CN117396473A

CN117396473A - Imidazopyridinyl inhibitors of plasma kallikrein

Info

Publication number: CN117396473A
Application number: CN202280033913.6A
Authority: CN
Inventors: N·帕帕约安努; J·M·特拉文斯; S·J·芬克; J·M·埃拉德; A·雷
Original assignee: Takeda Pharmaceutical Co Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 2021-03-17
Filing date: 2022-03-16
Publication date: 2024-01-12
Also published as: WO2022197755A1; JP2024510502A; EP4308227A1

Abstract

The present invention provides compounds and compositions thereof that are useful as inhibitors of plasma kallikrein and exhibit desirable properties for the plasma kallikrein.

Description

Imidazopyridinyl inhibitors of plasma kallikrein

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional application No. 63/162,494, filed on 3/17 of 2021, which provisional application is incorporated herein by reference in its entirety.

I. Background of the invention

Plasma kallikrein (PKa) is a serine protease zymogen in the blood that is converted to its catalytically active form by factor XIIa and contributes to the innate inflammatory response and the intrinsic cascade of blood clotting. The mechanism leading to activation of this pathway in vivo includes interaction with polyphosphates released by activated platelets, and the absence of C1 inhibitors (C1-INH) as the primary physiological inhibitors of PKa. PKa mediated cleavage of high molecular weight kininogen results in potent vasodilators and pro-inflammatory nonapeptide Bradykinin (BK), which activates bradykinin 2 receptor. Subsequent cleavage of BK by carboxypeptidase yields des-Arg9-BK which activates the B1 receptor. Both B1 and B2 receptors are expressed by vascular, glial and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer as well as in the inner and outer nuclear layers. Activation of B1 and B2 receptors causes vasodilation and increases vascular permeability.

PKa is also associated with a number of disorders, such as Hereditary Angioedema (HAE), an autosomal dominant disease characterized by pain, unpredictable, recurrent inflammation affecting the hands, feet, face, abdomen, genitourinary tract and throat. The prevalence of HAE is not yet established, but it is estimated that there are about 1 out of every 50,000, with no known differences between races. HAE is caused by insufficient levels (type I) or dysfunctions (type II) of C1-INH that inhibit PKa, bradykinin and other serine proteases in the blood. Individuals with Hereditary Angioedema (HAE) lack C1-INH and therefore produce excessive bradykinin, which in turn causes painful, debilitating and possibly fatal swelling episodes. HAE may lead to mortality of up to 40% mainly due to obstruction of the upper airway if left untreated.

II summary of the invention

The present disclosure is based, at least in part, on the development of a variety of compounds that bind to and effectively inhibit the activity of plasma kallikrein. Accordingly, provided herein are compounds and uses thereof for targeting plasma kallikrein and/or treating plasma kallikrein mediated diseases and conditions, novel intermediates, and methods for preparing the compounds disclosed herein. The present disclosure also extends to pharmaceutical compositions comprising any of the compounds, as well as to the use of the compounds or compositions herein for the treatment, in particular the treatment, of autoimmune diseases such as HAE.

In some embodiments, the invention provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein Cy ^A 、Cy ^B 、L、L’、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ And R is ⁸ Whether defined individually or in combination, and described in classes and subclasses herein. In certain embodiments, the present invention provides compounds of formula (I) -formula (VI-c) as defined and described in classes and subclasses herein.

In some embodiments, the invention also provides methods of using compounds of formula (I) -formula (VI-c).

Advantageously, the compounds of the present disclosure have therapeutic activity and adequate levels of bioavailability and/or adequate half-life for use as therapeutic agents.

III, detailed description of the invention

A. Definition of the definition

The compounds of the present invention include those generally described above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions will apply unless otherwise indicated. For the purposes of the present invention, the 75 th edition identifies the chemical element according to the CAS version of the periodic Table of the elements, handbook of Chemistry and Physics. In addition, general principles of organic chemistry are described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999 and "March's Advanced Organic Chemistry", 5 th edition, editions: smith, M.B. and March, J., john Wiley & Sons, new York:2001, the entire contents of which are hereby incorporated by reference.

Abbreviations used herein have their conventional meaning in the chemical and biological arts. The chemical structures and formulas listed herein are constructed according to standard rules of chemical valence known in the chemical arts.

As used herein, the term "aliphatic" or "aliphatic group" 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 (also referred to herein as "carbocyclyl", "alicyclic" or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation but is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise indicated, aliphatic groups contain 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In some 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, "cycloaliphatic" (or "carbocyclyl" or "cycloalkyl") refers to a monocyclic C that is fully saturated or contains one or more units of unsaturation, but which is not aromatic ₃ -C ₇ Hydrocarbons, which have a molecular balanceSeparate individual connection points. Suitable aliphatic groups include, but are not limited to, straight or branched substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl, or (cycloalkyl) alkenyl.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized 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 ⁺ (as in N-substituted pyrrolidinyl)).

As used herein, the term "unsaturated" means a moiety having 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. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

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

The term "aryl" refers to mono-and bi-cyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In some embodiments, the 8-10 membered bicyclic aryl is an optionally substituted naphthyl ring. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that may bear one or more substituents, including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthalimidyl, phenanthridinyl, tetrahydronaphthyl, and the like.

The terms "heteroaryl" and "heteroaryl-" refer to compounds having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; sharing 6, 10 or 14 pi electrons in the ring array; and having one to five heteroatoms in addition to carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolazinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which the heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, wherein the attached group or point is on the heteroaromatic ring (or at least one attached group or point is on the heteroaromatic ring in the case of a divalent fused heteroarylene ring system). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [2,3-b ] -1, 4-oxazin-3 (4H) -one. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which include an optionally substituted ring.

As used herein, the terms "heterocyclyl", "heterocyclic group" and "heterocycle" are used interchangeably to refer to a stable 5-to 7-membered monocyclic or 7-to 10-membered bicyclic heterocyclic moiety which is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used in the context of a ring atom includes substituted nitrogen. As examples, in saturated or partially unsaturated rings having 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or ⁺ NR (as in N-substituted pyrrolidinyl).

The heterocyclic ring may be any that produces a stable structureTo the side groups of which heteroatoms or carbon atoms are attached, and any ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazanylRadical, oxazal- >Radical, thiazal->Group, morpholinyl, and quinuclidinyl. The terms "heterocyclyl", "heterocyclyl ring", "heterocyclic group (heterocyclic group)", "heterocyclic moiety" and "heterocyclic group (heterocyclic radical)" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, in which the linking group or point is on the heterocyclyl ring. The heterocyclyl may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl moieties are independently optionally substituted.

As used herein, the term "partially unsaturated" refers to a cyclic moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

As used herein and unless otherwise indicated, the word "sub" is used to describe a divalent group. Thus, any of the above terms may be modified with the word "sub" to describe the bivalent form of that portion. For example, a divalent carbocyclic ring is "carbocyclylene", a divalent aryl ring is "arylene", a divalent benzene ring is "phenylene", a divalent heterocyclic ring is "heterocyclylene", a divalent heteroaryl ring is "heteroaryl", a divalent alkyl chain is "alkylene", a divalent alkenyl chain is "alkenylene", a divalent alkynyl chain is "alkynylene", and the like.

The compounds of the invention, as described herein, may contain "optionally substituted" moieties when specified. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. "substituted" applies to one or more hydrogens either explicitly or implicitly in the structure (e.g.,at least refer toAnd->At least refer to->). Furthermore, in polycyclic systems, the substituents may replace a hydrogen on any individual ring unless otherwise indicated (e.g.)>At least refer to ). Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, surgeryThe term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow the compound to be prepared, detected, and in certain embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a 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 ；-O(CH ₂ ) _0-4 OR ^o ；-(CH ₂ ) _0-4 CH(OR ^o ) ₂ ；-(CH ₂ ) _0-4 SR ^o The method comprises the steps of carrying out a first treatment on the surface of the Can be R ^o Substituted- (CH) ₂ ) _0-4 Ph; can be R ^o Substituted- (CH) ₂ ) _0-4 O(CH ₂ ) _0-1 Ph; can be R ^o Substituted-ch=chph; can be R ^o Substituted- (CH) ₂ ) _0-4 O(CH ₂ ) _0-1 -a pyridinyl group; -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) ₂ 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 a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occurring R, despite the above definition ^o Together with their 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 two independently occurring R ^o Ring formed with their 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 ^· Is unsubstituted or substituted with one or more halogens only in the case of "halo" preceding, 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. At R ^o Suitable divalent substituents on saturated carbon atoms of (c) include =o and =s.

Suitable divalent substituents on the saturated carbon atoms of the "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 groups, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to the ortho-substitutable carbon 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 groups, or unsubstituted having 0-4 hetero atoms independently selected from nitrogen, oxygen, or sulfurA 5-6 membered saturated, partially unsaturated or aryl ring.

R ^* Suitable substituents on aliphatic groups of (2) 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 halogens only in the case of "halo" preceding, 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 (b)Each of which is->Independently hydrogen, C 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 their intervening atoms, 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 aliphatic radicals 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 halogens only in the case of "halo" preceding, 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.

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. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al, J.pharmaceutical Sciences,1977,66,1-19, incorporated herein by reference, describe in detail pharmaceutically acceptable salts.

In certain embodiments, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structures; such as the R and S configuration, Z and E double bond isomers, and Z and E conformational isomers of each asymmetric center. Thus, single stereochemical isomers, enantiomers, diastereomers and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise indicated, what is described hereinThe depicted structures are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having a composition comprising hydrogen replaced by deuterium or tritium or carbon replaced by deuterium or tritium ¹³ C or ¹⁴ C-enriched carbon-displaced compounds of the present structure are within the scope of the present invention. Such compounds may be used, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the invention. In some embodiments, the compounds of the present disclosure are provided as a single enantiomer or a single diastereomer. By single enantiomer is meant an enantiomeric excess of 80% or more, such as 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%. A single diastereomeric excess means an excess of 80% or greater, e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.

As used herein, the term "oxo" means an oxygen double bonded to a carbon atom to form a carbonyl group.

Symbols other than when used as a bond depicting unknown or mixed stereochemistryRepresenting the point of attachment of the chemical moiety to the remainder of the molecule or formula.

The article "a" is used herein to refer to one or more (i.e., at least one) grammatical object of the article. For example, "an element" means one element or more than one element.

The term "dosing regimen" (or "treatment regimen") as used herein is a set of unit doses (typically more than one) that are administered individually to a subject, typically at time interval. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may involve one or more doses. In some embodiments, the dosing regimen comprises a plurality of doses, wherein each dose is separated from each other by a period of the same length; in some embodiments, the dosing regimen comprises multiple doses and at least two different time periods separating the individual doses.

As will be appreciated from the context, a "reference" compound is a compound that is sufficiently similar to a particular target compound to allow for a relevant comparison. In some embodiments, information about a reference compound is obtained simultaneously with information about a particular compound. In some embodiments, the information about the reference compound is past. In some embodiments, information about the reference compound is stored, for example, in a computer readable medium. In some embodiments, comparison of a particular compound of interest to a reference compound establishes identity, similarity, or variability of the particular compound of interest relative to the compound.

As used herein, the phrase "therapeutic agent" refers to any agent that has a therapeutic effect and/or causes a desired biological and/or pharmacological effect when administered to a subject.

As used herein, the term "therapeutically effective amount" refers to the amount of therapeutic agent that imparts a therapeutic effect to a subject being treated at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of the perceived effect). In particular, a "therapeutically effective amount" refers to an amount of a therapeutic agent that is effective to treat, ameliorate or prevent a desired disease or disorder or exhibits a detectable therapeutic or prophylactic effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and/or also lessening the severity or frequency of the symptoms of the disease. A therapeutically effective amount is typically administered in a dosage regimen that may comprise a plurality of unit doses. The therapeutically effective amount (and/or the appropriate unit dose within an effective dosage regimen) may vary for any particular therapeutic agent, for example, depending on the route of administration, combination with other agents. In addition, the particular therapeutically effective amount (and/or unit dose) for any particular subject may depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular therapeutic agent used; the specific composition used; age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and/or rate of excretion or metabolism of the particular therapeutic agent being used; duration of treatment; and similar factors well known in the medical arts.

As used herein, the term "treatment" refers to the administration of any substance (e.g., provided composition) that partially or completely alleviates, ameliorates, alleviates, inhibits one or more symptoms, characteristics and/or etiologies of a particular disease, disorder and/or condition, delays its onset, reduces its severity and/or reduces its incidence. Such treatment may be for subjects that do not exhibit signs of the associated disease, disorder, and/or condition and/or for subjects that exhibit only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be directed to a subject exhibiting one or more established signs of the associated disease, disorder, and/or condition. In some embodiments, the treatment may be for a subject that has been diagnosed with a related disease, disorder, and/or condition. In some embodiments, the treatment may be for a subject known to have one or more susceptibility factors statistically correlated with an increased risk of developing a related disease, disorder, and/or condition.

B. Compounds of formula (I)

In some embodiments, compounds are provided having formula I:

or a pharmaceutically acceptable salt thereof, wherein

Cy ^A Is phenylene or a 5-to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, or a 7-to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^A Is 0-4-R ^A Group substitution;

each R ^A Independently selected from oxo, halogen, -CN, -C (O) R, -C (O) ₂ R、-C(O)N(R) ₂ 、-NO ₂ 、-N(R) ₂ 、-N(R)C(O)R、-N(R)C(O) ₂ R、-N(R)S(O) ₂ R、-OR、-OC(O)R、-OC(O)N(R) ₂ 、-SR、-S(O)R、-S(O) ₂ R、-S(O)N(R) ₂ 、-S(O) ₂ N(R) ₂ Or an optionally substituted group selected from: c (C) _1-6 Aliphatic, phenyl, 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, or 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur;

each R is independently hydrogen or optionally substituted C _1-6 An aliphatic group;

Cy ^B selected from phenyl, 8 to 10 membered bicyclic aryl, 5 to 6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, or 7 to 10 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^B Is 0-5-R ^B Group substitution;

each R ^B Independently selected from oxo, halogen, haloalkyl, -CN, -C (O) R, -C (O) ₂ R、-C(O)N(R) ₂ 、-NO ₂ 、-N(R) ₂ 、-N(R)C(O)R、-N(R)C(O) ₂ R、-N(R)S(O) ₂ R、-OR、-OC(O)R、-OC(O)N(R) ₂ 、-SR、-S(O)R、-S(O) ₂ R、-S(O)N(R) ₂ 、-S(O) ₂ N(R) ₂ Or an optionally substituted group selected from: c (C) _1-6 Aliphatic groups, 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl groups having 1 to 2 heteroatoms selected from oxygen, nitrogen or sulfur, or 5 to 6 membered heteroaryl groups having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur;

L is optionally substituted C _1-3 Hydrocarbon chains in which 1 to 3 methylene units are optionally and independently replaced by-O-, -NR ^z -, -S-, -SO-or-SO ₂ -substitution; or L is an optionally substituted 5-to 6-membered saturated or partially unsaturated heterocyclyl (heterocyclic) group having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur;

each R ^z Independently selected from hydrogen, - (CH) ₂ ) _0-3 OR、-(CH ₂ ) _0-3 C (O) OR OR optionally substituted C _1-6 An aliphatic group;

x is-O-or–NR ^y -；

R ^y Is hydrogen or optionally substituted C _1-6 An aliphatic group;

l' is a covalent bond or optionally substituted C _1-3 Hydrocarbon chain, wherein the carbon of L' may optionally be linked to R ^y Together form a 3 to 7 membered heterocyclic ring;

each R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Independently selected from hydrogen or-L ^C -R ^C Wherein

Each L ^C Independently selected from covalent bonds or optionally substituted C _1-6 Hydrocarbon chains in which 1 to 3 methylene units are optionally and independently replaced by-O-or-NR-;

each R ^C Independently selected from halogen, haloalkyl, -CN, -C (O) R, -C (O) ₂ R、-C(O)N(R) ₂ 、-NO ₂ 、-N(R) ₂ 、-N(R)C(O)R、-N(R)C(O) ₂ R、-N(R)S(O) ₂ R、-OR、-OC(O)R、-OC(O)N(R) ₂ 、-SR、-S(O)R、-S(O) ₂ R、-S(O)N(R) ₂ 、-S(O) ₂ N(R) ₂ 、Cy ^C Or is selected from C _1-6 An optionally substituted group of aliphatic groups;

each Cy ^C 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl independently selected from 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms selected from oxygen, nitrogen or sulfur, 5 to 6 membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, 6 to 12 membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, bridged bicyclic, or 6 to 12 membered saturated or partially unsaturated bicyclic spiro heterocyclyl having 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, wherein Cy is ^C Is 0-4-L ^D -R ^D Group substitution;

each L ^D Independently selected from covalent bonds or optionally substituted C _1-6 Hydrocarbon chains in which 1 to 3 methylene units are optionally and independently replaced by-O-or-NR-;

each R ^D Independently selected from oxo, halogen, haloalkyl, -CN,-C(O)R、-C(O) ₂ R、-C(O)N(R) ₂ 、-NO ₂ 、-N(R) ₂ 、-N(R)C(O)R、-N(R)C(O) ₂ R、-N(R)S(O) ₂ R、-OR、-OC(O)R、-OC(O)N(R) ₂ 、-SR、-S(O)R、-S(O) ₂ R、-S(O)N(R) ₂ 、-S(O) ₂ N(R) ₂ Or an optionally substituted group selected from: c (C) _1-6 Aliphatic, phenyl, 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, or 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur; and is also provided with

R ⁸ Selected from hydrogen, -OR OR optionally substituted C _1-6 Aliphatic groups.

It is understood that "oxo" refers to a double bond oxygen substitution on carbon "c=o" wherein the carbon atom is part of a structure or group substituted with oxo. For example, when Cy ^C quilt-L ^D -R ^D Substituted, and wherein L ^D Is a covalent bond and R ^D When oxo, the carbon atom substituted by oxo (i.e., carbon in c=o) is Cy ^C Is a part of (e.g., cy) ^C Is of the structure of-L at the 2-position ^D -R ^D Substituted cyclopentyl wherein L ^D Is a covalent bond and R ^D Is corresponding toOxo groups of (a).

In some embodiments, cy ^A Is phenylene, wherein Cy ^A Is 0-4-R ^A And (3) group substitution. In some embodiments, cy ^A Is phenylene, wherein Cy ^A Is 0-2-R ^A And (3) group substitution.

In some embodiments, cy ^A Is a 5-to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^A Is 0-4-R ^A And (3) group substitution.

In some embodiments, cy ^A Is a 6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^A Is 0-4-R ^A And (3) group substitution. In one placeIn some embodiments, cy ^A Is a 6-membered monocyclic heteroarylene group having 1 to 3 nitrogen heteroatoms, wherein Cy ^A Is covered with 0-4R ^A And (3) group substitution. In some embodiments, cy ^A Is covered by 0-1R ^A A group-substituted pyridyldiyl group. In some embodiments, cy ^A Is covered by 0-1R ^A Pyrimidinediyl groups substituted with groups. In some embodiments, cy ^A Is covered by 0-1R ^A A pyridazinediyl group substituted with a group. In some embodiments, cy ^A Is covered by 0-1R ^A Triazinediyl substituted with groups. In some embodiments, cy ^A Is unsubstituted pyridyldiyl. In some embodiments, cy ^A Is unsubstituted pyrimidinediyl.

In some embodiments, cy ^A Is a 5-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^A Is 0-2-R ^A And (3) group substitution. In some embodiments, cy ^A Is unsubstituted thiadiazoldiyl. In some embodiments, cy ^A Is an unsubstituted oxadiazoldiyl group. In some embodiments, cy ^A Is an unsubstituted triazolediyl group.

In some embodiments, cy ^A Is a 7 to 12 membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^A Is 0-4-R ^A And (3) group substitution. In some embodiments, cy ^A Is a 9 membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy ^A Is 0-1-R ^A And (3) group substitution. In some embodiments, cy ^A Is a 10 membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy ^A Is 0-1-R ^A And (3) group substitution. In some embodiments, cy ^A Is covered with 0-1-R ^A Triazolopyridinediyl groups substituted with groups. In some embodiments, cy ^A Is covered with 0-1-R ^A Group-substituted imidazopyridinediyl. In some embodiments, cy ^A Is covered with 0-1-R ^A A group-substituted triazolopyrazadiyl group.

In some embodiments, cy ^A Selected from the group consisting of:

wherein represents the point of attachment to L.

In some embodiments, cy ^A Selected from the group consisting of:

wherein represents the point of attachment to L.

In some embodiments, cy ^A Selected from the group consisting of:

wherein represents the point of attachment to L.

In some embodiments, cy ^A Selected from the group consisting of:

wherein represents the point of attachment to L.

In some embodiments, each R ^A Independently selected from oxo, halogen, -CN, -C (O) ₂ R、-N(R) ₂ 、-OR、-SR、-S(O)R、-S(O) ₂ R or an optionally substituted group selected from: c (C) _1-6 Aliphatic groups, 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl groups, or 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl groups having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur.

In some embodiments, optionally substituted R ^A The substituents on the radicals are independently halogen, - (CH) ₂ ) _0-4 OR ^o Or- (CH) ₂ ) _0-4 N(R ^o ) ₂ Wherein each R is ^o Independently as defined above and described in classes and subclasses herein.

In some embodiments, R ^A Is oxo. In some embodiments, R ^A Is halogen. In some embodiments, R ^A is-CN. In some embodiments, R ^A is-C (O) ₂ R is defined as the formula. In some embodiments, R ^A is-N (R) _2。 In some embodiments, R ^A is-OR. In some embodiments, R ^A is-SR. In some embodiments, R ^A is-SR, wherein R is optionally substituted C _1-6 Aliphatic groups. In some embodiments, R ^A is-S (O) R. In some embodiments, R ^A is-S (O) R, wherein R is optionally substituted C _1-6 Aliphatic groups. In some embodiments, R ^A is-S (O) ₂ R is defined as the formula. In some embodiments, R ^A is-S (O) ₂ R, wherein R is optionally substituted C _1-6 Aliphatic groups.

It should be understood that references herein to embodiments of "single instance" in which substituents are defined are not limited to monosubstituted embodiments. For example, "in some embodiments, R ^A Is oxo "including where R ^A Is oxo and may include one or more additional R as defined herein ^A Embodiments of the groups.

In some embodiments, R ^A Is C substituted by halogen _1-6 Aliphatic groups. In some embodiments, R ^A Is a single instance of being (CH) ₂ ) _0-4 OR substituted C _1-6 Aliphatic group, wherein R ^o Selected from hydrogen or C _1-6 Aliphatic groups. In some embodiments, R ^A Is a single instance of being (CH) ₂ ) _0-4 N(R ^o ) ₂ Substituted C _1-6 Aliphatic groups, wherein each R ^o Independently selected from hydrogen or C _1-6 Aliphatic groups.

In some embodiments, R ^A Is an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R ^A Is an optionally substituted cyclopropyl group.

In some embodiments, R ^A Is an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur. In some embodiments, R ^A Is an optionally substituted 3-to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen and nitrogen. In some embodiments, R ^A Is an optionally substituted oxetanyl group. In some embodiments, R ^A Is optionally halogen or- (CH) ₂ ) _0-4 OR ^o Substituted oxetanyl. In some embodiments, R ^A Is pyrrolidinyl.

In some embodiments, cy ^B Selected from phenyl, a 5 to 6 membered heteroaryl group having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, or a 7 to 10 membered heteroaryl group having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^B Is 0-4-R ^B And (3) group substitution.

In some embodiments, cy ^B Selected from phenyl and 5 to 6 membered heteroaryl groups having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^B Is 0-4-R ^B And (3) group substitution.

In some embodiments, cy ^B Is phenyl, wherein Cy ^B Is 0-4-R ^B And (3) group substitution. In some embodiments, cy ^B Is phenyl, wherein Cy ^B Is 0-3-R ^B And (3) group substitution.

In some embodimentsIn Cy ^B Is a 6 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^B Is 0-4-R ^B And (3) group substitution. In some embodiments, cy ^B Is a 6 membered heteroaryl group having 1-3 nitrogens, wherein Cy ^B Is 0-4-R ^B And (3) group substitution. In some embodiments, cy ^B Is covered with 0-2-R ^B Pyrimidinyl substituted with a group. In some embodiments, cy ^B Is covered with 0-2-R ^B A group-substituted pyridyl group. In some embodiments, cy ^B Is covered with 0-1-R ^B A group-substituted pyrazinyl group. In some embodiments, cy ^B Is covered with 0-1-R ^B A group-substituted pyridazinyl group. In some embodiments, cy ^B Is covered with 0-1-R ^B 1,3, 5-triazinyl groups substituted with radicals.

In some embodiments, cy ^B Is a 5 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^B Is 0-4-R ^B And (3) group substitution. In some embodiments, cy ^B Is a 5 membered heteroaryl having 1-2 heteroatoms independently selected from sulfur and nitrogen, wherein Cy ^B Is 0-4-R ^B And (3) group substitution. In some embodiments, cy ^B Is covered with 0-2-R ^B Thienyl substituted with groups. In some embodiments, cy ^B Is covered with 0-1-R ^B A thiazolyl group substituted with a group. In some embodiments, cy ^B Is covered with 0-1-R ^B A group-substituted thiadiazolyl group.

In some embodiments, cy ^B Selected from the group consisting of:

in some embodiments, cy ^B Selected from the group consisting of:

in some embodiments, each R ^B Independently selected from oxo, halogen, -CN, -NO ₂ 、-N(R) ₂ 、-N(R)C(O) ₂ R, -OR, OR an optionally substituted group selected from: c (C) _1-6 Aliphatic or 5 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, each R ^B Independently selected from halogen, -OR, OR optionally substituted 5 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

In some embodiments, optionally substituted R ^B The substituents on the radicals are independently selected from oxo, halogen and- (CH) ₂ ) _0-4 OR ^o Wherein R is ^o As defined above and described in classes and subclasses herein.

In some embodiments, R ^B Is oxo. In some embodiments, R ^B Is halogen. In some embodiments, R ^B Is fluorine. In some embodiments, R ^B A single example of (a) is chlorine. In some embodiments, R ^B is-CN. In some embodiments, R ^B is-NO ₂ . In some embodiments, R ^B is-N (R) ₂ . In some embodiments, R ^B is-N (R) C (O) ₂ R is defined as the formula. In some embodiments, R ^B is-OR. In some embodiments, R ^B is-OMe.

In some embodiments, R ^B Is optionally substituted C _1-6 Aliphatic groups. In some embodiments, R ^B Is C substituted by halogen _1-6 Aliphatic groups.

In some embodiments, R ^B is-N (R) C (O) ₂ R, wherein each R is independently selected from hydrogen or optionally- (CH) ₂ ) _0-4 R ^o Substituted C _1-6 Aliphatic groups.

In some embodiments, R ^B is-OR, wherein each R is independently selected from hydrogen OR optionally halogen, - (CH) ₂ ) _0-4 OR ^o Or (CH) ₂ ) _0-4 C(O)OR ^o Substituted C _1-6 Aliphatic groups.

In some embodiments, R ^B Is a 5 membered heteroaryl group having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R ^B Is tetrazolyl.

In some embodiments, L is optionally substituted C _1-3 Hydrocarbon chains in which 1 to 3 methylene units are optionally replaced by-O-, -NR ^z -, -S-or-SO ₂ -substitution. In some embodiments, L is optionally substituted C _1-3 Hydrocarbon chains in which 1 methylene unit is optionally replaced by-O-or-NR ^z -substitution.

In some embodiments, L is optionally substituted C ₁ A hydrocarbon chain.

In some embodiments, L is optionally substituted C ₁ Hydrocarbon chains in which 1 methylene unit is replaced by a 5-membered saturated or partially unsaturated heterocyclic group having 1 nitrogen heteroatom, optionally by- (CH) ₂ ) _0-4 OR ^o Substitution, wherein R ^o As defined above and described in classes and subclasses herein.

In some embodiments, L is-CH ₂ -. In some embodiments, L is optionally substitutedWherein represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is optionally substituted +.>Wherein represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is optionally substituted +.>Wherein represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is +.>Wherein represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is +.>Wherein represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is +. >Wherein represents and Cy ^A Is connected to the connecting point of (c).

In some embodiments, L is optionally substituted C ₂ Hydrocarbon chain in which 1 methylene unit is optionally substituted by-NR ^z -or-O-substitution. In some embodiments, L is optionally substituted C ₂ Hydrocarbon chain, wherein is linked to Cy ^A Is of the methylene unit of (2) is of the type-NR ^z -or-O-substitution. In some embodiments, L is optionally substituted C ₂ Hydrocarbon chain, wherein is linked to Cy ^A Is of the methylene unit of (2) is of the type-NR ^z -substitution. In some embodiments, L is optionally substituted C ₂ Hydrocarbon chain, wherein is linked to Cy ^A The methylene units of (C) are replaced by-O-. In some embodiments, L is x-NHCH (Me) -, wherein x represents Cy ^A Is connected to the connecting point of (c). In some embodiments, L isWherein represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is +.>Wherein represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is a-NHCH ₂ -, where x represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is x-N (CH ₃ )CH ₂ -, where x represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is +.>Wherein represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is +.>Wherein represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L is x-OCH (Me) -, wherein x represents Cy ^A Is connected to the connecting point of (c). In some embodiments, L is a-OCH ₂ -, where x represents and Cy ^A Is connected to the connecting point of (c). In some embodiments, L comprises Cy ^A And->Diatomic spacers in between.

In some embodiments, L is an optionally substituted 5-to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, L is an optionally substituted 5-membered saturated or partially unsaturated heterocyclyl having 1 heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L is optionally substituted pyrrolidinediyl.

In some embodiments, the optional substituents on L are independently selected from- (CH) ₂ ) _0-4 R ^o 、-(CH ₂ ) _0-4 OR ^o 、-(CH ₂ ) _0-4 OC(O)R ^o And- (CH) ₂ ) _0-4 N(R ^o ) ₂ Wherein each R is ^o Independently as defined above and described in classes and subclasses herein.

In some embodiments, X is-O-. In some embodiments, X is-NR ^y -。

In some embodiments, R ^y Is hydrogen. In some embodiments, R ^y Is optionally substituted C _1-6 Aliphatic groups.

In some embodiments, L' is a covalent bond. In some embodiments, L' is optionally substituted C _1-3 A hydrocarbon chain. In some embodiments, L' is-CH ₂ -. In some embodiments, L' is-CH (CH ₃ ) -. In some embodiments, L' isWherein represents and Cy ^B Is connected to the connecting point of (c). In some embodiments, L' is +.>Wherein represents and Cy ^B Is connected to the connecting point of (c). In some embodiments, L' is optionally substituted with- (CH) ₂ ) _0-4 R ^o Or- (CH) ₂ ) _0-4 OR ^o Substituted methylene units wherein R ^o Independently as defined above and described in classes and subclasses herein. In some embodiments, R ^o Is hydrogen or C _1-6 Aliphatic groups.

In certain embodiments, the carbon of L' may optionally be combined with R ^z Together forming a 3 to 7 membered heterocyclic ring. In certain embodiments, the carbon of L' may optionally be combined with R ^y Together forming a 4 membered heterocyclic ring.

In some embodiments, R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each of which is independently selected from hydrogen or L ^C -R ^C Wherein each L ^C Independently selected from covalent bonds or optionally substituted C _1-6 Hydrocarbon chains in which 1 to 3 methylene units are optionally and independently replaced by-O-or-NR-; and wherein each R ^C Independently selected from halogen, -CN, -C (O) R, -C (O) ₂ R、-C(O)N(R) ₂ 、-N(R) ₂ 、-N(R)C(O)R、-N(R)C(O) ₂ R、-N(R)S(O) ₂ R、-S(O) ₂ R、-S(O) ₂ N(R) ₂ 、Cy ^C Or is selected from C _1-6 An optionally substituted group of aliphatic groups.

In some embodiments，R ³ Selected from hydrogen or L ^C -R ^C Wherein L is ^C Is a covalent bond and R ^C Is halogen. In some embodiments, R ³ Is hydrogen.

In some embodiments, R ⁴ Selected from hydrogen or L ^C -R ^C Wherein L is ^C Selected from covalent bonds or optionally substituted C _1-6 Hydrocarbon chains in which 1 to 3 methylene units are optionally and independently replaced by-O-or-NR-; and wherein R is ^C Selected from halogen, -CN, -C (O) R, -C (O) ₂ R、-C(O)N(R) ₂ 、-N(R) ₂ 、-N(R)C(O)R、-N(R)C(O) ₂ R、-N(R)S(O) ₂ R、-OR、-S(O) ₂ R、-S(O) ₂ N(R) ₂ 、Cy ^C Or is selected from C _1-6 An optionally substituted group of aliphatic groups.

In some embodiments, R ⁴ Selected from hydrogen or L ^C -R ^C Wherein L is ^C Is a covalent bond and wherein R ^C Selected from halogen, -CN, -C (O) R, -C (O) ₂ R、-C(O)N(R) ₂ 、-N(R) ₂ 、-N(R)C(O)R、-N(R)C(O) ₂ R、-N(R)S(O) ₂ R、-OR、-S(O) ₂ R、-S(O) ₂ N(R) ₂ 、Cy ^C Or is selected from C _1-6 An optionally substituted group of aliphatic groups. In some embodiments, R ⁴ Is hydrogen.

In some embodiments, R ⁴ Selected from the group consisting of:

at R ⁴ In some embodiments of C _1-6 The optional substituents on the aliphatic radical are selected from- (CH) ₂ ) _0-4 R ^o 、-(CH ₂ ) _0-4 OR ^o 、-CN、-(CH ₂ ) _0-4 N(R ^o ) ₂ And- (CH) ₂ ) _0-4 C(O)OR ^o Wherein each R is ^o Independently as defined above and described in classes and subclasses herein.

At R ⁴ In some embodiments of (2), cy ^C 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl selected from 1 to 2 heteroatoms selected from oxygen, nitrogen or sulfur, 5 to 6 membered monocyclic heteroaryl selected from 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, 6 to 12 membered saturated or partially unsaturated fused bicyclic heterocyclyl selected from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, bridged bicyclic, or 6 to 12 membered saturated or partially unsaturated bicyclic spiro heterocyclyl selected from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, wherein Cy is Cy ^C Is 0-4-L ^D -R ^D And (3) group substitution. At R ⁴ In some embodiments of (2), cy ^C Is a 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 2 heteroatoms selected from oxygen, nitrogen or sulfur.

At R ⁴ In some embodiments of (2), cy ^C Selected from the group consisting of:

at R ⁴ In some embodiments of (2), R ^D Selected from oxo, halogen, -C (O) ₂ R、-N(R) ₂ -OR an optionally substituted group selected from: c (C) _1-6 Aliphatic, phenyl, 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur.

At R ⁴ R of (2) ^D In some embodiments of the group, R ^D The optional substituents on the ring are selected from halogen, - (CH) ₂ ) _0-4 R ^o 、-(CH ₂ ) _0-4 OR ^o 、-(CH ₂ ) _0-4 N(R ^o ) ₂ 、-(CH ₂ ) _0-4 C(O)OR ^o and-OP (O) (OR) ^o ) ₂ Wherein each R is ^o Independently as defined above and described in classes and subclasses herein.

At R ⁴ In some embodiments of L ^D Is a covalent bond.

In some embodiments, R ⁵ Is hydrogen.

In some embodiments, R ⁵ Is L ^C -R ^C Wherein L is ^C Is a covalent bond and R ^C Is Cy ^C . In some embodiments, cy ^C Is cyclopropyl.

In some embodiments, R ⁶ Selected from hydrogen or L ^C -R ^C Wherein L is ^C Is a covalent bond, and wherein R ^C Selected from halogen, -N (R) ₂ 、-OR、Cy ^C Or optionally substituted C _1-6 Aliphatic groups. In some embodiments, R ⁶ Is hydrogen.

At R ⁶ In some embodiments of (2), cy ^C Is composed of 0-4L ^D -R ^D A 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl substituted with a group. At R ⁶ In some embodiments of (2), cy ^C Is composed of 0-4L ^D -R ^D A cyclopropyl group substituted with a group. In some embodiments, L ^D Is a covalent bond and R ^D Selected from halogen and optionally substituted C _1-6 Aliphatic groups. At R ⁶ In some embodiments of (2), cy ^C Is unsubstituted cyclopropyl.

In some embodiments, R ⁷ Selected from hydrogen or L ^C -R ^C Wherein L is ^C Is a covalent bond, and wherein R ^C Is Cy ^C 。

In some embodiments, R ⁷ Is hydrogen.

At R ⁷ In some embodiments of (2), cy ^C The method comprises the following steps:

in some embodiments, R ⁸ Is hydrogen.

In some embodiments, R ⁸ Selected from-OR OR optionally substituted C _1-6 Aliphatic groups.

In some embodiments, compounds are provided having formula II-a or II-b:

or a pharmaceutically acceptable salt thereof, wherein Cy ^A 、Cy ^B 、L、L’、R ^y 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Whether defined individually or in combination, and described in classes and subclasses herein.

It will be appreciated that unless otherwise specified or prohibited by the foregoing definition of formula II-a or formula II-b, the variable Cy is as defined above and as described in classes and subclasses herein ^A 、Cy ^B 、L、L’、R ^y 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ The embodiments of (a) apply to the compounds of formula II-a or formula II-b, either alone or in combination.

In some embodiments, compounds are provided having the formula III-a-1, III-b-1, III-a-2, III-b-2, III-a-3, or III-b-3:

or a pharmaceutically acceptable salt thereof, wherein Cy ^A 、R ^B 、L、L’、R ^y 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Whether defined individually or in combination, and described in classes and subclasses herein.

It will be appreciated that unless otherwise specified or prohibited by the preceding definition of formula III-a-1, formula III-b-1, formula III-a-2, formula III-b-2, formula III-a-3 or formula III-b-3, the variable Cy as defined above and as described in classes and subclasses herein is ^A 、Cy ^B 、L、L’、R ^y 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ The embodiments of (a) apply to the compounds of formula III-a-1, formula III-b-1, formula III-a-2, formula III-b-2, formula III-a-3 or formula III-b-3, either alone or in combination.

In some embodiments, compounds are provided having the formula IV-a-1, IV-b-1, IV-a-2, or IV-b-2:

or a pharmaceutically acceptable salt thereof, wherein R ^A 、Cy ^B 、L、L’、R ^y 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Whether defined individually or in combination, and described in classes and subclasses herein.

It will be appreciated that unless otherwise specified or prohibited by the foregoing definitions of formula IV-a-1, formula IV-b-1, formula IV-a-2 or formula IV-b-2, the variables R as defined above and as described in classes and subclasses herein ^A 、Cy ^B 、L、L’、R ^y 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ The embodiments of (a) apply to the compounds of formula IV-a-1, formula IV-b-1, formula IV-a-2 or formula IV-b-2, either alone or in combination.

In some embodiments, compounds are provided having formula V:

or a pharmaceutically acceptable salt thereof, wherein Cy ^A 、Cy ^B 、L、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Whether defined individually or in combination, and described in classes and subclasses herein.

It will be appreciated that unless otherwise specified or prohibited by the foregoing definition of formula V, the variable Cy is as defined above and as described in classes and subclasses herein ^A 、Cy ^B 、L、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ The embodiments of (a) apply to the compounds of formula V, either alone or in combination.

In some embodiments, compounds are provided having the formula VI-a, VI-b or VI-c:

or a pharmaceutically acceptable salt thereof, wherein Cy ^A 、Cy ^B 、X、L’、R ^o 、R ^z 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Whether defined individually or in combination, and described in classes and subclasses herein.

It will be appreciated that unless otherwise specified or prohibited by the foregoing definition of formula VI-a, formula VI-b or formula VI-c, the variable Cy is as defined above and as described in classes and subclasses herein ^A 、Cy ^B 、X、L’、R ^o 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ The embodiments of (a) apply to the compounds of formula VI-a, formula VI-b or formula VI-c, either alone or in combination.

In certain embodiments, the provided compound is selected from the group consisting of:

3-chlorobenzyl (I-1) carbamate (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl);

(6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamic acid (R) -1- (3-chlorophenyl) ethyl ester (I-2);

(6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamic acid (S) -1- (3-chlorophenyl) ethyl ester (I-3);

3-methoxybenzyl (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamate;

1- (3-chlorobenzyl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) -1-methylurea (I-5);

1- (3-chlorophenyl) propyl (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamate;

1- (3-chloro-2-fluorophenyl) ethyl (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamate;

(6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamic acid 5-chloro-2- (1H-tetrazol-1-yl) benzyl ester (I-8);

(6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamic acid 2- (3-chlorophenyl) -2-hydroxyethyl ester (I-9);

1- (5-chloro-2- (1H-tetrazol-1-yl) benzyl) -3- (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl) urea (I-10);

(4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl) carbamic acid 5-chloro-2- (1H-tetrazol-1-yl) benzyl ester (I-11);

(4- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methoxy) pyridin-2-yl) carbamic acid 5-chloro-2- (1H-tetrazol-1-yl) benzyl ester (I-12);

3-chlorobenzyl (I-13) carbamate (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl);

3-chlorobenzyl (I-14) carbamate (3- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl);

1- (3-chlorophenyl) ethyl (I-15) carbamate (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl);

3-chlorobenzyl (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-imidazo [4,5-c ] pyridin-6-yl) carbamate (I-16);

1- (3-chlorophenyl) ethyl (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-imidazo [4,5-c ] pyridin-6-yl) carbamate (I-17);

3-chlorobenzyl (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] pyridin-4-yl) carbamate (I-18);

3-chlorobenzyl (2- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] pyridin-4-yl) carbamate (I-19);

3-chlorobenzyl (I-20) carbamate (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl);

1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) ethyl (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl) carbamate;

(2- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -2H-pyrazolo [4,3-c ] pyridin-4-yl) carbamic acid 5-chloro-2- (1H-tetrazol-1-yl) benzyl ester (I-22);

(1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-imidazo [4,5-c ] pyridin-6-yl) carbamic acid 5-chloro-2- (1H-tetrazol-1-yl) benzyl ester (I-23);

1- (3-chlorobenzyl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (I-24);

3- (3-chlorophenyl) -N- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) azetidine-1-carboxamide (I-25);

(4-chloropyridin-2-yl) methyl (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamate (I-26);

1- ((4-chloropyridin-2-yl) methyl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (I-27);

(6- ((2R, 4S) -2- (6-Cyclopropylimidazo [1,2-a ] pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) carbamic acid (4-chloropyridin-2-yl) methyl ester (I-28);

1- ((4-chloropyrimidin-2-yl) methyl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (I-29);

1- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) -3- ((4-methoxypyrimidin-2-yl) methyl) urea (I-30);

n- (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) -3-phenylazetidine-1-carboxamide (I-31);

1- (4-chlorobicyclo [4.2.0] oct-1 (6), 2, 4-trien-7-yl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (I-32);

n- (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) -3- (pyrimidin-2-yl) azetidine-1-carboxamide (I-33); and

(4-methylpyrimidin-2-yl) methyl 6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamate (I-34);

or a pharmaceutically acceptable salt thereof.

The compounds explicitly disclosed herein may be claimed as individual compounds, including where stereochemistry is not mentioned.

C. Pharmaceutical composition

In another aspect, the invention provides pharmaceutical compositions comprising a compound of the present disclosure (including a compound of formula (I) -formula (VI-c)) or a compound of formula (I) -formula (VI-c) or an exemplary compound in combination with a pharmaceutically acceptable excipient (e.g., carrier).

Pharmaceutical compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein. As described above, the compounds of formula (I) -formula (VI-c) included in the pharmaceutical compositions may be covalently linked to a carrier moiety. Alternatively, the compounds of formula (I) -formula (VI-c) included in the pharmaceutical compositions are not covalently linked to a carrier moiety.

As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient, such as a pharmaceutically, physiologically acceptable organic or inorganic carrier material suitable for enteral or parenteral administration, that does not adversely react with the active agent. Suitable pharmaceutically acceptable carriers include water, saline solutions (such as ringer's solution), alcohols, oils, gelatin, and carbohydrates (such as lactose, amylose, or starch), fatty acid esters, hydroxymethyl cellulose, and polyvinylpyrrolidone. Such articles may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or aromatic substances, and the like, which do not deleteriously react with the compounds of the invention.

The compounds of the invention may be administered alone or may be co-administered to a subject. Co-administration is intended to include administration of the compounds either alone or in combination (more than one compound) simultaneously or sequentially. The preparation may also be combined with other active substances (e.g. to reduce metabolic degradation) when desired.

In some embodiments, a test agent as described herein may be incorporated into a pharmaceutical composition for administration by methods known to those skilled in the art and described herein for the provided compounds.

D. Formulations

The compounds of the present invention may be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Thus, the compounds of the invention may be administered by injection (e.g., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal). In some embodiments, the compounds of the present disclosure are administered orally. In addition, the compounds described herein may be administered by inhalation, e.g., intranasal administration. In addition, the compounds of the present invention may be administered transdermally. It is also contemplated that the compounds of the present invention may be administered using a variety of routes of administration (e.g., intramuscular, oral, transdermal). Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the present invention.

For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid in admixture with the finely divided active component. In tablets, the active ingredient is mixed with a carrier having the necessary binding characteristics in suitable proportions and compacted in the shape and size desired.

Powders and tablets preferably contain from 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "article of manufacture" is intended to encompass a formulation of the active compound with an encapsulating material as a carrier providing a capsule, wherein the active ingredient, with or without other carriers, is surrounded by a carrier, which carrier is thus associated therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

To prepare suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is uniformly dispersed therein by stirring. The melted homogeneous mixture is then poured into a suitably sized mold, allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions, and emulsions, such as water or water/propylene glycol solutions. For parenteral injection, the liquid preparation may be formulated in solution in an aqueous polyethylene glycol solution.

Particularly suitable mixtures of the compounds of the present invention are injectable sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants, including suppositories, when parenteral use is required or desired. In particular, carriers for parenteral administration include aqueous solutions of glucose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers and the like. Ampoules are suitable unit doses. The compounds of the invention may also be incorporated into liposomes or administered via a transdermal pump or patch. Pharmaceutical mixtures suitable for use in the present invention include, for example, those described in Pharmaceutical Sciences (17 th edition, mack pub. Co., easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents.

Also included are solid form preparations which are intended to be converted, immediately prior to use, into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical product is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged article of manufacture containing discrete amounts of the article of manufacture, such as packaged tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be the appropriate number of any of these unit dosage forms in packaged form.

The amount of active ingredient in the unit dose article may be varied or adjusted depending on the particular application and potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

Some compounds may have limited solubility in water and thus may require surfactants or other suitable cosolvents in the composition. Such co-solvents include: polysorbates 20, 60, and 80; pluronic F-68, F-84 and P-103; cyclodextrin; and polyoxyethylene 35castor oil (polyoxyl 35 caster oil). Such co-solvents are typically used at levels between about 0.01% and about 2% by weight.

It may be desirable to have a viscosity that is greater than the viscosity of a simple aqueous solution to reduce variability in dispensing the formulation, to reduce physical separation of components of a suspension or emulsion of the formulation, and/or to otherwise improve the formulation. Such viscosity enhancing (viscosity building) agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically used at levels between about 0.01% and about 2% by weight.

The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight anionic high permeability polymers, curdlan and finely dispersed drug carrier matrices. These components are discussed in more detail in U.S. patent nos. 4,911,920, 5,403,841, 5,212,162 and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.

E. Effective dose

The pharmaceutical compositions provided herein include compositions containing a therapeutically effective amount (i.e., an amount effective to achieve its intended purpose) of the active ingredient therein. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in a method of treating HAE, such compositions will contain an amount of the active ingredient effective to achieve the desired result (e.g., inhibiting PKa and/or reducing the amount of bradykinin in a subject).

The dose and frequency of administration (single or multiple doses) of the compound may vary depending on a variety of factors, including the route of administration; the recipient's body type, age, sex, health condition, body weight, body mass index, and diet; the nature and extent of the symptoms of the disease being treated (e.g., a disease responsive to PKa inhibition); the presence of other diseases or other health related problems; the type of concurrent therapy; and complications of any disease or treatment regimen. Other therapeutic regimens or agents may be used in conjunction with the methods and compounds of the invention.

For any of the provided compounds or test agents, a therapeutically effective amount can be initially determined from a cell culture assay. The target concentration will be the concentration of active compound that is capable of reducing the activity of the PKa enzyme, e.g. measured using the described method.

A therapeutically effective amount for a human can be determined from an animal model. For example, dosages for humans may be formulated to achieve concentrations found to be effective in animals. As described above, the dosage in humans can be adjusted by monitoring the PKa inhibition and adjusting the dosage up or down.

The dosage may vary depending on the needs of the patient and the compound used. In the context of the present invention, the dose administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the presence, nature and extent of any adverse side effects. In some embodiments, the compounds of the present disclosure or pharmaceutical compositions comprising the compounds are provided as unit doses.

In one aspect, the compounds provided herein exhibit one or more improved Pharmacokinetic (PK) properties (e.g., C _max 、t _max 、C _min 、t _1/2 AUC, CL, bioavailability, etc.). In some embodiments, the reference compound is a PKa inhibitor known in the art. In some embodiments, the reference compound is a PKa inhibitor selected from those disclosed in PCT publication No. WO 2019/178129.

F. Therapeutic method

The present disclosure provides compounds and pharmaceutical compositions comprising the compounds for use in medicine, i.e., in therapy. The present disclosure further provides the use of any of the compounds described herein for inhibiting the activity of PKa, which would be beneficial for the treatment of PKa-mediated diseases and disorders. Exemplary PKa-mediated disorders include edema, which refers to swelling of the entire body of a subject or a portion thereof due to inflammation or injury when small blood vessels become leaky and release fluid into nearby tissues. In some examples, the edema is HAE. In other examples, edema occurs in the eye, such as Diabetic Macular Edema (DME). The present disclosure provides methods of inhibiting the activity of PKa. In certain embodiments, the present application provides methods of inhibiting the activity of PKa in vitro by contacting any of the compounds described herein with a PKa molecule in a sample (such as a biological sample). In certain embodiments, the present application provides methods of inhibiting the activity of PKa in vivo via delivery of an effective amount of any of the compounds described herein to a subject in need of treatment by a suitable route.

In certain embodiments, the methods comprise administering any of the compounds described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof (e.g., a subject such as a human patient suffering from, for example, edema). In certain embodiments, the methods comprise administering to a subject in need thereof a compound of formula (I) -formula (VI-c), or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the methods comprise administering to a subject in need thereof a pharmaceutical composition comprising a compound of formula (I) -formula (VI-c) or a pharmaceutically acceptable salt.

In certain embodiments, the subject to be treated by any of the methods described herein is a human patient suffering from, suspected of suffering from, or at risk of suffering from edema (e.g., HAE or Diabetic Macular Edema (DME)). Subjects with edema can be identified by routine medical examination (e.g., laboratory testing). A subject suspected of having edema may exhibit one or more symptoms of the disease/disorder. The subject at risk for edema may be a subject with one or more risk factors associated with the disease, e.g., a lack of C1-INH for HAE.

In certain embodiments, provided herein are methods of alleviating one or more symptoms of HAE in a human patient suffering from an HAE episode. Such patients may be identified by routine medical procedures. An effective amount of one or more provided compounds may be administered to a human patient via suitable routes, such as those described herein. The compounds described herein may be used alone, or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g.,or->) A PKa inhibitor (e.g., ai Kala peptide or ranunculacer mab (lanadelumab)) or a bradykinin B2 receptor antagonist (e.g., )。

In other embodiments, provided herein are methods of reducing the risk of HAE onset in a human HAE patient in the resting stage. Such patients may be based on a variety of factors (including HAE attacksHistory) to identify. An effective amount of one or more of the compounds may be administered to a human patient via suitable routes, such as those described herein. The compounds described herein may be used alone, or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g.,or->) A PKa inhibitor (e.g., ai Kala peptide or ranaviumab (lanadelumab)) or a bradykinin B2 receptor antagonist (e.g., ∈)>)。

In some embodiments, provided herein are prophylactic treatments of HAE with one or more compounds described herein for a human patient at risk of having an onset of HAE. In some embodiments, a patient suitable for prophylactic treatment of HAE is a human subject suffering from HAE (e.g., having a history of HAE onset). In some embodiments, a patient suitable for such prophylactic treatment is a human subject, wherein a physician determines that a history of HAE episodes requires a prophylactic approach (e.g., a human subject experiences episodes exceeding a particular average number of episodes over a period of time, including (as a non-limiting example) one, two, or more episodes per month). Alternatively, a patient suitable for prophylactic treatment may be a human subject having no history of HAE episodes but having one or more HAE risk factors (e.g., family history, genetic defects in the C1-INH gene, etc.). Such prophylactic treatment may involve the compounds described herein as the only active agent, or involve additional anti-HAE agents, such as those described herein.

In certain embodiments, provided herein are methods of preventing or reducing edema in an eye of a subject (e.g., a human patient). In some examples, the human patient is a diabetic patient suffering from, suspected of suffering from, or at risk of suffering from Diabetic Macular Edema (DME). DME is a proliferative form of diabetic retinopathy, characterized in thatRetinal layer swelling, neovascularization, vascular leakage, and retinal thickening in diabetes due to fluid leakage in the blood vessels in the macula. To practice such methods, an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt thereof, may be delivered to the eye of a subject in need of treatment. For example, the compound may be delivered locally by intraocular injection or intravitreal injection. The subject may be treated with a compound as described herein as the only active agent or in combination with other DME treatments. Non-limiting examples of DME treatments include laser photocoagulation, steroids, VEGF pathway targeting agents (e.g.,(Ranitimab) or(albesipu)) and/or an anti-PDGF agent.

In certain embodiments, the methods disclosed herein comprise administering to a subject an effective amount of a compound of formula (I) -formula (VI-c), or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

In certain embodiments, the subject being treated is an animal. The animal may be of any sex and may be at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a study animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

Certain methods described herein may comprise administering one or more additional agents in combination with a compound described herein. The one or more additional agents may be administered simultaneously with the compound of formula (I) -formula (VI-c) or at a different time than the compound of formula (I) -formula (VI-c). For example, the compounds of formula (I) -formula (VI-c) and any additional agents may be administered at the same schedule or at different schedules. All or some doses of the compounds of formula (I) -formula (VI-c) may be administered before, after, within the dosing schedule of the additional agent, or in a combination thereof. The timing of administration of the compounds of formula (I) -formula (VI-c) and the additional agent may be different for different additional agents.

In certain embodiments, the additional agent comprises an agent useful for treating edema such as HAE or DME. Examples of such agents are provided herein.

Also provided is the use of a compound of the present disclosure for the manufacture of a medicament for the disorders/diseases disclosed herein.

In the context of this specification, "comprising" is to be interpreted as "including". Embodiments of the invention that include certain features/elements are also intended to extend to alternative embodiments that "consist of" or "consist essentially of the relevant elements/features. Embodiments of the invention may be combined where technically appropriate.

Technical references such as patents and applications are incorporated herein by reference.

Any embodiment specifically and explicitly recited herein may form the basis of disclaimers, alone or in combination with one or more additional embodiments.

The background section of the specification contains relevant technical information and may be used as a basis for modification. The subject matter headings herein are used to divide the file into sections and are not intended to interpret the meaning of the disclosure provided herein.

This specification claims priority from U.S. provisional application No. 63/162,494 filed on 3/17 of 2021, which provisional application is incorporated herein by reference. The present application may be used as a basis for modifying the present description, particularly in terms of the chemical structures disclosed therein.

IV. examples

Synthesis of intermediates

Synthesis of 1- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) -2, 2-trifluoroethan-1-one

Synthesis of 5-Cyclopropylpyridin-2-amine 5-bromopyridin-2-amine (10 g,58 mmol), cyclopropylboronic acid (12 g,120 mmol), SPhos (2.4 g,5.8 mmol) and K ₃ PO ₄ (43 g,200 mmol) in N ₂ Under an atmosphere and suspended in toluene (220 mL) and water (22 mL). The resulting suspension was degassed for 10min and Pd (OAc) was added ₂ (0.65 g,2.9 mmol). The reaction mixture was taken up in N at 95 ℃ ₂ Stirring for 16h under an atmosphere. The mixture was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phase was washed with brine (150 mL), passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 10% -95% EtOAc/hexanes to give the title compound (5.3 g, 68%) as a red solid. ESI-MS (m+h) +:135.0,1H NMR (400 MHz, DMSO) delta 7.78 (d, J=2.5 Hz, 1H), 7.07 (dd, J=2.5, 8.6Hz, 1H), 6.39 (d, J=8.4 Hz, 1H), 5.66 (s, 2H), 1.80-1.72 (m, 1H), 0.86-0.81 (m, 2H), 0.56-0.52 (m, 2H).

6-Cyclopropylimidazo [1,2-a ]]Synthesis of Ethyl pyridine-2-carboxylate A solution of 5-cyclopropylpyridin-2-amine (5.3 g,40 mmol) and ethyl 3-bromo-2-oxopropionate (5.9 mL,47 mmol) in ethanol (110 mL) was stirred at reflux for 1 hour. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and taken up in Na ₂ CO ₃ (saturated aqueous solution, 60 mL) was washed through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20% -80% EtOAc/hexanesThe title compound (5 g, 54%) was obtained as an orange solid. ESI-MS (m+h) +:231.2,1H NMR (400 MHz, CDCl) ₃ )δ8.10-8.09(m,1H),7.91-7.89(m,1H),7.57(d,J＝9.5Hz,1H),6.99(dd,J＝1.6,9.5Hz,1H),4.45(q,J＝7.1Hz,2H),1.94-1.86(m,1H),1.44(t,J＝7.2Hz,3H),1.03-0.97(m,2H),0.73-0.68(m,2H)。

(6-Cyclopropylimidazo [1, 2-a)]Synthesis of pyridin-2-yl) methanol in N ₂ LiAlH will be described below ₄ (1M in THF, 42.99mmol,42.99 mL) was added to 6-cyclopropylimidazo [1,2-a ] cooled to 0deg.C]A solution of pyridine-2-carboxylic acid ethyl ester (21.50 mmol,4.95 g) in THF (25 mL). The mixture was stirred for 1 hour, then EtOAc (5 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour, followed by washing with water (30 mL) and brine (30 mL). The organics were dried over MgSO ₄ Drying followed by concentration in vacuo afforded the title compound, which was used without further purification. 1H NMR (400 MHz, CDCl) ₃ )δ7.86(s,1H),7.46-7.42(m,2H),6.92(dd,J＝1.8,9.4Hz,1H),4.82(s,2H),3.88-3.84(m,1H),1.87(s,1H),0.99-0.93(m,2H),0.69-0.64(m,2H)。

Synthesis of (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methylamine

Synthesis of 2- (bromomethyl) -6-cyclopropylimidazo [1,2-a ] pyridine

A mixture of 5-cyclopropylpyridin-2-amine (640 mg,5.0 mmol) and 1, 3-dibromopropan-2-one (1.61 g,7.5 mmol) in DME (20.0 mL) was reacted in N ₂ And stirring at 90℃for 16h. The reaction mixture was cooled to room temperature and saturated NaHCO ₃ The solution (50 mL) was quenched and extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (50 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The crude residue was purified by column chromatography (eluent: DCM/meoh=50/1-30/1) to give a yellow solid2- (bromomethyl) -6-cyclopropylimidazo [1, 2-a)]Pyridine (880 mg, 70%). ESI-MS [ M+H ]] ⁺ ：252.2。

Synthesis of 2- (azidomethyl) -6-cyclopropylimidazo [1,2-a ] pyridine

2- (bromomethyl) -6-cyclopropylimidazo [1,2-a]Pyridine (753 mg,3 mmol) and NaN ₃ (244 mg,3.75 mmol) in DMF (10.0 mL) in N ₂ And stirred at room temperature for 16h. The mixture was diluted with EtOAc (100 mL) and washed with brine (3 x 50 mL). The organic layer was purified by Na ₂ SO ₄ Drying and concentration in vacuo afforded 2- (azidomethyl) -6-cyclopropylimidazo [1,2-a ] as a yellow solid]Pyridine (730 mg, crude material) was used in the next step without purification. ESI-MS [ M+H ]] ⁺ ：214.2。

Synthesis of (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methylamine

2- (azidomethyl) -6-cyclopropylimidazo [1,2-a ]]Pyridine (730 mg, crude material) and PPh ₃ A mixture of (983 mg,3.75 mmol) in MeOH (25 mL) was stirred at reflux for 2h. The mixture was concentrated in vacuo and purified by preparative TLC (eluent: DCM/meoh=10/1) to give (6-cyclopropylimidazo [1, 2-a) as a yellow oil ]Pyridin-2-yl) methylamine (450 mg,81%, 2 steps). ESI-MS [ M+H ]]+：188.2。

Synthesis of 2- ((2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidin-2-yl) -6-cyclopropylimidazo [1,2-a ] pyridine

Synthesis of methyl (2R, 4S) -4-hydroxypyrrolidine-2-carboxylate

To a solution of (2R, 4S) -4-hydroxypyrrolidine-2-hydrochloride (5 g,29.8 mmol) in MeOH (50 mL) at 0deg.C was slowly added SOCl ₂ (10.6 g,89.4 mmol). After stirring at 80℃for 12h, the reaction was concentrated in vacuo to give methyl (2R, 4S) -4-hydroxypyrrolidine-2-carboxylate (4 g, crude material) as a grey solid. ESI-MS [ M+H ]]+：146.2。

Synthesis of (2R, 4S) -4-hydroxypyrrolidine-1, 2-dicarboxylic acid 1-benzyl ester 2-methyl ester

To a solution of (2R, 4S) -4-hydroxypyrrolidine-2-carboxylic acid methyl ester (4 g,27.5 mmol) in THF (80 mL) at 0deg.C was added saturated NaHCO ₃ Aqueous (60 ml) followed by CbzCl (5.6 g,33.1 mmol). The reaction mixture was stirred at 0deg.C for 1h, then extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Drying and concentration in vacuo gave the crude material, which was purified by silica gel chromatography (EtOAc/pe=1/5) to give (2 r,4 s) -4-hydroxypyrrolidine-1, 2-dicarboxylic acid 1-benzyl 2-methyl ester (5.8 g, 75%) as a yellow oil. ESI-MS [ M+H ] ] ⁺ ：280.1。

Synthesis of 1-benzyl 2-methyl (2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-1, 2-dicarboxylic acid

A mixture of (2R, 4S) -4-hydroxypyrrolidine-1, 2-dicarboxylic acid 1-benzyl ester 2-methyl ester (4 g,14.3 mmol), TMSCl (2.3 g,21.5 mmol) and imidazole (1.9 g,28.6 mmol) in DCM (40 mL) was stirred at room temperature for 12h. The reaction was washed with water (50 mL) followed by extraction with EtOAc (3X 50 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude material which was purified by silica gel chromatography (EtOAc/pe=1/3) to give (2 r,4 s) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-1, 2-dicarboxylic acid 1-benzyl ester 2-methyl ester (4 g, 71%) as a yellow oil. ESI-MS [ M+H ]] ⁺ ：394.1。

Synthesis of (2R, 4S) -1- ((benzyloxy) carbonyl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-2-carboxylic acid

To a solution of (2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-1, 2-dicarboxylic acid 1-benzyl ester 2-methyl ester (4 g,10.2 mmol) in THF (40 mL) was added LiOH (1.25 g,30.6 mmol) and water (4 mL). The reaction mixture was stirred at room temperature for 2h, then concentrated in vacuo to remove THF. The pH of the resulting residue was adjusted to 3-4 with HCl (1.0M) and the mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude material (2R, 4S) -1- ((benzyloxy) carbonyl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-2-carboxylic acid (3.3 g, 87%) as a yellow oil. ESI-MS [ M+H ]] ⁺ ：394.1。

Synthesis of benzyl (2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (chlorocarbonyl) pyrrolidine-1-carboxylate

To a solution of (2 r,4 s) -1- ((benzyloxy) carbonyl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-2-carboxylic acid (2 g, crude material from the previous step) in DCM (20 mL) was added DMF (2 drops) and (COCl) 2 (1.0 g,7.91 mmol) at 0 ℃. After stirring at room temperature for 1h, the filtrate was concentrated in vacuo to give benzyl (2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (chlorocarbonyl) pyrrolidine-1-carboxylate (2.1 g crude material) as a yellow oil which was used without further purificationIn the next step. ESI-MS [ M+H ]] ⁺ ：394.1。

Synthesis of benzyl (2R, 4S) -2- (2-chloroacetyl) -4-hydroxypyrrolidine-1-carboxylate

To a solution of benzyl (2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (chlorocarbonyl) pyrrolidine-1-carboxylate (400 mg,1 mmol) in DCM (20 mL) was added TMSCH2N ₂ (1 mL,2.0M in hexane). After stirring at room temperature for 12h, the solution was concentrated in vacuo to give the crude material, which was redissolved in DCM (10 mL), followed by addition of HCl (4.0M in 1, 4-dioxane, 0.5 mL). After stirring for a further 10min at room temperature, the solution was concentrated in vacuo to give the crude material which was purified by silica gel chromatography (eluent: etOAc/pe=1/5) to give benzyl (2 r,4 s) -2- (2-chloroacetyl) -4-hydroxypyrrolidine-1-carboxylate (150 mg, 36%) as a yellow oil. ESI-MS [ M+H ] ] ⁺ ：298.2。

Synthesis of benzyl (2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) pyrrolidine-1-carboxylate

A solution of (2R, 4S) -2- (2-chloroacetyl) -4-hydroxypyrrolidine-1-carboxylic acid benzyl ester (150 mg,0.51 mmol), 5-cyclopropylpyridin-2-amine (134 mg,1.0 mmol) and DIPEA (399 mg,2.55 mmol) in 1.4-dioxane (10 mL) was stirred at 95℃for 12h. The resulting mixture was concentrated in vacuo to give the crude material which was purified by silica gel chromatography (eluent: DCM/meoh=15/1) to give (2 r,4 s) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a) as a yellow solid]Benzyl pyridin-2-yl) pyrrolidine-1-carboxylate (150 mg, 58%). ESI-MS [ M+H ]] ⁺ ：492.1。

(2R, 4S) -4- ((tert-Butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a)]Benzyl pyridin-2-yl) pyrrolidine-1-carboxylate (150 mg,0.31 mmol) and Pd/C (20 mg) in MeOH (10 mL) in H ₂ The mixture was stirred at room temperature for 5 hours. The reaction was filtered, followed by washing with MeOH (30 mL). The filtrate was concentrated in vacuo to give 2- ((2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidin-2-yl) -6-cyclopropylimidazo [1,2-a ] as a yellow solid ]Pyridine (110 mg), which was used without further purification. ESI-MS [ M+H ]] ⁺ ：358.2。

Example 1

Synthesis of 3-chlorobenzyl (I-1) carbamate (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl)

6-chloro-N- ((6-cyclopropylimidazo [1, 2-a)]Synthesis of pyridin-2-yl methyl) pyrimidin-4-amine 4, 6-dichloropyrimidine (302 mg,2.6 mmol), (6-cyclopropylimidazo [1, 2-a)]A solution of pyridin-2-yl) methylamine hydrochloride (400 mg,2.1 mmol) and DIPEA (0.93 mL,5.3 mmol) in iPrOH (20 mL) was heated at 80℃for 2h. The reaction mixture was concentrated in vacuo and the residue was taken up in Et ₂ And (3) grinding. The crude solid was redissolved in DCM (35 mL) and washed with water. The combined organics were passed through a hydrophobic frit followed by concentration in vacuo to give the title compound as a colourless oil (560 mg, 87%). 1H NMR (400 MHz, DMSO). Delta.8.33-8.29 (m, 2H), 8.21-8.20 (m, 1H), 7.68 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.98 (dd, J=1.5, 9.3Hz, 1H), 6.63 (s, 1H), 4.61 (s, 2H), 1.95-1.88 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.64 (m, 2H).

N- ((6-cyclopropyl imidazo [1, 2-a)]Synthesis of pyridin-2-yl) methyl) -6- (methoxyamino) pyrimidin-4-amine 6-chloro-N- ((6-cyclopropylimidazoleAnd [1,2-a ]]A solution of pyridin-2-yl) methyl-pyrimidin-4-amine (1.6 g,5.5 mmol) and O-methyl-hydroxylamine hydrochloride (6.9 g,82 mmol) in ethanol (40 mL) was heated at 85℃for 24h. The reaction mixture was treated with NaHCO ₃ (saturated aqueous) dilute and extract with EtOAc. The combined organics were dried over MgSO ₄ Drying, filtration and concentration in vacuo afforded the title compound (1.52 g, 90%) as a brown gum, which was used without further purification. ESI-MS (m+h) +:311,1H NMR (400 MHz, DMSO) δ9.56 (br s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.62 (s, 1H), 7.49-7.40 (m, 1H), 7.37 (d, J=9.3 Hz, 1H), 6.95 (dd, J=1.4, 9.2Hz, 1H), 5.84 (s, 1H), 4.50 (s, 2H), 3.32 (s, 3H), 1.96-1.85 (m, 1H), 0.95-0.85 (m, 2H), 0.70-0.60 (m, 2H).

N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Synthesis of pyridin-2-yl) methyl pyrimidine-4, 6-diamine N- ((6-cyclopropylimidazo [1, 2-a)]A solution of pyridin-2-yl) methyl) -6- (methoxyamino) pyrimidin-4-amine (1.5 g,4.9 mmol) and iron powder (1.4 g,24 mmol) in acetic acid (13 mL) and ethanol (80 mL) was heated at 70℃for 2h. The reaction mixture was cooled and passed throughThe pad was filtered and eluted with EtOAc. The filtrate was concentrated and loaded onto an SCX column, washed with MeOH/DCM (1:9). The product was purified using (7N NH) ₃ Eluting with MeOH)/DCM (1:9) and concentrating in vacuo to afford the title compound as a brown solid (1.2 g, 84%). ESI-MS (m+h) +:281.1H NMR (400 MHz, DMSO). Delta.8.30-8.29 (m, 1H), 7.87 (s, 1H), 7.57 (s, 1H), 7.36 (d, J=9.3 Hz, 1H), 6.99 (t, J=5.8 Hz, 1H), 6.95 (dd, J=1.8, 9.3Hz, 1H), 6.02 (s, 2H), 5.41 (s, 1H), 4.43 (d, J=5.5 Hz, 2H), 1.94-1.86 (m, 1H), 0.93-0.87 (m, 2H), 0.68-0.62 (m, 2H).

(6- (((6-Cyclopropylimidazo [1, 2-a))]Synthesis of pyridin-2-yl methyl) amino) pyrimidin-4-yl carbamic acid 3-chlorobenzyl ester phosgene (20% in toluene, 0.42mL,0.80 mmol) was added dropwise to a stirred solution of 3-chlorobenzyl alcohol (0.12 mL,1.0 mmol) and DIPEA (0.44 mL,2.5 mmol) in DCM (14 mL) at 0deg.C. The mixture was stirred at 0 ℃ for 30min, then warmed to room temperature and stirred for 1h. The resulting solution was added to N over 1h ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) Pyrimidine-4, 6-diamine (140 mg,1.0 mmol) and DIPEA (0.35 mL,2.0 mmol) in MeCN (5.0 mL). The mixture was stirred at room temperature for 18h, followed by the addition of K ₂ CO ₃ (10% in water) and the phases separated. The combined organics were dried over MgSO ₄ Dried and then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with a 1% -10% MeOH/DCM gradient) followed by preparative HPLC to give the title compound (1.1 mg, 1%). ESI-MS (m+h) +:449.2,1HNMR (400 MHz, DMSO). Delta.10.18 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.82 (br s, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 7.43-7.33 (m, 4H), 7.03-6.93 (m, 2H), 5.16 (s, 2H), 4.56 (br s, 2H), 1.94-1.86 (m, 1H), 0.94-0.88 (m, 2H), 0.68-0.62 (m, 2H).

Example 2

Synthesis of (R) -1- (3-chlorophenyl) ethyl (I-2) carbamate (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl)

Synthesis of (R) -1- (3-chlorophenyl) ethyl carbamate trichloroacetyl isocyanate (46. Mu.L, 0.38 mmol) was added dropwise to a stirred solution of (R) -1- (3-chlorophenyl) ethyl-1-ol (50 mg,0.32 mmol) in DCM (3 mL) at 0deg.C. After stirring for 80min with cooling, the reaction mixture was concentrated in vacuo. The residue was redissolved in MeOH (3.0 mL) and K was added ₂ CO ₃ (8.8 mg,0.064 mmol). The reaction mixture was stirred at room temperature for 2d, then diluted with DCM and water. The organic layer was separated over MgSO ₄ Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0% -50% EtOAc/cyclohexane to give the title compound as a colorless oil (36 mg, 57%) which was used directly in the next step.

(6- (((6-Cyclopropylimidazo [1, 2-a))]Synthesis of (R) -1- (3-chlorophenyl) ethyl carbamate (18 mg,0.090 mmol), 6-chloro-N- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) azoxystrobinPyridin-4-amine (27 mg,0.090 mmol), tris (dibenzylideneacetone) dipalladium (0) (17 mg,0.018 mmol), xantphos (21 mg,0.036 mmol) and Cs ₂ CO ₃ (44 mg,0.14 mmol) in 1, 4-dioxane (1.0 mL) was degassed with nitrogen followed by heating at 90℃for 18h. After cooling to room temperature, the reaction mixture was diluted with 10% MeOH/DCM, and purified byThe pad was filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (4.7 mg, 11%). ESI-MS (m+h) +:463.4,1H NMR (400 MHz, DMSO). Delta.10.12 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.77 (br s, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.43-7.33 (m, 4H), 6.98-6.92 (m, 2H), 5.82-5.75 (m, 1H), 4.54 (s, 2H), 1.94-1.86 (m, 1H), 1.50 (d, J=6.6 Hz, 3H), 0.94-0.87 (m, 2H), 0.68-0.62 (m, 2H). Using a compound selected from the group consisting of (6- (((6-cyclopropylimidazo [1,2-a ])]Pyridin-2-yl) methyl) amino) pyrimidin-4-yl carbamic acid (R) -1- (3-chlorophenyl) ethyl ester similar procedure from 6-chloro-N- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) pyrimidin-4-amine and the appropriate alcohol coupling partner were synthesized into the compounds in table 1.

TABLE 1

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Example 8

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzyl (I-8) carbamate (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl)

Synthesis of tert-butyl (4-chloro-2- (hydroxymethyl) phenyl) carbamate (2-amino-5-chlorophenyl) methanol (0.50 g, 3.2 mmol) was added to a solution of di-tert-butyl dicarbonate (0.83 g,3.8 mmol) in THF (5.0 mL). The reaction mixture was stirred at 40 ℃ for 2 days. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with 0% -30% EtOAc/cyclohexane to give the title compound which was used directly in the next step. 1H NMR (400 MHz, CDCl) ₃ )δ7.83(d,J＝8.6Hz,1H),7.65(br s,1H),7.23(dd,J＝2.4,8.7Hz,1H),7.13-7.11(m,1H),4.60(d,J＝5.6Hz,2H),2.62(t,J＝5.6Hz,1H),1.51(s,9H)。

Synthesis of tert-butyl (2- ((carbamoyloxy) methyl) -4-chlorophenyl) carbamate the title compound (0.15 g, 86%) was synthesized from tert-butyl (4-chloro-2- (hydroxymethyl) phenyl) carbamate and trichloroacetyl isocyanate in a similar manner to (R) -1- (3-chlorophenyl) ethyl carbamate. 1H NMR (400 MHz, CDCl) ₃ )δ7.83(s,1H),7.76(d,J＝8.1Hz,1H),6.79-6.74(m,2H),5.09(br s,2H),5.02(s,2H),1.51(s,9H)。

Synthesis of 2- ((tert-butoxycarbonyl) amino) -5-chlorobenzyl) carbamate of (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamate in a similar manner to (R) -1- (3-chlorophenyl) ethyl (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamate tert-butyl (2- ((carbamoyloxy) methyl) -4-chlorophenyl) carbamate and 6-chloro-N- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) pyrimidin-4-amine the title compound was synthesized and then used directly in the next step (0.21 g, 74%).

(6- (((6-Cyclopropylimidazo [1, 2-a))]Synthesis of pyridin-2-yl methyl) amino) pyrimidin-4-yl 2-amino-5-chlorobenzyl carbamate HCl (4.0M in 1, 4-dioxane, 20 μL,0.080 mmol) was added to 2- ((tert-butoxycarbonyl) amino) -5-chlorobenzyl- (6- (((6-cyclopropylimidazo [1,2-a ])]Pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamate (60 mg,0.053 mmol) in 1, 4-dioxane (0.5 mL). The mixture was stirred at room temperature for 4h, then by addition of NaHCO ₃ (saturated aqueous) quench and extract with DCM. The combined organics were passed through a hydrophobic frit followed by vacuum concentration to give the title compound which was used in the next step without further purificationIs a kind of medium.

(6- (((6-Cyclopropylimidazo [1, 2-a))]Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzyl carbamate of pyridin-2-yl methyl) amino) pyrimidin-4-yl ₃ (4.4 mg,0.067 mmol) and triethyl orthoformate (29. Mu.L, 0.17 mmol) were added to (6- (((6-cyclopropylimidazo [1,2-a ])]Pyridin-2-yl) methyl) amino) pyrimidin-4-yl 2-amino-5-chlorobenzyl carbamate (25 mg,0.054 mmol) in acetic acid (50 μl). The mixture was stirred at room temperature for 18h. The reaction was diluted with water and extracted with EtOAc. The combined organics were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by preparative HPLC to give the title compound (11 mg, 39%). ESI-MS (m+h) +:517.3,1H NMR (400 MHz, DMSO). Delta.10.22 (s, 1H), 9.89 (s, 1H), 8.29-8.29 (m, 1H), 8.16 (s, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.84 (br s, 1H), 7.77-7.70 (m, 2H), 7.60 (s, 1H), 7.36 (d, J=9.4 Hz, 1H), 6.95 (dd, J=1.8, 9.3Hz, 2H), 5.04 (s, 2H), 4.55 (s, 2H), 1.94-1.86 (m, 1H), 0.93-0.87 (m, 2H), 0.68-0.63 (m, 2H).

Example 9

Synthesis of 2- (3-chlorophenyl) -2-hydroxyethyl (I-9) carbamate (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl)

Synthesis of 1- (3-chlorophenyl) ethane-1, 2-diol OsO was prepared ₄ (2.5% in tBuOH, 0.45mL,0.036 mmol) was added dropwise to a solution of 3-chlorostyrene (1.0 g,7.2 mmol) and N-methyl-morpholine oxide (1.3 g,11 mmol) in water (9.0 mL) and tBuOH (27 mL). The mixture was stirred at room temperature for 18h. Adding Na ₂ SO ₃ (1.0M in water, 20 mL) and the mixture was stirred for 30min, followed by extraction with DCM. The combined organics were dried over MgSO ₄ Drying and concentration in vacuo gave the title compound which was used without further purification. 1H NMR (400 MHz, CDCl) ₃ ) Delta 7.38 (s, 1H), 7.33-7.21 (m, 3H), 4.79 (dd, j=3.4, 8.0hz, 1H), 3.76 (dd, j=3.4, 11.2hz, 1H), 3.70 (t, j=4.7 hz, 1H), 3.65-3.59 (m, 1H), one exchangeable proton is not presentVisible.

Synthesis of 2- ((tert-butyldimethylsilyl) oxy) -1- (3-chlorophenyl) ethan-1-ol imidazole (0.54 g,7.9 mmol) and tert-butyldimethylsilyl chloride (1.2 g,7.9 mmol) were added to a solution of 1- (3-chlorophenyl) ethane-1, 2-diol (1.3 g,7.2 mmol) in DCM (35 mL). The mixture was stirred at room temperature for 18h. The mixture was filtered and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 20% EtOAc/cyclohexane to give the title compound (1.5 g, 70%). 1H NMR (400 MHz, CDCl) ₃ ) Delta 7.38 (s, 1H), 7.31-7.20 (m, 3H), 4.72 (dd, j=3.5, 8.3hz, 1H), 3.76 (dd, j=3.5, 10.1hz, 1H), 3.52 (dd, j=8.5, 10.0hz, 1H), 0.91 (s, 9H), 0.06 (d, j=3.3 hz, 6H), exchangeable protons are not visible.

Synthesis of 2- ((tert-butyldimethylsilyl) oxy) -1- (3-chlorophenyl) ethyl carbamate the title compound (0.35 g, 61%) was synthesized starting with 2- ((tert-butyldimethylsilyl) oxy) -1- (3-chlorophenyl) ethyl-1-ol and trichloroacetyl isocyanate in a similar manner as (R) -1- (3-chlorophenyl) ethyl carbamate. 1H NMR (400 MHz, CDCl) ₃ )δ7.34(s,1H),7.29-7.18(m,3H),5.69-5.64(m,1H),4.68(br s,2H),3.87-3.75(m,2H),0.87-0.85(m,9H),0.00(d,J＝1.9Hz,6H)。

Synthesis of (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamic acid 2- ((tert-butyldimethylsilyl) oxy) -1- (3-chlorophenyl) ethyl ester the title compound was synthesized starting with (R) -1- (3-chlorophenyl) ethyl carbamate in a similar manner to (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) ethyl carbamate in 2- ((tert-butyldimethylsilyl) oxy) -1- (3-chlorophenyl) ethyl carbamate and 6-chloro-N- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) pyrimidin-4-amine (0.25 g, quantitative). ESI-MS (m+h) +:593.3.

synthesis of (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamic acid 2- (3-chlorophenyl) -2-hydroxyethyl ester TBAF (3.3M in THF, 0.15mL,0.51 mmol) was added to a solution of (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamic acid 2- ((tert-butyldimethylsilyl) oxy) -1- (3-chlorophenyl) ethyl ester (0.20 g,0.10 mmol) in THF (2.0 mL). The mixture was stirred at room temperature for 1h. Water was added and the mixture was extracted with DCM. The organic extract was passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the product as a 85:15 mixture of isomers (3 mg, 6%). ESI-MS (m+h) +:479.3,1H NMR (major isomer) (400 MHz, DMSO). Delta.9.95 (s, 1H), 8.23-8.19 (m, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.55-7.51 (m, 1H), 7.41-7.38 (m, 1H), 7.30-7.26 (m, 4H), 6.92-6.86 (m, 2H), 5.68 (s, 1H), 4.77-4.73 (m, 1H), 4.48 (s, 2H), 4.06 (d, J=5.6 Hz, 2H), 1.87-1.79 (m, 1H), 0.87-0.80 (m, 2H), 0.61-0.57 (m, 2H).

Example 10

Synthesis of 1- (5-chloro-2- (1H-tetrazol-1-yl) benzyl) -3- (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl) urea (I-10)

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzoic acid

To 2-amino-5-chlorobenzoic acid (100 mg,0.58 mmol) and NaN ₃ (38 mg,0.58 mmol) to a mixture in triethoxymethane (3 mL) was added P ₂ O ₅ (16 mg,0.12 mmol). The mixture was stirred at 130℃for 3h. After cooling the reaction to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organics were purified over Na ₂ SO ₄ Drying and concentration in vacuo afforded the crude product, which was purified by recrystallization from DCM to give 5-chloro-2- (1H-tetrazol-1-yl) benzoic acid (55 mg, 42%) as a yellow solid. ESI-MS [ M+H ]]+：225.1。

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzamide

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To 5-chloro-2- (1H-tetrazol-1-yl) benzoic acid (55 mg,0.24 mmol), NH ₄ To a solution of Cl (26 mg,0.49 mmol), HOBt (66 mg,0.49 mmol), EDCI (94 mg,0.49 mmol) in DMF (5 mL) was added DIPEA (127 mg,0.98 mmol). The mixture was stirred at 25℃for 16h, followed by the addition of water (30 mL). The mixture was extracted with EtOAc (20 ml x 3) and the combined organics were taken over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give 5-chloro-2- (1H-tetrazol-1-yl) benzamide as a yellow oil (40 mg, 73%). ESI-MS [ M+H ] ]+：224.0。

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzonitrile

To a mixture of 5-chloro-2- (1H-tetrazol-1-yl) benzamide (40 mg,0.18 mmol) in DMF (2 mL) was added POCl at 0deg.C ₃ (165 mg,1.08 mmol). The mixture was stirred at 25℃for 16h. Water (20 mL) was added and the mixture was extracted with DCM (10 mL. Times.3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried and concentrated in vacuo to give 5-chloro-2- (1H-tetrazol-1-yl) benzonitrile (30 mg, 81%) as an oil. ESI-MS [ M+H ]]+：206.1。

Synthesis of (5-chloro-2- (1H-tetrazol-1-yl) phenyl) methylamine

To 5-chloro-2- (1H-tetrazol-1-yl) benzonitrile (30 mg,0.15 mmol) in NH ₃ To a mixture in MeOH (2 mL,7M in MeOH) was added Rani (30 mg). The mixture is put in H ₂ And stirred at 25 ℃ for 1h, then filtered and the filter cake washed with MeOH (10 mL). The filtrate was concentrated in vacuo to give (5-chloro-2- (1H-tetrazol-1-yl) phenyl) methylamine (21 mg, 67%) as a yellow oil, which was used in the next step without purification. ESI-MS [ M+H ]]+：210.1。

Synthesis of 2-bromo-N- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) pyridin-4-amine

A mixture of (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methylamine (935 mg,5 mmol), 2-bromo-4-fluoropyridine (1.1 g,6.25 mmol) and DIPEA (1.29 g,10 mmol) in iPrOH (30 mL) was stirred at 100deg.C for 12h. The reaction was cooled to room temperature and concentrated in vacuo to give the crude material, which was purified by silica gel column chromatography (eluent: PE/etoac=1/1) to give 2-bromo-N- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) pyridin-4-amine (1 g, 58%) as a yellow solid. ESI-MS [ M+H ] +:344.2

Synthesis of N- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -2- ((diphenylmethylene) amino) pyridin-4-amine

2-bromo-N- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl pyridin-4-amine (1 g,2.9 mmol), diphenylazomethine (1.1 g,5.8 mmol), pd ₂ (dba) ₃ A mixture of (265 mg,0.29 mmol), BINAP (360 mg,0.58 mmol) and tBuONa (835 mg,8.7 mmol) in toluene (25 mL) was stirred at 90℃for 12h. The reaction was diluted with water (40 mL) followed by extraction with EtOAc (40 mL. Times.3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave the crude product, which was purified by silica gel column chromatography (eluent: PE/etoac=2/1) to give N- ((6-cyclopropylimidazo [1, 2-a) as a yellow solid]Pyridin-2-yl) methyl) -2- ((diphenylmethylene) amino) pyridin-4-amine (760 mg, 59%). ESI-MS [ M+H ]]+：444.1。

N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Synthesis of pyridin-2-yl) methyl) pyridin-2, 4-diamine

N- ((6-Cyclopropylimidazo [1, 2-a) at 0deg.C]Pyridin-2-yl) methyl) -2- ((diphenylmethylene) amino) pyridin-4-amine (013 mg,1 mmol) in MeOH (10 mL) was added HCl (2 mL, 4M solution in MeOH). The resulting reaction was stirred at room temperature for 1h. The reaction was concentrated in vacuo to give the crude product, which was taken up with NH ₃ (5 mL, 7M solution in MeOH) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM/meoh=10/1) to give N as a yellow solid ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) pyridine-2, 4-diamine (260 mg, 93%). ESI-MS [ M+H ]]+：280.2。

Synthesis of 1- (5-chloro-2- (1H-tetrazol-1-yl) benzyl) -3- (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl) urea

Will N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]A solution of pyridin-2-yl) methyl pyridine-2, 4-diamine (28 mg,0.1 mmol), bis (1H-imidazol-1-yl) methanone (32 mg,0.2 mmol) and triethylamine (50 mg,0.5 mmol) in DCM (1.0 mL) was stirred at room temperature for 3H. A solution of (5-chloro-2- (1H-tetrazol-1-yl) phenyl) methylamine (42 mg,0.2 mmol) in DCM (0.5 mL) was then added. The mixture was stirred at room temperature for 2h. The reaction mixture was concentrated in vacuo to give the crude material, which was purified by preparative TLC (eluent: DCM/meoh=20/1) to give 1- (5-chloro-2- (1H-tetrazol-1-yl) benzyl) -3- (4- (((6-cyclopropylimidazo [1, 2-a)) as a white solid]Pyridin-2-yl) methyl) amino) pyridin-2-yl) urea (10.9 mg, 21%). ESI-MS [ M+H ]] ⁺ ：515.2。1H NMR(400MHz,DMSO)δ9.85(s,1H),9.35(s,1H),8.96(s,1H),8.27(s,1H),7.60-7.57(m,5H),7.35(d,J＝9.3Hz,1H),7.10(s,1H),6.94(dd,J＝9.3,1.6Hz,1H),6.27-6.21(m,2H),4.29-4.23(m,4H),1.91-1.85(m,1H),0.88-0.85(m,2H),0.65-0.61(m,2H)。

Example 11

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzyl (I-11) carbamate (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl)

Synthesis of (2-amino-5-chlorophenyl) methanol

To a solution of 2-amino-5-chlorobenzaldehyde (0.50 g,3.2 mmol) in THF (10 mL) was added NaBH ₄ (0.18 g,4.8 mmol) and the resulting mixture was stirred at room temperature for 3h. The reaction mixture was quenched with water (30 mL), extracted with EtOAc (30 mL x 3) and washed with brine (40 mL x 2). The combined organic phases were taken up in Na ₂ SO ₄ Drying and concentration in vacuo gave the crude product, which was purified by column chromatography (eluent: PE/etoac=2/1) to give (2-amino-5-chlorophenyl) methanol (0.40 g, 80%) as a yellow solid. ESI-MS: [ M+H ]]+,156.1

Synthesis of (5-chloro-2- (1H-tetrazol-1-yl) phenyl) methanol

To a solution of (2-amino-5-chlorophenyl) methanol (0.36 g,2.3 mmol) in trimethoxy methane (5 mL) at 0deg.C was added NaN ₃ (0.37 g,5.7 mmol). The mixture was stirred at 0deg.C for 40min. Subsequently, acetic acid (0.05 mL) was added, and the mixture was stirred at 80 ℃ for 16h. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (20 mL x 3) and washed with brine (30 mL x 2). The combined organic phases were taken up in Na ₂ SO ₄ Drying and concentration in vacuo gave the crude product, which was purified by column chromatography (eluent: PE/etoac=1/1) to give (5-chloro-2- (1H-tetrazol-1-yl) phenyl) methanol (0.21 g, 43%) as a yellow solid. ES (ES) I-MS：[M+H]+,211.1

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzyl (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl) carbamate

Will N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]A solution of pyridin-2-yl) methyl pyridine-2, 4-diamine (35 mg,0.13 mmol), bis (1H-imidazol-1-yl) methanone (41 mg,0.25 mmol) and triethylamine (64 mg,0.63 mmol) in DCM (1.5 mL) was stirred at room temperature for 3H. A solution of (5-chloro-2- (1H-tetrazol-1-yl) phenyl) methanol (53 mg,0.25 mmol) in DCM (0.5 mL) was then added. The mixture was stirred at room temperature for 2h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM/meoh=12/1) to give (4- (((6-cyclopropylimidazo [1, 2-a)) as a white solid]Pyridin-2-yl) methyl) amino) pyridin-2-yl) carbamic acid 5-chloro-2- (1H-tetrazol-1-yl) benzyl ester (11.9 mg, 18%). ESI-MS [ M+H ]] ⁺ ：516.2,1H NMR(400MHz,DMSO)δ9.94-9.80(m,2H),8.28(s,1H),7.88(s,1H),7.73-7.68(m,3H),7.60(s,1H),7.35(d,J＝9.3Hz,1H),7.12(t,J＝5.5Hz,1H),7.03(s,1H),6.94(dd,J＝9.3,1.4Hz,1H),6.28(dd,J＝5.7,1.8Hz,1H),4.98(s,2H),4.32(d,J＝5.5Hz,2H),1.91-1.85(m,1H),0.90-0.85(m,2H),0.65-0.61(m,2H)。

Example 12

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzyl (4- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methoxy) pyridin-2-yl) carbamate (I-12)

Synthesis of 2- (((2-bromopyridin-4-yl) oxy) methyl) -6-cyclopropylimidazo [1,2-a ] pyridine

At 0℃to (6-cyclopropylimidazo [1, 2-a)]To a solution of pyridin-2-yl) methanol (0.50 g,2.7 mmol) in DMF (5 mL) was added NaH (0.32 g,60% in mineral oil, 8.0 mmol) and the mixture stirred at 0deg.C for 0.5h. A solution of 2-bromo-4-fluoropyridine (0.93 g,5.3 mmol) in DMF (1 mL) was then added and the mixture was stirred at room temperature for 3h. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (30 ml x 2), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave the crude product, which was purified by column chromatography (eluent: DCM/meoh=50/1) to give 2- (((2-bromopyridin-4-yl) oxy) methyl) -6-cyclopropylimidazo [1, 2-a) as a yellow oil]Pyridine (0.65 g, 70%). ESI-MS: [ M+H ]] ⁺ ,344.1

Synthesis of 4- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methoxy) -N- (4-methoxybenzyl) pyridin-2-amine

2- (((2-bromopyridin-4-yl) oxy) methyl) -6-cyclopropylimidazo [1, 2-a)]Pyridine (0.65 g,1.9 mmol), (4-methoxyphenyl) methylamine (0.78 g,5.9 mmol), pd-PEPPI-IPentCl ₂ MePy (0.16 g,0.19 mmol) and Cs ₂ CO ₃ (1.9 g,5.9 mmol) in NMP (10 mL) in N ₂ And stirring at 100deg.C for 18h. Passing the reaction mixture throughThe mixture was filtered and the filter cake was washed with DCM/MeOH (10/1, 100 mL). The filtrate was concentrated in vacuo to give the crude material which was purified by column chromatography (eluent: DCM/meoh=25/1) to give 4- ((6-cyclopropylimidazo [1, 2-a) as a yellow oil]Pyridin-2-yl) methoxy) -N- (4-methoxybenzyl) pyridin-2-amine (0.70 g, 92%). ESI-MS: [ M+H ]] ⁺ ,401.2

Synthesis of 4- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methoxy) pyridin-2-amine

To 4- ((6-cyclopropylimidazo [1, 2-a) at 0deg.C ]Pyridin-2-yl) methoxy) -N- (4-methoxybenzyl) pyridin-2-amine (0.70 g,1.8 mmol) to a solution of TFA (10 mL) in DCM (10 mL) was added and the mixture stirred at room temperature for 2h. The reaction was taken up with saturated NaHCO ₃ The aqueous solution (50 mL) was quenched, extracted with EtOAc (30 mL. Times.3) and washed with brine (100 mL. Times.2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave the crude material, which was purified by column chromatography (eluent: DCM/meoh=10/1) to give 4- ((6-cyclopropylimidazo [1, 2-a) as a brown solid]Pyridin-2-yl) methoxy) pyridin-2-amine (0.50 g, quantitative). ESI-MS: [ M+H ]] ⁺ ,281.2。

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzyl (4- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methoxy) pyridin-2-yl) carbamate

4- ((6-Cyclopropylimidazo [1, 2-a)]A mixture of pyridin-2-yl-methoxy) pyridin-2-amine (50 mg,0.18 mmol), bis (1H-imidazol-1-yl) methanone (43 mg,0.27 mmol) and triethylamine (54 mg,0.54 mmol) in DCM (5 mL) was stirred at room temperature for 5H, then (5-chloro-2- (1H-tetrazol-1-yl) phenyl) methanol (75 mg,0.36 mmol) was added and stirred at room temperature for 16H. The reaction mixture was concentrated in vacuo to give the crude material, which was purified by preparative TLC (eluent: DCM/meoh=10/1) to give (4- ((6-cyclopropylimidazo [1, 2-a) as a white solid ]Pyridin-2-yl) methoxy) pyridin-2-yl) carbamic acid 5-chloro-2- (1H-tetrazol-1-yl) benzyl ester (10 mg, 11%). ESI-MS: [ M+H ]] ⁺ ,517.2；1H NMR(400MHz,DMSO)δ10.31(s,1H),9.90(s,1H),8.35(s,1H),8.10(d,J＝5.8Hz,1H),7.93(d,J＝1.8Hz,1H),7.88(s,1H),7.78-7.70(m,2H),7.45-7.41(m,2H),7.03-6.99(m,1H),6.83-6.79(m,1H),5.23(s,2H),5.06(s,2H),1.96-1.91(m,1H),0.96-0.89(m,2H),0.72-0.66(m,2H)。

Example 13

Synthesis of 3-chlorobenzyl (I-13) carbamate (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl)

Synthesis of 3-chlorobenzyl (2, 2-trichloroacetyl) carbamate

To a solution of (3-chlorophenyl) methanol (0.8 g,5.6 mmol) in DCM (10 mL) was added 2, 2-trichloroacetyl isocyanate (1.27 g,6.8 mmol) at room temperature and the mixture was stirred at room temperature for 18h. The mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo to give 3-chlorobenzyl (2, 2-trichloroacetyl) carbamate (1.5 g, crude) as a white solid, which was used directly in the next step. ESI-MS [ M+H ]]+：329.9

Synthesis of 3-chlorobenzyl carbamate

3-chlorobenzyl (2, 2-trichloroacetyl) carbamate (1.5 g, crude material) and K ₂ CO ₃ A mixture of (1.9 g,13.8 mmol) in MeOH (10 mL) was stirred at room temperature for 2h. The mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: etOAc/PE,0 to 30%) to give 3-chlorobenzyl carbamate (700 mg,67%,2 steps) as a white solid. ESI-MS [ M+H ] ]+：186.0

Synthesis of 1- (3-chlorophenyl) ethyl (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl) carbamate

3-chlorobenzyl carbamate (65 mg,0.35 mmol), 2-bromo-N- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl pyridin-4-amine (120 mg,0.35 mmol), pd ₂ (dba) ₃ (32 mg,0.035 mmol), xantphos (40 mg,0.070 mmol) and Cs ₂ CO ₃ (228 mg,0.70 mmol) in 1, 4-dioxane (5 mL) with N ₂ Deaeration and stirring for 16h at 90 ℃. Passing the mixture throughThe mixture was filtered and the filter cake was washed with DCM/MeOH (10/1, 50 mL). The filtrate was concentrated in vacuo to give the crude material, which was purified by preparative TLC (eluent: DCM/meoh=20/1) to give (4- (((6-cyclopropylimidazo [1, 2-a)) as a white solid]Pyridin-2-yl) methyl) amino) pyridin-2-yl) carbamic acid 1- (3-chlorophenyl) ethyl ester (20 mg,13% yield). ESI-MS [ M+H ]]+：448.1,1H NMR(400MHz,DMSO)δ9.79(s,1H),8.30(s,1H),7.73(d,J＝5.8Hz,1H),7.63(s,1H),7.50(s,1H),7.43-7.34(m,4H),7.15-7.08(m,2H),6.96(dd,J＝9.3,1.7Hz,1H),6.30(dd,J＝5.8,2.0Hz,1H),5.13(s,2H),4.35(d,J＝5.8Hz,2H),1.92-1.85(m,1H),0.97-0.79(m,2H),0.70-0.61(m,2H)。

Example 14

Synthesis of 3-chlorobenzyl (I-14) carbamate (3- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl)

Synthesis of ethyl 2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) acetate

A mixture of ethyl 4-chloro-3-oxobutanoate (3.0 g,18 mmol) and 5-cyclopropylpyridin-2-amine (2.0 g,15 mmol) in ethanol (30 mL) was stirred at 90℃for 24h. The reaction mixture was then concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (eluting with 20% -60% EtOAc/PE) to give ethyl 2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) acetate (1.3 g, 36%) as a white solid. ESI-MS [ M+H ] +:245.1

Synthesis of 2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) acetic acid

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To 2- (6-cyclopropyl imidazo [1, 2-a)]To a solution of ethyl pyridin-2-yl) acetate (1.3 g,5.3 mmol) in THF (15 mL) and water (5 mL) was added NaOH (0.32 g,8.0 mmol). The mixture was heated to 90 ℃ for 1h. After cooling to room temperature, the resulting mixture was taken up in HCl (2N in H ₂ O) to ph=6. The resulting precipitate was collected by filtration and then dried in vacuo to give 2- (6-cyclopropylimidazo [1, 2-a) as a brown solid]Pyridin-2-yl) acetic acid (850 mg, 74%). ESI-MS [ M+H ]]+：217.1。

(E) Synthesis of (E) -5-bromo-2-hydrazono-1, 2-dihydropyrazine

A mixture of 2, 5-dibromopyrazine (1.6 g,6.7 mmol) and hydrazine hydrate (1.7 g,34 mmol) in i-PrOH (20 mL) was stirred at 65℃for 16h. The reaction mixture was treated with NaHCO ₃ (saturated aqueous, 30 mL) and extracted with EtOAc (40 mL. Times.5). The combined organics were washed with brine (20 mL), dried over Na ₂ SO ₄ Dried and concentrated in vacuo to give (E) -5-bromo-2-hydrazono-1, 2-dihydropyrazine (1.1 g, crude material) as a yellow solid. ESI-MS [ M+H ]] ⁺ ：189.0。

(E) Synthesis of-N' - (5-bromopyrazin-2 (1H) -ylidene) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) acethydrazide

(E) -5-bromo-2-hydrazono-1, 2-dihydropyrazine (400 mg,2.1 mmol), 2- (6-cyclopropylimidazo [1, 2-a) ]A mixture of pyridin-2-yl) acetic acid (550 mg,2.5 mmol), EDCI (1.2 g,6.4 mmol), HOBt (0.86 g,6.4 mmol) and DIPEA (1.6 g,12 mmol) in DMF (10 mL) was stirred at room temperature for 16h. The reaction mixture was quenched with water (60 mL) and extracted with EtOAc (50 mL x 5). The combined organics were washed with brine (50 mL), dried over Na ₂ SO ₄ Drying, followed by concentration in vacuo, gives the crude product which is purified by column chromatography (eluent: DCM/meoh=10/1) to give (E) -N' - (5-bromopyrazine-2 (1H) -ylidene) -2- (6-cyclopropylimidazo [1, 2-a) as a yellow solid]Pyridin-2-yl) acethydrazide (450 mg, 56%). ESI-MS [ M+H ]] ⁺ ：387.0。

Synthesis of 6-bromo-3- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) - [1,2,4] triazolo [4,3-a ] pyrazine

To (E) -N' - (5-bromopyrazin-2 (1H) -ylidene) -2- (6-cyclopropylimidazo [1, 2-a) at room temperature]Pyridin-2-yl) Acetylhydrazine (290 mg,0.75 mmol), C ₂ Cl ₆ (0.71 g,3.0 mmol) and PPh ₃ (0.79 g,3.0 mmol) in DCM (20 mL) to which Et is added ₃ N (0.30 g,3.0 mmol) and the mixture was stirred under nitrogen at room temperature for 16h. The reaction mixture was diluted with DCM (50 mL), washed with water (30 mL) and brine (30 mL), and dried over Na ₂ SO ₄ Drying and concentration in vacuo gave the crude product, which was purified by column chromatography (eluent: DCM/meoh=0-10/1) to give 6-bromo-3- ((6-cyclopropylimidazo [1, 2-a) as a yellow solid ]Pyridin-2-yl) methyl) - [1,2,4]Triazolo [4,3-a ]]Pyrazine (190 mg, 69%). ESI-MS [ M+H ]] ⁺ ：369.0。

Synthesis of 3-chlorobenzyl (3- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl) carbamate

6-bromo-3- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) - [1,2,4]Triazolo [4,3-a ]]Pyrazine (60 mg,0.16 mmol), 3-chlorobenzyl carbamate (30 mg,0.25 mmol), pd ₂ (dba) ₃ (15 mg,0.016 mmol), xantphos (19 mg,0.033 mmol) and Cs ₂ CO ₃ (0.16 g,0.49 mmol) in 1, 4-dioxane (8 mL) in N ₂ And stirred at 70℃for 10h. Passing the reaction mixture throughThe mixture was filtered and the filter cake was washed with DCM/MeOH (10/1, 100 mL). The filtrate was concentrated in vacuo to give the crude material, which was purified by column chromatography (eluent: DCM/meoh=10/1) and preparative HPLC to give the desired product as a white solid (2.5 mg, 3.3%). ESI-MS [ M+H ]] ⁺ ：474.1,1H NMR(400MHz,MeOD)δ9.11(d,J＝1.4Hz,1H),8.57(s,1H),8.18(s,1H),7.71(s,1H),7.41(s,1H),7.40-7.29(m,4H),7.08(d,J＝9.2Hz,1H),5.15(s,2H),4.72(s,2H),1.97-1.91(m,1H),1.00-0.93(m,2H),0.73-0.67(m,2H)。

Example 15

Synthesis of 1- (3-chlorophenyl) ethyl (I-15) carbamate (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl)

Synthesis of 1- (3-chlorophenyl) ethyl (2, 2-trichloroacetyl) carbamate

To a solution of 1- (3-chlorophenyl) ethan-1-ol (1.0 g,6.4 mmol) in DCM (10 mL) was added 2, 2-trichloroacetyl isocyanate (1.37 g,7.3 mmol) at room temperature and the mixture was stirred at room temperature for 18h. The mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo to give 1- (3-chlorophenyl) ethyl (2, 2-trichloroacetyl) carbamate (2 g, crude) as a white solid, which was used directly in the next step. ESI-MS [ M+H ]]+：343.9。

Synthesis of 1- (3-chlorophenyl) ethyl carbamate

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1- (3-chlorophenyl) ethyl (2, 2-trichloroacetyl) carbamate (1.0 g, crude material) and K ₂ CO ₃ A mixture of (1.2 g,8.7 mmol) in MeOH (10 mL) was stirred at room temperature for 2h. The mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: etOAc/PE,0 to 30%) to give 1- (3-chlorophenyl) ethyl carbamate (500 mg,78% yield) as a white solid. ESI-MS [ M+H ]]+：200.0

1- (3-chlorophenyl) ethyl carbamate (70 mg,0.35 mmol), 2-bromo-N- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl pyridin-4-amine (120 mg,0.35 mmol), pd ₂ (dba) ₃ (32 mg,0.035 mmol), xantphos (40 mg,0.070 mmol) and Cs ₂ CO ₃ (228 mg,0.70 mmol) in 1, 4-dioxane (5 mL) with N ₂ Deaeration and stirring for 16h at 90 ℃. Passing the mixture throughThe mixture was filtered and the filter cake was washed with DCM/MeOH (10/1, 50 mL). The filtrate was concentrated in vacuo to give the crude material, which was purified by column chromatography (eluent: DCM/meoh=0% -5%) to give (4- (((6-cyclopropylimidazo [1, 2-a)) as a white solid]Pyridin-2-yl) methyl) amino) pyridin-2-yl) carbamic acid 1- (3-chlorophenyl) ethyl ester (15 mg,9% yield). ESI-MS [ M+H ]]+：462.2,1H NMR(400MHz,DMSO)δ9.73(s,1H),8.30-8.27(m,1H),7.72(d,J＝5.8Hz,1H),7.61(s,1H),7.51-7.49(m,1H),7.43-7.32(m,4H),7.10-7.03(m,2H),6.98-6.93(m,1H),6.31-6.27(m,1H),5.80-5.73(m,1H),4.33(d,J＝5.8Hz,2H),1.94-1.85(m,1H),1.48(d,J＝6.6Hz,3H),0.93-0.87(m,2H),0.68-0.63(m,2H)。

Example 16

Synthesis of 3-chlorobenzyl (I-16) carbamate (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-imidazo [4,5-c ] pyridin-6-yl)

Synthesis of 2-chloro-N- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -5-nitropyridin-4-amine

2, 4-dichloro-5-nitropyridine (1 g,5.18 mmol), (6-cyclopropylimidazo [1, 2-a)]A mixture of pyridin-2-yl) methylamine (1.1 g,6.22 mmol) and DIPEA (2 g,15.54 mmol) in THF (20 mL) was stirred at 60℃for 6h. The mixture was treated with NaHCO ₃ (saturated aqueous, 50 mL) and extracted with EtOAc (50 mL. Times.3). The combined organic layers were washed with brine (50 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM/meoh=0% -6%) to give 2-chloro as a white solid -N- ((6-cyclopropyl imidazo [1, 2-a)]Pyridin-2-yl) methyl) -5-nitropyridin-4-amine (1.5 g, 84%). ESI-MS [ M+H ]]+：344.2。

6-chloro-N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Synthesis of pyridin-2-yl) methyl) pyridine-3, 4-diamine

To 2-chloro-N- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -5-nitropyridin-4-amine (1.5 g,4.37 mmol) and NH ₄ To a mixture of Cl (2.3 g,43.7 mmol) in EtOH/water (20 mL/5 mL) was added Fe (2.4 g,43.7 mmol). The resulting reaction mixture was taken up in N ₂ And stirred at 100℃for 3h. After cooling to room temperature, the mixture was quenched with water (50 mL) and extracted with DCM (50 mL x 5). The combined organic layers were washed with brine (50 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM/meoh=0% -5%) to give 6-chloro-N as a yellow solid ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) pyridine-3, 4-diamine (1.2 g, 88%). ESI-MS [ M+H ]]+：314.2。

Synthesis of 5- (2, 2-difluorocyclopropyl) -N, N-bis (4-methoxybenzyl) pyridin-2-amine

By reacting 6-chloro-N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]A mixture of pyridin-2-yl) methyl pyridine-3, 4-diamine (1.2 g,3.83 mmol) and PTSA (65.0 mg,0.38 mmol) in trimethoxy methane (5 ml) was stirred at 60℃for 12h. Water (50 mL) was added and the mixture was extracted with DCM (50 mL. Times.3). The combined organic layers were washed with brine (50 mL), and dried over Na ₂ SO ₄ Drying and concentration in vacuo gave the crude material, which was purified by column chromatography (eluent: PE/etoac=20/1-2/1) to give 6-chloro-1- ((6-cyclopropylimidazo [1, 2-a) as a yellow solid]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Pyridine (500 mg, 40%). ESI-MS [ M+H ]]+：324.2。

Synthesis of 1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -N- (4-methoxybenzyl) -1H-imidazo [4,5-c ] pyridin-6-amine

To 6-chloro-1- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Pyridine (500 mg,1.55 mmol), PMBNH ₂ (318.5 mg,2.32 mmol) and Cs ₂ CO ₃ (1.5 g,4.65 mmol) to a mixture of Pd-PEPPI-iPont-Cl-O-methylpyridine (134 mg,0.16 mmol) in DMF (10 mL) was added. The reaction mixture was taken up in N ₂ And stirring at 85℃for 16h. Water (100 mL) was added and the mixture extracted with EtOAc (100 mL. Times.3). The combined organic layers were washed with brine (50 mL), and dried over Na ₂ SO ₄ Drying and concentration in vacuo gave the crude material, which was purified by column chromatography (eluent: PE/etoac=10/1-2/1) to give 6-chloro-1- ((6-cyclopropylimidazo [1, 2-a) as a yellow solid]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Pyridine (300 mg, 46%). ESI-MS [ M+H ]]+：425.2。

Synthesis of 1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-imidazo [4,5-c ] pyridin-6-amine

6-chloro-1- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]A solution of pyridine (300 mg,0.71 mmol) in TFA (4 mL) was stirred at room temperature for 12h. The mixture was concentrated in vacuo and the residue was taken up in NaHCO ₃ (saturated aqueous, 50 mL) and extracted with DCM (50 mL. Times.3). The combined organic layers were washed with brine (30 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by preparative TLC (DCM/meoh=20/1) to give 1- ((6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Pyridin-6-amine (140 mg, 65%). ESI-MS [ M+H ]]+：305.2。

Synthesis of 3-chlorobenzyl (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-imidazo [4,5-c ] pyridin-6-yl) carbamate

To a mixture of CDI (29 mg,0.18 mmol) in THF (3 mL) at 0deg.C was added 1- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Pyridin-6-amine (50 mg,0.16 mmol) and the mixture was stirred at room temperature for 2h. (3-chlorophenyl) methanol (28 mg,0.20 mmol) was then added thereto, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL. Times.3). The organic layer was washed with brine (30 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by column chromatography (MeOH/DCM, 0 to 5%) to give (1- ((6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Pyridin-6-yl) carbamic acid 3-chlorobenzyl ester (22 mg, 29%). ESI-MS [ M+H ]] ⁺ ：473.1,1H NMR(400MHz,DMSO)δ10.24(s,1H),8.64(d,J＝0.9Hz,1H),8.39(s,1H),8.32(s,1H),7.97(d,J＝0.9Hz,1H),7.73(s,1H),7.51(s,1H),7.43-7.35(m,4H),7.01-6.96(m,1H),5.54(s,2H),5.17(s,2H),1.96-1.85(m,1H),0.95-0.85(m,2H),0.70-0.60(m,2H)。

Example 17

Synthesis of 1- (3-chlorophenyl) ethyl (I-17) carbamate (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-imidazo [4,5-c ] pyridin-6-yl)

(1- ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Synthesis of 1- (3-chlorophenyl) ethyl pyridin-6-yl) carbamate 1- ((6-cyclopropylimidazo [1, 2-a) was added to a mixture of CDI (29 mg,0.18 mmol) in THF (3 mL) at 0deg.C]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Pyridin-6-amine (50 mg,0.16 mmol) and the resulting mixture was stirred at room temperature for 2h. 1- (3-chlorophenyl) ethan-1-ol (31 mg,0.20 mmol) was then added and the mixture was stirred at room temperature for an additional 18h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL. Times.3). The organic layer was washed with brine (30 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by column chromatography (MeOH/DCM, 0 to 5%) to give (1- ((6-cyclopropylimidazo [1, 2-a) as a white solid ]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Pyridin-6-yl) carbamic acid 1- (3-chlorophenyl) ethyl ester (35 mg, 45%). ESI-MS [ M+H ]]+：487.2。1H NMR(400MHz,DMSO)δ10.19(s,1H),8.64(d,J＝0.9Hz,1H),8.38(s,1H),8.31(s,1H),7.93(d,J＝0.9Hz,1H),7.70(s,1H),7.52(s,1H),7.43-7.32(m,4H),7.00-6.95(m,1H),5.83-5.78(m,1H),5.52(s,2H),1.95-1.84(m,1H),1.51(d,J＝6.6Hz,3H),0.92-0.87(m,2H),0.67-0.62(m,2H)。

Example 18 and example 19

Synthesis of 3-chlorobenzyl (I-18) carbamate (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] pyridin-4-yl) carbamate and 3-chlorobenzyl (I-19) carbamate (2- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] pyridin-4-yl) carbamate

Synthesis of 4-chloro-1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] pyridine

To 2- (chloromethyl) -6-cyclopropylimidazo [1,2-a ]]To a solution of pyridine (673 mg,3.26 mmol) in DMF (30 mL) was added 4-chloro-1H-pyrazolo [4,3-c]Pyridine (500 mg,3.26 mmol) and Cs ₂ CO ₃ (2.13 g,6.52 mmol) and the mixture was stirred at room temperature for 5h. Water (100 mL) was added and the mixture extracted with EtOAc (3X 100 mL). Will be combined withThe organic layer was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo afforded the crude material, which was purified by preparative TLC (DCM/meoh=50/1) to give 4-chloro-1- ((6-cyclopropylimidazo [1, 2-a) as a yellow solid]Pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]Pyridine and 4-chloro-2- ((6-cyclopropylimidazo [1, 2-a) ]Pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]Pyridine (900 mg,85%, mixture). ESI-MS [ M+H ]]+：324.1。

Synthesis of 1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -N- (4-methoxybenzyl) -1H-pyrazolo [4,3-c ] pyridin-4-amine

To 4-chloro-1- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]To a solution of pyridine (350 mg,1.08mmol, mixture) in DMF (1 mL) and DME (1.6 mL) was added (4-methoxyphenyl) methylamine (222 mg,1.62 mmol), pd-PEPPI-iPont-Cl-o-methylpyridine (42 mg,0.05 mmol) and Cs ₂ CO ₃ (1.05 g,3.24 mmol). In use N ₂ After degassing for 1min, the reaction was irradiated in a microwave reactor at 95 ℃ for 2h. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were washed with brine (20 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM: meoh=0% -10%) to give 1- ((6-cyclopropylimidazo [1, 2-a) as a yellow oil]Pyridin-2-yl) methyl) -N- (4-methoxybenzyl) -1H-pyrazolo [4,3-c]Pyridin-4-amines and 2- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -N- (4-methoxybenzyl) -2H-pyrazolo [4,3-c]Pyridin-4-amine (300 mg,66%, mixture). ESI-MS [ M+H ] ] ⁺ ：425.2。

Synthesis of 1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] pyridin-4-amine

1- ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -N- (4-methoxybenzyl) -1H-pyrazolo [4,3-c]A solution of pyridin-4-amine (300 mg,0.71mmol, mixture) in trifluoroacetic acid (10 mL) was stirred at 70℃for 3h. The mixture was treated with NaHCO ₃ (saturated aqueous, 100 mL) and extracted with EtOAc (30 mL. Times.4). The combined organic layers were washed with brine (20 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo to give 1- ((6-cyclopropylimidazo [1, 2-a) as a yellow oil]Pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]Pyridin-4-amines and 2- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]Pyridin-4-amine (180 mg,83% yield, mixture) was used without purification. ESI-MS [ M+H ]] ⁺ ：305.1。

Synthesis of 3-chlorobenzyl (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] pyridin-4-yl) carbamate

To 1- ((6-cyclopropylimidazo [1, 2-a) at room temperature]Pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]To a mixture of pyridin-4-amine (180 mg,0.71mmol, mixture) in DCM (8 mL) was added CDI (170 mg,1.05 mmol) and Et ₃ N (266 mg,2.63 mmol) and the mixture was stirred at room temperature for 2h. (3-chlorophenyl) methanol (150 mg,1.05 mmol) was added, and the mixture was stirred at room temperature for 16h. The reaction was quenched with water (30 mL) followed by extraction with EtOAc (30 mL. Times.3). The organic layer was washed with brine (30 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by preparative TLC (DCM: meoh=25:1) to give (1- ((6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]3-chlorobenzyl pyridin-4-yl) carbamate (62.8 mg,19% yield) and (2- ((6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) methyl) -2H-pyrazolo [4,3-c]Pyridin-4-yl) carbamic acid 3-chlorobenzyl ester (16.7 mg, 6%).

3-chlorobenzyl (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] pyridin-4-yl) carbamate: ESI-MS [ M+H ] +:473.1,1H NMR (400 MHz, DMSO). Delta.10.54 (s, 1H), 8.28 (s, 1H), 8.25 (s, 1H), 8.04-7.97 (m, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.49-7.43 (m, 1H), 7.41-7.37 (m, 3H), 7.32 (d, J=9.3 Hz, 1H), 6.97-6.90 (m, 1H), 5.67 (s, 2H), 5.20 (s, 2H), 1.90-1.83 (m, 1H), 0.89-0.84 (m, 2H), 0.63-0.59 (m, 2H).

3-chlorobenzyl (2- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -2H-pyrazolo [4,3-c ] pyridin-4-yl) carbamate:

ESI-MS[M+H] ⁺ ：473.1。1H NMR(400MHz,DMSO)δ10.52(s,1H),8.72(s,1H),8.32(s,1H),7.80(s,1H),7.73-7.65(m,1H),7.48(s,1H),7.41-7.35(m,4H),7.11-7.05(m,1H),6.97(dd,J＝9.4,1.7Hz,1H),5.68(s,2H),5.15(s,2H),1.92-1.87m,1H),0.90-0.86(m,2H),0.65-0.61(m,2H)。

example 20

Synthesis of 3-chlorobenzyl (I-20) carbamate (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl)

2, 4-dichloro-5-nitropyridine (1 g,5.18 mmol), (6-cyclopropylimidazo [1, 2-a)]A mixture of pyridin-2-yl) methylamine (1.1 g,6.22 mmol) and DIPEA (2 g,15.54 mmol) in THF (20 mL) was stirred at 60℃for 6h. The mixture was treated with NaHCO ₃ (saturated aqueous, 50 mL) and extracted with EtOAc (50 mL. Times.3). The combined organic layers were washed with brine (50 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM/meoh=0% -6%) to give 2-chloro-N- ((6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) methyl) -5-nitropyridin-4-amine (1.5 g, 84%). ESI-MS [ M+H ]]+：344.2。

To 2-chloro-N- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -5-nitropyridin-4-amine (1.5 g,4.37 mmol) and NH ₄ To a mixture of Cl (2.3 g,43.7 mmol) in EtOH/water (20 mL/5 mL) was added Fe (2.4 g,43.7 mmol). The resulting reaction mixture was taken up in N ₂ And stirred at 100℃for 3h. After cooling to room temperature, the mixture was quenched with water (50 mL) and extracted with DCM (50 mL x 5). The combined organic layers were washed with brine (50 mL), and dried over Na ₂ SO ₄ Drying and concentrating. The residue was purified by column chromatography (eluent: DCM/meoh=0% -5%) to give 6-chloro-N as a yellow solid ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) pyridine-3, 4-diamine (1.2 g, 88%). ESI-MS [ M+H ]]+：314.2。

Synthesis of 6-chloro-1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H- [1,2,3] triazolo [4,5-c ] pyridine

To 6-chloro-N at room temperature ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]To a solution of pyridin-2-yl) methyl pyridine-3, 4-diamine (500 mg,1.59 mmol) in AcOH (15 ml) was added NaNO ₂ (165 mg,2.38 mmol) in H ₂ O (15 ml). The resulting solution was stirred at this temperature for 30min, then extracted with ethyl acetate (30 ml x 3). The combined organic layers were evaporated in vacuo and the residue was purified by silica gel chromatography (MeOH: dcm=1:20) to give 6-chloro-1- ((6-cyclopropylimidazo [1, 2-a) as a yellow solid]Pyridin-2-yl) methyl) -1H- [1,2,3]Triazolo [4,5-c ]]Pyridine (400 mg, 77%). ESI-MS [ M+H ]] ⁺ ：325.1。

Synthesis of 1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -N- (4-methoxybenzyl) -1H- [1,2,3] triazolo [4,5-c ] pyridin-6-amine

To 6-chloro-1- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -1H- [1,2,3]Triazolo [4,5-c ]]Pyridine (400 mg,1.23 mmol), PMBNH ₂ (349mg, 2. Mmol) and Cs ₂ CO ₃ (1.46 g,4.5 mmol) to a mixture of Pd-PEPPI-iPont-Cl-O-methylpyridine (100 mg,0.12 mmol) in DMF (10 mL). The reaction mixture was taken up in N ₂ And stirring at 85℃for 16h. Water (100 mL) was added and the mixture extracted with EtOAc (100 mL. Times.3). The combined organic layers were washed with brine (50 mL), and dried over Na ₂ SO ₄ Drying and concentration in vacuo gave the crude material, which was purified by column chromatography (eluent: PE/etoac=10/1-2/1) to give 1- ((6-cyclopropylimidazo [1, 2-a) as a yellow solid]Pyridin-2-yl) methyl) -N- (4-methoxybenzyl) -1H- [1,2,3]Triazolo [4,5-c ]]Pyridin-6-amine (300 mg, 56%). ESI-MS [ M+H ]]+：426.2。

Synthesis of 1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H- [1,2,3] triazolo [4,5-c ] pyridin-6-amine

1- ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -N- (4-methoxybenzyl) -1H- [1,2,3]Triazolo [4,5-c ]]A solution of pyridin-6-amine (300 mg,0.71 mmol) in TFA (4 mL) was stirred at room temperature for 12h. The mixture was concentrated and the residue was taken up with NaHCO ₃ (saturated aqueous, 50 mL) and extracted with DCM (50 mL. Times.3). The combined organic layers were washed with brine (30 mL), and dried over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by preparative TLC (DCM/meoh=20/1) to give 1- ((6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) methyl) -1H- [1,2,3]Triazolo [4,5-c ]]Pyridin-6-amine (140 mg) ，65％)。ESI-MS[M+H] ⁺ ：306.2。

Synthesis of 3-chlorobenzyl (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl) carbamate

1- ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -1H- [1,2,3]Triazolo [4,5-c ]]Pyridin-6-amine (35 mg,0.11 mmol), CDI (37 mg,0.22 mmol) and Et ₃ A mixture of N (264 mg,3.6 mmol) in DCM (2 mL) was stirred at 45℃for 16h. (3-chlorophenyl) methanol (196 mg,1.38 mmol) was added, and the mixture was stirred at 45℃for 2h. The reaction was quenched with water (30 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with water (30 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration gave the crude material, which was purified by preparative TLC (eluent: DCM/meoh=10/1) to give (1- ((6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) methyl) -1H- [1,2,3]Triazolo [4,5-c ]]Pyridin-6-yl) carbamic acid 3-chlorobenzyl ester (14.3 mg, 28%). ESI-MS [ M+H ]] ⁺ ：474.1.1H NMR(400MHz,DMSO)δ10.64(s,1H),9.17(s,1H),8.31(s,1H),8.08(s,1H),7.80(s,1H),7.50(s,1H),7.42-7.31(m,4H),6.95(d,J＝8.5Hz,1H),5.98(s,2H),5.17(s,2H),1.91-1.85(m,1H),0.88-0.85(m,2H),0.65-0.61(m,2H)。

Example 21

Synthesis of 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) ethyl (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl) carbamate (I-21)

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzaldehyde

To a solution of (5-chloro-2- (1H-tetrazol-1-yl) phenyl) methanol (500 mg,2.37 mmol) in DCM (20 mL) was added PCC (1.023 g,4.75 mmol) at room temperature. The mixture was stirred at room temperature for 4h. The reaction was concentrated to give the crude material which was purified by silica gel chromatography (eluent: DCM/meoh=20/1) to give 5-chloro-2- (1H-tetrazol-1-yl) benzaldehyde (423 mg, 86%) as a yellow oil. ESI-MS [ M+H ] ] ⁺ ：209.0。

Synthesis of 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) ethan-1-ol

At N ₂ And to a solution of 5-chloro-2- (1H-tetrazol-1-yl) benzaldehyde (100 mg,0.48 mmol) in THF (0.3 mL) at-78deg.C was added methylmagnesium bromide (3M in THF, 0.32mL,0.96 mmol). The mixture was stirred at-78 ℃ for 2h. The reaction was treated with saturated NH ₄ Aqueous Cl (20 mL) was quenched and extracted with EtOAc (30 mL. Times.3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo afforded the crude material, which was purified by preparative TLC (eluent: DCM/meoh=20/1) to give 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) ethan-1-ol as a white solid (32 mg, 30%). ESI-MS [ M+H ]] ⁺ ：225.0。

Synthesis of 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) ethyl (4- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyridin-2-yl) carbamate

To N at room temperature ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]To a solution of pyridin-2-yl) methyl pyridine-2, 4-diamine (20 mg,0.071 mmol) in DCM (1.5 mL) was added CDI (23 mg,0.142 mmol) and Et ₃ N (0.05 mL,36mg,0.355 mmol). The mixture was stirred at 45℃for 2h. Followed by the addition of 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) Ethyl-1-ol (32 mg,0.14 mmol) and the reaction mixture was stirred at 45℃for 16h. The reaction mixture was concentrated in vacuo to give the crude material, which was purified by silica gel chromatography (eluent: DCM/meoh=20/1) to give (4- (((6-cyclopropylimidazo [1, 2-a)) as a white solid ]Pyridin-2-yl) methyl) amino) pyridin-2-yl) carbamic acid 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) ethyl ester (5.9 mg, 16%). ESI-MS [ M+H ]] ⁺ ：530.2。1H NMR(400MHz,DMSO)δ9.91(s,1H),9.78(s,1H),8.29(s,1H),7.87(d,J＝2.1Hz,1H),7.70-7.66(m,3H),7.60(s,1H),7.37(d,J＝9.3Hz,1H),7.10(t,J＝5.5Hz,1H),6.97-6.94(m,2H),6.27(dd,J＝5.8,2.0Hz,1H),5.39(q,J＝6.5Hz,1H),4.31(d,J＝5.7Hz,2H),1.92-1.87(m,1H),1.43(d,J＝6.6Hz,3H),0.92-0.88(m,2H),0.68-0.64(m,2H)。

Example 22

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzyl (I-22) 2- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -2H-pyrazolo [4,3-c ] pyridin-4-yl) carbamate

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzyl (2- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -2H-pyrazolo [4,3-c ] pyridin-4-yl) carbamate

2- ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -2H-pyrazolo [4,3-c]Pyridin-4-amine (10 mg,0.033 mmol), CDI (16 mg,0.1 mmol) and Et ₃ A mixture of N (10 mg,0.1 mmol) in DCM (2 mL) was stirred at 45℃for 16h. (5-chloro-2- (1H-tetrazol-1-yl) phenyl) methanol (35 mg,0.17 mmol) was added. The mixture was stirred at 45℃for a further 2h. The reaction was quenched with water (30 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with water (30 mL), dried over anhydrous Na ₂ SO ₄ Drying and vacuum concentrating to obtain crude material, and passing it through preparation typePurification by TLC (eluent: DCM/meoh=10/1) afforded (2- ((6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) methyl) -2H-pyrazolo [4,3-c ]Pyridin-4-yl) carbamic acid 5-chloro-2- (1H-tetrazol-1-yl) benzyl ester (1.6 mg, 9%). ESI-MS [ M+H ]] ⁺ ：541.1。1H NMR(400MHz,DMSO)δ10.57(s,1H),9.91(s,1H),8.73(s,1H),8.34(s,1H),7.91-7.73(m,5H),7.39(d,J＝9.3Hz,1H),7.30-6.99(m,2H),5.71(s,2H),5.08(s,2H),1.95-1.89(m,1H),0.94-0.89(m,2H),0.69-0.65(m,2H)。

Example 23

Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzyl (I-23) carbamate (1- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) -1H-imidazo [4,5-c ] pyridin-6-yl)

(1- ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Synthesis of 5-chloro-2- (1H-tetrazol-1-yl) benzyl pyridin-6-yl) carbamate 1- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]A mixture of pyridin-6-amine (49 mg,0.16 mmol), CDI (162 mg,1 mmol) and TEA (101 mg,1 mmol) in THF (5 mL) was stirred at 45℃for 16h. (5-chloro-2- (1H-tetrazol-1-yl) phenyl) methanol (210 mg,1 mmol) was added and the mixture was stirred at 45℃for a further 2H. The reaction was quenched with water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo to give the crude material, which was purified by prep. HPLC to give (1- ((6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) methyl) -1H-imidazo [4,5-c]Pyridin-6-yl) carbamic acid 5-chloro-2- (1H-tetrazol-1-yl) benzyl ester (10 mg, 12%). ESI-MS [ M+H ] ]+：541.2。1H NMR(400MHz,DMSO)δ＝10.30(s,1H),9.92(s,1H),8.65(s,1H),8.40(s,1H),8.33(s,1H),7.91(s,2H),7.73(s,3H),7.36(d,J＝9.4,1H),6.99-6.97(m,1H),5.53(s,2H),5.05(s,2H),1.94-1.85(m,1H),0.93-0.87(m,2H),0.67-0.62(m,2H)。

Example 24

Synthesis of 1- (3-chlorobenzyl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (I-24)

Synthesis of 6-chloro-N- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) pyrimidin-4-amine

To (6-cyclopropyl imidazo [1, 2-a)]To a solution of pyridin-2-yl) methylamine hydrochloride (4.6 g,21 mmol) and 4, 6-dichloropyrimidine (4.6 g,31 mmol) in iPrOH (48 mL) was added DIPEA (8.0 g,62 mmol). The mixture was stirred at 40℃for 4h. The reaction mixture was concentrated in vacuo and the residue was purified by column on silica gel (eluting with 0% -5% MeOH/DCM) to give 6-chloro-N- ((6-cyclopropylimidazo [1, 2-a) as a pale solid]Pyridin-2-yl) methyl) pyrimidin-4-amine (4.2 g, 67%). ESI-MS [ M+H ]] ⁺ ：300.2。

N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Synthesis of pyridin-2-yl) methyl) -N6- (2, 4-dimethoxybenzyl) pyrimidine-4, 6-diamine

6-chloro-N- ((6-cyclopropylimidazo [1, 2-a)]A solution of pyridin-2-yl) methyl pyrimidin-4-amine (1.4 g,4.7 mmol), (2, 4-dimethoxyphenyl) methylamine (1.2 g,7.2 mmol) and DIPEA (1.8 g,14 mmol) in i-PrOH (5.0 mL) and 1-methylpyrrolidin-2-one (5.0 mL) was stirred in a sealed tube. In use N ₂ After degassing for 1min, the resulting mixture was irradiated in a microwave reactor at 160℃for 8h. The reaction mixture was then concentrated in vacuo to give the crude material, which was purified by silica gel column chromatography eluting with 0% -10% MeOH/DCM to give N as a yellow solid ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) Methyl) -N6- (2, 4-dimethoxybenzyl) pyrimidine-4, 6-diamine (0.79 g, 39%). ESI-MS [ M+H ]] ⁺ ：431.2。

N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Synthesis of pyridin-2-yl) methyl) pyrimidine-4, 6-diamine

To N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) -N6- (2, 4-dimethoxybenzyl) pyrimidine-4, 6-diamine (0.79 g,1.8 mmol) to a mixture of DCM (40 mL) was added TFA (8.2 mL,0.11 mol). After stirring overnight at room temperature, the resulting mixture was concentrated in vacuo to give the crude material. Adding NH ₃ (7.0N in MeOH) to adjust the pH to 12. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with 0% -10% MeOH/DCM to give N as a pale solid ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) pyrimidine-4, 6-diamine (0.35 g, 70%). ESI-MS [ M+H ]] ⁺ ：281.1。

Synthesis of 1- (3-chlorobenzyl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea

Under nitrogen to N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]To a solution of pyridin-2-yl) methyl pyrimidine-4, 6-diamine (0.10 g,0.36 mmol) and CDI (0.29 g,1.8 mmol) in DCM (3.0 mL) was added Et ₃ N (0.36 g,3.6 mmol). After stirring for 2h at 40℃a solution of (3-chlorophenyl) methylamine (0.25 g,1.8 mmol) in DCM (3.0 mL) was added. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by preparative TLC (DCM/meoh=10/1) to give 1- (3-chlorobenzyl) -3- (6- (((6-cyclopropylimidazo [1, 2-a)) as a pale solid ]Pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (11 mg, 6.8%). ESI-MS [ M+H ]] ⁺ ：448.1,1H NMR(400MHz,DMSO)δ9.13(s,1H),8.28-8.21(m,2H),8.13(s,1H),7.72(s,1H),7.59(s,1H),7.34-7.24(m,5H),6.95(d,J＝10.9Hz,1H),6.57(s,1H),4.53(d,J＝9.4Hz,2H),4.35(d,J＝6.0Hz,2H),1.93-1.87(m,1H),0.92-0.88(m,2H),0.67-0.63(m,2H)。

Example 25

Synthesis of 3- (3-chlorophenyl) -N- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) azetidine-1-carboxamide (I-25)

Synthesis of tert-butyl 3- (3-chlorophenyl) azetidine-1-carboxylate

To a solution of 3-chlorophenyl) boronic acid (936 mg,6.0 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (1.7 g,6.0 mmol) in IPA (20 mL) was added NiI ₂ (373 mg,1.2 mmol). The reaction mixture was stirred at 80℃for 16h. The reaction was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave tert-butyl 3- (3-chlorophenyl) azetidine-1-carboxylate (360 mg) as a pale yellow solid, which was used without further purification. ESI-MS [ M+H ]]+：268.1。

Synthesis of 3- (3-chlorophenyl) azetidine

To a solution of tert-butyl 3- (3-chlorophenyl) azetidine-1-carboxylate (360 mg) in DCM (10 mL) was added HCl (2.0M solution in EtOH, 2 mL). The resulting mixture was stirred at room temperature for 16h. The reaction was concentrated in vacuo to give 3- (3-chlorophenyl) azetidine (as the hydrochloride salt) (250 mg) as a white solid, which was isolated from the next step The purification is performed. ESI-MS [ M+H ]] ⁺ ：168.2

Synthesis of 3- (3-chlorophenyl) -N- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) azetidine-1-carboxamide

To 3- (3-chlorophenyl) azetidine hydrochloride (50 mg, crude material), N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]To a solution of pyridin-2-yl) methyl pyrimidine-4, 6-diamine (50 mg,0.18 mmol) and TEA (55 mg,0.54 mmol) in THF (10 mL) was added triphosgene (35 mg,0.12 mmol). The reaction mixture was stirred at 60℃for 16h. After cooling to 25 ℃, water (50 mL) was added and the mixture was extracted with EtOAc (30 mL X3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave the crude material, which was purified by column chromatography (eluent: DCM/meoh=20/1) to give 3- (3-chlorophenyl) -N- (6- (((6-cyclopropylimidazo [1, 2-a)) as a white solid]Pyridin-2-yl) methyl) amino) pyrimidin-4-yl azetidine-1-carboxamide (15 mg, yield: 18%). ESI-MS [ M+H ]] ⁺ ：474.2。 ¹ H NMR(400MHz,DMSO)δ8.42(s,1H),8.30(s,1H),7.80(s,1H),7.53(s,1H),7.42-7.18(t,J＝16.2Hz,5H),6.36(s,1H),4.94(s,2H),4.20(s,2H),3.77(s,3H),2.05-1.94(m,1H),0.99-0.93(m,2H),0.75-0.65(m,2H)。

Example 26

Synthesis of (4-chloropyridin-2-yl) methyl (I-26) carbamate (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl)

Synthesis of (4-chloropyridin-2-yl) methyl carbamate

To a mixture of (4-chloropyridin-2-yl) methanol (0.5 g,3.5 mmol) in DCM (10 mL) was added 2, 2-trichloroacetyl isocyanate (0.79 g,4.2 mmol) at 0deg.C. The mixture was stirred at 0℃for 2h. It was then concentrated in vacuo and the residue was redissolved in MeOH (10 mL). Adding K ₂ CO ₃ (1.4 g,10.5 mmol). The mixture was stirred at room temperature for 1h. The mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), and dried over Na ₂ SO ₄ Drying and vacuum concentration gave the crude product. The crude product was purified by column chromatography on silica gel (eluent: etOAc/pe=0% -50%) to give methyl carbamate (4-methylpyrimidin-2-yl) as a white solid (0.46 g, 71% yield). ESI-MS [ M+H ]]+：187.1。

Synthesis of (4-chloropyridin-2-yl) methyl (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamate

(4-Chloropyridin-2-yl) methyl carbamate (75 mg,0.40 mmol), 6-chloro-N- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl pyrimidin-4-amine (0.10 g,0.33 mmol), pd ₂ (dba) ₃ (45 mg,0.050 mmol), xantphos (29 mg,0.050 mmol) and Cs ₂ CO ₃ (0.14 g,1.0 mmol) in 1, 4-dioxane (5 mL) in N ₂ And stirred at 80℃for 6h. After cooling to room temperature, the mixture was passed through The mixture was filtered and the filter cake was washed with DCM/MeOH (10/1, 50 mL). The filtrate was concentrated in vacuo to give the crude material, which was purified by preparative TLC (eluent: DCM/meoh=8/1) to give (6- (((6-cyclopropylimidazo [1, 2-a)) as a pale yellow solid]Pyridin-2-yl) methyl) amino) pyrimidin-4-yl methyl carbamate (4-chloropyridin-2-yl) (4.3 mg, yield 2.4%). ESI-MS [ M+H ]]+：450.2,1H NMR(400MHz,DMSO)δ10.30(s,1H),8.54(d,J＝5.3Hz,1H),8.29(s,1H),8.18(s,1H),7.85(s,1H),7.65(s,1H),7.61(s,1H),7.50(dd,J＝5.3,1.9Hz,1H),7.36(d,J＝9.3Hz,1H),7.01(s,1H),6.95(dd,J＝9.3,1.6Hz,1H),5.21(s,2H),4.56(s,2H),1.94-1.87(m,1H),0.93-0.87(m,2H),0.67-0.64(m,2H)。

Example 27

Synthesis of 1- ((4-chloropyridin-2-yl) methyl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (I-27)

1- ((4-chloropyridin-2-yl) methyl) -3- (6- (((6-cyclopropylimidazo [1, 2-a)]Synthesis of pyridin-2-yl-methyl) amino) pyrimidin-4-yl-urea ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]To a solution of pyridin-2-yl) methyl pyrimidine-4, 6-diamine (50 mg,0.18 mmol) in DCM (3.0 mL) was added bis (1H-imidazol-1-yl) methanone (87 mg,0.54 mmol) and Et ₃ N (0.11 g,1.1 mmol). After stirring for 5h at 40℃a solution of (4-chloropyridin-2-yl) methylamine (76 mg,0.53 mmol) in DCM (1.0 mL) was added. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by prep HPLC to give 1- ((4-chloropyridin-2-yl) methyl) -3- (6- (((6-cyclopropylimidazo [1, 2-a) as a white solid) ]Pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (4.2 mg, 5.2%). ESI-MS [ M+H ]] ⁺ ：449.2。1H NMR(400MHz,DMSO)δ＝9.22(s,1H),8.50(d,J＝5.1Hz,1H),8.40(s,1H),8.29(s,1H),8.14(s,1H),7.72(s,1H),7.60(s,1H),7.48-7.39(m,2H),7.37-7.35(m,1H),6.95(d,J＝10.0Hz,1H),6.58(s,1H),4.53(s,2H),4.45(d,J＝5.6Hz,2H),1.94-1.87(m,1H),0.93-0.84(m,2H),0.69-0.60(m,2H)。

Example 28

Synthesis of (4-chloropyridin-2-yl) methyl (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) carbamate (I-28)

Synthesis of 2- ((2R, 4S) -1- (6-bromopyrimidin-4-yl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidin-2-yl) -6-cyclopropylimidazo [1,2-a ] pyridine

To 2- ((2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidin-2-yl) -6-cyclopropylimidazo [1,2-a]To a solution of pyridine (714mg, 2 mmol) and 4, 6-dibromopyrimidine (569 mg,2.4 mmol) in iPrOH (10 mL) was added DIPEA (775 mg,6 mmol). The mixture was stirred at 60℃for 2h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column purification (eluting with 0% -5% MeOH/DCM) to give 2- ((2 r,4 s) -1- (6-bromopyrimidin-4-yl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidin-2-yl) -6-cyclopropylimidazo [1,2-a ] as a yellow solid]Pyridine (611 mg, 60%). ESI-MS [ M+H ]] ⁺ ：515.2。

Synthesis of (4-chloropyridin-2-yl) methyl (6- ((2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) pyrrolidin-1-yl) pyrimidin-4-yl) carbamate

To 2- ((2R, 4S) -1- (6-bromopyrimidin-4-yl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidin-2-yl) -6-cyclopropylimidazo [1,2-a]Pyridine (0.15 g,0.29 mmol), carbamic acid (4-chloropyridin-2-yl) methyl ester (65 mg,0.35 mmol) and Cs ₂ CO ₃ (0.28 g,0.86 mmol) Pd was added to a solution in 1, 4-dioxane (2.0 mL) ₂ (dba) ₃ (26 mg,0.028 mmol) and Xantphos (16 mg,0.028 mmol). The reaction mixture was stirred under nitrogen at 80 ℃ for 2h. Passing the reaction mixture throughThe mixture was filtered and the filter cake was washed with DCM/MeOH (10/1, 20 mL). The filtrate was concentrated in vacuo to give the crude material which was purified by silica gel column chromatography eluting with 20% -100% EA/PE to give (6- ((2 r,4 s) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a) as a yellow solid]Pyridin-2-yl) pyrrolidin-1-yl-pyrimidin-4-yl-carbamic acid (4-chloropyridin-2-yl) methyl ester (80 mg, 44%). ESI-MS [ M+H ]] ⁺ ：620.2。

Synthesis of (4-chloropyridin-2-yl) methyl (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) carbamate

To (6- ((2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a) at room temperature]Pyridin-2-yl) pyrrolidin-1-yl-pyrimidin-4-yl) methyl carbamate (4-chloropyridin-2-yl) (0.25 g,0.40 mmol) to a mixture of 1, 4-dioxane (1.0 mL) was added HCl (1.0 mL,4n in 1, 4-dioxane). After stirring at room temperature for 1h, the resulting mixture was concentrated in vacuo and purified by prep. HPLC to give (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1, 2-a) as a pale solid ]Pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl methyl carbamate (4-chloropyridin-2-yl) ester (30 mg, yield: 15%). ESI-MS [ M+H ]] ⁺ ：506.1, ¹ H NMR(400MHz,CD ₃ OD)δ8.45(d,J＝5.3Hz,1H),8.24-8.10(m,2H),7.63(s,1H),7.51(s,1H),7.42-7.35(m,2H),7.08(d,J＝8.4Hz,1H),6.99(s,1H),5.21(s,3H),4.61-4.57(m,1H),3.99-3.95(m,2H),2.46-2.36(m,2H),1.95-1.88(m,1H),0.98-0.94(m,2H),0.71-0.67(m,2H)。

Example 29

Synthesis of 1- ((4-chloropyrimidin-2-yl) methyl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (I-29)

Synthesis of tert-butyl (6-chloropyrimidin-4-yl) ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) carbamate

6-chloro-N- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl pyrimidin-4-amine (1 g,3.36 mmol), (Boc) ₂ A mixture of O (870 mg,4 mmol), DMAP (81 mg,0.66 mmol) and TEA (1.01 g,10 mmol) in THF (30 mL) was stirred at 80℃for 16h. The mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM: meoh=10:1) to give the product as a white solid (1 g,74.4% yield). ESI-MS [ M+H ]] ⁺ ：400.3。

Synthesis of tert-butyl (6-azidopyrimidin-4-yl) ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) carbamate

(6-Chloropyrimidin-4-yl) ((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl carbamic acid tert-butyl ester (800 mg,2.0 mmol) and NaN ₃ A mixture of (390 mg,6.0 mmol) in DMF (30 mL) was stirred at 90℃for 3h. The mixture was treated with H ₂ O (60 mL) was diluted followed by extraction with EtOAc (50 mL. Times.3). The combined organic layers were washed with brine (50 mL), and dried over Na ₂ SO ₄ Drying followed by concentration gave the crude product (700 mg, crude material) which was used in the next step without further purification. ESI-MS [ M+H ]]+：407.2。

Synthesis of tert-butyl (6-aminopyrimidin-4-yl) ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) carbamate

(6-azidopyrimidin-4-yl) ((6-cyclopropylimidazo [1, 2-a)]A mixture of tert-butyl pyridin-2-yl) methyl carbamate (700 mg, crude material) and Pd/C (100 mg, 10%) in MeOH (10 mL) in H ₂ And stirring at room temperature for 10min. The mixture was filtered and concentrated in vacuo to give the crude product (600 mg, crude) as a white solid, which was used in the next step without further purification. ESI-MS [ M+H ]]+：381.2。

Synthesis of tert-butyl ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) (6- ((phenoxycarbonyl) amino) pyrimidin-4-yl) carbamate

To a mixture of tert-butyl (6-aminopyrimidin-4-yl) ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) carbamate (100 mg, crude material) and DIPEA (170 mg,1.31 mmol) in DCM (10 mL) was added phenyl chloroformate (82 mg,0.525 mol) at-78 ℃. The mixture was allowed to warm to room temperature and stirred for 16h. The mixture was concentrated in vacuo to give a crude residue which was purified by preparative TLC (PE: etoac=1:1) to give the product as a white solid (100 mg,60%,3 steps).

Synthesis of tert-butyl (6- (3- ((4-chloropyrimidin-2-yl) methyl) ureidopyrimidin-4-yl) ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) carbamate

To a mixture of tert-butyl ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) (6- ((phenoxycarbonyl) amino) pyrimidin-4-yl) carbamate (50 mg,0.1 mmol) and DIPEA (28.7 mg,0.77 mmol) in 1, 4-dioxane (5 mL) was added (4-chloropyrimidin-2-yl) methylamine (28.7 mg,0.2 mmol). The mixture was stirred at 70℃for 16h. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC (DCM: meoh=10:1) to give the product as a white solid (30 mg, 54.5%). ESI-MS [ M+H ] +:550.2.

synthesis of 1- ((4-chloropyrimidin-2-yl) methyl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea

To (6- (3- ((4-chloropyrimidin-2-yl) methyl) ureido) pyrimidin-4-yl) ((6-cyclopropylimidazo [1, 2-a)]To a solution of tert-butyl pyridin-2-yl) methyl carbamate (25 mg,0.045 mmol) in DCM (4 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 1h, then concentrated in vacuo. The residue was purified by preparative TLC (DCM: meoh=10:1) to give the product as a white solid (12.3 mg,60% yield). ESI-MS [ M+H ] ] ⁺ ：450.1。1H NMR(400MHz,DMSO)δ9.45-9.39(m,1H),8.77(d,J＝5.4Hz,1H),8.64(s,1H),8.21(s,2H),7.99(s,2H),7.79-7.73(m,1H),7.64-7.62(m,2H),6.73(s,1H),4.71(s,2H),4.56(d,J＝5.7Hz,2H),2.13-2.02(m,1H),1.09-0.97(m,2H),0.81-0.72(m,2H)。

Example 30

Synthesis of 1- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) -3- ((4-methoxypyrimidin-2-yl) methyl) urea (I-30)

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(6-aminopyrimidin-4-yl) ((6-cyclopropylimidazo [1, 2-a)]A mixture of tert-butyl pyridin-2-yl) methyl carbamate (20 mg,0.05 mmol), phenyl chloroformate (15 mg,0.10 mmol) and pyridine (20 mg,0.25 mmol) in THF (10 mL) was stirred at 50℃for 16h. The mixture was concentrated in vacuo to give a colorless oil(crude material ((6-cyclopropyl imidazo [1, 2-a))]Pyridin-2-yl) methyl) (6- ((phenoxycarbonyl) amino) pyrimidin-4-yl) carbamic acid tert-butyl ester (60 mg, crude) which was used without further purification. ESI-MS [ M+H ]] ⁺ ：501.2

Synthesis of tert-butyl ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) (6- (3- ((4-methoxypyrimidin-2-yl) methyl) ureido) pyrimidin-4-yl) carbamate

((6-cyclopropyl imidazo [1, 2-a)]To a solution of tert-butyl pyridin-2-yl) methyl) (6- ((phenoxycarbonyl) amino) pyrimidin-4-yl) carbamate (60 mg, crude material from the previous step) in 1, 4-dioxane (4.0 mL) was added a solution of (4-methoxypyrimidin-2-yl) methylamine (14 mg,0.10 mmol) and DIPEA (0.13 g,1.0 mmol) in 1, 4-dioxane (2.0 mL). After stirring at 70 ℃ for 16 hours, the resulting mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC (DCM/meoh=10/1) to give ((6-cyclopropylimidazo [1, 2-a) as a white solid ]Pyridin-2-yl) methyl) (6- (3- ((4-methoxypyrimidin-2-yl) methyl) ureido) pyrimidin-4-yl) carbamic acid tert-butyl ester (10 mg,37%,2 steps). ESI-MS [ M+H ]] ⁺ ：546.2。

Synthesis of 1- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) -3- ((4-methoxypyrimidin-2-yl) methyl) urea

At 0℃to ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) (6- (3- ((4-methoxypyrimidin-2-yl) methyl) ureido) pyrimidin-4-yl) carbamic acid tert-butyl ester (10 mg,0.018 mmol) to a mixture of 1, 4-dioxane (4.0 mL) was added HCl (1.0 mL,4n in 1, 4-dioxane). After stirring at 25℃for 2h, the resulting mixture was concentrated in vacuo to give the crude material, which was purified by preparative TLC (DCM/MeOH=10/1) to give 1- (6) as a white solid((6-Cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl) amino) pyrimidin-4-yl) -3- ((4-methoxypyrimidin-2-yl) methyl) urea (1.3 mg, yield: 16%). ESI-MS [ M+H ]] ⁺ ：446.2。1H NMR(400MHz,DMSO)δ9.30(s,1H),8.46(d,J＝5.8Hz,1H),8.28(s,1H),8.13(s,1H),7.75–7.66(m,1H),7.58(s,1H),7.35(d,J＝9.3Hz,1H),6.94(dd,J＝9.3,1.6Hz,1H),6.81(d,J＝5.8Hz,1H),6.56–6.48(m,1H),4.56–4.48(m,2H),4.45(d,J＝5.4Hz,2H),3.92(s,3H),1.94–1.85(m,1H),0.93–0.86(m,2H),0.68–0.62(m,2H)。

Example 31

Synthesis of N- (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) -3-phenylazetidine-1-carboxamide (I-31)

Synthesis of 2- (azetidin-3-yl) pyrimidine hydrochloride

A mixture of tert-butyl 3- (pyrimidin-2-yl) azetidine-1-carboxylate (300 mg,1.28 mmol) in HCl (4M solution in 1, 4-dioxane, 3 mL) was stirred at room temperature for 1h. The reaction mixture was concentrated in vacuo to give 2- (azetidin-3-yl) pyrimidine hydrochloride (150 mg, crude material) as a white solid. ESI-MS [ M+H ] ] ⁺ ：136.2。

Synthesis of 4-nitrophenyl 3- (pyrimidin-2-yl) azetidine-1-carboxylate

A mixture of 2- (azetidin-3-yl) pyrimidine hydrochloride (150 mg, crude material), 4-nitrophenyl chloroformate (177 mg,0.88 mmol) and DIPEA (178 mg,4.4 mmol) in DCM (5 mL) was stirred at room temperature for 16h. Reactant is reactedConcentration in vacuo afforded the crude product, which was purified by preparative TLC (eluent: DCM/meoh=50/1) to give 4-nitrophenyl 3- (pyrimidin-2-yl) azetidine-1-carboxylate (200 mg, 76%) as a colorless oil. ESI-MS [ M+H ]] ⁺ ：301.2。

Synthesis of 6- ((2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) pyrrolidin-1-yl) pyrimidin-4-amine

2- ((2R, 4S) -4- ((tert-Butyldimethylsilyl) oxy) pyrrolidin-2-yl) -6-cyclopropylimidazo [1,2-a]A mixture of pyridine (200 mg,0.56 mmol), 6-chloropyrimidin-4-amine (72 mg,0.56 mmol) and DIPEA (361 mg,2.8 mmol) in i-PrOH (5 mL) was stirred in a sealed tube. In use N ₂ After degassing for 1min, the reaction was irradiated in a microwave reactor at 140 ℃ for 8h. The reaction was concentrated in vacuo to give the crude product, which was purified by preparative TLC (eluent: DCM/meoh=10/1) to give 6- ((2 r,4 s) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a) as a yellow solid ]Pyridin-2-yl) pyrrolidin-1-yl) pyrimidin-4-amine (160 mg, 63%). ESI-MS [ M+H ]]+：451.2。

Synthesis of N- (6- ((2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) pyrrolidin-1-yl) pyrimidin-4-yl) -3-phenylazetidine-1-carboxamide

To 6- ((2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a) at 0 ℃C]To a solution of pyridin-2-yl) pyrrolidin-1-yl-pyrimidin-4-amine (45 mg,0.1 mmol) in anhydrous DMF (3 mL) was added NaH (12 mg, 60% dispersion in mineral oil, 0.3 mmol). The mixture was stirred at 0deg.C for 0.5h, 4-nitrophenyl 3-phenylazetidine-1-carboxylate (30 mg,0.1 mmol) was added in the absence of waterA solution in DMF (2 mL) and the resulting mixture was stirred at room temperature for an additional 1h. The reaction mixture was treated with saturated NH ₄ Aqueous Cl (20 mL) was quenched and extracted with EtOAc (30 mL. Times.3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo afforded the crude material, which was purified by preparative TLC (eluent: DCM/meoh=20/1) to give N- (6- ((2 r,4 s) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a) as a yellow solid ]Pyridin-2-yl) pyrrolidin-1-yl) pyrimidin-4-yl) -3-phenylazetidine-1-carboxamide (20 mg, 33%). ESI-MS [ M+H ]] ⁺ ：610.2。

Synthesis of N- (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) -3-phenylazetidine-1-carboxamide

N- (6- ((2R, 4S) -4- ((tert-Butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a)]A solution of pyridin-2-yl) pyrrolidin-1-yl) -pyrimidin-4-yl-3-phenylazetidine-1-carboxamide (20 mg,0.033 mmol) in HCl (4M solution in 1, 4-dioxane, 2 mL) was stirred at room temperature for 1h. The reaction mixture was concentrated in vacuo to give the crude material which was purified by prep. HPLC to give N- (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) -3-phenylazetidine-1-carboxamide (5 mg, 31%). ESI-MS [ M+H ]] ⁺ ：496.2。1H NMR(400MHz,CD ₃ OD)δ8.13(s,2H),7.63(s,1H),7.44–7.29(m,5H),7.27-7.22(m,1H),7.12-7.04(m,2H),5.19(s,1H),4.87(s,1H),4.65–4.52(m,1H),4.46-4.42(m,2H),4.02-3.97(m,3H),3.84-3.78(m,1H),2.50–2.45(m,2H),2.00–1.79(m,1H),1.02–0.86(m,2H),0.79–0.56(m,2H)。

Example 32

Synthesis of 1- (4-chlorobicyclo [4.2.0] oct-1 (6), 2, 4-trien-7-yl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (I-32)

Synthesis of 2-carboxy-5-chlorobenzodiazonium chloride

To a mixture of 2-amino-4-chlorobenzoic acid (5.0 g,29.3 mmol) in EtOH (50 mL) and MTBE (50 mL) was added concentrated HCl (20 mL) at 0deg.C. Isoamyl nitrite (3.4 g,29.3 mmol) was then added at 0deg.C. The reaction mixture was stirred at 0℃for 1h. The reaction was warmed to room temperature and filtered. The precipitate was dried in vacuo to give the product 2-carboxy-5-chlorobenzenediazonium chloride (4.0 g, 63%) as a white solid.

Synthesis of ethyl 4-chlorobicyclo [4.2.0] oct-1, 3, 5-triene-7-carboxylate

A mixture of 4-chloro-2- (chlorodiazenyl) benzoic acid (4.0 g,18.3 mmol), methyl acrylate (7.9 g,91.5 mmol) and propylene (3.8 g,91.5 mmol) in 1, 2-dichloroethane (50.0 mL) was stirred at 60℃for 2h. The reaction was concentrated in vacuo to give the crude product, which was purified by column chromatography (eluent: DCM/meoh=15/1) to give 4-chlorobicyclo [4.2.0] as a colorless oil]Octyl-1, 3, 5-triene-7-carboxylate (1.1 g, 28%). ESI-MS [ M+H ]] ⁺ ：211.2。

Synthesis of 4-chlorobicyclo [4.2.0] oct-1, 3, 5-triene-7-carboxamide

To 4-chlorobicyclo [4.2.0] at 0deg.C]To a mixture of ethyl octyl-1, 3, 5-triene-7-carboxylate (1.0 g,4.76 mmol) in THF (20 mL) was added NH ₄ OH (20 mL). The reaction mixture was stirred at room temperature for 48h. Water (30 mL) was added and extracted with EtOAc (50 mL. Times.3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentrating in vacuo to give 4-chlorobicyclo [4.2.0] as a yellow solid]Octyl-1, 3, 5-triene-7-carboxamide (700 mg, crude) was used in the next step without further purification. ESI-MS [ M+H ]] ⁺ ：182.2。

Synthesis of 4-chlorobicyclo [4.2.0] oct-1, 3, 5-triene-7-amine

To 4-chlorobicyclo [4.2.0] at 0deg.C ]Octyl-1, 3, 5-triene-7-carboxamide (350 mg, crude material) in MeCN/H ₂ To the mixture in O (10 mL/5 mL) was added (CF ₃ CO ₂ ) 2PhI (1.63 g,3.32 mmol). The reaction mixture was stirred at room temperature for 16h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL. Times.3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave the crude material, which was purified by silica gel column chromatography (eluent: DCM/meoh=20/1) to give 4-chlorobicyclo [4.2.0] as a yellow oil]Oct-1, 3, 5-trien-7-amine (100 mg, 27%). ESI-MS [ M+H ]] ⁺ ：154.2。

Synthesis of 1- (4-chlorobicyclo [4.2.0] oct-1 (6), 2, 4-trien-7-yl) -3- (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea

4-chlorobicyclo [4.2.0]Oct-1, 3, 5-trien-7-amine (31 mg,0.2 mmol), N ⁴ - ((6-Cyclopropylimidazo [1, 2-a)]A mixture of pyridin-2-yl) methyl pyrimidine-4, 6-diamine (56 mg,0.2 mmol) and CDI (65 mg,0.4 mmol) in DCM (5 mL) was stirred at room temperature for 5h. The reaction was quenched with water (20 mL) and extracted with DCM (30 mL. Times.3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave the crude product, which was purified by prep. HPLC to give 1- (4-chlorobicyclo [ 4.2.0) as a white solid ]Oct-1 (6), 2, 4-trien-7-yl) -3- (6- (((6-cyclopropylimidazo [1, 2-a))]Pyridin-2-yl) methyl) amino) pyrimidin-4-yl) urea (5 mg, 5%). ESI-MS [ M+H ]] ⁺ ：460.2。1H NMR(400MHz,DMSO)δ9.01(s,1H),8.42–8.30(m,2H),8.12–8.10(m,1H),7.75(s,1H),7.64–7.60(m,1H),7.38–7.20(m,3H),6.97–6.94(m,1H),6.62(s,1H),5.25–5.20(m,1H),4.53(s,2H),3.64–3.55(m,1H),3.02–2.95(m,1H),1.94–1.87(m,1H),0.93–0.88(m,2H),0.68–0.64(m,2H)。

Example 33

Synthesis of N- (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) -3- (pyrimidin-2-yl) azetidine-1-carboxamide (I-33)

Synthesis of 2- (azetidin-3-yl) pyrimidine hydrochloride

A mixture of tert-butyl 3- (pyrimidin-2-yl) azetidine-1-carboxylate (300 mg,1.28 mmol) in HCl (4M solution in 1, 4-dioxane, 5 mL) was stirred at room temperature for 1h. The reaction mixture was concentrated in vacuo to give 2- (azetidin-3-yl) pyrimidine (as hydrochloride salt) as a yellow solid (200 mg, crude material). ESI-MS [ M+H ]] ⁺ ：136.2。

Synthesis of 4-nitrophenyl 3- (pyrimidin-2-yl) azetidine-1-carboxylate

To 2- (azetidin-3-yl) pyrimidine hydrochloride (200 mg, crude) and DIPEA (4) at 0 ℃53mg,3.51 mmol) in DCM (10.0 mL) was added a solution of 4-nitrophenyl chloroformate (353 mg,1.76 mmol) in DCM (5.0 mL). The reaction mixture was stirred at room temperature for 1h. The reaction was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo gave the crude material, which was purified by silica gel column chromatography (eluent: DCM/meoh=50/1) to give 4-nitrophenyl 3- (pyrimidin-2-yl) azetidine-1-carboxylate as a yellow solid (200 mg,52%,2 steps). ESI-MS [ M+H ]] ⁺ ：301.2。

Synthesis of N- (6- ((2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) pyrrolidin-1-yl) pyrimidin-4-yl) -3- (pyrimidin-2-yl) azetidine-1-carboxamide

To 6- ((2R, 4S) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a) at 0 ℃C]To a solution of pyridin-2-yl) pyrrolidin-1-yl-pyrimidin-4-amine (45 mg,0.1 mmol) in anhydrous DMF (2.0 mL) was added LiHMDS (1M in THF, 0.3 mL). The resulting mixture was stirred at 0℃for 0.5h. A solution of 4-nitrophenyl 3- (pyrimidin-2-yl) azetidine-1-carboxylate (30 mg,0.1 mmol) in anhydrous DMF (1 mL) was then added and stirred at room temperature for an additional 1h. The reaction was treated with saturated NH ₄ Aqueous Cl (20 mL) was quenched and extracted with EtOAc (30 mL. Times.3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo afforded the crude material, which was purified by preparative TLC (eluent: DCM/meoh=20/1) to give N- (6- ((2 r,4 s) -4- ((tert-butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a) as a yellow solid ]Pyridin-2-yl) pyrrolidin-1-yl) pyrimidin-4-yl) -3- (pyrimidin-2-yl) azetidine-1-carboxamide (30 mg, 49%). ESI-MS [ M+H ]] ⁺ ：612.2。

Synthesis of N- (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) -3- (pyrimidin-2-yl) azetidine-1-carboxamide

N- (6- ((2R, 4S) -4- ((tert-Butyldimethylsilyl) oxy) -2- (6-cyclopropylimidazo [1, 2-a)]A mixture of pyridin-2-yl) pyrrolidin-1-yl) -pyrimidin-4-yl-3- (pyrimidin-2-yl) azetidine-1-carboxamide (30 mg,0.05 mmol) in HCl (4M solution in 1, 4-dioxane, 2 mL) was stirred at room temperature for 1h. The reaction mixture was concentrated in vacuo to give the crude material which was purified by prep. HPLC to give N- (6- ((2R, 4S) -2- (6-cyclopropylimidazo [1, 2-a) as a white solid]Pyridin-2-yl) -4-hydroxypyrrolidin-1-yl) pyrimidin-4-yl) -3- (pyrimidin-2-yl) azetidine-1-carboxamide (12 mg, 48%). ESI-MS [ M+H ]] ⁺ ：498.2。1H NMR(400MHz,CD ₃ OD)δ8.77(d,J＝4.9Hz,2H),8.13(s,2H),7.62(s,1H),7.37-7.33(m,2H),7.17–6.96(m,2H),5.16(s,1H),4.59-4.56(m,1H),4.54–4.21(m,4H),4.20–3.84(m,3H),2.44-2.43(m,2H),1.99–1.83(m,1H),1.05–0.83(m,2H),0.78–0.51(m,2H)。

Example 34

Synthesis of (4-methylpyrimidin-2-yl) methyl (I-34) carbamate (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl)

/>

Synthesis of 6-bromo-N- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) pyrimidin-4-amine

To a solution of (6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methylamine hydrochloride (4476 mg,2 mmol) and 4, 6-dibromopyrimidine (569 mg,2.4 mmol) in iPrOH (10 mL) was added DIPEA (775 mg,6 mmol). The mixture was stirred at 60℃for 4h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column (eluting with 0% -5% MeOH/DCM) to give 6-bromo-N- ((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) pyrimidin-4-amine (470 mg, 69%) as a yellow solid. ESI-MS [ M+H ] +:345.2.

synthesis of (4-methylpyrimidin-2-yl) methyl carbamate

To a solution of (4-methylpyrimidin-2-yl) methanol (500 mg,4 mmol) in DCM (15 mL) was added 2, 2-trichloroacetyl isocyanate (1.5 g,8 mmo) at 0deg.C. The resulting mixture was stirred at 0℃for 1h. The mixture was then concentrated in vacuo, then redissolved in MeOH (15 mL). Adding K ₂ CO ₃ (1.67 g,12 mmol) and the mixture was stirred at room temperature for 3h. The mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), and dried over Na ₂ SO ₄ Drying, followed by vacuum concentration, gives the crude product. The crude product was purified by preparative TLC (DCM: meoh=10:1) to give methyl carbamate (4-methylpyrimidin-2-yl) as a white solid (150 mg,22.5% yield). ESI-MS [ M+H ] ]+：168.1。

Synthesis of (4-methylpyrimidin-2-yl) methyl (6- (((6-cyclopropylimidazo [1,2-a ] pyridin-2-yl) methyl) amino) pyrimidin-4-yl) carbamate

(4-methylpyrimidin-2-yl) methyl carbamate (100 mg,0.60 mmol), 6-bromo-N- ((6-cyclopropylimidazo [1, 2-a)]Pyridin-2-yl) methyl pyrimidin-4-amine (162 mg,0.47 mmol), pd ₂ (dba) ₃ (110 mg,0.12 mmol), xantphos (139 mg,0.24 mmol) and Cs ₂ CO ₃ (587 mg,1.8 mmol) in 1, 4-dioxane (15 mL) under N ₂ And stirring at 70℃for 16h. After cooling to room temperature, the mixture was passed throughThe mixture was filtered and the filter cake was washed with DCM/MeOH (10/1, 50 mL). The filtrate was concentrated in vacuo to give the crude material, which was purified by prep HPLC to give (6- (((6-cyclopropylimidazo [1,2-a ]) as a white solid]Pyridin-2-yl) methyl) amino) pyrimidin-4-yl methyl carbamate (4-methylpyrimidin-2-yl) (29 mg,14% yield). ESI-MS [ M+H ]]+：431.2，1H NMR(400MHz,DMSO)δ10.27(s,1H),8.62(d,J＝5.1Hz,1H),8.32-8.26(m,1H),8.17(s,1H),7.78(s,1H),7.59(s,1H),7.38-7.29(m,2H),6.99–6.91(m,2H),5.23(s,2H),4.55(s,2H),2.45(s,3H)1.96-1.85(m,1H),0.95–0.85(m,2H),0.69-0.61(m,2H)。

Example 35

Inhibitory Activity of exemplary Compounds against plasma kallikrein.

Inhibition of human activated kallikrein by compounds was evaluated in two forms of assays employing fluorescent peptide substrates. In one assay format, the concentration of reagents is as follows: 20mM Tris pH 7.5, 1mM EDTA, 150mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 500pM activated kallikrein, 300uM Pro-Phe-Arg-7-amido-4-methylcoumarin (PFR-AMC) substrate. The enzyme and inhibitor were pre-incubated for 30min at room temperature before initiating the reaction with the substrate. After priming with substrate, the reaction was incubated for 10min at room temperature and fluorescence emission at 460nm from 380nm excitation was measured with a microplate reader. In another assay format, the concentration of reagents is as follows: 20mM Tris pH 7.5, 1mM EDTA, 150mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 5pM activated kallikrein, 300uM PFR-AMC substrate. The enzyme and inhibitor were pre-incubated for 30min at room temperature before initiating the reaction with the substrate. After priming with substrate, the reaction was incubated for 18h at room temperature and fluorescence emission at 460nm from 380nm excitation was measured with a microplate reader.

Table 2 provides the results of the assay with a form of 500pM activated kallikrein. For the compounds listed in table 2, EC are reported according to the following ranges ₅₀ Value: a is less than or equal to 5.0nM;5.0nM<B≤50nM；50nM<C≤500nM；500nM<D≤9000nM；9000nM<E。

TABLE 2

Example 36

Pure human and rat plasma assay

To analyze the inhibition of plasma kallikrein in an ex vivo environment, the efficacy of compounds was measured in a contact pathway activated plasma assay. In the fluorogenic peptide substrate assay, test compounds dissolved in DMSO are added to human or rat plasma collected from sodium citrate in 96-well microwell plates. Alternatively, citrate plasma (citrate plasma) is collected from rats to which the compound is administered orally or intravenously. 10nM human FXIIa (Enzyme Research Laboratories) diluted in PKa buffer (20 mM Tris-HCl pH 7.5, 150mM NaCl, 1mM EDTA, 0.1% PEG-8000 and 0.1% Triton X-100) was added to the plasma followed by the addition of 100. Mu.M fluorogenic synthetic plasma kallikrein substrate PFR-AMC (also diluted in PKa buffer). The final plasma concentration in the reaction was 78%. Fluorescence was monitored immediately over a period of 5 minutes in a microplate reader by excitation/emission wavelengths of 360nm/480nm, respectively. The resulting linear increase in fluorescence emission (reflecting the PKa proteolysis of the PFR-AMC substrate) was fitted to extract the proteolysis rate (time-varying fluorescence units) which was then plotted against the compound inhibitor concentration. The resulting map was fitted to a standard 4 parameter IC50/IC90 equation to determine the min/max value, IC50/90 and slope. All experimental steps were performed at room temperature. Table 3 provides the results of the assay.

For the compounds listed in Table 3, IC ₉₀ Values are reported according to the following ranges: a is less than or equal to 2500nM;2500nM<B≤7500nM；7500nM<C≤15000nM。

TABLE 3 Table 3

Compounds of formula (I)	Human plasma assay: IC90
		I-8	A
I-10	B
		I-11	B
I-12	C
		I-13	C
I-15	B
		I-21	B
I-26	A
		I-28	A

While we have described many embodiments of the invention, it is apparent that our basic examples can be varied to provide other embodiments that utilize the compounds and methods of the invention. It is, therefore, to be understood that the scope of the invention is defined by the appended claims rather than by the specific embodiments shown by way of example.

Exemplary enumeration implementation

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

x is-O-or-NR ^y -；

R ^y Is hydrogen or optionally substituted C _1-6 An aliphatic group;

Each R ^D Independently selected from oxo, halogen, haloalkyl, -CN, -C (O) R, -C (O) ₂ R、-C(O)N(R) ₂ 、-NO ₂ 、-N(R) ₂ 、-N(R)C(O)R、-N(R)C(O) ₂ R、-N(R)S(O) ₂ R、-OR、-OC(O)R、-OC(O)N(R) ₂ 、-SR、-S(O)R、-S(O) ₂ R、-S(O)N(R) ₂ 、-S(O) ₂ N(R) ₂ Or an optionally substituted group selected from: c (C) _1-6 Aliphatic, phenyl, 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, or 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur; and is also provided with

2. The compound of embodiment 1 wherein Cy ^A Is a 5-to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^A Is 0-4-R ^A And (3) group substitution.

3. The compound of embodiment 1 or 2, wherein Cy ^A Is a 6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^A Is 0-4-R ^A And (3) group substitution.

4. The compound of any one of embodiments 1-3, wherein Cy ^A Selected from the group consisting of:

wherein represents the point of attachment to L.

5. The compound of any one of embodiments 1-3, wherein Cy ^A Is covered by 0-1R ^A A group-substituted pyridyldiyl group.

6. The compound of any one of embodiments 1-3, wherein Cy ^A Is covered by 0-1R ^A Pyrimidinediyl groups substituted with groups.

7. The compound of embodiment 1 wherein Cy ^A Is a 7 to 12 membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^A Is 0-4-R ^A And (3) group substitution.

8. The compound of embodiment 7 wherein Cy ^A Is triazolopyridinyl, imidazopyridinediyl or triazolopyrazinyl, wherein Cy ^A Is 0-1-R ^A And (3) group substitution.

9. The compound of any one of the preceding embodiments, wherein Cy ^B Selected from phenyl and 5 to 6 membered heteroaryl groups having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^B Is 0-4-R ^B And (3) group substitution.

10. The compound of any one of the preceding embodiments, wherein Cy ^B Is phenyl, wherein Cy ^B Is 0-3-R ^B And (3) group substitution.

11. The compound of any one of embodiments 1-9, wherein Cy ^B Is a 6 membered heteroaryl group having 1-3 nitrogens, wherein Cy ^B Is 0-4-R ^B And (3) group substitution.

12. The compound of any one of the preceding embodiments, wherein Cy ^B Is covered with 0-2-R ^B Pyrimidinyl substituted with radicals. In some embodiments, cy ^B Is covered with 0-2-R ^B A group-substituted pyridyl group.

13. The compound of any one of the preceding embodiments, wherein Cy ^B Selected from the group consisting of:

14. the compound of any one of the preceding embodiments, wherein each R ^B Independently selected from halogen, -OR, OR an optionally substituted group selected from: c (C) _1-6 Aliphatic or 5 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

15. The compound of any of the preceding embodiments, wherein L is optionally substituted C _1-3 Hydrocarbon chains in which 1 methylene unit is optionally replaced by-O-or-NR ^z -substitution.

16. The compound of any of the preceding embodiments, wherein L is optionally substituted C ₂ Hydrocarbon chain in which 1 methylene unit is optionally substituted by-NR ^z -or-O-substitution.

17. The compound of any of the preceding embodiments, wherein L is optionally substituted C ₂ Hydrocarbon chain, wherein is linked to Cy ^A Is of the methylene unit of (2) is of the type-NR ^z -or-O-substitution.

18. The compound of any of the preceding embodiments, wherein L is optionally substituted C ₂ Hydrocarbon chain, wherein is linked to Cy ^A Is of the methylene unit of (2) is of the type-NR ^z -substitution.

19. The compound of any of embodiments 1-17 wherein L is optionally substituted C ₂ Hydrocarbon chain, wherein is linked to Cy ^A The methylene units of (C) are replaced by-O-.

20. The compound of embodiment 18 wherein L is-NHCH ₂ -, where x represents and Cy ^A Is connected to the connecting point of (c).

21. The compound of embodiment 19 wherein L is x-OCH ₂ -, where is representative ofWith Cy ^A Is connected to the connecting point of (c).

22. The compound of any of embodiments 1-14 wherein L is an optionally substituted 5-membered saturated or partially unsaturated heterocyclylene having 1 heteroatom independently selected from oxygen, nitrogen and sulfur. In some embodiments, L is optionally substituted pyrrolidinediyl.

23. The compound of any of embodiments 1-14 or 22 wherein L isWherein represents and Cy ^A Is connected to the connecting point of (c).

24. The compound of any one of the preceding embodiments, wherein L comprises Cy ^A And (3) withDiatomic spacers in between.

25. The compound of any one of the preceding embodiments, wherein X is-O-.

26. The compound of any one of the preceding embodiments, wherein X is-NR ^y -。

27. The compound of embodiment 26 wherein R ^y Is hydrogen.

28. The compound of embodiment 26 wherein R ^y Is optionally substituted C _1-6 Aliphatic groups.

29. The compound of any of the preceding embodiments, wherein L' is optionally substituted C _1-3 A hydrocarbon chain.

30. The compound of any of the preceding embodiments, wherein L' is-CH (CH) ₃ )-。

31. The compound of any of the preceding embodiments, wherein L' isWherein represents and Cy ^B Is connected to the connecting point of (c).

32. The compound of any of the preceding embodiments, wherein L' is optionally substituted with- (CH) ₂ ) _0-4 R ^o Or- (CH) ₂ ) _0-4 OR ^o Substituted methylene units wherein R ^o Is hydrogen or C _1-6 Aliphatic groups.

33. The compound of any of embodiments 1-28 wherein L' is CH ₂ 。

34. The compound of any of embodiments 1-28 wherein the carbon of L' can be optionally substituted with R ^z Together forming a 3 to 7 membered heterocyclic ring.

35. The compound of embodiment 34 wherein the carbon of L' is bonded to R ^y Together forming a 4 membered heterocyclic ring.

36. The compound of any one of the preceding embodiments, wherein R ³ Is hydrogen.

37. The compound of any one of the preceding embodiments, wherein R ⁴ Is hydrogen.

38. The compound of any one of the preceding embodiments, wherein R ⁵ Is hydrogen.

39. The compound of any one of the preceding embodiments, wherein R ⁶ Selected from hydrogen or L ^C -R ^C Wherein L is ^C Is a covalent bond, and wherein R ^C Selected from halogen, -N (R) ₂ 、-OR、Cy ^C Or optionally substituted C _1-6 Aliphatic groups.

40. The compound of embodiment 37, wherein Cy ^C Is composed of 0-4L ^D -R ^D A 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl substituted with a group.

41. The compound of embodiment 38, wherein Cy ^C Is composed of 0-4L ^D -R ^D A cyclopropyl group substituted with a group.

42. The compound of any one of the preceding embodiments, wherein Cy ^C Is unsubstituted cyclopropyl.

43. The compound of any one of the preceding embodiments, wherein R ⁷ Is hydrogen.

44. The compound of any one of the preceding embodiments, wherein R ⁸ Is hydrogen.

45. The compound of any one of the preceding embodiments, wherein the compound has formula II-a or II-b:

or a pharmaceutically acceptable salt thereof.

46. The compound of any one of the preceding embodiments, wherein the compound has the formula III-a-1, III-b-1, III-a-2, III-b-2, III-a-3, or III-b-3:

or a pharmaceutically acceptable salt thereof.

47. The compound of any one of the preceding embodiments, wherein the compound has the formula IV-a-1, IV-b-1, IV-a-2, or IV-b-2:

or a pharmaceutically acceptable salt thereof.

48. The compound of any one of the preceding embodiments, wherein the compound has formula V:

or a pharmaceutically acceptable salt thereof.

49. The compound of any one of the preceding embodiments, wherein the compound has formula VI-a, VI-b, or VI-c:

Or a pharmaceutically acceptable salt thereof.

50. The compound according to any one of the preceding embodiments, wherein the compound is selected from compounds I-1 to I-34 or a pharmaceutically acceptable salt thereof.

51. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments.

52. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, further comprising a pharmaceutically acceptable excipient.

53. The composition of embodiment 51 or 52, wherein the composition is suitable for oral administration.

54. A method of treating a plasma kallikrein mediated disease or condition using a compound or composition of any of the preceding embodiments.

55. The method of embodiment 54, wherein the disease or disorder is hereditary angioedema.

56. The method of embodiment 54, wherein the disease or disorder is diabetic macular edema.

57. A method of treating hereditary angioedema, the method comprising administering the compound or composition of any of the preceding embodiments to a patient in need thereof.

58. A method of treating diabetic macular edema comprising administering to a patient in need thereof a compound or composition of any one of the preceding embodiments.

59. The method of any one of embodiments 55 or 57, wherein administration of the compound partially or completely inhibits one or more symptoms, features, and/or etiologies of hereditary angioedema, delays its onset, reduces its severity, and/or reduces its incidence.

60. The method of embodiment 59, wherein the compound is administered orally.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

each R ^B Independently selected from oxo, halogen, haloalkyl, -CN, -C (O) R, -C (O) ₂ R、-C(O)N(R) ₂ 、-NO ₂ 、-N(R) ₂ 、-N(R)C(O)R、-N(R)C(O) ₂ R、-N(R)S(O) ₂ R、-OR、-OC(O)R、-OC(O)N(R) ₂ 、-SR、-S(O)R、-S(O) ₂ R、-S(O)N(R) ₂ 、-S(O) ₂ N(R) ₂ Or an optionally substituted group selected from: c (C) _1-6 Aliphatic groups, 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, or having 1-4 independent groupsA 5 to 6 membered heteroaryl group selected from heteroatoms of oxygen, nitrogen and sulfur;

l is optionally substituted C _1-3 Hydrocarbon chains in which 1 to 3 methylene units are optionally and independently replaced by-O-, -NR ^z -, -S-, -SO-or-SO ₂ -substitution; or L is an optionally substituted 5-to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur;

x is-O-or-NR ^y -；

R ^y Is hydrogen or optionally substituted C _1-6 An aliphatic group;

each Cy ^C Independently selected from 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 5 to 6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and 1-3A 6 to 12 membered saturated or partially unsaturated fused bicyclic heterocyclyl group, bridged bicyclic, or a 6 to 12 membered saturated or partially unsaturated bicyclic spiro heterocyclyl group having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy ^C Is 0-4-L ^D -R ^D Group substitution;

2. The compound of claim 1, wherein Cy ^A Is a 5-to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^A Is 0-4-R ^A And (3) group substitution.

3. The compound of claim 1 or 2, wherein Cy ^A Selected from the group consisting of:

wherein represents the point of attachment to L.

4. The compound of claim 1, wherein Cy ^A Is a 7 to 12 membered bicyclic heteroarylene having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^A Is 0-4-R ^A And (3) group substitution.

5. The compound of claim 1 or 4, wherein Cy ^A Is triazolopyridinyl, imidazopyridinediyl or triazolopyrazinyl, wherein Cy ^A Is 0-1-R ^A And (3) group substitution.

6. The compound of any one of the preceding claims, wherein Cy ^B Selected from phenyl and 5 to 6 membered heteroaryl groups having 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein Cy ^B Is 0-4-R ^B And (3) group substitution.

7. The compound of any one of the preceding claims, wherein Cy ^B Selected from the group consisting of:

8. the compound of any one of the preceding claims, wherein each R ^B Independently selected from halogen, -OR, OR an optionally substituted group selected from: c (C) _1-6 Aliphatic or 5 membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

9. The compound of any one of the preceding claims, wherein L is optionally substituted C _1-3 Hydrocarbon chains in which 1 methylene unit is optionally replaced by-O-or-NR ^z -substitution.

10. A compound according to any one of the preceding claims, wherein L is-NHCH ₂ -or-OCH ₂ -, where x represents and Cy ^A Is connected to the connecting point of (c).

11. The compound of any one of claims 1-8, wherein L is an optionally substituted 5-membered saturated or partially unsaturated heterocyclylene having 1 heteroatom independently selected from oxygen, nitrogen, and sulfur.

12. The compound of any one of the preceding claims, wherein L' is optionally substituted C _1-3 A hydrocarbon chain.

13. The compound of any one of the preceding claims, wherein L' is-CH (CH ₃ )-、CH ₂ 、Wherein represents and Cy ^B Is connected to the connecting point of (c).

14. The compound of any one of claims 1-11, wherein the carbon of L' is optionally substituted with R ^z Together forming a 3 to 7 membered heterocyclic ring.

15. The compound of claim 16, wherein the carbon of L' is in combination with R ^y Together forming a 4 membered heterocyclic ring.

16. The compound of any one of the preceding claims, wherein R ³ Is hydrogen.

17. The compound of any one of the preceding claims, wherein R ⁴ Is hydrogen.

18. The compound of any one of the preceding claims, wherein R ⁵ Is hydrogen.

19. The compound of any one of the preceding claims, wherein R ⁶ Selected from hydrogen or L ^C -R ^C Wherein L is ^C Is a covalent bond, and wherein R ^C Selected from halogen,-N(R) ₂ 、-OR、Cy ^C Or optionally substituted C _1-6 Aliphatic groups.

20. The compound of any one of the preceding claims, wherein Cy ^C Is unsubstituted cyclopropyl.

21. The compound of any one of the preceding claims, wherein R ⁷ Is hydrogen.

22. The compound of claim 1, wherein the compound has formula II-a or II-b:

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound has the formula III-a-1, III-b-1, III-a-2, III-b-2, III-a-3, or III-b-3:

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, wherein the compound has the formula IV-a-1, IV-b-1, IV-a-2, or IV-b-2:

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein the compound has formula V:

Or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1, wherein the compound has formula VI-a, VI-b, or VI-c:

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound is selected from compounds I-1 to I-34 or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of the preceding claims.

29. A method of treating a plasma kallikrein mediated disease or condition using a compound or composition as defined in any preceding claim.

30. The method of claim 29, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.