

rel- (1R, 3S) -3- (2- (2- (3-methylisoxazol-5-yl) acetamido) thiazol-5-yl) cyclopentyl ester of isopropyl carbamate

2- (3-Oxocyclopentyl) malonic acid dimethyl ester

Step 1: to a solution of 2-cyclopenten-1-one (25.5 mL,305 mmol) in anhydrous toluene (250 mL) was added dimethyl malonate (140 mL,1.22 mol). 1,5, 7-Triazabicyclo [4.4.0] dec-5-ene (1.27 g,9.14 mmol) was then added and the mixture was stirred at room temperature under nitrogen for 20h. The mixture was concentrated to 1/2 volume under reduced pressure. The crude product was filtered through a short pad of silica gel (4 cm. Times.4 cm) eluting several times with AcOEt. The filtrate was concentrated under reduced pressure (70-75 ℃ C. Water bath, 2 h) to give the title compound (86 g) as a yellow oil.

LCMS: is insensitive to MS.

¹ H NMR(400MHz,DMSO):δ3.67(s；3H)；3.65(s；3H)；3.52(s；1H)；2.65-2.76(m；1H)；2.29(dd；J＝18.10；7.54Hz；1H)；2.15-2.19(m；2H)；1.96-2.05(m；2H)；1.53-1.64(m；1H)。

2- (3-Oxocyclopentyl) acetic acid methyl ester

Step 2: a mixture of methyl 3- (dimethyl-l 3-oxo-2- (3-oxocyclopentyl) propionate (40.0 g, 87 mmol) and dodecanedioic acid (34.4 g,149 mmol) was heated at 210℃for 20h (metal bille temperature). The mixture was then distilled under reduced pressure (vacuum: 8-10 mbar, metal belle temperature: 180-190 ℃, internal temperature: 70-100 ℃, using distillation receiver) using a fractionating tower to give the title compound (17.1 g, 59%) as a clear oil.

¹ H NMR(400MHz,CDCl ₃ ):δ3.68(s；3H)；2.55-2.67(m；1H)；2.43-2.51(m；3H)；2.26-2.35(m；1H)；2.14-2.25(m；2H)；1.88(dd；J＝18.23；10.09Hz；1H)；1.51-1.62(m；1H)。

2- (3, 3-Dimethoxycyclopentyl) acetic acid methyl ester

Step 3: a mixture of montmorillonite (21.0 g,64.0 mmol) and trimethyl orthoformate (35.0 mL,320 mmol) was stirred at room temperature for 2h. A solution of methyl 2- (3-oxocyclopentyl) acetate (10.0 g,64.0 mmol) in pentane (48 mL) was then slowly added over 10 minutes and the mixture stirred at room temperature for 20h. The mixture was then filtered through a short pad of celite and rinsed with pentane. The filtrate was concentrated under reduced pressure to give the title compound (12.7 g, 98%) as a transparent oil.

¹ H NMR(400MHz,CDCl ₃ ):δ3.65(s；3H)；3.18(s；6H)；2.30-2.44(m；3H)；2.08(dd；J＝13.22；7.51Hz；1H)；1.84-1.92(m；2H)；1.72-1.80(m；1H)；1.42(dd；J＝13.18；8.58Hz；1H)；1.27-1.37(m；1H)。

2- (3, 3-Dimethoxycyclopentyl) ethan-1-ol

Step 4: a solution of methyl 2- (3, 3-dimethoxycyclopentyl) acetate (3.00 g,14.8 mmol) in THF (15.0 mL) was treated dropwise at room temperature with a 2M solution of lithium borohydride in THF (8.90 mL,17.8 mmol). Methanol (720 ul,17.8 mmol) was then added dropwise and the mixture stirred at room temperature for 20h. Then adding saturated NH ₄ Cl solution (30 mL) and the mixture was diluted with ether (50 mL). The layers were then separated and the organic phase was extracted with ether (30 ml,2 x). The combined organic phases were then washed with brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude compound was purified by column over 40g silica gel using EtOAc in hexanes gradient (0-50%) using ELSD detector to give the title compound (1.8 g, 70%) as a clear oil.

¹ H NMR(400MHz,CDCl ₃ ):δ3.65(q；J＝5.92Hz；2H)；3.19(d；J＝3.99Hz；6H)；2.02-2.13(m；2H)；1.84-1.90(m；2H)；1.72-1.79(m；1H)；1.58-1.65(m；2H)；1.27-1.42(m；3H)。

2- (3, 3-Dimethoxycyclopentyl) acetaldehyde

Step 5: to 2- (3, 3-Dimethoxycyclopentyl) ethan-1-ol (800 mg,4.59 mmol) in CH ₂ Cl ₂ To a solution in (50 mL) was added sodium bicarbonate (1.54 g,18.4 mmol) and the mixture was stirred for 5 min. The mixture was cooled to 0deg.C and dess-martin periodate (2.92 g,6.89 mmol) was added in portions. The mixture was stirred at 0 ℃ for 30 minutes, then the ice bath was removed and the mixture was stirred at room temperature for 2h. Addition of saturated NaHCO ₃ Solution (30 mL) and Na ₂ S ₂ O ₄ (30 mL) and the mixture was stirred for 30 minutes. ThenThe mixture was diluted in DCM (70 mL). The aqueous phase was extracted with DCM (30 mL, 2X). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give the title compound (890 mg) as an oil.

¹ H NMR(400MHz,CDCl ₃ ):δ9.75(s；1H)；3.19(s；6H)；2.49(s；3H)；2.06-2.15(m；1H)；1.85-1.94(m；2H)；1.74-1.82(m；1H)；1.30-1.43(m；2H)。

2-chloro-2- (3, 3-dimethoxy cyclopentyl) acetaldehyde

Step 6: to crude 2- (3, 3-dimethoxycyclopentyl) acetaldehyde (1.00 g,5.23 mmol) (90% purity) in CH ₂ Cl ₂ To a solution in (45 mL) was added L- (-) -prolinamide (119 mg,1.05 mmol), and the mixture was stirred at 0deg.C for 10 min. N-chlorosuccinimide (698 mg,5.23 mmol) was added dropwise to CH at 0deg.C over 5 min ₂ Cl ₂ (20 mL) and then the mixture was stirred at 0deg.C for 1h. The ice bath was then removed and the mixture was stirred at room temperature for 9h. The mixture was cooled to 0 ℃ and pentane (40 mL) was added and the mixture was stirred at 0 ℃ for 10 minutes. The mixture was then filtered through celite, followed by concentration under reduced pressure. The residue was diluted in pentane (50 mL) and washed with brine (10 mL,2 x), taken up in Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give the crude title compound (670 mg, 62%) as a clear oil.

¹ H NMR(400MHz,CDCl ₃ ):δ9.45(dd；J＝6.67；2.89Hz；1H)；4.13(td；J＝7.88；2.85Hz；1H)；3.20(s；6H)；2.58-2.64(m；1H)；1.99-2.10(m；1H)；1.75-1.94(m；4H)；1.62-1.69(m；1H)。

5- (3, 3-dimethoxy cyclopentyl) thiazol-2-amine

Step 7: a suspension of thiourea (494 mg,6.48 mmol) in dioxane (10 mL) was sonicated followed by the addition of triethylamine (3.16 mL,22.7 mmol) at room temperature and the mixture stirred for 10 min. A solution of 2-bromo-2- (3, 3-dimethoxycyclopentyl) acetaldehyde (670 mg,3.24 mmol) in dioxane (17 mL) was then added and the mixture was quickly transferred to a preheated heating bath set at 80 ℃ and heated for 20h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted in ether (70 mL) and washed with half saturated brine (10 mL,2 x). The aqueous phase was then extracted with ether (30 mL, 2X). The combined organic phases were taken up in Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by column on silica gel using a gradient of 10% MeOH in DCM to give the title compound as a brown oil (200 mg, 27%).

¹ H NMR(400MHz,CDCl ₃ ):δ6.76(s；1H)；4.76(bs；2H)；3.26-3.30(m；1H)；3.22(d；J＝3.47Hz；6H)；2.30(dd；J＝13.18；7.68Hz；1H)；2.06-2.13(m；1H)；1.96-2.02(m；1H)；1.84-1.90(m；1H)；1.69-1.80(m；2H)。ESI-MS(m/z+):229.1[M+H]。

N- (5- (3, 3-dimethoxy cyclopentyl) thiazol-2-yl) -2- (3-methyl isoxazol-5-yl) acetamide

Step 8: to 5- (3, 3-Dimethoxycyclopentyl) thiazol-2-amine (480 mg,2.10 mmol) on CH at 0deg.C ₂ Cl ₂ To a solution in (30 mL) was added 3-methyl-5-isoxazoleacetic acid (333 mg,2.31 mmol). N, N-diisopropylethylamine (1.10 mL,6.31 mmol) was then added followed by a 50% solution of propylphosphonic anhydride (3.75 mL,6.31 mmol) in EtOAc and the mixture was slowly warmed to room temperature (over 4 hours). The mixture was then diluted in DCM (30 mL) and saturated brine solution (10 mL) was added. The phases were separated and the aqueous phase was extracted with DCM (20 mL, 2X). The combined organic phases were taken up in Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. Will remain behindThe material was purified by column on silica gel using a gradient of EtOAc in DDM (0-60%) to give the title compound as a pale yellow solid (270 mg, 42%).

¹ HNMR(400MHz,CDCl ₃ ):δ10.68(br s；1H)；7.19(s；1H)；6.19(s；1H)；3.97(s；2H)；3.56-3.65(m；1H)；2.73(dd；J＝18.07；7.52Hz；1H)；2.44-2.56(m；2H)；2.28-2.37(m；2H)；2.31(s,3H),2.00-2.10(m；1H)。ESI-MS(m/z+):306.1[M+H]。

N- (5- ((1R, 3S) -3-hydroxycyclopentyl) thiazol-2-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 9: li (CH) was added dropwise to a mixture of 2- (3-methylisoxazol-5-yl) -N- (5- (3-oxocyclopentyl) thiazol-2-yl) acetamide (250 mg,1Eq, 819. Mu. Mol) in THF (10 mL) at-65℃under nitrogen atmosphere ₃ CH ₂ ) ₃ BH (1.64 mL,1 molar, 2Eq,1.64 mmol). The mixture was stirred at-65℃for 1h. The mixture was treated with NaHCO at-65 ℃ ₃ (aqueous solution) quenching followed by addition of H at-10deg.C ₂ O ₂ And stirred for 1h. The reaction mixture was diluted with water (15 mL) and the aqueous phase was extracted three times with EA (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. This yielded N- (5- (3-hydroxycyclopentyl) thiazol-2-yl) -2- (3-methylisoxazol-5-yl) acetamide (200 mg,651 μmol, 79.5%) as a yellow amorphous solid. The crude material obtained was purified by preparative HPLC (column: XBridge Shield RP OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH4HCO3+0.1% NH 3H 2O), mobile phase B: ACN; flow: 60mL/min; gradient: 25% B to 50% B,50% B over 8 min; wavelength: 220nm; RT1 (min): 7.48; number of runs: 0). Lyophilization afforded N- (5- ((cis) -3-hydroxycyclopentyl) thiazol-2-yl) -2- (3-methylisoxazol-5-yl) acetamide (150 mg,488 μmol, 75.0%) as an off-white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝308.0；HPLC tR＝0.630min。

(cis) -3- (2- (2- (3-methylisoxazol-5-yl) acetamido) thiazol-5-yl) cyclopentyl (4-nitrophenyl) carbonate

Step 10: a round bottom flask was charged with N- (5- ((cis) -3-hydroxycyclopentyl) thiazol-2-yl) -2- (3-methylisoxazol-5-yl) acetamide (145 mg,1Eq, 472. Mu. Mol), DCM (6 mL), 4-nitrophenyl chloroformate (95.1 mg,1Eq, 472. Mu. Mol), py (112 mg, 114. Mu.L, 3Eq,1.42 mmol), DMAP (5.76 mg,0.1Eq, 47.2. Mu. Mol) and a stirring bar, and the solution was stirred at 25℃for 16 hours. The reaction mixture was concentrated in vacuo to give (cis) -3- (2- (2- (3-methylisoxazol-5-yl) acetamido) thiazol-5-yl) cyclopentyl ester (4-nitrophenyl) ester (250 mg, crude) as an off-white amorphous solid, which was used in the next step without further purification.

m/z(ES ⁺ )[M+H] ⁺ ＝473.0；HPLC tR＝0.978min。

(cis) -isopropylcarbamic acid 3- (2- (2- (3-methylisoxazol-5-yl) acetamido) thiazol-5-yl) cyclopentyl ester

Step 11: a round bottom flask was charged with (cis) -3- (2- (2- (3-methylisoxazol-5-yl) acetamido) thiazol-5-yl) cyclopentyl ester (4-nitrophenyl) ester (135 mg,1Eq, 286. Mu. Mol), 2-MeTHF (5 mL), DIEA (73.9 mg, 99.5. Mu.L, 2Eq, 571. Mu. Mol), propan-2-amine (33.8 mg,2Eq, 571. Mu. Mol) and a stirring bar, and the solution was stirred at 25℃for 16 hours. The reaction mixture was diluted with water (10 mL) and the aqueous phase was extracted three times with EA (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by preparative HPLC (column: XBridge Shield RP OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH4HCO3+0.1% NH 3H 2O), mobile phase B: ACN; flow: 60mL/min; gradient: 25% B to 50% B,50% B over 8 min; wavelength: 220nm; RT1 (min): 7.48; number of runs: 0). Lyophilization afforded (cis) -isopropylcarbamic acid 3- (2- (2- (3-methylisoxazol-5-yl) acetamido) thiazol-5-yl) cyclopentyl ester (80 mg,0.20mmol, 71%) as an off-white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝393.2；HPLC tR＝0.978min。

Step 12: the resulting material (cis) -isopropylcarbamic acid 3- (2- (2- (3-methylisoxazol-5-yl) acetamido) thiazol-5-yl) cyclopentyl ester (80 mg,0.20 mmol) was purified by chiral preparative HPLC (column CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex (0.2% dea) -HPLC, mobile phase B: meOH: dcm=1:1; flow: 20mL/min; gradient: 50% B to 50% B in 11 min; wavelength: 220/254nm; rt1 (min): 7.17; rt2 (min): 8.83; sample solvent: meOH: dcm=1:1; injection volume: 0.5mL; run number: 5). Lyophilization gives the isopropyl carbamic acid rel- (1 r,3 s) -3- (2- (2- (3-methylisoxazol-5-yl) acetamido) thiazol-5-yl) cyclopentyl ester (32 mg,82 μmol, 40%) as an off-white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝393.10；HPLC tR＝0.797min。

¹ H NMR(400MHz,DMSO-d ₆ )12.28(s,1H),7.22(d,J＝1.0Hz,1H),6.96(d,J＝7.9Hz,1H),6.28(s,1H),5.00(s,1H),4.00(s,2H),3.58(h,J＝6.7Hz,1H),3.32-3.22(m,1H),2.50(s,1H),2.21(s,3H),2.05(d,J＝9.9Hz,1H),1.91(s,1H),1.70(dd,J＝20.7,10.5Hz,2H),1.58(s,1H),1.03(d,J＝6.6Hz,6H)。

Example 21

Isopropyl carbamic acid ((1 s,3 s) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclobutyl) methyl ester and

isopropyl carbamic acid ((1 s,3 s) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclobutyl) methyl ester

3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutane-1-carboxylic acid methyl ester

Step 1: a round bottom flask was charged with methyl 3- (hydroxymethyl) cyclobutane-1-carboxylate (2.5 g,1Eq,17 mmol), imidazole (3.5 g,3Eq,52 mmol), DMF (10 mL) and stir bar. Tert-butyldiphenylsilyl hypochlorite (12 g,2.5Eq,43 mmol) was added and the solution stirred at 25℃for 16 hours. The mixture was diluted with water and the aqueous phase was extracted three times with EA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. This gave methyl 3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutane-1-carboxylate (5 g, crude) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝383.30；HPLC tR＝1.143min。

3- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -3-oxopropanenitrile

Step 2: to a solution of methyl 3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutane-1-carboxylate (5 g,1Eq,0.01 mol) in THF (30 mL) was added CH ₃ CN (1 g,1mL,2Eq,0.03 mol). Nitrogen was then bubbled through the reaction mixture for 2 minutes and cooled to-78℃and LiHMDS (3 g,20mL,1.5Eq,0.02 mol) was added dropwise to the reaction. The mixture was stirred at-78 ℃ for 1h. The mixture was evaporated and extracted with ethyl acetate (3×40 ml), taken up in Na ₂ SO ₄ Dried and evaporated in vacuo. The crude residue was purified by flash chromatography (mobile phase A: water, mobile phase B: ACN; flow: 60mL/min; gradient: 60% B to 80% B over 7 min); the solvent was evaporated to give the title compound 3- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -3-oxopropanenitrile (2.68 g,6.84mmol, 50%) as a yellow oil.

m/z(ES ⁺ )[M+Na] ⁺ ＝414.10；HPLC tR＝1.425min。

1- (tert-butyl) -5- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-amine

Step 3: a round bottom flask was charged with tert-butylhydrazine hydrochloride (1.28 g,1.5Eq,10.3 mmol) and NaOH (0.27 g,1Eq,6.84 mmol) in EtOH (13 mL) and a stirring bar. The resulting mixture was stirred for 1-2 hours. 3- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -3-oxopropanenitrile (2.68 g,1Eq,6.84 mmol) was then dissolved in EtOH (5 mL) and the above mixture was added. The resulting solution was stirred at 50℃for 2 hours. The resulting crude material was purified by flash chromatography (acetonitrile/water/0.1% formic acid) and concentrated in vacuo to give 1- (tert-butyl) -5- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-amine (1.98 g,4.29mmol, 62.7%) as a brown oil.

m/z(ES ⁺ )[M+H] ⁺ ＝462.25；HPLC tR＝1.599min。

N- (1- (tert-butyl) -5- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 4: into a round bottom flask was charged 1- (tert-butyl) -5- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -1H-pyrazole3-amine (1.98 g,1Eq,4.29 mmol), DCM (10 mL) and stirring rod, 2- (3-methylisoxazol-5-yl) acetic acid (328 mg,1.5Eq,6.43 mmol), DIEA (1.66 g,3Eq,12.9 mmol), T ₃ P (5.45 g,50% Wt,2Eq,8.58 mmol). The solution was stirred at 25℃for 2 hours. The solution was quenched with water and the organic phase was collected. The aqueous phase was extracted three times with EA. The organic phases were combined and concentrated. The resulting crude material was purified by flash chromatography (acetonitrile/water) and concentrated in vacuo to give N- (1- (tert-butyl) -5- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (2.50 g,4.27mmol, 99.7%) as a brown amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝585.40；HPLC tR＝1.575min。

N- (1- (tert-butyl) -5- (3- (hydroxymethyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 5: a round bottom flask was charged with N- (1- (tert-butyl) -5- (3- (((tert-butyldiphenylsilyl) oxy) methyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (2.5 g,1Eq,4.3 mmol), THF (15 mL) and a stir bar. TBAF (8.5 mL,1 molar, 2Eq,8.5mmol in 2.2 g) was added and the solution was stirred at 25℃for 2 days. The mixture was diluted with water and the aqueous phase was extracted three times with EA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography (MeCN/nh3.h2o in water) and concentrated in vacuo to give N- (1- (tert-butyl) -5- (3- (hydroxymethyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (900 mg,2.60mmol, 61%) as a brown amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝347.20；HPLC tR＝0.800min。

Isopropyl carbamic acid (3- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclobutyl) methyl ester

Step 6: a round bottom flask was charged with N- (1- (tert-butyl) -5- (3- (hydroxymethyl) cyclobutyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (450 mg,1Eq,1.30 mmol), DIEA (504 mg, 679. Mu.L, 3Eq,3.90 mmol), 2-isocyanatopropane (221 mg,2Eq,2.60 mmol), toluene (15 mL) and stirring bar. The solution was stirred at 80 ℃ for 20 hours and concentrated in vacuo. The resulting crude material was purified by flash chromatography (acetonitrile/water) and concentrated in vacuo to give isopropyl carbamic acid (3- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclobutyl) methyl ester (320 mg,742 μmol, 57.1%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝432.35；HPLC tR＝0.835min。

Isopropyl carbamic acid (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclobutyl) methyl ester

Step 7: a round bottom flask was charged with isopropyl carbamic acid (3- (1- (tert-butyl) -3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclobutyl) methyl ester (320 mg,1Eq, 742. Mu. Mol), FA (15 mL) and a stirring bar, and the solution was stirred at 70℃for 16 hours. The resulting mixture was concentrated in vacuo to give isopropyl carbamic acid (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclobutyl) methyl ester (330 mg,0.66mmol,89%,75% purity) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝376.05；HPLC tR＝0.775min。

Step 8: isopropyl carbamic acid (3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclobutyl) methyl ester (250 mg,1eq,666 μmol) was purified by chiral preparative HPLC (column CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex (0.2% dea) -HPLC; mobile phase B: meOH: dcm=1:1; flow: 20mL/min; gradient: 80% B to 80% B over 10 min; wavelength: 220/254nm; rt1 (min): 4.18; rt2 (min): 7.47; sample solvent: meOH: dcm=1:1; injection volume: 1mL; number of runs: 3). Lyophilization afforded isopropyl carbamic acid ((1 s,3 s) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclobutyl) methyl ester (87 mg,0.23mmol, 70%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝376.25；HPLC tR＝1.168min。

¹ H NMR(400MHz,DMSO-d ₆ )12.14(s,1H),10.64(s,1H),7.05(d,J＝7.9Hz,1H),6.35(s,1H),6.23(s,1H),4.04(d,J＝7.2Hz,2H),3.83(s,2H),3.57(ddt,J＝21.7,15.8,7.4Hz,3H),2.46(s,1H),2.21(s,4H),2.16(d,J＝8.1Hz,3H),1.05(d,J＝6.5Hz,6H)。

Lyophilization afforded isopropyl carbamic acid ((1 s,3 s) -3- (3- (2- (3-methylisoxazol-5-yl) acetamido) -1H-pyrazol-5-yl) cyclobutyl) methyl ester (33.7 mg,89.8 μmol, 27.0%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝376.20；HPLC tR＝1.128min。

¹ H NMR(400MHz,DMSO-d ₆ )12.14(s,1H),10.64(s,1H),7.05(d,J＝7.9Hz,1H),6.35(s,1H),6.23(s,1H),4.04(d,J＝7.2Hz,2H),3.83(s,2H),3.57(ddt,J＝21.7,15.8,7.4Hz,3H),2.58(s,1H),2.21(s,4H),2.16(d,J＝8.1Hz,3H),1.05(d,J＝6.5Hz,6H)。

Example 22

N- (5- ((1R, 3r,5S,6 r) -6- (dimethylcarbamoyl) bicyclo [3.1.0] hex-3-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide

2- (5-bromo-1H-pyrazol-3-yl) isoindoline-1, 3-dione

Step 1: 5-bromo-1H-pyrazol-3-amine (2.5 g,15 mmol) and isobenzofuran-1, 3-dione (2.7 g,19 mmol) were combined in AcOH (25 mL) at room temperature under nitrogen. The reaction mixture was stirred at 125℃for 16h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 2- (5-bromo-1H-pyrazol-3-yl) isoindoline-1, 3-dione (4.4 g,15mmol, 98%) as a yellow solid.

m/z(ES+)[M+H]+＝303.20；HPLC tR＝0.962min。

2- (5-bromo-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) isoindoline-1, 3-dione

Step 2: to 2- (5-bromo-1H-pyrazol-3-yl) isoindoline-1, 3-dione (4 g,0.01 mol) and K at room temperature under nitrogen atmosphere ₂ CO ₃ To a solution of (6 g,0.04 mol) in MeCN (30 mL) was added 1- (chloromethyl) -4-methoxybenzene (3 g,0.02 mol). The reaction mixture was stirred at 80℃for 16h. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EA (3X 250 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE/EA (2/1)) to give 2- (5-bromo-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) isoindoline-1, 3-dione (5 g,0.01mol, 90%) as an off-white solid 。

m/z(ES+)[M+H]+＝413.95；HPLC tR＝0.939min。

(3- (1, 3-dioxoisoindolin-2-yl) -1- (4-methoxybenzyl) -1H-pyrazol-5-yl) boronic acid and 2- (1- (4-methoxybenzyl) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-3-yl) isoindolin-1, 3-dione

Step 3: to a solution of 2- (5-bromo-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) isoindoline-1, 3-dione (5 g,0.01 mol) and 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (6 g,0.02 mol) in 1, 4-dioxane (20 mL) was added potassium acetate (4 g,0.04 mol) and PdCl at room temperature under nitrogen atmosphere ₂ (dppf)-CH ₂ Cl ₂ Adducts (1 g,1 mmol). The reaction mixture was stirred at 100℃for 16h. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EA (3×250 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE/EA (1/1)) to give a mixture of (3- (1, 3-dioxoisoindolin-2-yl) -1- (4-methoxybenzyl) -1H-pyrazol-5-yl) boronic acid and 2- (1- (4-methoxybenzyl) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-3-yl) isoindolin-1, 3-dione (2.6 g,4.5mmol,40%,80% purity) as an off-white solid.

m/z(ES+)[M+H] ⁺ = 378.25; HPLC tR=0.951 min (boric acid)

(1S, 5S, 6R) -3- (((trifluoromethyl) sulfonyl) oxy) bicyclo [3.1.0] hex-2-ene-6-carboxylic acid ethyl ester

Step 4: to a solution of ethyl (1R, 5S,6 r) -3-oxo-bicyclo [3.1.0] hexane-6-carboxylate (2.5 g,15 mmol) and 2, 6-di-tert-butyl-4-methylpyridine (5.5 g,27 mmol) in DCE (30 mL) was added dropwise trifluoromethanesulfonic anhydride (6.3 g,22 mmol) at 0deg.C. The reaction was stirred at 70 ℃ overnight. The resulting mixture was cooled to room temperature and diluted with DCM, washed with 10% citric acid, water and brine. The organic phase was concentrated under reduced pressure. The crude was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; a mobile phase, ACN in water, gradient from 40% to 90% in 10 min; the detector, UV 254nm, gave (1S, 5S, 6R) -3- (((trifluoromethyl) sulfonyl) oxy) bicyclo [3.1.0] hex-2-ene-6-carboxylic acid ethyl ester (840 mg,2.80mmol, 19%) as a brown oil.

m/z(ES ⁺ )[M+H] ⁺ ＝301.10；HPLC tR＝0.954min。

(1S, 5S, 6R) -3- (5- (1, 3-dioxoisoindolin-2-yl) -1- (4-methoxybenzyl) -1H-pyrazol-3-yl) bicyclo [3.1.0] hex-2-ene-6-carboxylic acid ethyl ester

Step 5: (1S, 5S, 6R) -3- (((trifluoromethyl) sulfonyl) oxy) bicyclo [3.1.0] in 1, 4-dioxane (10 mL) in a vial ]1-2-ene-6-carboxylic acid ethyl ester (500 mg,1.67 mmol), (3- (1, 3-dioxoisoindolin-2-yl) -1- (4-methoxybenzyl) -1H-pyrazol-5-yl) boronic acid (812 mg,2.16 mmol), K ₃ PO ₄ (1.06 g,5.00 mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride complex with dichloromethane (136 mg,167 μmol). The reaction was treated with N ₂ Three purges followed by heating at 50 ℃ for 16 hours. The crude was diluted with EtOAc, washed with 10% citric acid, water and brine. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE/EA (1:3)) to give (1 s,5s,6 r) -3- (5- (1, 3-dioxoisoindolin-2-yl) -1- (4-methoxybenzyl) -1H-pyrazol-3-yl) bicyclo [3.1.0 as a white solid]Ethyl hex-2-ene-6-carboxylate (900m g,1.5mmol,89%,80% purity).

m/z(ES ⁺ )[M+H] ⁺ ＝484.30；HPLC tR＝1.253min。

(1S, 5S, 6R) -3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) bicyclo [3.1.0] hex-2-ene-6-carboxylic acid ethyl ester

Step 6: the round bottom flask was charged with EtOAc (8 mL) and hydrazine hydrate (1 mL) and a stir bar. (1S, 5S, 6R) -3- (5- (1, 3-dioxoisoindolin-2-yl) -1- (4-methoxybenzyl) -1H-pyrazol-3-yl) bicyclo [3.1.0] hex-2-ene-6-carboxylic acid ethyl ester (850 mg,1.76 mmol) was then added at 0℃and the resulting solution was stirred at 0-25℃for 1H. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting reaction mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 10 min; the detector, UV 254nm, gave (1S, 5S, 6R) -3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) bicyclo [3.1.0] hex-2-ene-6-carboxylic acid ethyl ester (530 mg,1.50mmol, 85.3%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝354.20；HPLC tR＝0.939min。

(1R, 3r,5S,6 r) -3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) bicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester

Step 7: to (1S, 5S, 6R) -3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) bicyclo [3.1.0] in a round bottom flask under nitrogen atmosphere]To a solution of ethyl hex-2-ene-6-carboxylate (450 mg,1.27 mmol) in EtOAc (10 mL) was added Pd (OH) ₂ C (89.4 mg). The mixture was hydrogenated at room temperature under a hydrogen atmosphere using a hydrogen balloon for 1 hour, filtered through a celite pad, and concentrated under reduced pressure to give (1 r,3r,5s,6 r) -3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) bicyclo [3.1.0 as a yellow oil]Hexane-6-carboxylic acid ethyl ester (430 mg,1.21mmol, 95.1%).

m/z(ES ⁺ )[M+H] ⁺ ＝356.25；HPLC tR＝0.882min。

(1R, 3r,5S,6 r) -3- (1- (4-methoxybenzyl) -5- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-3-yl) bicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester

Step 8: to a mixture of ethyl (1 r,3r,5s,6 r) -3- (5-amino-1- (4-methoxybenzyl) -1H-pyrazol-3-yl) bicyclo [3.1.0] hexane-6-carboxylate (450 mg,1.27 mmol), lithium 3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxylate (268 mg,1.52 mmol) and DIEA (2.45 g,19.0 mmol) in EtOAc (10 mL) was added dropwise T3P (9.67 g,50% wt,15.2 mmol) under nitrogen at 0 ℃. The mixture was stirred at 25 ℃ for 12 hours and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; a mobile phase, ACN in water, gradient from 10% to 80% in 15 min; the detector, UV 254nm, gave (1R, 3r,5S,6 r) -3- (1- (4-methoxybenzyl) -5- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazole-3-yl) bicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester (430 mg, 847. Mu. Mol, 66.9%) as a pale yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝508.35；HPLC tR＝1.129min。

(1 r,3r,5s,6 r) -3- (1- (4-methoxybenzyl) -5- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazole-3-yl) bicyclo [3.1.0] hexane-6-carboxylic acid

Step 9: (1R, 3r,5S,6 r) -3- (1- (4-methoxybenzyl) -5- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) bicyclo [3.1.0 in MeOH (2 mL) in a round bottom flask]Hexane-6-carboxylic acid ethyl ester (275 mg, 542. Mu. Mol) and stirring bar. Added to MeOH H ₂ LiOH (104 mg,4.33 mmol) in O (8 mL) and the solution was stirred at 25 ℃ for 16 hours.The resulting mixture was concentrated in vacuo. The residue was acidified to pH-6 with H Cl (aqueous solution, 3M). The resulting mixture was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, AC N in water, gradient 0% to 50% in 15 min; the detector, UV 254nm, gave (1R, 3r,5S,6 r) -3- (1- (4-methoxybenzyl) -5- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) bicyclo [3.1.0 as a pale yellow solid]Hexane-6-carboxylic acid (240 mg, 500. Mu. Mol, 92.4%).

m/z(ES ⁺ )[M+H] ⁺ ＝480.35；HPLC tR＝0.972min。

N- (3- ((1R, 3r,5S,6 r) -6- (dimethylcarbamoyl) bicyclo [3.1.0] hex-3-yl) -1- (4-methoxybenzyl) -1H-pyrazol-5-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide

Step 10: to a mixture of (1 r,3r,5s,6 r) -3- (1- (4-methoxybenzyl) -5- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazole-3-yl) bicyclo [3.1.0] hexane-6-carboxylic acid (230 mg, 480. Mu. Mol), dimethylamine (1.20 mL,2m in THF, 2.40 mmol) and N-ethyl-N-isopropyl-2-amine (496 mg,3.84 mmol) in EtOAc (10 mL) was added dropwise T3P (916 mg,50% wt,2.88 mmol) under nitrogen atmosphere at 0 ℃. The mixture was stirred at 25 ℃ for 2 hours and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; a mobile phase, ACN in water, gradient from 10% to 80% in 15 min; the detector, UV 254nm, gave N- (3- ((1R, 3r,5S,6 r) -6- (dimethylcarbamoyl) bicyclo [3.1.0] hex-3-yl) -1- (4-methoxybenzyl) -1H-pyrazol-5-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (210 mg, 415. Mu. Mol, 86.4%) as a pale yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝507.40；HPLC tR＝1.002min。

Step 11: a round bottom flask was charged with N- (3- ((1R, 3r,5S,6 r) -6- (dimethylcarbamoyl) bicyclo [3.1.0] hex-3-yl) -1- (4-methoxybenzyl) -1H-pyrazol-5-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (200 mg, 395. Mu. Mol) and a stir bar. TFA (6 mL) was added and the solution was stirred at 75 ℃ for 5 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 100% in 18 min; the detector, UV 254nm, gave N- (5- ((1R, 3r,5S,6 r) -6- (dimethylcarbamoyl) bicyclo [3.1.0] hex-3-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (135.1 mg, 349.6. Mu. Mol, 88.6%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝387.20；HPLC tR＝9.742min。

¹ H NMR(400MHz,DMSO-d ₆ )δ10.55(s,1H),6.91(s,1H),6.68(s,1H),4.53(s,2H),4.15(s,3H),3.52(s,3H),3.44(td,J＝9.5,4.7Hz,1H),3.02(s,3H),2.91(s,3H),2.46(td,J＝9.7,9.2,4.5Hz,2H),2.07(dd,J＝13.9,3.4Hz,2H),2.00-1.93(m,2H),1.65(t,J＝3.1Hz,1H)。

Example 23

N- (5- ((1 s,3 r) -3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide and

n- (5- ((1R, 3S) -3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

4- (prop-1-en-2-yl) pyridazin-3-ols

Step 1: a round bottom flask was charged with 6-chloropyridazin-3 (2H) -one (10 g,1Eq,77 mmol), 4, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (23 g,1.8Eq,0.14 mol), potassium carbonate (32 g,3Eq,0.23 mol), dioxane/H2O (20 mL) and a stirring bar followed by evacuation and purging with nitrogen three times. Pd (dppf) Cl2 (2.8 g,0.05Eq,3.8 mmol) was added. The mixture was stirred at 100℃for 2 hours. The solution was concentrated. The crude material obtained was purified by flash chromatography (acetonitrile/water). Lyophilization afforded 4- (prop-1-en-2-yl) pyridazin-3-ol (4.0 g, 31%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝171.05HPLC tR＝0.725min。

4-isopropyl-pyridazin-3 (2H) -one

Step 2: a round bottom flask was charged with 4- (prop-1-en-2-yl) pyridazin-3-ol (4 g,1Eq,0.03 mol), pd/C (0.5 g), meOH (20 mL) and a stirring bar followed by evacuation and purging with hydrogen three times. The mixture was stirred at 25℃for 2 hours. The mixture was filtered, and the filtrate was concentrated to give 4-isopropylpyridazin-3 (2H) -one (3.7 g, 91%) as a yellow oil.

m/z(ES ⁺ )[M+H] ⁺ ＝139.10；HPLC tR＝0.675min。

3-chloro-4-isopropylpyridazine

Step 3: a round bottom flask was charged with 4-isopropylpyridazin-3-ol (3.7 g,1Eq,27 mmol), POCl3 (15 mL) and a stirring bar and the solution was stirred at 85℃for 4 hours. The reaction mixture was poured into ice water. The solution was extracted three times with EA. The organics were combined and concentrated. The crude material obtained was purified by flash chromatography (acetonitrile/water). Lyophilization afforded 3-chloro-4-isopropylpyridazine (3.8 g,24mmol, 91%) as a black oil.

m/z(ES ⁺ )[M+H] ⁺ ＝157.05；HPLC tR＝0.692min。

N- (1- (tert-butyl) -5- (cis-3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 5: the resealable reaction vial was charged with 3-chloro-4-isopropylpyridazine (205 mg,1.5eq,1.31 mmol), N- (1- (tert-butyl) -5- (cis-3-hydroxycyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (302 mg,1eq, 873. Mu. Mol), toluene (5 mL), t-Buona (0.25 g,3eq,2.62 mmol), BINAP (163 mg,0.3eq, 262. Mu. Mol), pd2 (dba) 3 (79.9 mg,0.1eq, 87.3. Mu. Mol) and stir bar, which was then evacuated and purged three times with nitrogen. The mixture was stirred at 100℃for 1 hour. The solution was concentrated. The crude material obtained was purified by flash chromatography (acetonitrile/water). Lyophilization afforded N- (1- (tert-butyl) -5- (cis-3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (183mg, 392 μmol, 44.9%) as a yellow amorphous oil.

m/z(ES ⁺ )[M+H] ⁺ ＝467.30；HPLC tR＝1.133min。

N- (5- (cis-3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 6: a round bottom flask was charged with N- (1- (tert-butyl) -5- (cis-3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazole-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (183mg, 1eq,392 μmol), FA (5 mL) and stir bar, and the solution was stirred at 75 ℃ for 3 hours. The solution was concentrated. The crude material obtained was purified by preparative HPLC (column CHIRALPAK IE, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH) ₃ MeOH) -HPLC, mobile phase B: etOH, dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 60% B to 60% B within 11 min; wavelength: 220/254nm; RT1 (min): 7.46; RT2 (min): 9.00; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 0.55mL; number of runs: 4) And (5) purifying. Concentration in vacuo afforded N- (5- (cis-3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (80 mg,0.19mmol, 50%) as a yellow amorphous oil.

m/z(ES ⁺ )[M+H] ⁺ ＝411.25；HPLC tR＝1.195min。

N- (5- ((1S, 3R) -3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide and N- (5- ((1R, 3S) -3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 7: n- (5- (cis-3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (80 mg,1Eq,0.19 mmol) was purified by chiral-HPLC (column CHIRALPAK IE, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH3-MeOH) - -, mobile phase B: etOH: DCM=1:1- -HPLC; flow: 20mL/min; gradient: 60% B to 60% B; wavelength: 220/254nm; RT1 (min): 7.46; RT2 (min): 9.00; sample solvent: etOH: DCM=1:1- -HPLC; injection volume: 0.55mL; run number: 4). Lyophilization afforded N- (5- ((1 s,3 r) -3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (31.2 mg,76.0 μmol, 39%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝411.15；HPLC tR＝0.655min。

N- (5- ((1 r,3 s) -3- ((4-isopropylpyridazin-3-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (30.1 mg,73.3 μmol, 38%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝411.15；HPLC tR＝0.663min。

Additional compounds prepared according to the methods of examples 22 and 23 are depicted in table 11 below.

Example 24

rel-N- (5- ((1 r,3 s) -3- ((5-isopropyl-1H-pyrazol-4-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

4-bromo-5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole

Step 1: a round bottom flask was charged with 4-bromo-5-isopropyl-1H-pyrazole (3 g,1Eq,0.02 mol), 4-toluenesulfonic acid (0.5 g,0.2Eq,3 mmol), 3, 4-dihydro-2H-pyran (2 g,1.5Eq,0.02 mol), THF (30 mL) and stirring bar. The solution was stirred at 50℃for 2 hours. The reaction mixture was concentrated in vacuo and the resulting crude material was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 25 min; detector, UV 220nm. Concentration in vacuo afforded 4-bromo-5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (2.9 g,11mmol, 70%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝272.95；HPLC tR＝0.722min。

(5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) boronic acid

Step 2: to a mixture of 4-bromo-5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (2.1 g,7.7 mmol) in THF (20 mL) was added dropwise n-BuLi (3 mL of a 2.5M solution in THF, 8 mmol) at-78 ℃ under nitrogen atmosphere. The mixture was stirred at-78 ℃ for 0.5 hours. Trimethyl borate (1.0 g,9.6 mmol) was added dropwise to the above mixture at-78 ℃. The resulting mixture was stirred at-78 ℃ for an additional 2 hours. The reactant is treated with NH ₄ Cl (saturated aqueous, 100 mL) was quenched and extracted with EA (3X 100 mL). The combined organic layers were washed with brine (2 x 100 ml), dried over Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 25 min; detector, UV 220nm. Lyophilization gave (5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) boronic acid (620 mg,2.60mmol, 34%) as a white solid for three days.

m/z(ES ⁺ )[M+H] ⁺ ＝239.10；HPLC tR＝0.649min。

5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-ol

Step 3: to a stirred solution of (5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) boronic acid (620 mg,2.60 mmol) in THF (8 mL) at 0deg.C was added dropwise H ₂ O ₂ (4 mL,30%, in H) ₂ O). The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was treated with H ₂ O (20 mL) was diluted and acidified with HCl (2N) and extracted four times with DCM (50 mL). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; a mobile phase, ACN in water, gradient from 10% to 50% in 10 min; the detector, UV 254nm, gave 5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-ol (500 mg,2.38mmol, 91.3%).

m/z(ES ⁺ )[M+H] ⁺ ＝211.00；HPLC tR＝0.637min。

N- (1- (tert-butyl) -3- (cis-3- ((5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 4: at 0℃under N ₂ To a stirred solution of N- (1- (tert-butyl) -3- (trans-3-hydroxycyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (200 mg,1Eq, 577. Mu. Mol), 5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-ol (121 mg,1Eq, 577. Mu. Mol) and triphenylphosphine (227 mg,1.5Eq, 866. Mu. Mol) in toluene (4 mL) with 4A MS was added dropwise DTBAD (199mg, 1.5Eq, 866. Mu. Mol) under an atmosphere. The resulting mixture was subjected to N at 40 ℃ ₂ Stirring is carried out for 4 hours under an atmosphere. The resulting mixture was filtered and the filter cake was washed with MeCN (5 x 3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the followingAnd (3) condition purification: column, C18 silica gel; a mobile phase, ACN in water, gradient from 10% to 50% in 10 min; the detector, UV 254nm, gave N- (1- (tert-butyl) -3- (cis-3- ((5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (102 mg,189 μmol, 32.8%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝539.50；HPLC tR＝1.096min。

N- (5- ((1S, 3R) -3- ((5-isopropyl-1H-pyrazol-4-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 5: a solution of N- (1- (tert-butyl) -3- (cis-3- ((5-isopropyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) oxy) cyclopentyl) -1H-pyrazol-5-yl) -2- (3-methylisoxazol-5-yl) acetamide (165 mg, 306. Mu. Mol) in FA (5 mL) was stirred at 90℃for 3 hours. The resulting mixture was concentrated to dryness and purified by reverse phase flash chromatography to give N- (5- ((1 s,3 r) -3- ((5-isopropyl-1H-pyrazol-4-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (55 mg,0.14mmol, 45%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝399.25；HPLC tR＝0.905min。

N- (5- (cis-3- ((5-isopropyl-1H-pyrazol-4-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (55 mg,0.14 mmol) was purified by preparative chiral-HPLC according to the following conditions: column: CHIRALPAK IG,2×25cm,5 μm; mobile phase a: hex (0.2% DEA) -HPLC, mobile phase B: meOH: dcm=1:1; flow rate: 20mL/min; gradient: 70% B to 70% B within 12 min; wavelength: 220/254nm; RT1 (min): 6.23; sample solvent: meOH: dcm=1:1; injection volume: 0.65mL; number of runs: 3. this yielded rel-N- (5- ((1 r,3 s) -3- ((5-isopropyl-1H-pyrazol-4-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (20 mg,50 μmol, 73%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝399.25；HPLC tR＝1.117min。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.25-11.74(m,2H),10.61(s,1H),7.27(s,1H),6.42-6.28(m,1H),6.22(s,1H),4.50(s,1H),3.82(s,2H),3.07(p,J＝8.7Hz,1H),2.91(d,J＝31.8Hz,1H),2.53(s,1H),2.20(s,3H),2.02(d,J＝7.6Hz,1H),1.87(d,J＝8.8Hz,2H),1.82-1.68(m,2H),1.15(dd,J＝7.0,2.7Hz,6H)。

N- (5- (cis-3- ((5-isopropyl-1H-pyrazol-4-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (55 mg,0.14 mmol) was purified by preparative chiral-HPLC according to the following conditions: column: CHIRALPAK IG,2×25cm,5 μm; mobile phase a: hex (0.2% DEA) -HPLC, mobile phase B: meOH: dcm=1:1; flow rate: 20mL/min; gradient: 70% B to 70% B within 12 min; wavelength: 220/254nm; RT2 (min): 9.18; sample solvent: meOH: dcm=1:1; injection volume: 0.65mL; number of runs: 3. this gave rel-N- (5- ((1 r,3 s) -3- ((5-isopropyl-1H-pyrazol-4-yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide (20 mg,50 μmol, 73%) as a white amorphous solid.

m/z(ES ⁺ )[M+H] ⁺ ＝399.25；HPLC tR＝1.121min。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.24-11.78(m,2H),10.61(s,1H),7.24(d,J＝39.1Hz,1H),6.37-6.13(m,2H),4.50(s,1H),3.82(s,2H),3.07(p,J＝8.8Hz,1H),2.87(s,1H),2.53(d,J＝2.0Hz,1H),2.20(s,3H),2.02(d,J＝7.3Hz,1H),1.87(d,J＝9.4Hz,2H),1.81-1.66(m,2H),1.15(dd,J＝7.0,2.7Hz,6H)。

Example 25

Rel- (1 r,3 s) -3- (3- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester; and

rel- (1R, 3S) -3- (3- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester of isopropyl carbamate

3- (chloromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester

3- (hydroxymethyl) -1H-pyrazole-5-carboxylic acid ethyl ester (20 g,1Eq,0.12 mol), SOCl were filled into resealable reaction vials ₂ (150 mL) and stir bar, followed by evacuation and purging with nitrogen three times. The mixture was stirred at 80℃for 1h. The reaction mixture was poured into crushed ice and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (10 g column; elution with PE/EA (ratio: 8/1)). Concentration in vacuo afforded 3- (chloromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester (20 g,0.11mol, 90%) as a colorless oil.

m/z(ES ⁺ )[M+H] ⁺ ＝189.10；HPLC tR＝0.869min。

3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid ethyl ester

m/z(ES ⁺ )[M+H] ⁺ ＝189.10；HPLC tR＝0.869min。

3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid

To a resealable reaction vial was added 3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid ethyl ester (12.8 g,1Eq,69.5 mmol) in MeOH (30 mL), naOH (4.17 g,52.1L,0.002 molar, 1.5Eq,104 mmol) in MeOH/H2O (2:1, 30 mL) to the above solution, and the mixture was stirred at 50℃for 2 hours. The reaction mixture was concentrated in vacuo and extracted with EA (20 ml). The aqueous phase was acidified to pH 5 with HCl (1M). The resulting mixture was extracted with EA (3X 50 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to give 3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid (4.3 g,28mmol, 40%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝157.10；HPLC tR＝0.140min。

N- (2, 2-dimethoxyethyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxamide

CDI (1.56 g,1.2Eq,9.61 mmol) was added in portions to a mixture of 3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid (1.25 g,1Eq,8.01 mmol) in MeCN (10 mL) at 25℃under nitrogen. The mixture was stirred at 60℃for 1-2h and 2, 2-dimethoxyethane-1-amine (842 mg,1Eq,8.01 mmol) was added. The mixture was stirred at 60℃for 2h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water. Concentration in vacuo afforded N- (2, 2-dimethoxyethyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxamide (1.4 g,5.8mmol, 72%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝244.20；HPLC tR＝0.644min。

7-hydroxy-2- (methoxymethyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one

The resealable reaction vial was charged with N- (2, 2-dimethoxyethyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxamide (1.4 g,1Eq,5.8 mmol), HCl (5M) (25 mL) and stirring bar were added, followed by evacuation and purging with nitrogen three times, and the mixture was stirred at 25℃for 3H. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; the mobile phase, meCN in water, 10%, was concentrated in vacuo to give 7-hydroxy-2- (methoxymethyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (1 g,5mmol, 90%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝198.15；HPLC tR＝0.259min。

2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4 (5H) -one

Into a round bottom flask was charged 7-hydroxy-2- (methoxymethyl) -6, 7-dihydropyrazolo [1,5-a ]]Pyrazin-4 (5H) -one (1 g,1Eq,5 mmol), toluene (20 mL) and stirring rod were added at 0deg.C 4A-Ms (0.2 g,1Eq,5 mmol), DMF (0.04 g,0.04mL,0.1Eq,0.5 mmol), SOCl ₂ (1 g,0.7mL,2Eq,0.01 mol). The solution was stirred at 80℃for 2 hours. The reaction mixture was filtered through a celite pad, the pad was washed with ACN, and the filtrate was concentrated in vacuo. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2- (methoxymethyl) pyrazolo [1,5-a ] as a yellow amorphous solid ]Pyrazin-4 (5H) -one (840 mg,4.69mmol, 90%).

m/z(ES ⁺ )[M+H] ⁺ ＝180.05；HPLC tR＝0.399min。

4-chloro-2- (methoxymethyl) pyrazolo [1,5-a ] pyrazines

Into a round bottom flask was charged 2- (methoxymethyl) pyrazolo [1,5-a]Pyrazin-4 (5H) -one (840 mg,1Eq,4.69 mmol), POCl ₃ (15 mL) and a stirring bar, and DMF (34.3 mg, 36.3. Mu.L, 0.1Eq, 469. Mu. Mol) was added, and the solution was stirred at 50℃for 16 hours. The reaction mixture was quenched with water. The crude material obtained was purified by flash chromatography (acetonitrile/water). Concentrated in vacuo to give 4-chloro-2- (methoxymethyl) pyrazolo [1,5-a ] as a brown amorphous solid]Pyrazine (600 mg,3.04mmol, 64.8%).

m/z(ES ⁺ )[M+H] ⁺ ＝198.00；HPLC tR＝0.696min。

1S, 3R) -3- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropyl carbamate

4-chloro-2-ethoxypyrazolo [1,5-a ]]Pyrazine (192 mg,1Eq, 973. Mu. Mol) and K ₂ CO ₃ (403 mg,3Eq,2.92 mmol) was added to a solution of (1S, 3R) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropyl carbamate (300 mg,1Eq, 973. Mu. Mol) in 1, 4-dioxane (10 mL). After bubbling nitrogen through the reaction mixture for 2 minutes, pd-PEPSI-IPentCl 2-methylpyridine (CAS number 1612891-29-8, 81.4mg,0.1Eq, 97.3. Mu. Mol) was added. The reaction mixture was heated at 80 ℃ with vigorous stirring for 16 hours. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 100% in 20 min; the detector, UV 220nm, gives (1S, 3R) -3- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1, 5-a) as a colorless oil ]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl cyclopentyl ester (60 mg,0.13mmol, 13%).

m/z(ES ⁺ )[M+H] ⁺ ＝470.40；HPLC tR＝0.628min。

(1R, 3S) -3- (3- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester of isopropyl carbamic acid

To a solution of (1S, 3R) -3- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropyl carbamate (55 mg,1Eq,0.12 mmol) was added FA (5 mL). The resulting solution was stirred at 80℃for 2h. LC/MS showed completion of the reaction mixture. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 10 min; the detector, UV 254nm, gave (1R, 3S) -3- (3- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester (30 mg, 72. Mu. Mol,61%,99% purity) as an off-white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝414.35；HPLC tR＝0.848min。

Cis-isopropylcarbamate 3- (3- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester (30 mg) was isolated by chiral separation (HPLC) using the following conditions (column: CHIRALPAK IG,2 x 25cm,5 μm; mobile phase a: hex (0.2% dea) -HPLC, mobile phase B: meOH: dcm=1:1; flow: 20mL/min; gradient: 30% B to 30% B over 20 min; wavelength: 220/254nm; rt1 (min): 10.43; sample solvent: meOH: DCM: 1:1; injection volume: 2.4mL; run number: 1) to give isopropylcarbamate rel- (1 r,3 s) -3- (3- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester (8.20.2 g, 99% isopropyl carbamate as a white solid, 2m, 99.3- ((2 m) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ester (8.2 g, 3- ((2.2% methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) as a white solid.

First eluting isomer:

m/z(ES ⁺ )[M+H] ⁺ ＝414.35；HPLC tR＝0.893min。

¹ H NMR(400MHz)12.10(s,1H),9.97(s,1H),8.02(d,J＝4.7Hz,1H),7.38(d,J＝4.8Hz,1H),7.28(s,1H),6.97(d,J＝7.7Hz,1H),6.62(s,1H),5.02(s,1H),4.56(s,2H),3.58(h,J＝6.6Hz,1H),3.33(s,4H),3.09(t,J＝8.9Hz,1H),2.10(m,1H),1.91(tt,J＝9.0,4.7Hz,1H),1.75(d,J＝9.4Hz,2H),1.04(dd,J＝6.7,2.6Hz,6H)。

second eluting isomer:

m/z(ES ⁺ )[M+H] ⁺ ＝414.35；HPLC tR＝0.899min。

¹ H NMR(400MHz)12.11(s,1H),9.97(s,1H),8.02(d,J＝4.7Hz,1H),7.38(d,J＝4.8Hz,1H),7.28(s,1H),6.97(d,J＝7.8Hz,1H),6.62(s,1H),5.02(s,1H),4.56(s,2H),3.58(h,J＝6.7Hz,1H),3.33(s,4H),3.13(m,1H),2.10(m,2H),1.91(tt,J＝8.9,4.7Hz,3H),1.04(dd,J＝6.6,2.7Hz,6H)。

example 26

4-chloro-2- (methoxymethyl) -4, 5-dihydropyrazolo [1,5-a ] pyrazines

3- (chloromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester

Step 1: the resealable reaction vial was charged with ethyl 3- (hydroxymethyl) -1H-pyrazole-5-carboxylate (20 g,1Eq,0.12 mol), SOCl2 (150 mL) and a stir bar, followed by evacuation and purging with nitrogen three times. The mixture was stirred at 80℃for 1h. The reaction mixture was poured into crushed ice and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue/crude product was purified by chromatography on silica gel (10 g column; elution with PE/EA (ratio: 8/1)). Concentration in vacuo afforded 3- (chloromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester (20 g,0.11mol, 90%) as a colorless oil.

3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid ethyl ester

Step 2: naOMe (6.3 g,1.1Eq,0.12 mol) in MeOH (15 mL) was added in portions to a mixture of ethyl 3- (chloromethyl) -1H-pyrazole-5-carboxylate (20 g,1Eq,0.11 mol) in MeOH (200 mL) at 0deg.C under nitrogen atmosphere. The mixture was stirred at 0deg.C for 10min. The mixture was then stirred at 50℃for 1h. The reaction mixture was concentrated in vacuo and taken up with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brineWashed, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 20 min; the detector, UV 250nm. Concentration in vacuo afforded 3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid ethyl ester (12.8 g,41mmol,39%,59% purity) as a colorless oil.

3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid

Step 3: to a resealable reaction vial was charged ethyl 3- (methoxymethyl) -1H-pyrazole-5-carboxylate (12.8 g,1eq,69.5 mmol) in MeOH (30 mL). To the above solution is added to MeOH/H ₂ NaOH (4.17 g,52.1mL,0.002 molar, 1.5Eq,104 mmol) in O (2:1, 30 mL) and the mixture was stirred at 50deg.C for 2 hours. The reaction mixture was concentrated in vacuo and extracted with EA (20 ml). The aqueous phase was acidified to pH 5 with HCl (1M). The resulting mixture was treated with EA (3X 50 ml)]) Extracted and subjected to anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to give 3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid (4.3 g,28mmol, 40%) as a white solid.

N- (2, 2-dimethoxyethyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxamide

Step 4: CDI (1.56 g,1.2Eq,9.61 mmol) was added in portions to a mixture of 3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid (1.25 g,1Eq,8.01 mmol) in MeCN (10 mL) at 25℃under nitrogen. The mixture was stirred at 60℃for 1-2h, after which 2, 2-dimethoxyethane-1-amine (842 mg,1Eq,8.01 mmol) was added. The mixture was stirred at 60℃for 2h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). Will be combinedIs washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, 10%. Concentration in vacuo afforded N- (2, 2-dimethoxyethyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxamide (1.4 g,5.8mmol, 72%) as a white solid.

7-hydroxy-2- (methoxymethyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one

Step 5: the resealable reaction vial was charged with N- (2, 2-dimethoxyethyl) -3- (methoxymethyl) -1H-pyrazole-5-carboxamide (1.4 g,1Eq,5.8 mmol) and HCl (5M) (25 mL) and a stirring bar were added, followed by evacuation and purging with nitrogen three times. The mixture was stirred at 25℃for 3h. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, 10%. Concentration in vacuo afforded 7-hydroxy-2- (methoxymethyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one (1 g,5mmol, 90%) as a white solid.

2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4 (5H) -one

Step 6: into a round bottom flask was charged 7-hydroxy-2- (methoxymethyl) -6, 7-dihydropyrazolo [1,5-a ]]Pyrazin-4 (5H) -one (1 g,1Eq,5 mmol), toluene (20 mL) and stirring rod were added at 0deg.C 4A-Ms (0.2 g,1Eq,5 mmol), DMF (0.04 g,0.04mL,0.1Eq,0.5 mmol) and SOCl ₂ (1 g,0.7mL,2Eq,0.01 mol) and the solution was stirred at 80℃for 2 hours. The reaction mixture was filtered through a celite pad, the pad was washed with ACN, and the filtrate was concentrated in vacuo. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2- (methoxymethyl) pyrazole as a yellow amorphous solidAnd [1,5-a ]]Pyrazin-4 (5H) -one (840 mg,4.69mmol, 90%).

4-chloro-2- (methoxymethyl) pyrazolo [1,5-a ] pyrazines

Step 7: into a round bottom flask was charged 2- (methoxymethyl) pyrazolo [1,5-a]Pyrazin-4 (5H) -one (840 mg,1Eq,4.69 mmol), POCl ₃ (15 mL) and stirring bar, and DMF (34.3 mg, 36.3. Mu.L, 0.1Eq, 469. Mu. Mol) was added. The solution was stirred at 50℃for 16 hours. The reaction mixture was quenched with water. The crude material obtained was purified by flash chromatography (acetonitrile/water). Concentrated in vacuo to give 4-chloro-2- (methoxymethyl) pyrazolo [1,5-a ] as a brown amorphous solid ]Pyrazine (600 mg,3.04mmol, 64.8%).

Example 27

Rel- (3R, 5R) -5- (3- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl carbamate and

rel- (3R, 5R) -5- (3- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl carbamate

(1- (tert-butyl) -3- ((2S, 4S) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamic acid benzyl ester

Step 1: a round bottom flask was charged with benzyl (1- (tert-butyl) -3- ((2S, 4S) -4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamate (1000 mg,1Eq,2.782 mmol), imidazole (568.2 mg,3Eq,8.347 mmol), T BS-Cl (1.048 g,2.5Eq,6.955 mmol) and stir bar. DMF (10 mL) was added and the solution was stirred at 25℃for 5 h. LC/MS showed the reaction was complete. The mixture was quenched with water. The reaction mixture was diluted with water (30 mL) and the aqueous phase was extracted three times with EA (80 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give benzyl (1- (tert-butyl) -3- ((2 s,4 s) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamate (1.2 g,2.0mmol,71%,78% purity) as a pale yellow oil.

1- (tert-butyl) -3- ((2S, 4S) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-amine

Step 2: benzyl (1- (tert-butyl) -3- ((2S, 4S) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamate (1.2 g,1Eq,2.5 mmol) and Pd/C (0.11 g,0.4Eq,1.0 mmol) in THF (10 mL) and EA (10 mL) were stirred at 25℃with H ₂ And (5) treating for 2 hours. LC/MS showed the reaction was complete. The reaction mixture was filtered, the solid was washed with ACN, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 30% to 70% in 10 min; detector, UV 254nm. Concentration in vacuo afforded 1- (tert-butyl) -3- ((2 s,4 s) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-amine (850 mg,2.4mmol,96%,97% purity) as a yellow oil.

N- (1- (tert-butyl) -3- ((2S, 4S) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) -2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-amine

Step 3: to 1- (tert-butyl) -3- ((2S, 4S) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl at 0deg.C ) To a stirred solution of 1H-pyrazol-5-amine (200 mg,1Eq, 589. Mu. Mol) in DMF (5 mL) was added 4A-Ms and NaH (141 mg,60% Wt,6Eq,3.53 mmol). The reaction was stirred at 0deg.C for 0.5h. At N ₂ Down to the above reactant added in DMF 4-chloro-2- (methoxymethyl) pyrazolo [1,5-a ]]Pyrazine (140 mg,1.2Eq, 707. Mu. Mol). The reaction was stirred at room temperature for 3h. LC/MS confirmed the completion of the reaction. The mixture was treated with NH ₄ Cl (aq) was quenched and extracted three times with EA (15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 60% gradient in 15 min; detector, UV 254nm, gives N- (1- (tert-butyl) -3- ((2S, 4S) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) -2- (methoxymethyl) pyrazolo [1,5-a ] as a pale yellow oil]Pyrazin-4-amine (210 mg,0.39mmol,67%,94% purity).

(3 s,5 s) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofuran-3-ol

Step 4: a round bottom flask was charged with N- (1- (tert-butyl) -3- ((2S, 4S) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) -2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-amine (210 mg,1Eq, 419. Mu. Mol) and a stirring rod. FA (4 mL) was added and the solution was stirred at 25 ℃ for 2h. LC/MS showed the reaction was complete. The resulting mixture was concentrated in vacuo and used directly in the next step. To a stirred solution of the residue in MeOH (4 mL) and water (1 mL) was added LiOH (100 mg,10Eq,4.19 mmol). The reaction was stirred at room temperature for 1h. LC/MS showed the reaction was complete. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 40% in 10 min; detector, UV 254nm. Concentrated in vacuo to give (3 s,5 s) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofuran-3-ol (130 mg,0.33mmol,79%,98% purity) as a pale yellow solid.

(3R, 5R) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate

Step 5: to (3S, 5S) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1, 5-a) at 0 DEG C]To a stirred solution of pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofuran-3-ol (125 mg,1eq,323 μmol) in DCM (4 mL) was added pyridine (76.8 mg,78.5 μl,3eq,970 μmol) and DMAP (3.95 mg,0.1eq,32.3 μmol). At N ₂ 4-nitrophenyl chloroformate (97.8 mg,1.5Eq, 485. Mu. Mol) in DCM was added to the above reaction. The reaction was stirred at room temperature for 16h. LC/MS showed the reaction was complete. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; a mobile phase, ACN in water, gradient from 10% to 50% in 10 min; the detector, UV 254nm, was concentrated in vacuo to give (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1, 5-a) carbonate as a pale yellow solid]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl tetrahydrofuran-3-yl ester (4-nitrophenyl) ester (64 mg,0.11mmol,33%,93% purity).

(3R, 5R) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl isopropyl carbamate

Step 6: the round bottom flask was charged with (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (4-nitrophenyl) ester (60 mg,1Eq,0.11 mmol), DIEA (42 mg, 57. Mu.L, 3Eq,0.33 mmol), propan-2-amine (9.6 mg,1.5Eq,0.16 mmol) and stir bar. 2Me-THF (3 mL) was added and the solution was stirred under nitrogen at 25℃for 16h. LC/MS showed the reaction was complete. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 20% to 60% in 10 min; the detector, UV 254nm, was concentrated in vacuo to give (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester (42 mg, 85. Mu. Mol,78%,95% purity) as a white oil.

(3R, 5R) -5- (5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl isopropyl carbamate

Step 7: into a round bottom flask was charged (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl isopropyl carbamate (40 mg,1Eq, 85. Mu. Mol) and a stirring rod. FA (2 mL) was added and the solution was stirred for 1h at 80 ℃. LC/MS showed the reaction was complete. The mixture was cooled to 25 ℃. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 10 min; the detector, UV 254nm, was concentrated in vacuo to give (3R, 5R) -5- (5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester (30 mg, 69. Mu. Mol,81%,95% purity) as a white solid.

Step 8: (3R, 5R) -5- (5- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl isopropyl carbamate (30 mg,1Eq, 72. Mu. Mol) was isolated by chiral separation (HPLC) using the following conditions: (column: DZ-CHIRALPAK IG-3, 4.6. Mu.m, 3.0 μm; mobile phase A: hex (0.2% DEA): (MeOH: DCM=1:1) =60:40; flow: 1mL/min; gradient: 0% B to 0% B; injection volume: 5. Mu.l mL) give the isopropyl carbamic acid rel- (3R, 5R) -5- (3- ((2- (methoxymethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester (8.2 mg, 20. Mu. Mol,54%,99.2% purity) as an off-white solid.

Example 28

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

(1- (tert-butyl) -3- ((2R, 4R) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamic acid benzyl ester

Step 1: a round bottom flask was charged with 1- (tert-butyl) -3- ((2R, 4R) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-amine (9.56 g,28.2 mmol), naHCO ₃ (11.8 g,141 mmol), meCN (100 mL) and a stir bar. Benzyl chloroformate (14.4 g,84.5 mmol) was then added at 0deg.C. The solution was stirred at 25℃for 16 hours. Concentrated in vacuo. The mixture was diluted with water (150 mL) and the aqueous phase was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo afforded (1- (tert-butyl) -3- ((2R, 4R) -4- ((tert-butyldimethylsilyl) oxy) tetrah-eral as a yellow oilBenzyl hydrofuran-2-yl) -1H-pyrazol-5-yl carbamate (22 g,23mmol,82%,50% purity) (crude). m/z (ES) ⁺ )[M+H] ⁺ ＝474.40；HPLC tR＝1.237min。

(1- (tert-butyl) -3- ((2R, 4R) -4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamic acid benzyl ester

Step 2: a round bottom flask was charged with benzyl (1- (tert-butyl) -3- ((2R, 4R) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamate (22 g,50% purity, 28 mmol), 4-toluenesulfonic acid (14 g,84 mmol) in ACN (200 mL) and a stir bar. The solution was stirred at 25℃for 2 hours. LCMS was normal. The resulting mixture was concentrated under vacuum. The mixture was neutralized to about pH 7. The reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted three times with EA (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was recrystallized from EA (100 ml) to give benzyl (1- (tert-butyl) -3- ((2 r,4 r) -4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamate (8.51 g,23.7mmol, 85%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝360.35；HPLC tR＝0.760min。

(1- (tert-butyl) -3- ((2R, 4R) -4- (((4-nitrophenoxy) carbonyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamic acid benzyl ester

Step 3: to a stirred solution of benzyl (1- (tert-butyl) -3- ((2 r,4 r) -4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamate (4.45 g,12.4 mmol) in DCM (40 mL) was added pyridine (2.94 g,37.1 mmol) and N, N-dimethylpyridin-4-amine (303 mg,2.48 mmol) at 0 ℃. At N ₂ To the above reaction was added 4-nitrophenyl chloroformate (3.74 g,18.6 mmol). The reaction was stirred at 25 ℃ for 4 hours. Will be spentThe mixture was concentrated in vacuo to give benzyl (1- (tert-butyl) -3- ((2 r,4 r) -4- (((4-nitrophenoxy) carbonyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamate (6.2 g,5.9mmol,48%,50% purity) as a pale yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝525.30；HPLC tR＝1.020min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5- (((benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 4: a round bottom flask was charged with benzyl (1- (tert-butyl) -3- ((2R, 4R) -4- (((4-nitrophenoxy) carbonyl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-5-yl) carbamate (6.2 g,12 mmol), 1-methylcyclopropane-1-amine hydrochloride (2.5 g,24 mmol), THF (60 mL), DIEA (6.1 g,8.2mL,47 mmol) and a stir bar. The solution was stirred at 25 ℃ under nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 10 min; detector, UV 254nm. Concentration in vacuo afforded (3 r,5 r) -5- (5- (((benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl (4.6 g,10mmol, 85%) carbamate as a white oil. m/z (ES) ⁺ )[M+H] ⁺ ＝457.35；HPLC tR＝0.694min。

Step 5: a solution of (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5- (((benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (9.2 g,20 mmol) in EA/THF=2:1 (90 mL) was bubbled nitrogen through the reaction mixture 3 times.Pd/C (920 mg) was then added. Thereafter let H ₂ Bubbling through the reaction mixture 3 times. The mixture was treated with H at room temperature ₂ Stirring for 3 hours. The mixture was evaporated and (1-methylcyclopropyl) carbamic acid (3 r,5 r) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (6.4 g,19mmol,94%,95% purity) was obtained as a white solid, which was used directly in the next step without purification. M/z (ES+) [ M+H ]] ⁺ ＝323.35；HPLC tR＝0.528min。

Example 29

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester

Step 1 to a stirred solution of ethyl 3- (hydroxymethyl) -1-methyl-1H-pyrazole-5-carboxylate (1 g,5 mmol) in MeCN (10 mL) at room temperature under nitrogen was added CuI (0.2 g,1 mmol). The mixture was heated to 50 ℃ and 2, 2-difluoro-2- (fluorosulfonyl) acetic acid (1 g,8 mmol) was added dropwise to MeCN over a period of 8 hours at 50 ℃. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 90% in 15 min; detector, UV 254nm. Concentration in vacuo afforded 3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (700 mg,2.99mmol, 60%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝235.00；HPLC tR＝0.836min。

3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxylic acid

Step 2. To a stirred solution of ethyl 3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxylate (700 mg,2.99 mmol) in MeOH (10 mL) was added LiOH (107 mg,4.48 mmol) in water (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 30min. The reaction was adjusted to ph=6 with 1N HCl. The resulting mixture was extracted with EtOAc (3X 10 mL). The organic phase was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 90% in 15 min; detector, UV 254nm. Concentration in vacuo afforded 3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxylic acid (610 mg,2.96mmol, 99.0%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝207.10；HPLC tR＝0.792min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 3. At room temperature under nitrogen atmosphere to [2170-88 ]]To a stirred solution of 3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxylic acid (120 mg,582 mmol) in EA (3 mL) was added (3 r,5 r) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester (188 mg,582 mmol), DIEA (7512 mg,5.82 mmol), T3P (2.96 g,50% Wt in EA, 4.66 mmol). The resulting mixture was stirred at 75 ℃ for 16 hours. The mixture was concentrated under reduced pressure and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 90% in 15 min; the detector, UV 254nm, was concentrated in vacuo to give (3R, 5R) -5- (1- (tert-butyl) -5- (3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (130 mg,255 μmo) carbamate as a yellow oil l,43.7％)。m/z(ES ⁺ )[M+H] ⁺ ＝511.45；HPLC tR＝0.838min。

Step 4. A stirred solution of (3R, 5R) -5- (1- (tert-butyl) -5- (3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (120 mg, 235. Mu. Mol) in FA (2 mL) was stirred at 75℃for 40min. The mixture was concentrated under reduced pressure. The mixture was purified by preparative HPLC (column: XBridge Shield RP OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 20% B to 43% B,43% B in 8 min; wavelength: 220nm; RT1 (min): 7.38 (1-methylcyclopropyl) carbamic acid (3 r,5 r) -5- (3- (3- ((difluoromethoxy) methyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester (24.9 mg,54.6 μmol,23.2%,99.6% purity) was obtained as a white solid. M/z (ES+) [ M+H ]] ⁺ ＝455.20；HPLC tR＝0.893min。 ¹ H NMR(400MHz,DMSO-d ₆ )12.51(s,1H),10.86(s,1H),7.51(s,1H),7.21(s,1H),6.99-6.49(m,2H),5.16(s,1H),4.86(s,3H),4.08(s,3H),3.85(s,2H),2.71(dd,J＝14.0,7.3Hz,1H),1.93(s,1H),1.25(s,3H),0.76-0.37(m,4H)。

Example 30

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxylic acid ethyl ester

To a stirred solution of ethyl 3- (hydroxymethyl) -1-methyl-1H-pyrazole-5-carboxylate (5 g,0.03 mol) in EtOAc (50 mL) was added potassium fluoride (5 g,0.08 mol), silver (I) triflate (0.01 kg,0.05 mol), selectfluor (0.01 kg,0.04 mol), 2-fluoropyridine (5 g,0.05 mol), and trifluoromethyl trimethylsilane (8 g,0.05 mol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 15 min; the detector, UV 254nm, was concentrated in vacuo to give ethyl 1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxylate (3 g,6mmol,20%,50% purity) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝253.15；HPLC tR＝1.279min。

1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxylic acid lithium

Step 2 to a stirred solution of ethyl 1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxylate (3 g,0.01 mol) in MeOH (30 mL) at room temperature under nitrogen was added LiOH (0.4 g,0.02 mol) in water (12 mL). The resulting mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 10% in 15 min; the detector, UV 254nm, was concentrated in vacuo to give lithium 1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxylate (1.5 g,6.7mmol, 60%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝225.10；HPLC tR＝1.589min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 3 to a solution of lithium 1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxylate (180 mg, 803. Mu. Mol) and (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (284 mg, 883. Mu. Mol) in ethyl acetate (6 mL) was added DIEA (1.04 g,8.03 mmol). T is added to the above reactant at 0 DEG C ₃ P (4.09 g,50% Wt, in EA, 6.42 mmol). The reaction was stirred at 75 ℃ overnight. The mixture was quenched with water, filtered and extracted with EA (3 x 20 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, 60% gradient in 8 min; the detector, UV 254nm, gave (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (400 mg, 757. Mu. Mol, 94.2%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝529.40；HPLC tR＝1.161min

To (3 r,5 r) -5- (1- (tert-butyl) -5- (1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (1-methylcyclopropyl) carbamate (595 mg,1.13 mmol) was added FA (10 mL). The reaction was stirred at 75℃for 3h. The mixture was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gelThe method comprises the steps of carrying out a first treatment on the surface of the Mobile phase, meCN in water, gradient from 50% to 60% in 8 min; detector, UV 254nm. Lyophilization afforded (3 r,5 r) -5- (3- (1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (384.4 mg,809 μmol,71.8%,99.4% purity) carbamate as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝473.10；HPLC tR＝0.871min。 ¹ H NMR(400MHz,DMSO-d ₆ )12.50(s,1H),10.90(s,1H),7.50(s,1H),7.29(s,1H),6.56(s,1H),5.12(s,3H),4.85(s,1H),4.10(s,3H),3.85(s,2H),2.77-2.69(m,1H),1.93(s,1H),1.25(s,3H),0.66 -0.39(m,4H)。

Example 31

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester compound 771

1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxylic acid ethyl ester

Step 1. To a stirred solution of ethyl 3- (hydroxymethyl) -1-methyl-1H-pyrazole-5-carboxylate (500 mg,2.71 mmol) in THF (20 mL) at 0deg.C under nitrogen was added 2, 2-trifluoroethyl triflate (1.89 g,8.14 mmol), naH (0.16 g,60% Wt,4.07 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (1X 10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 90% in 15 min; detector, UV 254nm. Concentration in vacuo gave 1-formazan as a yellow oilEthyl 3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxylate (310 mg,1.16mmol, 42.9%). m/z (ES) ⁺ )[M+H] ⁺ ＝267.25；HPLC tR＝0.879min

1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxylic acid ester

Step 2 to a stirred solution of ethyl 1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxylate (300 mg,1.13 mmol) in MeOH (5 mL) at room temperature under nitrogen was added LiOH (40.5 mg,1.69 mmol) in water (2 mL). The resulting mixture was stirred at room temperature for 40min. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 90% in 15 min; the detector, UV 254nm, was concentrated in vacuo to give lithium 1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxylate (200 mg, 840. Mu. Mol, 74.5%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝239.20；HPLC tR＝0.653min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 3 to a stirred solution of (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (264 mg, 819. Mu. Mol) in EA (10 mL) was added lithium (200 mg, 819. Mu. Mol), DIEA (1.06 g,8.19 mmol), T1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxylate under nitrogen atmosphere at room temperature ₃ P (4.17 g,50% Wt in EA, 6.55 mmol). The resulting mixture was stirred at 80℃for 90min. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3X 40 mL). Combining the organic mattersThe layers were washed with brine (1X 40 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 90% in 15 min; the detector, UV 254nm, was concentrated in vacuo to give (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (250 mg, 461. Mu. Mol, 56.2%) as a yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝543.35；HPLC tR＝0.878min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

Step 4. A stirred solution of (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (245 mg, 452. Mu. Mol) in FA (5 mL) was stirred at 80℃for 4 hours. The mixture was concentrated under reduced pressure. The mixture was purified by preparative HPLC (column: XBridge Shield RP OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 25% B to 45% B,45% B within 8 min; wavelength: 254nm; RT1 (min): 7.12 (1-methylcyclopropyl) carbamic acid (3 r,5 r) -5- (3- (1-methyl-3- ((2, 2-trifluoroethoxy) methyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester (129 mg,261 μmol,57.7%,98.3% purity) was obtained as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝487.20；HPLC tR＝1.399min。 ¹ H NMR(400MHz,DMSO-d ₆ )12.47(s,1H),10.86(s,1H),7.52(s,1H),7.17(s,1H),6.52(s,1H),5.16(s,1H),4.84(t,J＝7.4Hz,1H),4.61(s,2H),4.14-4.05(m,5H),3.84(d,J＝4.8Hz,2H),2.70(dt,J＝13.6,7.6Hz,1H),1.94(dd,J＝14.9,6.8Hz,1H),1.25(s,3H),0.61(d,J＝5.2Hz,2H),0.48(q,J＝4.7Hz,2H)。

Example 32

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxylic acid methyl ester

Step 1. A round bottom flask was charged with 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (400 mg,2.56 mmol), 1-trifluoro-2-iodoethane (640 mg,3.07 mmol), K ₂ CO ₃ (1.06 g,7.69 mmol) and a stirring bar. DMF (8 mL) was added and the solution was stirred at 100deg.C for 3 hours. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed three times with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give methyl 1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxylate (390 mg,1.4mmol,53%,83% purity) as a yellow amorphous solid. m/z (ES) ⁺ )[M+H] ⁺ ＝239.00；HPLC tR＝0.875min。

1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxylic acid

Step 2. 1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxylic acid methyl ester (380 mg,1.60 mmol) in THF (4 mL), and LiOH (115 mg, 4mL H) were charged to a round bottom flask ₂ O, 4.79 mmol) and stirring bar. The resulting solution was stirred at 25℃for 1 hour. Will beThe pH value of the mixture is adjusted to 6-7. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxylic acid (350 mg,1.2mmol,77%,79% purity) as a yellow amorphous solid. m/z (ES) ⁺ )[M+H] ⁺ ＝225.25；HPLC tR＝0.705min

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxamide) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

To a mixture of (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (198mg, 613. Mu. Mol), 1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxylic acid (200 mg, 705. Mu. Mol) and DIEA (317 mg,2.45 mmol) in EA (6 mL) was added dropwise T3P (780 mg of a 1M solution in EA, 50% Wt,1.23 mmol) under nitrogen. The mixture was stirred at 25℃for 3 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 100% in 20 min; the detector, UV 254nm, gave (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxamide) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (240 mg, 454. Mu. Mol, 74.1%) as a transparent amorphous solid. m/z (ES) ⁺ )[M+H] ⁺ ＝529.10；HPLC tR＝0.931min。

Step 4. A round bottom flask was charged with (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (235 mg, 445. Mu. Mol) and a stirring bar. FA (7 mL) was added and the solution was stirred at 75 ℃ for 4 hours. The mixture was concentrated in vacuo. The crude material obtained was purified by preparative HPLC (column XBridge Shield RP, 18OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 28% B to 48% B,48% B within 8 min; wavelength: 254nm; RT1 (min): 7.38 And (3) purifying. Lyophilization afforded (3 r,5 r) -5- (3- (1-methyl-3- (2, 2-trifluoroethoxy) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (183.7 mg,388.8 μmol, 87.5%) carbamate as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝473.05；HPLC tR＝1.018min。 ¹ H NMR(400MHz,DMSO-d ₆ )12.53(s,1H),10.82(s,1H),7.50(s,1H),6.62(d,J＝48.9Hz,2H),5.16(s,1H),4.80(q,J＝8.9Hz,3H),3.97(s,3H),3.85(s,2H),2.70(dt,J＝13.1,6.9Hz,1H),1.93(s,1H),1.25(s,3H),0.65-0.37(m,4H)。

Example 33

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (imidazo [1,2-c ] pyrimidin-5-ylamino) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (imidazo [1,2-c ] pyrimidin-5-ylamino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 1. 5-chloroimidazo [1,2-c ]]Pyrimidine (57.2 mg,1.2Eq, 372. Mu. Mol), K ₂ CO ₃ (129 mg,3Eq, 930. Mu. Mol) and xantphos (35.9 mg,0.2Eq, 62.0. Mu. Mol) were added to (1-methylcyclopropyl)) (3R, 5R) -5- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl carbamate (100 mg,1Eq, 310. Mu. Mol) in 1, 4-dioxane (5 mL). After bubbling nitrogen through the reaction mixture for 1 minute, pd was added ₂ (dba) ₃ (56.8 mg,0.2Eq, 62.0. Mu. Mol). The reaction mixture was heated at 80 ℃ with vigorous stirring for 16 hours. After cooling, the reaction was treated by adding 15mL of water and extracting with ethyl acetate, over Na ₂ SO ₄ Dried and evaporated in vacuo. The crude residue was purified by flash chromatography (mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 35mL/min; gradient: 30% B to 60% B) purification within 15 min; the solvent was evaporated to give the title compound (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (imidazo [1, 2-c) as a yellow solid]Pyrimidin-5-ylamino) -1H-pyrazol-3-yl-tetrahydrofuran-3-yl ester (70 mg,0.16mmol, 51%). m/z (ES) ⁺ )[M+H] ⁺ ＝440.40；HPLC tR＝0.592min

Step 2, (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (imidazo [1, 2-c)]A solution of pyrimidin-5-ylamino) -1H-pyrazol-3-yl-tetrahydrofuran-3-yl ester (50 mg,1Eq,0.11 mmol) in FA (7.5 mL) was divided equally into five portions. Five parts of the mixture were heated at 100℃for 1.5 hours. The product can be found in LCMS. 5 batches were pooled together for purification. After cooling, the reaction was evaporated in vacuo. The crude residue was purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 10% B to 35% B,35% B within 9 min; wavelength: 220nm; RT1 (min): 7.85,8.65 (min)) purification; lyophilization gives (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (imidazo) as a white solid[1,2-c]Pyrimidin-5-ylamino) -1H-pyrazol-5-yl-tetrahydrofuran-3-yl ester (4.3 mg, 11. Mu. Mol, 9.9%). m/z (ES) ⁺ )[M+H] ⁺ ＝384.15；HPLC tR＝0.741min。 ¹ H NMR(400MHz,DMSO-d6)δ12.51(s,1H),10.16(s,1H),8.37(s,1H),7.65(s,1H),7.57(s,1H),7.52(s,1H),6.98(s,1H),6.70(s,1H),5.18(s,1H),4.87(s,1H),3.86(s,2H),2.72(s,1H),1.97(s,1H),1.25(s,3H),0.61(s,2H),0.48(s,2H)。

Example 34

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- ((2- (difluoromethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

5- (difluoromethyl) -N- (2, 2-dimethoxyethyl) -1H-pyrazole-3-carboxamide

Step 1. To a mixture of 5- (difluoromethyl) -1H-pyrazole-3-carboxylic acid (2 g,0.01 mol) and CDI (3 g,0.02 mol) in MeCN (20 mL) was added dropwise 2, 2-dimethoxyethane-1-amine (4 g,0.04 mol) at 60℃for 1.5H. The mixture was stirred at 60℃for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (6 g column; elution with PE/EA (ratio: 1/1)). Concentration in vacuo afforded 5- (difluoromethyl) -N- (2, 2-dimethoxyethyl) -1H-pyrazole-3-carboxamide (5 g,0.02 mol) (crude) as a tan viscous gum. m/z (ES) ⁺ )[M+H] ⁺ ＝250.00；HPLC tR＝0.608min。

2- (difluoromethyl) -7-hydroxy-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one

Step 2. Charging a round bottom flask with 5- (difluoromethyl) -N- (2)2-Dimethoxyethyl) -1H-pyrazole-3-carboxamide (5 g,0.02 mol), HCl (5M, 50 mL) and stirring rod. The solution was stirred at 25℃for 3 hours. The precipitated solid was collected by filtration and washed with EA (3 x 10 ml) to give 2- (difluoromethyl) -7-hydroxy-6, 7-dihydropyrazolo [1,5-a ] as an off-white amorphous solid]Pyrazin-4 (5H) -one (2.4 g,12mmol, 60%). m/z (ES) ⁺ )[M+H] ⁺ ＝204.15HPLC tR＝0.173min。

2- (difluoromethyl) pyrazolo [1,5-a ] pyrazin-4 (5H) -one

Step 3 charging 2- (difluoromethyl) -7-hydroxy-6, 7-dihydropyrazolo [1,5-a ] into a round bottom flask]Pyrazin-4 (5H) -one (2.2 g,1Eq,11 mmol), polyphosphoric acid (20 mL) and a stir bar. The solution was stirred at 110℃for 1 hour. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 55% in 10 min; detector, UV 254nm, gives 2- (difluoromethyl) pyrazolo [1,5-a ] as an off-white amorphous solid ]Pyrazin-4 (5H) -one (1 g,5mmol, 50%). m/z (ES) ⁺ )[M+H] ⁺ ＝186.00HPLC tR＝0.600min。

4-chloro-2- (difluoromethyl) pyrazolo [1,5-a ] pyrazines

Step 4. Charging 2- (difluoromethyl) pyrazolo [1,5-a ] into a round bottom flask]Pyrazin-4 (5H) -one (1 g,1Eq,5 mmol), POCl3 (10 mL), DMF (0.04 g,0.1Eq,0.5 mmol) and stirring bar. The solution was stirred at 50℃for 16 hours. The reaction mixture was concentrated in vacuo. The reaction was poured into ice water and saturated NaHCO ₃ Ph=7 to 8 was adjusted and the aqueous phase was extracted three times with EA (30 mL). The combined organic layersWashed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 60% in 10 min; detector, UV 254nm, gives 4-chloro-2- (difluoromethyl) pyrazolo [1,5-a ] as an off-white amorphous solid]Pyrazine (540 mg,2.65mmol, 50%). m/z (ES) ⁺ )[M+H] ⁺ ＝204.15；HPLC tR＝0.603min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (difluoromethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 5 charging 4-chloro-2- (difluoromethyl) pyrazolo [1,5-a ] into a round bottom flask]Pyrazine (95 mg,0.47 mmol), DMF (2.5 mL), (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (0.15 g,0.47 mmol), cs ₂ CO ₃ (0.45g,1.4mmol)、Pd(dppf)Cl ₂ (38 mg, 47. Mu. Mol) and a stirring bar, followed by evacuation and purging with nitrogen three times. The mixture was stirred at 60℃for 2 hours. The reaction mixture was diluted with water (5 mL) and the aqueous phase was extracted three times with EA (15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 60% in 10 min; detector, UV 254nm, gives (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (difluoromethyl) pyrazolo [1, 5-a) as a yellow oil]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofuran-3-yl ester (87 mg,0.18mmol, 38%). m/z (ES) ⁺ )[M+H] ⁺ ＝490.10HPLC tR＝0.808min。

Step 6. Charging (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (difluoromethyl) pyrazolo [1, 5-a) into a round bottom flask]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofuran-3-yl ester (82 mg,0.17 mmol), FA (2 mL), and stir bar. The solution was stirred at 80 ℃ for 1 hour and concentrated. The crude material obtained was purified by preparative HPLC (column XBridge Prep OBD C, column 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 23% B to 46% B,46% B in 8 min; wavelength: 254nm; RT1 (min): 7.23 And (3) purifying. Lyophilization gives (3R, 5R) -5- (3- ((2- (difluoromethyl) pyrazolo [1, 5-a)) carbamic acid (1-methylcyclopropyl) as an off-white solid]Pyrazin-4-yl) amino) -1H-pyrazol-5-yl-tetrahydrofuran-3-yl ester (41 mg,95 μmol, 56%). M/z (ES+) [ M+H ]]+＝434.10；HPLC tR＝0.721min。 ¹ H NMR(400MHz,DMSO-d ₆ )12.43(s,1H),10.27(s,1H),8.16(s,1H),7.53(s,3H),7.20(d,J＝54.5Hz,1H),6.81(s,1H),5.17(s,1H),4.86(s,1H),3.86(s,2H),2.72(s,1H),1.95(s,1H),1.25(s,3H),0.61(s,2H),0.48(q,J＝4.9,4.4Hz,2H)。

Example 34

Additional compounds listed in table 12 were synthesized according to the procedure described herein.

Example 35

N- (5-cyclopentyl-4-fluoro-1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

3-cyclopentyl-2-fluoro-3-oxopropionitrile

Step 1 to a solution of cyclopentanecarbonyl chloride (390 mg, 365. Mu.L, 1Eq,3.00 mmol) and monofluoroacetonitrile (177 mg, 167. Mu.L, 1Eq,3.00 mmol) in THF (9 mL) was added LHMDS (1.00 g,6.00mL,1 molar, 2Eq,6.00 mmol) at-78 ℃. The reaction was slowly warmed to room temperature over 2 hours. The reaction was quenched with water and diluted with EtOAc (100 mL). The organic layer was washed with 10% citric acid (50 mL) followed by brine (50 mL). The crude was used directly in the subsequent step without any further purification.

1- (tert-butyl) -3-cyclopentyl-4-fluoro-1H-pyrazol-5-amine

Step 2 to a solution of tert-butylhydrazine hydrochloride (560 mg,1.5Eq,4.50 mmol) in EtOH (8 mL) was added NaOH (180 mg,1.5Eq,4.50 mmol). The reaction was stirred at room temperature for 50min, followed by the addition of 3-cyclopentyl-2-fluoro-3-oxopropionitrile (4636 mg,1Eq,3.00 mmol). The reaction was then stirred at reflux for more than 2 days. The reaction was concentrated and redissolved in DCM (50 mL). The resulting suspension was filtered and concentrated. The crude residue was then purified by a 24g silica gel column using a gradient of a mixture of EtOAc in heptane (0-40%) to give the title compound as a brown solid (213.4 mg,947.1 μmol, 31.6%). LC-MS (ESI) ⁺ )m/z:153.1(M+H) ⁺ 。

N- (1- (tert-butyl) -5-cyclopentyl-4-fluoro-1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

To a solution of 1- (tert-butyl) -5-cyclopentyl-4-fluoro-1H-pyrazol-3-amine (62.1 mg,1eq,276 μmol) in DCM (1.0 mL) was added 2- (3-methylisoxazol-5-yl) acetic acid (58.3 mg,1.5eq,413 μmol), DIPEA (107 mg,144 μl,3eq,827 μmol) and propylphosphonic anhydride (526 mg,489 μl,50% Wt,3eq,827 μmol) at ℃ was added. The reaction was stirred for 1 hour. The reaction was diluted with EtOAc (100 mL) and washed with 10% citric acid (50 mL), followed by brine (50 mL). The crude residue was then purified by a 12g silica gel column using a gradient of a mixture of EtOAc in heptane (0-100%) to give the title compound (44.7 mg,276 μmol, 49.7%). LC-MS (ESI) ⁺ )m/z:349.40(M+H) ⁺ 。

Step 4. N- (1- (tert-butyl) -5-cyclopentyl-4-fluoro-1H-pyrazol-3-yl) -2- (3-methylisoxazol-5-yl) acetylA solution of the amine (47.7 mg,1Eq, 137. Mu. Mol) in formic acid (1 mL) was stirred at 70 ℃. Concentrated and purified by preparative HPLC (20-50% ACN in water containing 0.1% FA) to give the title compound (27.2 mg,93.1 μmol, 68.0%) as a white solid. LC-MS (ESI) ⁺ )m/z:293.33(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ12.31(s,1H),10.06(s,1H),6.22(s,1H),3.84(s,2H),3.00(t,J＝8.4Hz,1H),2.20(s,3H),1.97(br,2H),1.83-1.47(m,6H)。

Example 36

N- (5-cyclopentylisothiazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

2- (5-bromoisothiazol-3-yl) isoindoline-1, 3-dione

Step 1. 5-bromoisothiazol-3-amine (168.2 mg,1Eq, 939.5. Mu. Mol), isobenzofuran-1, 3-dione (139.2 mg,1Eq, 939.5. Mu. Mol) in acetic acid (1 mL) was added to the vial. The reaction was stirred at 100 ℃ overnight. The crude was concentrated and used directly in the next step.

2- (5- (cyclopent-1-en-1-yl) isothiazol-3-yl) isoindoline-1, 3-dione

Steps 2 and 3 Vial 2- (5-bromoisothiazol-3-yl) isoindoline-1, 3-dione (290 mg,1Eq,0.939 mmol), pd (dppf) Cl) in a Mixed solvent of 1, 4-dioxane (4 mL) and Water (1 mL) ₂ (42.8 mg,0.07Eq, 65.7. Mu. Mol), 2- (cyclopent-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (273 mg,0.28mL,1.5Eq,1.41 mmol) and potassium carbonate (324 mg,2.5Eq,2.35 mmol). The resulting reaction mixture was stirred at 80℃for 3 hours. The reaction was diluted with DCM (50 mL) and taken up 10% citric acid (25 mL) was washed. The separated organic layer was concentrated and redissolved in AcOH (5 mL). The crude was stirred at 100℃for 3 hours. The reaction mixture was concentrated and purified by 24g silica gel column using a gradient of EtOAc in heptane (0-60%) to give the title compound (51.2 mg,173 μmol, 18.4%). LC-MS (ESI) ⁺ )m/z:297.22(M+H) ⁺ 。

2- (5-cyclopentylisothiazol-3-yl) isoindoline-1, 3-dione

Step 4. 2- (5- (cyclopent-1-en-1-yl) isothiazol-3-yl) isoindoline-1, 3-dione (57 mg,1Eq,0.19 mmol) in ethanol (5 mL) and ethyl acetate (5 mL) were subjected to Pd (OH) at 60℃at a flow rate of 1mL/min under a hydrogen pressure of 10 bar ₂ The H-cube of the cartridge lasted 7 hours. The crude was concentrated to give the title compound (14 mg, 47. Mu. Mol, 24%). LC-MS (ESI) ⁺ )m/z:299.17(M+H) ⁺ 。

5-Cyclopentylisothiazol-3-amine

Step 5 to a solution of 2- (5-cyclopentylisothiazol-3-yl) isoindoline-1, 3-dione (14 mg,1Eq, 47. Mu. Mol) in EtOH (0.5 mL) was added hydrazine (4.5 mg, 4.4. Mu.L, 3Eq,0.14 mmol). The reaction was stirred at 60℃for 3 hours. Filtered and washed with EtOAc. The crude was used directly in the next step.

N- (5-cyclopentylisothiazol-3-yl) -2- (3-methylisoxazol-5-yl) acetamide

Step 6 5-Cyclopentylisothiazol-3-amine (8.0 mg,1Eq, 48. Mu. Mol), 2- (3-methylisoxazol-5-yl) acetic acid (13 mg,2Eq, 95. Mu. Mol), 2,4, added to a vial in DCM (1 mL) at RT 6-tripropyl-1,3,5,2,4,6-trioxatriphosphohexane 2,4, 6-trioxide (0.12 g,0.11mL,50% Wt,4Eq,0.19 mmol) and DIPEA (25 mg, 33. Mu.L, 4Eq,0.19 mmol). The reaction was stirred for 1 hour. The reaction was diluted with EtOAc (10 mL) and washed with 10% citric acid (5 mL), followed by brine (5 mL). The crude residue was then purified by a 4g silica gel column using a gradient of a mixture of EtOAc in heptane (0-100%) to give the title compound (4.0 mg,0.01 μmol, 30%). LC-MS (ESI) ⁺ )m/z:292.27(M+H) ⁺ 。

Example 37

Isopropyl carbamic acid (1 r,3 s) -3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl ester

(1- (tert-butyl) -5- ((1S, 3R) -3- (((4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) carbamic acid benzyl ester

Step 1. N- { 1-tert-butyl-5- [ (1R, 3S) -3-hydroxycyclopentyl ] at 25 ℃]A mixture of benzyl-1H-pyrazol-3-yl } carbamate (500.0 mg,1.39 mmol), pyridine (335.0. Mu.L, 4.17 mmol), 4-nitrophenyl chloroformate (560.0 mg,2.78 mmol), and DMAP (16.9 mg, 139.0. Mu. Mol) in DCM (20.0 mL) was stirred for 12 hours. The mixture was washed with aqueous citric acid (20 mL, 10%), brine (20 mL), and dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give (1S, 3R) -3- (3- { [ (benzyloxy) carbonyl carbonate as a yellow oil ]Amino } -1-tert-butyl-1H-pyrazol-5-yl) cyclopentyl 4-nitrophenyl ester crude product (400.0 mg,55.0% yield) was used directly in the next step. LC-MS (ESI) ⁺ )m/z:523.4(M+H) ⁺ 。

(1R, 3S) -3- (3- (((benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl isopropyl carbamate

Step 2 (1S, 3R) -3- (3- { [ (benzyloxy) carbonyl carbonate]A mixture of amino } -1-tert-butyl-1H-pyrazol-5-yl) cyclopentyl 4-nitrophenyl ester (400.0 mg, 765.0. Mu. Mol), propan-2-amine (135.0 mg,2.29 mmol) and DIEA (295.0 mg,2.29 mmol) in THF (5.0 mL) was stirred at 60℃for 2 hours. The mixture was concentrated to give a residue which was purified by silica gel chromatography (ethyl acetate in petroleum ether = 0% to 30%) to give N- { 1-tert-butyl-5- [ (1 r,3 s) -3- { [ (propan-2-yl) carbamoyl as a yellow oil]Oxy } cyclopentyl]-benzyl 1H-pyrazol-3-yl } carbamate product (260.0 mg,76.9% yield). LC-MS (ESI) ⁺ )m/z:443.6(M+H) ⁺ 。

Isopropyl carbamic acid (1 r,3 s) -3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl ester

Step 3. N- { 1-tert-butyl-5- [ (1R, 3S) -3- { [ (propan-2-yl) carbamoyl]Oxy } cyclopentyl]A mixture of benzyl-1H-pyrazol-3-yl } carbamate (260.0 mg, 587.0. Mu. Mol) and Pd/C (50.0 mg,10% wet) in EtOAc (4.0 mL) was reacted at 20deg.C under H ₂ (15 Psi) for 12 hours. The mixture was filtered and the filtrate was concentrated to give (1 s,3 r) -3- (3-amino-1-tert-butyl-1H-pyrazol-5-yl) cyclopentyl ester product (150.0 mg,82.8% yield, crude) as a yellow oil, which was used directly in the next step. LC-MS (ESI) ⁺ )m/z:309.3(M+H) ⁺ 。

Isopropyl carbamic acid (1 r,3 s) -3- (1- (tert-butyl) -3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl ester

Step 4 (1S, 3R) -3- (3-amino-1- (tert-butyl) isopropylcarbamic acid) -1H-pyrazol-5-yl) cyclopentyl ester (110.0 mg, 356.6. Mu. Mol), 2-chloropyrimidine (49.0 mg, 428.0. Mu. Mol), xantPhos (41.3 mg, 71.3. Mu. Mol), pd ₂ (dba) ₃ (32.7 mg, 35.7. Mu. Mol) and Cs ₂ CO ₃ (232.4 mg, 713.3. Mu. Mol) in dioxane (4.0 mL) at 100deg.C under N ₂ Stirring is carried out for 12 hours under protection. The mixture was washed with ethyl acetate (20 mL) and H ₂ O (20 mL) dilution. The aqueous layer was separated and extracted with ethyl acetate (20 mL. Times.2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give a residue which is purified by silica gel chromatography (ethyl acetate in petroleum ether = 0% to 60%) to give the (1 s,3 r) -3- (1- (tert-butyl) -3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl carbamate product as a yellow solid (80.0 mg,58.0% yield). LC-MS (ESI) ⁺ )m/z:387.3(M+H) ⁺ 。

Step 5A mixture of (1R, 3S) -3- (1- (tert-butyl) -3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropyl carbamate (60.0 mg, 155.0. Mu. Mol) in TFA (2.0 mL) was stirred at 75deg.C for 4 hours. The mixture was concentrated to give a residue, which was purified by preparative HPLC (NH ₃ ·H ₂ O) purification gave the (1R, 3S) -3- (3- (pyrimidin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl ester product as a white solid (27.2 mg,53.0% yield). LC-MS (ESI) ⁺ )m/z:331.1(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δppm 11.92(s,1H),9.48(s,1H),8.41(d,J＝3.2Hz,2H),6.95(d,J＝6.8Hz,1H),6.76(s,1H),6.41(s,1H),5.00(s,1H),3.54-3.62(m,1H),3.05(s,1H),2.40-2.49(m,1H),2.01(s,1H),1.83-1.93(m,1H),1.73(d,J＝7.6Hz,2H),1.63(s,1H),1.03(d,J＝6.4Hz,6H)。

Additional compounds prepared according to the method of example 37 are depicted in table 13 below.

TABLE 13 additional exemplary Compounds

Example 38

Rel- (1S, 3R) -3- (5- (2- (methyl (7H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopropylcarbamate the rel- (1S, 3R) -3- (5- (2- (methyl (7H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl ester of cyclopropylcarbamic acid

Rel- (1R, 3S) -3- (5- (2-bromoacetamido) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropyl carbamate

Step 1 to a solution of rel 3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropyl carbamate (110 mg,1Eq, 357. Mu. Mol) in THF (3 mL) was added 2-bromoacetyl bromide (144 mg,2Eq, 713. Mu. Mol) and Na ₂ CO ₃ (75.6 mg,2Eq, 713. Mu. Mol). The mixture was stirred at room temperature for 2h. LCMS was normal. The mixture was evaporated, diluted with ethyl acetate (3×30 mL) and washed with water, taken up in Na ₂ SO ₄ Dried and evaporated in vacuo. The crude residue was purified by flash chromatography (mobile phase A: water, mobile phase B: ACN; flow: 60mL/min; gradient: 30% B to 45% B over 7 min); the solvent was evaporated to give the title compound rel-3- (5- (2-bromoacetamido) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl ester (103 mg,240 μmol, 67.3%) as a pale yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝429.00；HPLC tR＝1.131min。

Rel- (1R, 3S) -3- (1- (tert-butyl) -5- (2- (methyl (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl-isopropyl carbamate

Step 2. To an ice-cold solution of rel-3- (5- (2-bromoacetamido) -1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl (103 mg,1Eq, 240. Mu. Mol) in DMF (2 mL) was added NaH (28.8 mg,60% wt,3Eq, 720. Mu. Mol). After 30min, N-methyl-9- (tetrahydro-2H-pyran-2-yl) is added) -9H-purin-6-amine (61.6 mg,1.1Eq, 264. Mu. Mol). The mixture was stirred at room temperature for 3 hours. LCMS was normal. The mixture was quenched with water (3 mL) and extracted with ethyl acetate (3X 20 mL) over Na ₂ SO ₄ Dried and evaporated in vacuo. The crude residue was purified by flash chromatography (mobile phase A: water, mobile phase B: ACN; flow: 40mL/min; gradient: 10% B to 30% B over 7 min); the solvent was evaporated to give the title compound rel-3- (1- (tert-butyl) -5- (2- (methyl (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl ester (113 mg,194 μmol, 81.0%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝582.50；HPLC tR＝1.042min。

Rel- (1R, 3S) -3- (5- (2- (methyl (9H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl isopropyl carbamate

Step 3. A solution of rel-3- (1- (tert-butyl) -5- (2- (methyl (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl ester (5X 10mg,1Eq, 86. Mu. Mol) in FA (5X 1 mL) was heated at 80℃for 1 hour. After cooling to room temperature, the mixture was concentrated and purified by preparative HPLC (column: XB ridge preparative OBD C18 column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 18% B to 22% B) purification within 7 min. The solvent was evaporated to give the title compound rel-3- (5- (2- (methyl (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl ester (25 mg,48 μmol, 55%) as a pale yellow solid. m/z (ES) ⁺ )[M+H] ⁺ ＝442.20；HPLC tR＝0.583min。

Rel- (1R, 3S) -3- (5- (2- (methyl (7H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl isopropyl carbamate

Rel- (1S, 3R) -3- (5- (2- (methyl (7H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl isopropyl carbamate

Rel-3- (5- (2- (methyl (9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl carbamate (25 mg, 57. Mu. Mol) was purified by chiral-HPLC (column CHIRALPAK IG, 2X 25cm,5 μm; mobile phase A: hex (0.2% DEA) - -, mobile phase B: etOH: DCM=1:1- -HPLC; flow: 20mL/min; gradient: 40% B to 40% B over 17 min; wavelength: 220/254nm; RT1 (min): 11.49; RT2 (min): 14.64). Lyophilization afforded rel- (1R, 3S) -3- (5- (2- (methyl (7H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl ester (4.3 mg, 9.7. Mu. Mol, 34%) as a white solid.

m/z(ES ⁺ )[M+H] ⁺ ＝442.25；HPLC tR＝0.709min。

1H NMR(400MHz,DMSO)δ1.00(dd,J＝6.7,3.9Hz,5H),1.12-1.28(m,3H),1.54-1.69(m,4H),1.82-1.91(m,1H),1.97(d,J＝9.7Hz,1H),2.35(s,1H),3.02(s,3H),3.49-3.58(m,1H),3.72(s,2H),4.49(s,1H),4.97(s,1H),5.11(s,2H),6.25(s,1H),6.91(d,J＝7.9Hz,1H),8.10(s,1H),8.21(s,1H),10.48(s,1H),12.04(s,1H),13.01(s,1H)。

Lyophilization afforded rel- (1S, 3R) -3- (5- (2- (methyl (7H-purin-6-yl) amino) acetamido) -1H-pyrazol-3-yl) cyclopentyl ester (3.8 mg, 8.6. Mu. Mol, 30%) as a white solid.

m/z(ES+)[M+H]+＝442.25；HPLC tR＝0.728min。

1H NMR(400MHz,DMSO)δ1.00(dd,J＝6.7,3.8Hz,5H),1.16-1.28(m,4H),1.54(s,1H),1.67(t,J＝11.4Hz,2H),1.82-1.91(m,1H),1.97(d,J＝9.8Hz,1H),2.39(s,1H),3.03(d,J＝9.1Hz,3H),3.54(s,1H),3.76(s,2H),4.49(s,1H),4.97(s,1H),5.12(s,2H),6.25(s,1H),6.91(d,J＝7.7Hz,1H),8.10(s,1H),8.20(s,1H),10.48(s,1H),12.04(s,1H),13.01(s,1H)。

Example 39

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1-methyl-3- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

3-bromo-1-methyl-1H-pyrazole-5-carboxylic acid lithium

Step 1 to a stirred solution of methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (500 mg,1eq,2.28 mmol) in THF (5 mL) at room temperature under nitrogen atmosphere was added LiOH (104 mg,4.34mL,1 molar, 1.9eq,4.34 mmol) in water. The resulting mixture was stirred at 50℃for 0.5 h. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 10% in 15 min; the detector, UV 254nm, was concentrated in vacuo to give lithium 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (400 mg,1.9mmol, 60%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝207.07；HPLC tR＝0.992min。

Step 2 to a solution of lithium 1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxylate (25 mg,0.12 mmol) and (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester (49 mg,0.15 mmol) in ethyl acetate (1 mL) was added DIEA (160 mg,1.2 mmol). T is added to the above reactant at 0 DEG C ₃ P (620 mg,50% Wt, in EA, 0.98 mmol). The reaction was stirred at 75deg.C overnight. The mixture was quenched with water, filtered and extracted with EA (3 x 20 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, 60% gradient over 30 min; the detector, UV 254nm, gave (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (60 mg, 120. Mu. Mol, 97%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝509.37；HPLC tR＝1.41min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -3- (1-methyl-3- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

Step 3. Adding NiCl to an 8mL vial ₂ Diglyme (1.1 mg, 4.9. Mu. Mol), 4-di-tert-butyl-2, 2-bipyridine (1.3 mg, 4.9. Mu. Mol), hexafluorophosphoric acid (4, 4 '-di-tert-butyl-2, 2' -bipyridine) bis [3, 5-difluoro-2- (5-trifluoromethyl-2-pyridinyl-kN) phenyl-kC]Iridium (III) (1.1 mg, 0.98. Mu. Mol) and (3R, 5R) -5- (3- (3-bromo-1-methyl-1H-pyrazole-5-carboxamido) -1- (tert-butyl) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (1-methylcyclopropyl) carbamate (50 mg, 98. Mu. Mol). The reaction was capped and purged 3 times with nitrogen, then the solid was dissolved in 1, 4-dioxane (1.00 mL). To the solution were added all 1-bromo-2- (trifluoromethoxy) ethane (38 mg,26 μl,0.20 mmol), tris (trimethylsilyl) silane (24 mg,30 μl,1eq,98 μmol) and 2, 6-lutidine (32 mg,34 μl,3eq,0.29 mmol) while purging with nitrogen. The reactants were then inserted into a Merck photoreactor and reacted at 100% light intensity for 150 minutes. The reaction was filtered through a pad of celite, then concentrated and redissolved in DMSO and placed on the AccQ prep system. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, 60% gradient over 30 min; detection of UV 254nm to give (3R, 5R) -5- (1- (tert-butyl) -3- (1-methyl-3- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (4 mg, 7. Mu. Mol, 8%) m/z (ES) ⁺ )[M+H] ⁺ ＝543.48；HPLC tR＝1.47min。

To the (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- ((trifluoromethoxy) methyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (1-methylcyclopropyl) carbamate residue (5 mg, 7. Mu. Mol) was added FA (2 mL). The reaction was stirred at 75℃for 1h. The mixture was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 50% to 60% in 30 min; detector, UV 254nm. Lyophilization afforded (3 r,5 r) -5- (3- (1-methyl-3- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane (1.3 mg,2.7 μmol,26%,99.4% purity) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝487.31；HPLC tR＝1.288min。

Additional compounds prepared according to the method of example 39 are depicted in table 14 below.

TABLE 14 additional exemplary Compounds

Example 40

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- ((2- ((S) -1-methoxyethyl) pyrazolo

(3R, 5R) -5- (3- ((2- ((R) -1-methoxyethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester (1-methylcyclopropyl) carbamic acid

[1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester

4-chloro-2- (1-methoxyvinyl) pyrazolo [1,5-a ] pyrazines

Step 1. 4-Chloropyrazolo [1,5-a ]]A stirred solution of methyl pyrazine-2-carboxylate (1 g,1Eq,5 mmol) in THF (14 mL) was cooled to 0deg.C and taken under N ₂ The reaction was treated with tabie's Reagent (1 eq,9.4ml,0.5m in toluene). The reaction was stirred at 0deg.C for 30min. After 30 minutes, the solution was warmed to room temperature and stirred for 1h. The mixture was carefully quenched with (0.1N) NaOH solution at 0 ℃. The mixture was treated with hexane and the solids were removed by filtration through a pad of celite. The solid was washed with hexane and the filtrate was passed through a second pad of celite to remove any newly formed solids. The organic layer was taken up with Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, 53% gradient over 8 min; detector, UV 254nm, gives 4-chloro-2- (1-methoxyvinyl) pyrazolo [1,5-a ] as a white solid ]Pyrazine (460 mg,2.19mmol, 50%).

m/z(ES+)[M+H] ⁺ ＝210.20；HPLC tR＝0.887min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (1-methoxyvinyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 2, inN ₂ Downward 4-chloro-2- (1-methoxyvinyl) pyrazolo [1,5-a]To a stirred solution of pyrazine (100 mg,1Eq, 477. Mu. Mol) and (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (154 mg,1Eq, 477. Mu. Mol) in DMF (3 mL) was added Cs ₂ CO ₃ (463 mg,3Eq,1.43 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ Adducts (77.9 mg,0.2Eq, 95.4. Mu. Mol). The reaction was stirred at 80 ℃ overnight. The mixture was diluted with water and the aqueous phase was extracted with EA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 40% to 50% in 10 min; detector, UV 254nm, gives (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (1-methoxyvinyl) pyrazolo [1, 5-a) as a colorless oil]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofurane-3-yl ester (80 mg,0.16mmol, 34%). m/z (ES) ⁺ )[M+H] ⁺ ＝496.20；HPLC tR＝0.824min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (1-methoxyethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 3, in N ₂ Downward (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (1-methoxyvinyl) pyrazolo [1, 5-a)]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofuran-3-yl ester (230 mg,1Eq, 464. Mu. Mol) Pd/C (49.4 mg,1Eq, 464. Mu. Mol) was added to a stirred solution of THF (5 mL) and ethyl acetate (5 mL). The reaction was stirred at room temperature under H ₂ Stirred for 1h. The mixture was filtered and concentrated to give (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (1-methoxyethyl) pyrazolo [1, 5-a) as a colorless oil]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofuran-3-yl ester (160 mg,322 μmol, 69.3%). m/z (ES) ⁺ )[M+H] ⁺ ＝498.25；HPLC tR＝0.746min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5- ((2- (1-methoxyethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 4. To (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (1-methoxyethyl) pyrazolo [1, 5-a)]To pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofuran-3-yl ester (160 mg,1Eq, 322. Mu. Mol) was added FA (5 mL). The reaction was stirred at 80℃for 1h. The mixture was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, 51% gradient in 8 min; detector, UV 254nm, gives (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5- ((2- (1-methoxyethyl) pyrazolo [1, 5-a) as a colorless oil ]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofurane-3-yl ester (90 mg,0.20mmol, 63%). m/z (ES) ⁺ )[M+H] ⁺ ＝442.35；HPLC tR＝0.603min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- ((2- ((S) -1-methoxyethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- ((2- ((R) -1-methoxyethyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

Step 5 (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5- ((2- (1-methoxyethyl) pyrazolo [1, 5-a)]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofurane-3-yl ester (90 mg,1eq,0.20 mmol) was subjected to preparative chiral-HPLC (column: CHIRALPAK IG,2×25cm,5 μm; mobile phase a: hex (0.5% 2m NH3-MeOH) -HPLC, mobile phase B: etOH, dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 13mi50% B to 50% B within n; wavelength: 220/254nm; RT1 (min): 6.04; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 0.8mL; number of runs: 3). Lyophilization gives (3R, 5R) -5- (3- ((2- ((S) -1-methoxyethyl) pyrazolo [1, 5-a) carbamic acid (1-methylcyclopropyl) as a white solid]Pyrazin-4-yl) amino) -1H-pyrazol-5-yl-tetrahydrofuran-3-yl ester (28.9 mg,64.7 μmol,64%,98.9% purity). m/z (ES) ⁺ )[M+H] ⁺ ＝442.15；HPLC tR＝1.377min。1H NMR(400MHz,DMSO-d6)12.36(s,1H),10.00(s,1H),8.05(s,1H),7.53(s,1H),7.41-7.23(m,2H),6.79(s,1H),5.17(s,1H),4.84(s,1H),4.55(q,J＝6.5Hz,1H),3.85(s,2H),3.22(s,3H),2.68(s,1H),1.93(d,J＝15.3Hz,1H),1.47(d,J＝6.5Hz,3H),1.25(s,3H),0.61(s,2H),0.48(q,J＝4.6Hz,2H)。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5- ((2- (1-methoxyethyl) pyrazolo [1, 5-a)]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofurane-3-yl ester (90 mg,1eq,0.20 mmol) was subjected to preparative chiral-HPLC (column: CHIRALPAK IG,2×25cm,5 μm; mobile phase a: hex (0.5% 2m NH3-MeOH) -HPLC, mobile phase B: etOH, dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 50% B to 50% B within 13 min; wavelength: 220/254nm; RT2 (min): 9.67; sample solvent: etOH, dcm=1:1— HPLC; injection volume: 0.8mL; number of runs: 3). Lyophilization gives (3R, 5R) -5- (3- ((2- ((R) -1-methoxyethyl) pyrazolo [1, 5-a) carbamic acid (1-methylcyclopropyl) as a white amorphous solid]Pyrazin-4-yl) amino) -1H-pyrazol-5-yl-tetrahydrofuran-3-yl ester (31.1 mg,63.1 μmol,62%,89.6% purity). m/z (ES) ⁺ )[M+H] ⁺ ＝442.15；HPLC tR＝1.377min。 ¹ H NMR(400MHz,DMSO-d ₆ )12.36(s,1H),10.18(d,J＝131.9Hz,1H),8.05(s,1H),7.53(s,1H),7.42-7.17(m,2H),6.79(s,1H),5.17(s,1H),4.84(s,1H),4.55(q,J＝6.5Hz,1H),3.85(s,2H),3.22(s,3H),2.71(s,1H),1.96(s,1H),1.47(d,J＝6.5Hz,3H),1.25(s,3H),0.60(d,J＝5.1Hz,2H),0.48(q,J＝4.5Hz,2H)。

Example 41

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- ((2- (trifluoromethyl) imidazo [1,2-c ] pyrimidin-5-yl) amino) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

(1-methylcyclopropyl) carbamic acid (3R, 5S) -5- (3- ((2- (trifluoromethyl) imidazo [1,2-c ] pyrimidin-5-yl) amino) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

7-chloro-5- (methylthio) -2- (trifluoromethyl) imidazo [1,2-c ] pyrimidine

Step 1. A round bottom flask was charged with 6-chloro-2- (methylthio) pyrimidin-4-amine (5 g,1Eq,0.03 mol), DMF (20 mL), 3-chloro-1, 1-trifluoropropan-2-one (6 g,1.5Eq,0.04 mol) was added and the solution stirred at 120℃for 16 hours. The residue was concentrated in vacuo and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase (acetonitrile/water), gradient 0% to 100% in 45 min; detector, UV 254nm. Concentration in vacuo afforded 7-chloro-5- (methylthio) -2- (trifluoromethyl) imidazo [1,2-c ] as a yellow amorphous solid]Pyrimidine (3.4 g,13mmol, 40%). m/z (ES) ⁺ )[M+H] ⁺ ＝267.85；HPLC tR＝0.875min。

7-chloro-2- (trifluoromethyl) imidazo [1,2-c ] pyrimidin-5-ol

Step 2. Charging a round bottom flask with 7-chloro-5- (methylthio) -2- (trifluoromethyl) imidazo [1,2-c ]]Pyrimidine (3.4 g,1Eq,13 mmol), meOH: H ₂ O=2:1 (20 mL), liOH (1.2 g,4eq,51 mmol) was added and the solution was stirred at 25 ℃ for 3 hours. The pH of the reaction mixture was adjusted to 7-8 with 1N HCl solution. The residue was concentrated in vacuo and diluted with water (15 mL) and the aqueous phase extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo afforded 7-chloro-2- (trifluormethyl) as a brown amorphous solid Radical) imidazo [1,2-c]Pyrimidin-5-ol (2.9 g,12mmol, 96%). m/z (ES) ⁺ )[M+H] ⁺ ＝237.90；HPLC tR＝0.700min。

5, 7-dichloro-2- (trifluoromethyl) imidazo [1,2-c ] pyrimidine

Step 3. Charging a round bottom flask with 7-chloro-2- (trifluoromethyl) imidazo [1,2-c ]]Pyrimidin-5-ol (1 g,1Eq,4 mmol), POCl ₃ (15 mL), DIEA (3 g,4mL,5Eq,0.02 mol) was added and the solution was stirred at 80℃for 3 h. The solution was concentrated in vacuo and taken up with NaHCO ₃ The solution (0 ℃) was quenched and quenched with NaHCO ₃ The pH was adjusted to 7-8. The aqueous phase was extracted three times with EA (40 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo afforded 5, 7-dichloro-2- (trifluoromethyl) imidazo [1,2-c ] as a brown oil]Pyrimidine (840 mg,3.28mmol, 80%). m/z (ES) ⁺ )[M+H] ⁺ ＝255.90；HPLC tR＝0.842min。

5-bromo-7-chloro-2- (trifluoromethyl) imidazo [1,2-c ] pyrimidine

Step 4. Charging a round bottom flask with 5, 7-dichloro-2- (trifluoromethyl) imidazo [1,2-c ]]Pyrimidine (700 mg,1Eq,2.73 mmol), ACN (10 mL), TMSBr (837 mg,2Eq,5.47 mmol) was added and the solution was stirred at 40℃for 3 hours. The crude product was purified by chromatography on silica gel (10 g column; elution with PE/EA (ratio: 15/1)). Concentration in vacuo afforded 5-bromo-7-chloro-2- (trifluoromethyl) imidazo [1,2-c ] as a brown amorphous solid ]Pyrimidine (720 mg,2.40mmol, 87.6%). m/z (ES) ⁺ )[M+H] ⁺ ＝299.80；HPLC tR＝0.867min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((7-chloro-2- (trifluoromethyl) imidazo [1,2-c ] pyrimidin-5-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 5 charging a resealable reaction vial with 5-bromo-7-chloro-2- (trifluoromethyl) imidazo [1,2-c]Pyrimidine (550 mg,1Eq,1.83 mmol), DMF (5 mL), (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (885 mg,1.5Eq,2.75 mmol), potassium carbonate (1.01 g,4Eq,7.32 mmol), and PdCl were added ₂ (dppf) (201 mg,0.15Eq, 275. Mu. Mol). The resulting mixture was stirred at 80 ℃ for 2.5 hours under a nitrogen atmosphere. The residue was concentrated in vacuo and purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase (acetonitrile/water), gradient 0% to 100% in 45 min; detector, UV 254nm. Lyophilization gives (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((7-chloro-2- (trifluoromethyl) imidazo [1, 2-c) as a yellow amorphous solid]Pyrimidin-5-yl) amino) -1H-pyrazol-3-yl-tetrahydrofurane-3-yl ester (295 mg,0.33mmol,18%,60% purity). m/z (ES) ⁺ )[M+H] ⁺ ＝542.05；HPLC tR＝0.900min。

Step 6. Charging (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (trifluoromethyl) imidazo [1,2 c) into a round bottom flask]Pyrimidin-5-yl) amino) -1H-pyrazol-3-yl-tetrahydrofuran-3-yl ester (140 mg,1Eq, 276. Mu. Mol), FA (6 mL) was added, and the solution was stirred at 100℃for 16 hours. The residue was concentrated in vacuo and passed through a preparative HPLC (column: xselect CSH C18 OBD column 30 x 150mm 5 μm, n; mobile phase A): water (0.1% fa), mobile phase B: ACN; flow rate: 60mL/min; gradient: 32% B to 44% B,44% B within 8 min; wavelength: 254, a base plate; 220nm; RT1 (min): 6.5,7.48 (min)) purification. Lyophilization gives (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- ((2- (trifluoromethyl) imidazo [1, 2-c)) as an off-white amorphous solid]Pyrimidin-5-yl) amino) -1H-pyrazol-5-yl-tetrahydrofurane-3-yl ester (1.9 mg, 4.2. Mu. Mol,1.5%, m/z (ES) ⁺ )[M+H] ⁺ = 452.15; HPLC tr=1.178 min) and (3 r,5 s) -5- (3- ((2- (trifluoromethyl) imidazo [1, 2-c) carbamic acid (1-methylcyclopropyl) as a white amorphous solid ]Pyrimidin-5-yl) amino) -1H-pyrazol-5-yl-tetrahydrofurane-3-yl ester (2 mg, 4. Mu. Mol,2%, m/z (ES) ⁺ )[M+H] ⁺ ＝452.15；HPLC tR＝1.258min)。

Example 42

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

3- (bromodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylic acid methyl ester

3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylic acid methyl ester

Step 1. To a mixture of 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (400 mg,2.56 mmol), dioxane (5 mL) was added NaH (0.18 g,7.69 mmol) in portions at 25 ℃ under nitrogen atmosphere. The mixture was stirred at 25℃for 30min, followed by the addition of 2-bromo-2, 2-difluoroacetic acid sodium salt (608 mg,3.07 mmol). The mixture was stirred at 25℃for 30h. The solid was filtered off. The filtrate was concentrated in vacuo. HCl added to dioxane (5mL), and concentrated in vacuo. DCM (5 mL) and XeF were added ₂ (1.31 g,7.69 mmol) and the mixture was stirred at 25℃for 30min. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo afforded a mixture of methyl 3- (bromodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylate and methyl 3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylate (180 mg, 26.8%) as a yellow oil.

3- (bromodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylic acid methyl ester: m/z (ES) ⁺ )[M+H] ⁺ ＝224.95；HPLC tR＝0.875min。

3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylic acid methyl ester: m/z (ES) ⁺ )[M+H] ⁺ ＝240.90；HPLC tR＝0.875min。

1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxylic acid

3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylic acid

Step 2. A resealable reaction vial was charged with a mixture of methyl 1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxylate and methyl 3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylate (160 mg,0.70 mmol), naOH (0.86 mL,0.86 mmol), meOH (5 mL) and a stirring bar, followed by evacuation and purging with nitrogen three times, and the mixture was stirred at 25℃for 1H. The reaction mixture was treated with H ₂ O (20 mL) was diluted and the aqueous phase was extracted three times with EA (20 mL), then adjusted to pH 1-3 with 1M HCl, and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo afforded a mixture of 1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxylic acid and 3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylic acid (120 mg, 80%) as a colorless oil.

1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxylic acid: m/z (ES) ⁺ )[M+H] ⁺ ＝210.95；HPLC tR＝0.750min。

3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylic acid: m/z (ES) ⁺ )[M+H] ⁺ ＝226.90；HPLC tR＝0.750min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamide) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 3 to a mixture of 1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxylic acid and 3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxylic acid (109 mg,0.50 mmol), DIEA (0.41 g,0.55mL,3.1 mmol) and (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (0.10 g,0.31 mmol) in EA (5 mL) was added dropwise T at 0deg.C under nitrogen atmosphere ₃ P (1.60 g,50% wt,2.5mmol in EA). The mixture was stirred at 80℃for 2h. The reaction mixture was treated with H ₂ O (50 mL) was diluted and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo afforded a mixture (300 mg, crude) of (3 r,5 r) -5- (1- (tert-butyl) -5- (1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (1-methylcyclopropyl) carbamate and (3 r,5 r) -5- (1- (tert-butyl) -5- (3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (1-methylcyclopropyl) carbamate as a yellow oil.

(1-methylcyclopropyl) carbamic acid (3 r,5 r) -5- (1- (tert-butyl) -5- (1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester: m/z (ES) ⁺ )[M+H] ⁺ ＝515.15；HPLC tR＝1.158min。

(1-methylcyclopropyl) carbamic acid (3 r,5 r) -5- (1- (tert-butyl) -5- (3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester: m/z (ES) ⁺ )[M+H] ⁺ ＝531.10；HPLC tR＝1.178min。

Step 4. A resealable reaction vial was charged with a mixture (190 mg, crude), FA (5 mL) and stirring rod of (1-methylcyclopropyl) -carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- (trifluoromethoxy) -1H-pyrazol-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester and (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazol-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester, followed by evacuation and purging with nitrogen three times, and the mixture was stirred at 70℃for 1.5H. The reaction was concentrated in vacuo. The crude material obtained was purified by preparative HPLC (column XBridge Prep OBD C, column 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 25% B to 55% B,55% B in 7 min; wavelength: 220nm; RT1 (min): 7.27 And (3) purifying. Lyophilization afforded (3 r,5 r) -5- (3- (1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (38.6 mg, 22.8%) as a white amorphous solid. m/z (ES) ⁺ )[M+H] ⁺ ＝459.15；HPLC tR＝1.318min。 ¹ H NMR(400MHz,DMSO-d6)δ12.57(s,1H),7.52(s,1H),7.12(s,1H),6.54(s,1H),5.16(s,1H),4.84(t,J＝7.9Hz,1H),4.06(s,3H),3.84(d,J＝4.6Hz,2H),2.70(dt,J＝14.4,7.5Hz,1H),1.93(t,J＝10.3Hz,1H),1.25(s,3H),0.61(d,J＝5.1Hz,2H),0.48(q,J＝4.6Hz,2H)。

The resealable reaction vial was charged with a mixture (190 mg, crude), FA (5 mL) and stirring rod of (1-methylcyclopropyl) -5- (1- (tert-butyl) -5- (1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester and (3 r,5 r) -5- (1- (tert-butyl) -5- (3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl (1-methylcyclopropyl) carbamate, followed by evacuation and purging with nitrogen three times, and the mixture was stirred at 70 ℃ for 1.5H. The reaction was concentrated in vacuo. The crude material obtained was purified by preparative HPLC (column XBridge Prep OBD C, column 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 25% B to 55% B,55% B in 7 min; wavelength: 220nm; RT1 (min): 7.27 And (3) purifying. Lyophilization afforded (3 r,5 r) -5- (3- (3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (50 mg, crude) carbamate as a white amorphous solid. The crude material obtained was purified by preparative HPLC (column XBridge Prep OBD C, column 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: meOH-HPLC; flow rate: 60mL/min; gradient: 49% B to 67% B,67% B in 8 min; wavelength: 254nm; RT1 (min): 7.85 And (3) purifying. Lyophilization afforded (3 r,5 r) -5- (3- (3- (chlorodifluoromethoxy) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (9.3 mg, 21%) as a white amorphous solid. m/z (ES) ⁺ )[M+H] ⁺ ＝475.15；HPLC tR＝0.876min。 ¹ H NMR(400MHz,DMSO-d6)δ12.57(s,1H),11.03(s,1H),7.51(s,1H),7.17(s,1H),6.56(s,1H),5.16(s,1H),4.85(s,1H),4.07(s,3H),3.85(s,2H),2.70(dt,J＝14.0,7.2Hz,1H),1.93(s,1H),1.25(s,3H),0.62(s,2H),0.48(s,2H)。

Additional compounds prepared according to the method of example 42 are depicted in table 15 below.

TABLE 15 additional exemplary Compounds

Example 43

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1-methyl-3- ((S) -2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1-methyl-3- ((R) -2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

1-methyl-3- (2, 2-trifluoro-1-hydroxyethyl) -1H-pyrazole-5-carboxylic acid methyl ester

Step 1. A resealable reaction vial was charged with 3-formyl-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (500 mg,2.97 mmol), trimethyl (trifluoromethyl) silane (719 mg,5.06 mmol), TBAF (155 mg,0.60 mmol), THF (5 mL) and stirring bars, then evacuated and purged three times with nitrogen, and the mixture was stirred at 25℃for 3H. The reaction was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 10 min; detector, UV 254nm. Concentration in vacuo afforded 1-methyl-3- (2, 2-trifluoro-1-hydroxyethyl) -1H-pyrazole-5-carboxylic acid methyl ester (400 mg, crude) as a colorless oil. m/z (ES) ⁺ )[M+H] ⁺ ＝239.20；HPLC tR＝0.720min。

1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxylic acid methyl ester

Step 2. To a mixture of methyl 1-methyl-3- (2, 2-trifluoro-1-hydroxyethyl) -1H-pyrazole-5-carboxylate (390 mg,1.64 mmol) in DMF (5 mL) was added NaH (0.12 g,4.91 mmol) in portions at 0deg.C under nitrogen atmosphere. The mixture was stirred at 0deg.C for 5min, followed by the addition of methyl iodide (697 mg,4.91 mmol). The mixture was stirred at 25℃for 1h. The reaction solution was used directly in the next step. m/z (ES) ⁺ )[M+H] ⁺ ＝253.00；HPLC tR＝0.788min。

1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxylic acid

Step 3. NaOH (3.27 mL,3.27 mmol) was added to the above reaction solution and stirred at 25℃for 1h. The reaction mixture was treated with H ₂ O (20 mL) was diluted and the aqueous phase was extracted three times with EA (30 mL), then adjusted to pH 1-3 with 1M HCl, and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo afforded 1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxylic acid (180 mg, 46.2%) as a colorless oil. m/z (ES) ⁺ )[M+H] ⁺ ＝239.20；HPLC tR＝0.720min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 4. To 1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxylic acid (160 mg,0.67 mmol), DIEA (720 mg,5.58 mmol) and (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (180 mg, 0.56)mmol) to a mixture of EA (5 mL) was added dropwise T ₃ P (6.39 g,10.00 mmol). The mixture was stirred at 80℃for 2h. The reaction mixture was treated with H ₂ O (30 mL) was diluted and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo afforded (3 r,5 r) -5- (1- (tert-butyl) -5- (1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (400 mg, crude) as a yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝543.45；HPLC tR＝0.945min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

Step 5. The resealable reaction vial was charged with (3R, 5R) -5- (1- (tert-butyl) -5- (1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (380 mg,0.70 mmol), FA (5 mL) and stirring bar, followed by evacuation and purging with nitrogen three times, and the mixture was stirred at 75℃for 2H. The reaction was concentrated in vacuo. The crude material obtained was purified by preparative HPLC (column XBridge Shield RP, 18 OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 26% B to 44% B,44% B in 8 min; wavelength: 220nm; RT1 (min): 7.35 And (3) purifying. Lyophilization afforded (3 r,5 r) -5- (3- (1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (190 mg, 55.8%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝487.30；HPLC tR＝0.820min。

Step 6 (3R, 5R) -5- (3- (1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (189 mg,0.39 mmol) was prepared by chiral preparative HPLC (column CHIRALPAK IG, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH) ₃ MeOH) -HPLC, mobile phase B: etOH, dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 40% B to 40% B within 10 min; wavelength: 220/254nm; RT1 (min): 5.27; RT2 (min): 7.46; sample solvent: etOH: DCM = 1:1-HPLC; injection volume: 0.45mL; number of runs: 5) And (5) purifying. Lyophilization afforded (3 r,5 r) -5- (3- (1-methyl-3- ((S) -2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (47.5 mg, 50.3%) as an amorphous white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝487.20；HPLC tR＝0.948min。 ¹ H NMR(400MHz,DMSO-d6)δ12.50(s,1H),10.94(s,1H),7.50(s,1H),7.30(s,1H),6.56(s,1H),5.16(s,1H),5.03(q,J＝6.9Hz,1H),4.85(s,1H),4.11(s,3H),3.85(s,2H),3.35(s,3H),2.71(dd,J＝14.3,7.5Hz,1H),1.93(s,1H),1.25(s,3H),0.62(s,2H),0.48(q,J＝5.1,4.7Hz,2H)。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1-methyl-3- (2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane (189 mg,0.39 mmol) was purified by chiral preparative HPLC (column: CHIRALPAK IG, 2X 25cm,5 μm; mobile phase A: hex (0.5% 2M NH) ₃ MeOH) -HPLC, mobile phase B: etOH, dcm=1:1— HPLC; flow rate: 20mL/min; gradient: 40% B to 40% B within 10 min; wavelength: 220/254nm; RT1 (min): 5.27; RT2 (min): 7.46; sample solvent: etOH:DCM = 1:1-HPLC; injection volume: 0.45mL; number of runs: 5) And (5) purifying. Lyophilization afforded (3R, 5R) -5- (3- (1-methyl-3- ((R) -2, 2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (38.6 mg, 40.8%) as an amorphous white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝487.20；HPLC tR＝0.948min。 ¹ H NMR(400MHz,DMSO-d6)δ12.50(s,1H),10.94(s,1H),7.50(s,1H),7.30(s,1H),6.56(s,1H),5.16(s,1H),5.03(q,J＝7.0Hz,1H),4.85(s,1H),4.11(s,3H),3.85(s,2H),3.35(s,3H),2.71(dd,J＝14.4,7.4Hz,1H),1.93(s,1H),1.25(s,3H),0.62(s,2H),0.55(d,J＝13.0Hz,1H),0.48(q,J＝5.1,4.7Hz,2H)。

Example 44

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (3- (methoxymethyl) -1- (trifluoromethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

3- (chloromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester

Step 1. Filling a resealable reaction vial with ethyl 3- (hydroxymethyl) -1H-pyrazole-5-carboxylate (2.00 g,0.01 mol), SOCl ₂ (20 mL) and a stirring bar, followed by evacuation and purging with nitrogen three times, and the mixture was stirred at 80℃for 2h. The reaction was concentrated in vacuo. The residue was diluted with water and then adjusted to pH 6-7 with sodium bicarbonate. The aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo afforded 3- (chloromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester (2.20 g, crude) as a colorless oil. m/z (ES) ⁺ )[M+H] ⁺ ＝189.20；HPLC tR＝0.645min。

3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid ethyl ester

Step 2. NaOMe (0.82 g,15.00 mmol) was added in portions to a mixture of ethyl 3- (chloromethyl) -1H-pyrazole-5-carboxylate (2.20 g,12.00 mmol) in MeOH (20 mL) at 0deg.C under nitrogen. The mixture was stirred at 25℃for 12h. The reaction was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 10 min; detector, UV 254nm. Concentration in vacuo afforded 3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid ethyl ester (1.60 g, 74%) as a colorless oil. m/z (ES) ⁺ )[M+H] ⁺ ＝185.05；HPLC tR＝0.633min。

3- (methoxymethyl) -1- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester

Step 3. ClSO was added dropwise to SiO2-OH (34 mg,0.42 mmol) at 25℃under a nitrogen atmosphere ₃ H (49 mg,0.42 mmol). The mixture was stirred at 25℃for 2h. The resealable reaction vial was charged with 3- (methoxymethyl) -1H-pyrazole-5-carboxylic acid ethyl ester (600 mg,3.26 mmol), HDMS (10 mL) and stirring bar, then evacuated and purged three times with nitrogen, and the mixture was stirred at 125 ℃ for 2H. The solid was filtered off. The filtrate was concentrated in vacuo. DCM (10 mL) was added followed by 3, 3-dimethyl-1- (trifluoromethyl) -1, 3-dihydro-1 l 3-benzo [ d ]][1,2]Iodaxolane (iodoxole) (1.40 g,4.20 mmol), liNTf ₂ (0.15 g,0.51 mmol) and HNTf ₂ (0.14 g,0.51 mmol), followed by evacuation and purging with nitrogen three times, and the mixture was stirred at 40℃for 16h. The reaction was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 50% in 10 min; detector, UV 254nm. Concentration in vacuo afforded 3- (methoxymethyl) -1- (trifluoromethyl) as a colorless oilEthyl) -1H-pyrazole-5-carboxylate (140 mg, crude). m/z (ES) ⁺ )[M+H] ⁺ ＝253.005；HPLC tR＝0.867min。

3- (methoxymethyl) -1- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid

Step 4. The resealable reaction vial was charged with ethyl 3- (methoxymethyl) -1- (trifluoromethyl) -1H-pyrazole-5-carboxylate (180 mg,0.21 mmol), naOH (428. Mu.L, 428. Mu. Mol), meOH (5 mL) and stirring rod, then evacuated and purged three times with nitrogen, and the mixture was stirred at 25℃for 1H. The reaction mixture was treated with H ₂ O (20 mL) was diluted and the aqueous phase was extracted three times with EA (20 mL) followed by adjustment to pH 1-3 with 1M HCl. The aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo afforded 3- (methoxymethyl) -1- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid (50 mg, crude) as a colorless oil. m/z (ES) ⁺ )[M+H] ⁺ ＝225.05；HPLC tR＝0.567min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (3- (methoxymethyl) -1- (trifluoromethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 5 to a mixture of 3- (methoxymethyl) -1- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid (119 mg,0.53 mmol), DIEA (625 mg,4.84 mmol) and (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (156 mg,0.48 mmol) in EA (5 mL) was added dropwise at 0deg.C under nitrogen atmosphere ₃ P (4.92 g,50% wt,3.87mmol in EA). The mixture was stirred at 80℃for 12h. The reaction mixture was treated with H ₂ O (20 mL) was diluted and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfateDrying and filtering. Concentration in vacuo afforded (3 r,5 r) -5- (1- (tert-butyl) -5- (3- (methoxymethyl) -1- (trifluoromethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (200 mg, 78.2%) as a yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝529.10；HPLC tR＝0.850min。

Step 6. The resealable reaction vial was charged with (3R, 5R) -5- (1- (tert-butyl) -5- (3- (methoxymethyl) -1- (trifluoromethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester (250 mg,0.47 mmol), FA (5 mL) and stirring bar, followed by evacuation and purging with nitrogen three times, and the mixture was stirred for 3H at 70 ℃. The reaction was concentrated in vacuo. The crude material obtained was purified by preparative HPLC (column XBridge Prep OBD C, column 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 20% B to 45% B,45% B in 7 min; wavelength: 220nm; RT1 (min): 7.63 And (3) purifying. Lyophilization afforded (3 r,5 r) -5- (3- (3- (methoxymethyl) -1- (trifluoromethyl) -1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (86.8 mg, 38.8%) as an off-white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝473.15；HPLC tR＝0.903min。 ¹ H NMR(400MHz,DMSO-d6)δ12.58(s,1H),11.36(s,1H),7.52(s,1H),7.17(s,1H),6.55(s,1H),5.16(s,1H),4.85(s,1H),4.47(s,2H),3.85(s,2H),3.33(s,3H),2.74-2.66(m,1H),1.92(s,1H),1.24(s,3H),0.67-0.43(m,4H)。

Example 45

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- (1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxylic acid methyl ester

Step 1 to a mixture of methyl 1H-pyrazole-4-carboxylate (110 mg,0.87 mmol) in DMF (5 mL) was added 1-bromo-2- (trifluoromethoxy) ethane (252 mg,1.31 mmol) and K ₂ CO ₃ (362 mg,2.62 mmol). The mixture was stirred at 50℃for 1 hour. The reaction mixture was treated with H ₂ O (15 mL) was diluted and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo afforded methyl 1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxylate (170 mg, 81.8%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝238.95；HPLC tR＝0.742min。

1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxylic acid

Step 2. A resealable reaction vial was charged with methyl 1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxylate (160 mg,0.67 mmol) and NaOH (54 mg,1.34 mmol), meOH (4 mL) and a stirring bar, then evacuated and purged three times with nitrogen, and the mixture was stirred at 25℃for 1 hour. The reaction mixture was treated with H ₂ O (15 mL) was diluted and the aqueous phase was extracted three times with EA (30 mL). The pH of the aqueous layer was adjusted to 1-3 with 1M HCl. The aqueous layer was extracted with 3X 30mL ethyl acetate. The organic layers were combined, washed with brine and dried. Concentration in vacuo afforded 1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxylic acid (100 mg, 66.4%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝224.95；HPLC tR＝0.458min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxamide) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 3 to a mixture of 1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxylic acid (91 mg,0.41 mmol) in EA (5 mL) was added (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (110 mg,0.34 mmol) and DIEA (441 mg,3.41 mmol) at 0deg.C under nitrogen atmosphere, followed by dropwise addition of T ₃ P (2.6 g,50wt,2.04mmol in EA). The mixture was stirred at 80℃for 2.5h. The reaction mixture was treated with H ₂ O (15 mL) was diluted and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentrated in vacuo to give (3 r,5 r) -5- (1- (tert-butyl) -5- (1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxamido) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl (150 mg, 83.2%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝529.15；HPLC tR＝0.783min。

Step 4. The resealable reaction vial was charged with (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- (1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxamido) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (145 mg,0.27 mmol), FA (6 mL) and stirring bar, followed by evacuation and purging with nitrogen three times, and the mixture was stirred at 75℃for 1.5 hours. The reaction was concentrated in vacuo. The crude material obtained was purified by preparative HPLC (column: XBridge Shield RP, 18 OBD column, 30 x 150mm,5 μm; mobile phase a: water (10 mmol/L NH) ₄ HCO ₃ +0.1％NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 60mL/min; gradient: 20% B to 40% B,40% B within 8 min; wavelength: 254nm; RT1 (min): 7.57 And (3) purifying. Lyophilization afforded (3 r,5 r) -5- (3- (1- (2- (trifluoromethoxy) ethyl) -1H-pyrazole-4-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (72.1 mg, 55.6%) as a white amorphous solid. m/z (ES) ⁺ )[M+H] ⁺ ＝473.35；HPLC tR＝0.687min。 ¹ H NMR(400MHz,DMSO-d6)δ12.39(s,1H),10.49(s,1H),8.41(s,1H),8.13(s,1H),7.53(s,1H),6.54(s,1H),5.16(s,1H),4.81(s,1H),4.51-4.44(m,4H),3.84(s,2H),2.75(s,1H),1.91(s,1H),1.25(s,3H),0.61(s,2H),0.48(s,2H)。

Additional compounds prepared according to the method of example 45 are depicted in table 16 below.

TABLE 16 additional exemplary Compounds

Example 46

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- ((2- ((trifluoromethoxy) methyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester

4-bromo-2- (bromomethyl) pyrazolo [1,5-a ] pyrazines

Step 1. Directed to (4-Chloropyrazolo [1,5-a ] under nitrogen at 0deg.C]To a stirred solution of pyrazin-2-yl) methanol (2 g,1eq,0.01 mol) in MeCN (20 mL) was added PBr3 (4 g,2mL,1.5eq,0.02 mol). The resulting mixture was stirred at 70℃for 1 hour. The mixture was adjusted to ph=7 and extracted with EtOAc (3×40mL) And (5) extracting. The combined organic layers were washed with brine (1×40 mL) and dried over anhydrous Na2SO 4. After filtration, the filtrate was concentrated under reduced pressure to give 4-bromo-2- (bromomethyl) pyrazolo [1,5-a ] as a yellow solid]Pyrazine (1.5 g,5.2mmol, 50%). m/z (ES) ⁺ )[M+H] ⁺ ＝290.80；HPLC tR＝0.850min。

4-bromo-2- ((trifluoromethoxy) methyl) pyrazolo [1,5-a ] pyrazines

Step 2 to a stirred solution of silver fluoride (2.0 g,0.34mL,3Eq,15 mmol) in MeCN (30 mL) under nitrogen at-30C was added trifluoromethyl triflate (4.5 g,4Eq,21 mmol). The mixture was stirred at-30C for 1h. Followed by the addition of 4-bromo-2- (bromomethyl) pyrazolo [1,5-a ]Pyrazine (1.5 g,1Eq,5.2 mmol). The resulting mixture was stirred at 25℃for 16 hours. The resulting mixture was filtered. The residue was purified by silica gel chromatography using the following conditions: gradient of 0% to 25% in EtOAc in PE over 20min afforded 4-bromo-2- ((trifluoromethoxy) methyl) pyrazolo [1,5-a as a yellow oil]Pyrazine (600 mg,2.03mmol, 39%). m/z (ES) ⁺ )[M+H] ⁺ ＝295.80；HPLC tR＝0.848min。

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- ((trifluoromethoxy) methyl) pyrazolo [1,5-a ] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 3 to a stirred solution of (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (227 mg,1Eq,1.01 mmol) in 1, 4-dioxane (3 mL) at room temperature under nitrogen was added 4-bromo-2- ((trifluoromethoxy) methyl) pyrazolo [1,5-a]Pyrazine (300 mg,1Eq,1.01 mmol), K ₂ CO ₃ (420mg,3Eq,3.04mmol)、xantphos(235mg,0.4Eq,405μmol)、Pd ₂ (dba) ₃ (186 mg,0.2Eq, 203. Mu. Mol). The resulting mixture was stirred at 60℃for 1 hour. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient from 10% to 90% in 15 min; detector, UV 254nm. Concentration in vacuo afforded (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- ((trifluoromethoxy) methyl) pyrazolo [1, 5-a) as a yellow oil ]Pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofuran-3-yl ester (160 mg,298 μmol, 29.4%). m/z (ES) ⁺ )[M+H] ⁺ ＝538.15；HPLC tR＝0.888min。

Step 4. To (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- ((trifluoromethoxy) methyl) pyrazolo [1, 5-a)]To pyrazin-4-yl) amino) -1H-pyrazol-3-yl-tetrahydrofuran-3-yl ester (150 mg,1Eq, 279. Mu. Mol) was added FA (3 mL). The reaction was stirred at 70℃for 1 hour. The mixture was concentrated and purified by preparative HPLC (column XBridge Prep OBD C column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH4HCO 3), mobile phase B: ACN; flow 60mL/min; gradient: 18% B to 40% B within 8min, 40% B; wavelength: 254nm; RT1 (min): 6.65). Lyophilization gives (3R, 5R) -5- (3- ((2- ((trifluoromethoxy) methyl) pyrazolo [1, 5-a) carbamic acid (1-methylcyclopropyl) as a white solid]Pyrazin-4-yl) amino) -1H-pyrazol-5-yl-tetrahydrofuran-3-yl ester (12.5 mg,26.0 μmol, 9.30%). m/z (ES) ⁺ )[M+H] ⁺ ＝482.20；HPLC tR＝0.696min。 ¹ H NMR(400MHz,DMSO-d ₆ )12.39(s,1H),10.16(s,1H),8.10(s,1H),7.58-7.21(m,3H),6.80(s,1H),5.35(s,2H),5.17(s,1H),4.92(d,J＝49.7Hz,1H),3.86(s,2H),2.73(dd,J＝14.7,7.2Hz,1H),1.96(d,J＝11.2Hz,1H),1.25(s,3H),0.60(d,J＝5.3Hz,2H),0.48(q,J＝4.5Hz,2H)。

Additional compounds prepared according to the method of example 46 are depicted in table 16 below.

TABLE 16 additional exemplary Compounds

Example 47

(1-methylcyclopropyl) carbamic acid (3S, 5S) -5- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) thiazol-5-yl) tetrahydrofurane-3-yl ester

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) thiazol-5-yl) tetrahydrofurane-3-yl ester

(5- (1-hydroxybut-3-yn-1-yl) thiazol-2-yl) carbamic acid tert-butyl ester

Step 1. A dry three-necked flask (tricol flash) equipped with an outlet was charged with activated zinc (1.75 g,26.3 mmol) and anhydrous THF (60.0 mL) was added under argon. A solution of 80% propargyl bromide in toluene (2.83 mL,26.3 mmol) was added at room temperature. The mixture was then cooled to 0-5 ℃ and a 1M solution of titanium (IV) chloride in DCM (438 ul,438 μmol) was slowly added. (note: the mixture becomes warm and releases vapor). Slow addition was performed to allow vapor to exit the flask. Once the addition was complete, the ice bath was removed and the mixture was stirred for 20 minutes. A solution of tert-butyl (5-formylthiazol-2-yl) carbamate (2.00 g,8.76 mmol) in THF (24.0 mL) was then added dropwise over 20 min at room temperature and the mixture stirred for 2h. Pouring the mixture into ice/saturated NH ₄ To a Cl solution (30 mL) and EtOAc (70 mL) was added and the mixture was stirred for 5 min. The excess zinc was then removed by filtration through celite and rinsed with EtOAC (30 mL). The organic phase was saturated with NaHCO ₃ Solution (20 mL), brine (10 mL, 2X) washed, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. Hexane (20 mL) was added and the mixture was concentrated under reduced pressure. This procedure was repeated 3 times. Ether (20 mL) was then added and the mixture sonicated, followed by standing in a refrigerator for 3-4 hours. The yellow liquid phase was then removed and the mixture concentrated under reduced pressure, followed by drying via a pump, to give the title compound (1.8 g, 77%) as a pale yellow solid. ESI-MS (m/z+):213.1 [ M+H ]]. Rf (50% EtOAc/hexanes): 0.23. ¹ H NMR(400MHz,CDCl3):δ10.48(br s；1H)；7.29(s；1H)；5.07(q；J＝5.38Hz；1H)；2.76(dd；J＝6.13；2.62Hz；2H)；2.45(d；J＝4.56Hz；1H)；2.14(t；J＝2.58Hz；1H)；1.57(s；9H)。

(5- (4-oxo-tetrahydrofuran-2-yl) thiazol-2-yl) carbamic acid tert-butyl ester

Step 2. A dry vial was charged with tert-butyl (5- (1-hydroxybut-3-yn-1-yl) thiazol-2-yl) carbamate (1.50 g,5.59 mmol) and DCE (121 mL) was added under argon. 2-bromopyridine 1-oxide (1.95 g,11.2 mmol) was then added. The mixture becomes more soluble. Methanesulfonic acid (33.5 mL,6.71 mmol) was added in one portion. A solution was obtained. Then gold (I) bis (trifluoromethanesulfonyl) imide triphenylphosphine (211 mg,280 μmol) was added in one portion under argon and the solution was stirred at room temperature for 3h. The mixture was then concentrated under reduced pressure. EtOAc (70 mL) and saturated NaHCO were added ₃ Solution (30 mL). The phases were separated and the aqueous phase was extracted with EtOAc (30 ml,2 x). The combined organic phases were washed with water (20 mL), brine (10 mL), then Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The mixture was purified by column over 25g silica gel using a gradient of EtOAc in hexanes mixture (0-60%). The purified compound contains some impurities and is therefore wet-milled with ether. The solid was collected and placed on a pump to give the title compound (760 mg, 48%) as a pale yellow solid. ESI-MS (m/z+): 229.0[ M+H-tBu]。Rf：0.32(50％Hexane solution of EtOAc). ¹ H NMR(400MHz,CDCl3):δ10.91(s；1H)；7.29(s；1H)；5.51(t；J＝7.38Hz；1H)；3.98-4.18(m；2H)；2.87-2.93(m；1H)；2.66(dd；J＝17.90；8.06Hz；1H)；1.58(s；9H)。

Racemic (5- ((2S, 4S) -4-hydroxytetrahydrofuran-2-yl) thiazol-2-yl) carbamic acid tert-butyl ester

To a solution of tert-butyl (5- (4-oxotetrahydrofuran-2-yl) thiazol-2-yl) carbamate (700 mg,2.46 mmol) in anhydrous THF (10.0 mL) was added dropwise 1M Super-Hydride solution in THF (3.69 mL,3.69 mmol) under argon at-65 ℃ and the mixture was stirred at-65 ℃ to-70 ℃ for 1h. The mixture was then poured into ice/water/saturated NH ₄ Cl solution (20 mL) and extracted with EtOAc (100 mL). The organic phase was then treated with saturated NaHCO ₃ Solution (20 mL) followed by brine (10 mL), over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude compound was purified by column on silica gel using a mixture of EtOAC in hexanes (0-100%) to give the title compound as a white solid (550 mg, 78%). ESI-MS (M/z+):231.1 (main peak [ M+H-tBu) ]),287.1[M+H]. Rf:0.65 (10% MeOH in DCM). ¹ H NMR(400MHz,CDCl3):δ11.20(br s；1H)；7.26(s；1H)；5.11(t；J＝7.16Hz；1H)；4.57(br s；1H)；3.97-3.99(m；1H)；3.87(dd；J＝9.88；4.36Hz；1H)；2.61-2.68(m；1H)；2.07(dd；J＝13.97；5.66Hz；1H)；1.80-1.82(m；1H)；1.57(s；9H)。

Racemic ((5- ((2S, 4S) -4- (((4-nitrophenoxy) carbonyl) oxy) tetrahydrofuran-2-yl) thiazol-2-yl) carbamic acid tert-butyl ester

Step 4. Racemic (5- ((2S, 4S) -4-hydroxytetrahydrofuran-2-yl) thiazol-2-yl) carbamic acid tert-butyl ester (500 mg,1.75 mmol) at 0 ℃) To a stirred solution of pyridine (414 mg,5.24 mmol) and DMAP (42.7 mg, 349. Mu. Mol) in DCM (6 mL) was added. At N ₂ To the above reaction was added 4-nitrophenyl chloroformate (528 mg,2.62 mmol). The reaction was stirred at 25 ℃ for 16 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 40% to 70% in 15 min; detector, UV 254nm. Concentration in vacuo afforded tert-butyl carbamate (750 mg,1.5mmol,88%,92% purity) as a white oil of rac ((5- ((2 s,4 s) -4- (((4-nitrophenoxy) carbonyl) oxy) tetrahydrofuran-2-yl) thiazol-2-yl). m/z (ES) ⁺ )[M+H] ⁺ ＝452.25；HPLC tR＝0.915min。

Racemic (5- ((2S, 4S) -4- (((1-methylcyclopropyl) carbamoyl) oxy) tetrahydrofuran-2-yl) thiazol-2-yl) carbamic acid tert-butyl ester

Step 5. A round bottom flask was charged with tert-butyl racemic (5- ((2S, 4S) -4- (((4-nitrophenoxy) carbonyl) oxy) tetrahydrofuranyl-2-yl) thiazol-2-yl) carbamate (750 mg,1.66 mmol), DIEA (429 mg,3.32 mmol), 1-methylcyclopropan-1-amine hydrochloride (715 mg,6.65 mmol), THF (10 mL) and stirring bar. The solution was stirred at 25 ℃ under nitrogen atmosphere for 16h. LCMS showed the reaction was complete. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 30% to 60% in 15 min; detector, UV 254nm. Concentration in vacuo afforded tert-butyl racemic (5- ((2 s,4 s) -4- (((1-methylcyclopropyl) carbamoyl) oxy) tetrahydrofuran-2-yl) thiazol-2-yl) carbamate (450 mg,1.1mmol,65%,92% purity) as a pale yellow oil. m/z (ES) ⁺ )[M+H] ⁺ ＝384.35；HPLC tR＝0.790min。

(3S, 5S) -5- (2-aminothiazol-5-yl) tetrahydrofuran-3-yl racemic (1-methylcyclopropyl) carbamate

Step 6. A round bottom flask was charged with tert-butyl racemic (5- ((2S, 4S) -4- (((1-methylcyclopropyl) carbamoyl) oxy) tetrahydrofuran-2-yl) thiazol-2-yl) carbamate (350 mg, 913. Mu. Mol) and a stirring bar. TFA (3 mL) was added and the solution was stirred at 25 ℃ for 15min. The mixture was treated with saturated NaHCO ₃ The solution was neutralized to pH 7. The reaction mixture was diluted with water (10 mL) and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give (3 s,5 s) -5- (2-aminothiazol-5-yl) tetrahydrofuran-3-yl ester (250 mg,882 μmol, 96.7%) as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝284.20；HPLC tR＝0.464min。

(3S, 5S) -5- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) thiazol-5-yl) tetrahydrofurane-3-yl racemic (1-methylcyclopropyl) carbamate

To a mixture of lithium 3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxylate (56 mg,0.32 mmol), racemic (1-methylcyclopropyl) carbamic acid (3 s,5 s) -5- (2-aminothiazol-5-yl) tetrahydrofuran-3-yl ester (75 mg,0.26 mmol) and DIEA (0.44 g,3.4 mmol) in EA (3 mL) was added dropwise 2,4, 6-tripropyl-1,3,5,2,4,6-trioxatriphosphohexane 2,4, 6-trioxide (0.84 g,50% wt,1.3 mmol) under nitrogen atmosphere at 0 ℃. The mixture was stirred at 25℃for 3h. The reaction mixture was diluted with water (7 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (EA/DCM; ratio: 15/1) to give (3S, 5S) -5- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5) carbamic acid (1-methylcyclopropyl) as a white solid -carboxamide) thiazol-5-yl) tetrahydrofuran-3-yl ester (50 mg,0.11mmol, 43%). m/z (ES) ⁺ )[M+H] ⁺ ＝436.30；HPLC tR＝0.710min。

Step 8. Isolation of racemic (1-methylcyclopropyl) carbamic acid (3 s,5 s) -5- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) thiazol-5-yl) tetrahydrofurane-3-yl ester (50 mg,1eq,0.11 mmol) by chiral separation (HPLC) using the following conditions (column: DZ-CHIRALPAK IG-3,4.6 x 50mm,3.0 μm; mobile phase a: hex (0.2% DEA): etOH: dcm=1:1) =60:40; flow: 1mL/min; gradient: 0% B to 0% B; injection volume: 5ul mL) gives (3 s,5 s) -5- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) thiazol-5-yl) tetrahydrofurane-3-yl) carbamate (9.5 mg,20 μ,34% purity as a white solid. m/z (ES) ⁺ )[M+H] ⁺ ＝436.25；HPLC tR＝1.255min. ¹ H NMR(400MHz,DMSO-d6)12.62(s,1H),7.56(s,2H),7.28(s,1H),5.17(s,1H),5.04(t,J＝7.4Hz,1H),4.37(s,2H),4.11(s,3H),3.85(m,2H),3.28(s,3H),2.76(dt,J＝14.4,7.5Hz,1H),1.88(d,J＝11.3Hz,1H),1.25(d,J＝6.3Hz,3H),0.63(s,2H),0.49(s,2H)。

The (3 s,5 s) -5- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) thiazol-5-yl) tetrahydrofurane-3-yl ester (50 mg,0.11 mmol) was isolated by chiral separation (HPLC) using the following conditions (column: DZ-CHIRALPAK IG-3,4.6 x 50mm,3.0 μm, mobile phase a: hex (0.2% DEA): etOH: dcm=1:1) =60:40, flow rate: 1mL/min, gradient: 0% B to 0% B; injection volume: 5ul mL) to give [ ] as a white solid (-) a [ - ] mobile phase a: hex (0.2% DEA) (3R, 5R) -5- (2- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) thiazol-5-yl) tetrahydrofurane-3-yl 1-methylcyclopropyl) carbamate (9.3 mg, 21. Mu. Mol,18%,97.7% purity). m/z (ES) ⁺ )[M+H] ⁺ ＝436.20；HPLC tR＝1.250min ¹ H NMR(400MHz,DMSO-d6)12.62(s,1H),7.56(s,2H),7.28(s,1H),5.17(s,1H),5.04(t,J＝7.6Hz,1H),4.36(s,2H),4.10(s,3H),3.85(m,2H),3.27(s,3H),2.75(dt,J＝14.4,7.5Hz,1H),1.89(t,J＝11.0Hz,1H),1.25(d,J＝6.9Hz,3H),0.64(s,2H),0.50(q,J＝4.1Hz,2H)。

Example 48

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- ((2- (methoxymethyl) imidazo [1,2-c ] pyrimidin-5-yl) amino) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

(1-methylcyclopropyl) carbamic acid (3R, 5S) -5- (3- ((2- (methoxymethyl) imidazo [1,2-c ] pyrimidin-5-yl) amino) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl ester

7-chloro-5-hydroxyimidazo [1,2-c ] pyrimidine-2-carboxylic acid ethyl ester

Step 1. A round bottom flask was charged with 2, 6-dichloropyrimidin-4-amine (3 g,0.02 mol), ethyl 3-bromo-2-oxopropionate (9 g,0.05 mol) and a stirring bar. AcOH (32 mL) was added and the solution was stirred at 120deg.C for 3 hours. The mixture was concentrated in vacuo. The pH of the mixture was adjusted to 6-7. The aqueous phase was extracted three times with DCM (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (10 g column; elution with DCM/MEOH (ratio: 30/1)). In true senseConcentrating in the air. The precipitated solid was collected by filtration and washed with EA (20 mL) to give 7-chloro-5-hydroxyimidazo [1,2-c as a pale pink solid ]Pyrimidine-2-carboxylic acid ethyl ester (1.09 g,4.51mmol, 20%). m/z (ES) ⁺ )[M+H] ⁺ ＝242.05；HPLC tR＝0.467min。

5-Hydroxyimidazo [1,2-c ] pyrimidine-2-carboxylic acid ethyl ester

Step 2. 7-chloro-5-hydroxyimidazo [1,2-c ] at 25 ℃]A stirred mixture of pyrimidine-2-carboxylic acid ethyl ester (1.09 g,4.51 mmol) and Pd/C (120 mg,1.13 mmol) in MeOH (15 mL) was treated with H ₂ Treatment is carried out for 1 hour. The reaction mixture was filtered through a pad of celite, the pad was washed with MeOH (50 ml), and the filtrate was concentrated in vacuo to give 5-hydroxyimidazo [1,2-c ] as a yellow solid]Pyrimidine-2-carboxylic acid ethyl ester (910 mg,4.39mmol, 97.4%). m/z (ES) ⁺ )[M+H] ⁺ ＝208.05；HPLC tR＝0.615min。

2- (hydroxymethyl) imidazo [1,2-c ] pyrimidin-5-ols

Step 3. 5-Hydroxyimidazo [1,2-c ] under a nitrogen atmosphere at 0deg.C]To a mixture of pyrimidine-2-carboxylic acid ethyl ester (500 mg,2.41 mmol) in THF (15 mL) was added dropwise LAH (3.62 mL of a 1M solution in THF, 3.62 mmol). The mixture was stirred at 25℃for 12 hours. The mixture was treated with Na ₂ SO ₄ ·10H ₂ And O quenching. The reaction mixture was filtered and the pad was quenched with slightly hot DCM/MeOH=4/1 (100 ml) and MeOH/H ₂ O=4/1 (100 ml) and the filtrate was concentrated in vacuo to give 2- (hydroxymethyl) imidazo [1,2-c ] as a brown solid]Pyrimidin-5-ol (480 mg,2.91mmol, crude). m/z (ES) ⁺ )[M+H] ⁺ ＝166.05；HPLC tR＝0.233min。

2- (chloromethyl) imidazo [1,2-c ] pyrimidin-5-ol

Step 4. Charging 2- (hydroxymethyl) imidazo [1,2-c ] into a round bottom flask]Pyrimidine-5-ols (2.7 g,16 mmol), SOCl ₂ (19 g,12mL,0.16 mol), DMF (0.01 mL), toluene (30 mL), and a stir bar. The solution was stirred at 110℃for 5 hours. The mixture was concentrated in vacuo to give 2- (chloromethyl) imidazo [1,2-c ] as a brown solid]Pyrimidin-5-ol (2.1 g,11mmol, crude). m/z (ES) ⁺ )[M+H] ⁺ ＝184.00；HPLC tR＝0.565min。

2- (methoxymethyl) imidazo [1,2-c ] pyrimidin-5-ols

Step 5. Charging 2- (chloromethyl) imidazo [1,2-c ] into a round bottom flask]Pyrimidine-5-ol (2.1 g,11 mmol), sodium methoxide (10 g,11mL,30% Wt,57 mmol) and stir bar. MeOH (40 mL) was added and the solution was stirred at 25 ℃ for 16 hours. The mixture was concentrated in vacuo. The pH of the mixture was adjusted to 6-7 with 2M HCl. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 20% in 25 min; detector, UV 254nm, gives 2- (methoxymethyl) imidazo [1,2-c ] as a white amorphous solid]Pyrimidin-5-ol (380 mg,2.12mmol, 19%). m/z (ES) ⁺ )[M+H] ⁺ ＝180.05；HPLC tR＝0.432min

5-chloro-2- (methoxymethyl) imidazo [1,2-c ] pyrimidine

Step 6. Charging 2- (methoxymethyl) imidazo [1,2-c ] into a round bottom flask ]Pyrimidin-5-ol (380 mg,2.12 mmol), DIEA (5.48 g,7.39mL,42.4 mmol), POCl ₃ (25 mL) and a stirring bar. The solution was stirred at 100℃for 6 hours. The mixture was concentrated in vacuo. With NaHCO ₃ The pH of the mixture was adjusted to 6-7. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 50% in 18 min; detector, UV 254nm, gives 5-chloro-2- (methoxymethyl) imidazo [1,2-c ] as a white solid]Pyrimidine (320 mg,1.62mmol, 76.4%). m/z (ES) ⁺ )[M+H] ⁺ ＝198.00；HPLC tR＝0.656min

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) imidazo [1,2-c ] pyrimidin-5-yl) amino) -1H-pyrazol-3-yl) tetrahydrofurane-3-yl ester

Step 7. Charging (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) tetrahydrofuran-3-yl ester (470 mg,1.47 mmol), 5-chloro-2- (methoxymethyl) imidazo [1,2-c]Pyrimidine (320 mg,1.62 mmol), xantphos (426 mg, 736. Mu. Mol), pd ₂ (dba) ₃ (270mg,294μmol)、K ₂ CO ₃ (610 mg,4.42 mmol) and a stirring bar, followed by evacuation and purging with nitrogen three times. 1, 4-dioxane (8 mL) was added, and the mixture was stirred at 80 ℃ for 12 hours. The mixture was quenched with water (20 mL) and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, meCN in water, gradient 0% to 80% in 18 min; detector, UV 254nm, gives (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) imidazo [1, 2-c) as a white solid]Pyrimidin-5-yl) amino) -1H-pyrazol-3-yl-tetrahydrofurane-3-yl ester (260 mg, 538. Mu. Mol, 36.5%). m/z (ES) ⁺ )[M+H] ⁺ ＝484.30；HPLC tR＝0.913min。

Step 8. Charging (1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (1- (tert-butyl) -5- ((2- (methoxymethyl) imidazo [1, 2-c) into a round bottom flask ]Pyrimidin-5-yl) amino) -1H-pyrazol-3-yl-tetrahydrofurane-3-yl ester (300 mg, 620. Mu. Mol) and stirring bars. HCOOH (8 mL) was added and the solution was stirred at 100 ℃ for 5 hours. The pH of the mixture was adjusted to 6-7. The aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by preparative HPLC (column XBridge Shield RP, 18 OBD column, 30X 150mm,5 μm; mobile phase A: water (10 mmol/L NH) ₄ HCO ₃ ) Mobile phase B: ACN; flow rate: 60mL/min; gradient: 6% B to 32% B in 11min, 32% B to 40% B,40% B in 12 min; wavelength: 220nm; RT1 (min): 10.47/11.2) purification. Lyophilization gives (3R, 5R) -5- (3- ((2- (methoxymethyl) imidazo [1, 2-c) carbamic acid (1-methylcyclopropyl)) as a white solid]Pyrimidin-5-yl) amino) -1H-pyrazol-5-yl-tetrahydrofuran-3-yl ester (49.2 mg, 115. Mu. Mol, 18.6%) and (1-methylcyclopropyl) carbamic acid (3R, 5S) -5- (3- ((2- (methoxymethyl) imidazo [1, 2-c)]Pyrimidin-5-yl) amino) -1H-pyrazol-5-yl-tetrahydrofuran-3-yl ester (57.4 mg,134 μmol, 21.6%).

(1-methylcyclopropyl) carbamic acid (3R, 5R) -5- (3- ((2- (methoxymethyl) imidazo [1, 2-c) ]Pyrimidin-5-yl) amino) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester: m/z (ES) ⁺ )[M+H] ⁺ ＝428.20；HPLC tR＝1.218min。 ¹ H NMR(400MHz,DMSO-d6)δ12.51(s,1H),10.12(s,1H),8.31(s,1H),7.59(d,J＝37.8Hz,2H),7.08(d,J＝130.3Hz,1H),6.67(d,J＝245.9Hz,1H),5.17(s,1H),4.86(s,1H),4.50(s,2H),3.85(d,J＝5.0Hz,2H),3.35(s,3H),2.69(d,J＝14.6Hz,1H),2.02(d,J＝50.7Hz,1H),1.24(s,3H),0.60(d,J＝5.1Hz,2H),0.52-0.36(m,2H)。

(1-methylcyclopropyl) carbamic acid (3R, 5S) -5- (3- ((2- (methoxymethyl) imidazo [1, 2-c)]Pyrimidin-5-yl) amino) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl ester: m/z (ES) ⁺ )[M+H] ⁺ ＝428.20；HPLC tR＝1.306min。 ¹ H NMR(400MHz,DMSO-d6)δ12.57(s,1H),10.13(s,1H),8.31(s,1H),8.02-7.14(m,2H),6.92(d,J＝6.4Hz,1H),6.69(d,J＝251.5Hz,1H),5.25(s,1H),5.03(s,1H),4.50(s,2H),4.13(d,J＝15.7Hz,1H),3.74(d,J＝10.3Hz,1H),3.36(s,3H),2.30(d,J＝24.5Hz,2H),1.27(s,3H),0.69-0.59(m,2H),0.51(d,J＝5.3Hz,2H)。

Additional compounds prepared according to the method of example 48 are depicted in table 17 below.

TABLE 17 additional exemplary Compounds

Example 49

Compounds of the present disclosure were tested in a fluorescence-based microfluidic mobility shift assay (PerkinElmer) of CDK 2/cyclin E.

Active wild-type CDK 2/cyclin E complexes were purchased from Eurofins (14-475). Stock solutions of compounds were prepared in DMSO and serially diluted to 11 concentrations by 3-fold dilution. 200nL of compound was transferred to individual wells in 384 well plates (Greiner, 781201) followed by the addition of a solution of 15uL 1.3 Xenzyme and ATP containing 0.13nM CDK2/cyclin E and 2660uM ATP in 1 Xreaction buffer containing 10mM Hepes pH 7.5, 0.01% Brij-35, 10mM MgCl ₂ 1mM EGTA, 0.05% BSA and 2mM DTT. The compounds were incubated at room temperature for 30 minutes in the presence of CDK 2/cyclin E complex and ATP. Catalysis was initiated by adding a 5uL 4x peptide solution of 6uM fluorescently labeled substrate peptide (FL peptide 18 (amino acid sequence 5-FAM-QSPKKG, perkinElmer, 760362)) in 1x reaction buffer And (5) carrying out chemical reaction.

The final reaction components were 0.1nM CDK2/cyclin E, 2000. Mu.M ATP and 1.5. Mu.M FL peptide 18 and 1% DMSO. The reaction was incubated at room temperature for 20 hours and quenched with 75uL of stop solution containing 0.5M EDTA. Samples were analyzed using a LabChip EZ reader (PerkinElmer).

The CDK2 biochemical Caliper assay results are presented in Table 1. Will have an IC of less than or equal to 100nM ₅₀ The compounds of (a) are represented by "a"; will have an IC greater than 100nM but less than or equal to 250nM ₅₀ The compound of (a) is represented by "B"; will have an IC greater than 250nM but less than or equal to 1 μM ₅₀ The compounds of (a) are represented by "C"; and will have an IC greater than 1 μm but less than or equal to 100. Mu.M ₅₀ The compound of (2) is represented as "D".

Example 50

The compounds described herein were also tested in the nanoBRET TE intracellular kinase assay. Test compounds were prepared in DMSO stock solutions. 45uL of stock solution was transferred to 384 well plates (Greiner, 781201) and 3-fold 11-point dilution was performed. 293-NB2 cells expressing nanoLuciferase-labeled targets were diluted in cell growth medium (DMEM+10% FBS+1% penicillin/streptomycin medium) and 7.5E4 cells/mL of 40uL cell solution were seeded in individual 384 well cell culture plates and incubated at 37 ℃/5% CO ₂ Incubation was carried out overnight at 100% humidity. 2uL of 20 Xfull nanoBRET K-10 tracer (Promega nanoBRET) is added to each well of the cell plate except the control well. 80nL of each concentration of compound was transferred from the compound plate to the corresponding wells in the cell culture plate by an Echo550 liquid handler. The plates were incubated at 37℃at 5% CO ₂ Incubation was carried out for 2 hours at 100% humidity. 20uL of 3 Xfull Nano-Glo substrate and ECD NanoLuc inhibitor (Promega NanoBRET) were added to each well. Chemiluminescence was then read on an EnVision reader (PerkinElmer).

The Cell nanoBRET assay results are presented in table 1. Will have an IC of less than or equal to 100nM ₅₀ The compounds of (a) are represented by "a"; will have an IC greater than 100nM but less than or equal to 250nM ₅₀ The compound of (a) is represented by "B"; will have a pH of greater than 250nM but less thanOr 1 μm or more of IC ₅₀ The compounds of (a) are represented by "C"; and will have an IC greater than 1 μm but less than or equal to 100. Mu.M ₅₀ The compound of (2) is represented as "D".

Example 51

The compounds described herein were also tested in a cell proliferation selectivity assay. OVCAR3, HCC1569 and SKOV3 cell lines were obtained from ATCC and cultured as recommended by the supplier. COV318, COV504 and COV644 cell lines were obtained from Sigma-Aldrich and cultured as recommended by the supplier. Genetic background and dependence of each cell line was determined using publicly available databases (cbioPortal and DepMap). Cell lines (COV 318, OVCAR3 and HCC 1569) that were expanded against CCNE1 were found to be dependent on CDK2, whereas cell lines (SKOV 3, COV504, COV 644) that were wild-type for CCNE1 were found to be independent of CDK2. Given that CDK1 is an essential gene, all six cell lines are CDK1 dependent. By inoculating cells in a 384-well plate at a predetermined density (in the range of 150 to 1500 cells per well) in a corresponding medium, followed by brief centrifugation at 1000x g, and subjecting the cells to 5% CO at 37 ℃C ₂ Proliferation assays were performed by incubation for 24 hours. The following day, the compounds were serially diluted (11-point, 3-fold dilution regimen, maximum concentration of 20 μm) and dispensed directly onto cells using an Echo 555 acoustic liquid processor (labyte). The cells were incubated with the compound at 37℃with 5% CO ₂ Incubate for 120 hours. The relative number of living cells in each well was determined according to the manufacturer's protocol using the CyQUANT direct cell proliferation assay kit (Invitrogen). Plates were read on an EnVision 2105 multimode plate reader (Perkin Elmer) using FITC filter sets. Dose response curve fitting and IC using Genedata Screener software ₅₀ And (5) calculating. Proliferation selectivity (i.e., selectivity index) of individual compounds as ICs between each of their CDK 2-independent and CDK 2-dependent cell lines ₅₀ Average of the ratios.

The proliferation selectivity index values for the exemplary compounds are shown in table 18 below. As will be appreciated by those skilled in the art, a small increase in the magnitude of the proliferation selectivity index may be indicative of a substantially increased therapeutic index for treating a CDK2 mediated disorder.

TABLE 18 proliferation selectivity index values for exemplary Compounds

Incorporated by reference

All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the event of a conflict, the present application, including any definitions herein, will control.

Equivalents (Eq.)

While specific embodiments of the present disclosure have been discussed, the foregoing description is illustrative and not restrictive. Many variations of the disclosure will become apparent to those of ordinary skill in the art upon review of the specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification and such variations.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. A compound of the formula I-A,

or a pharmaceutically acceptable salt thereof, wherein:

q is L ¹ ；

z is hydrogen or L ² -R ^Z ；

w is hydrogen or Cy ^C ；

R ^A 、R ^B and R is ^C Each instance of (2) is independently R ¹ Or R is ² Wherein R is ^A Quilt R ³ Q of (2) ^A Example substitution，R ^B Quilt R ³ Q of (2) ^B Substituted by examples, and R ^C Quilt R ³ Q of (2) ^C Example substitution; or (b)

2. The compound of claim 1, wherein W is hydrogen.

3. The compound of claim 1, wherein W is Cy ^C 。

4. A compound according to any one of claims 1 to 3 wherein Z is selected from-OR ^Z 、-NHR ^Z -、-SR ^Z 、-NHC(O)NHR ^Z 、-OC(O)NHR ^Z and-NHC (O) OR ^Z 。

5. The compound of any one of claims 1-4, wherein R ^Z Is selected from C _1-6 Aliphatic groups and optionally substituted groups of saturated or partially unsaturated 3-to 7-membered carbocyclic rings.

6. A compound of the formula I,

or a pharmaceutically acceptable salt thereof, wherein:

q is L ¹ ；

p is hydrogen or-L ² -R ^P ；

R ^P Is R;

R ¹ is independently oxo, halogen, -CN, -NO ₂ 、-OR、-SR、-NR ₂ 、-S(O) ₂ R、-S(O) ₂ NR ₂ 、-S(O)R、-S(O)NR ₂ 、-C(O)R、-C(O)OR、-C(O)NR ₂ 、-C(NR)NR ₂ 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR ₂ 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(NR)R、-N(R)C(O)NR ₂ 、-N(R)C(NR)NR ₂ 、-N(R)S(O) ₂ NR ₂ 、-N(R)S(O)R、-N(R)S(O) ₂ R；

each R is independentlyHydrogen or an optionally substituted group selected from: c (C) _1-6 Aliphatic, saturated or partially unsaturated 3-to 7-membered carbocyclic ring, phenyl, 3-to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

7. A compound of formula II, III, IV, V, VI or VII,

or a pharmaceutically acceptable salt thereof, wherein:

q is L ¹ ；

x is selected from O, NR ^X And S;

y is selected from O, NR ^Y And S;

R ^X and R is ^Y Independently R;

p is hydrogen or-L ² -R ^P ；

R ^P Is R;

L ¹ and L ² Each of which is independently a covalent bond, or C _1-5 Saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently replaced by: -CH (R) ^L )-、-C(R ^L ) ₂ -、C _3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N (R) ^L )-、-NHC(O)-、-N(R ^L )C(O)-、-C(O)NH-、-C(O)N(R ^L )-、-NHS(O) ₂ -、-N(R ^L )S(O) ₂ -、-S(O) ₂ NH-、-S(O) ₂ N(R ^L ) -, -O-, -C (O) -, -OC (O) -, -C (O) O-, -S (O) -or-S(O) ₂ -; wherein said C _3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with R ¹ Or C _1-6 Aliphatic group substitution;

R ³ is independently oxo, halogen, -CN, -NO ₂ 、-OR、-SR、-NR ₂ 、-S(O) ₂ R、-S(O) ₂ NR ₂ 、-S(O)R、-S(O)NR ₂ 、-S(O) ₂ F、-OS(O) ₂ F、-C(O)R、-C(O)OR、-C(O)NR ₂ 、-C(NR)NR ₂ 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR ₂ 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(NR)R、-N(R)C(O)NR ₂ 、-N(R)C(NR)NR ₂ 、-N(R)S(O) ₂ NR ₂ 、-N(R)S(O)R、-N(R)S(O) ₂ R or an optionally substituted group selected from: c (C) _1-6 Aliphatic, phenyl, having 1-2 independent groupsA 3-7 membered saturated or partially unsaturated heterocyclic ring selected from heteroatoms selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

8. The compound of any one of claims 1 or 2-7, wherein Cy ^C Is a 5-6 membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen and sulfur.

9. The compound of any one of claims 1-8, wherein Q is selected from-NH-,wherein->Representation and Cy ^A Covalent bond of>Representing and W or Cy ^C Is a covalent bond of (c).

10. The compound of any one of claims 1-9, wherein Q is-NH-.

11. The compound of any one of claims 1-10, wherein Cy ^A Is a heteroarylene group having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.

12. The compound of any one of claims 1-11, wherein Cy ^A Selected from:

wherein->Represents a covalent bond with Q andrepresentation and Cy ^B Is a covalent bond of (c).

13. The compound of any one of claims 1-12, wherein Cy ^B Is a divalent 3-7 membered saturated or partially unsaturated carbocyclic ring.

14. The compound of any one of claims 1-12, wherein Cy ^B Selected from:

wherein->Representation and Cy ^A Covalent bond of>Representing a covalent bond with P, X or Z.

15. The compound of any one of claims 1-14, wherein R ^B Selected from-CH ₃ 、-CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ 、

16. The compound of any one of claims 1-15, wherein n is 0, 1, 2, 3, or 4.

17. The compound of any one of claims 2-16, wherein P is selected from-OR ^P 、-NHR ^P -、-SR ^P 、-NHC(O)NHR ^P 、-OC(O)NHR ^P and-NHC (O) OR ^P 。

18. The compound of any one of claims 2-17, wherein R ^P Is selected from C _1-6 Aliphatic groups and optionally substituted groups of saturated or partially unsaturated 3-to 7-membered carbocyclic rings.

19. The compound of any one of claims 1-18, wherein the compound is selected from those depicted in table 1, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound of any one of claims 1-19 and a pharmaceutically acceptable carrier.

21. A method of inhibiting CDK2 signaling activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-19 or a pharmaceutical composition of claim 20.

22. A method of treating a CDK2 mediated disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-19 or a pharmaceutical composition of claim 20.

23. A method of treating a disorder in a subject, wherein the disorder is ovarian cancer, endometrial cancer, gastric cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, gastric cancer, sarcoma cancer, liver cancer, esophageal cancer, laryngeal cancer, multiple myeloma, colorectal cancer, rectal cancer, skin cancer, or pancreatic cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-19 or a pharmaceutical composition of claim 20.

24. The method of claim 23, wherein the bladder cancer is urothelial cancer.

25. The method of claim 23, wherein the liver cancer is hepatocellular carcinoma.

26. The method of claim 23, wherein the lung cancer is lung squamous cell carcinoma or non-small cell lung cancer.

27. The method of claim 23, wherein the laryngeal carcinoma is laryngeal squamous cell carcinoma.

28. The method of claim 23, wherein the skin cancer is melanoma.