CN118201928A - 6-Heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors - Google Patents

6-Heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors Download PDF

Info

Publication number
CN118201928A
CN118201928A CN202280074285.6A CN202280074285A CN118201928A CN 118201928 A CN118201928 A CN 118201928A CN 202280074285 A CN202280074285 A CN 202280074285A CN 118201928 A CN118201928 A CN 118201928A
Authority
CN
China
Prior art keywords
optionally substituted
compound
nitrogen
sulfur
oxygen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202280074285.6A
Other languages
Chinese (zh)
Inventor
C·E·马斯
J·R·格林伍德
J·徐
S·蒙达尔
P·加纳科塔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aijie Si Treatment Co
Original Assignee
Aijie Si Treatment Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aijie Si Treatment Co filed Critical Aijie Si Treatment Co
Priority claimed from PCT/US2022/049220 external-priority patent/WO2023086319A1/en
Publication of CN118201928A publication Critical patent/CN118201928A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present disclosure provides 6-heteroaryloxy benzimidazoles and azabenzimidazole compounds and compositions thereof that are useful for inhibiting JAK 2.

Description

6-Heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
RELATED APPLICATIONS
The present application claims priority and benefit from U.S. application Ser. No. 63/277,343, filed on Ser. No. 2021, 11, 9, and U.S. application Ser. No. 63/354,403, filed on 6, 22, 2022, each of which is hereby incorporated by reference in its entirety.
Background
Janus kinase 2 (JAK 2) is a non-receptor tyrosine kinase involved in JAK-STAT signaling pathway that plays a role in cellular processes such as immunity, cell division and cell death. JAK-STAT pathway dysfunction is associated with a variety of diseases including cancer and other proliferative diseases as well as diseases of the immune system. For example, substantially all BCR-ABL1 negative myeloproliferative neoplasms are associated with mutations that activate JAK 2. In particular, JAK2V617F is the most prevalent mutation in myeloproliferative neoplasms, occurring in about 70% of all patients, and up to 95% of polycythemia vera patients. (Vainchenker, W., kralovics, R.blood 2017,129 (6): 667-79). Even less common mutations (such as those in MPL and CALR) have been shown to effect JAK2 activation, thereby eliciting and/or driving disease progression. (Vainchenker, W. Et al, F1000Research 2018,7 (F1000 Faculty Rev): 82). In addition, JAK2 polymorphisms are associated with various autoimmune diseases and inflammatory disorders (such as psoriasis and inflammatory bowel disease). (O' Shea, J.J. et al, ann. Rheum. Dis.2013, month 4, 72:i111-ii 115). Increased signaling through JAK2 and other members of the JAK family is also associated with atopic dermatitis. (Rodrigues, M.A. and Torres, T.J. Derm. Treat.2019,31 (1): 33-40).
JAK inhibitors (e.g., JAK 2) are classified based on their binding pattern. All JAK inhibitors currently approved are type I inhibitors, i.e. inhibitors that bind to ATP binding sites in the active conformation of the kinase domain, thereby blocking catalysis (Vainchenker, w. However, increased phosphorylation of JAK2 activation loops was observed with type I inhibitors and may lead to acquired resistance in certain patients (Meyer s.c., levine, r.l. clin. Cancer res.2014,20 (8): 2051-9). On the other hand, inhibitors of type II bind to ATP binding sites in the inactive conformation of the kinase domain, and thus avoid the hyperphosphorylation observed with inhibitors of type I (Wu, S.C. et al CANCER CELL, 13, 2015, 28 (1): 29-41).
Disclosure of Invention
The present disclosure provides compounds useful for inhibiting JAK 2. In some embodiments, the provided compounds are particularly useful for treating and/or preventing diseases, disorders, or conditions associated with JAK 2.
In some embodiments, the present disclosure provides compounds of formula I
Or a pharmaceutically acceptable salt thereof, wherein ring A, n, L, W, X, Y, Z, R 1、R2、Ra and R c are as defined herein.
In some embodiments, the present disclosure provides compounds of formula II
Or a pharmaceutically acceptable salt thereof, wherein ring A, n, W, X, Y, Z, R 1、R2 and R c are as defined herein.
In some embodiments, the present disclosure provides compounds of formula III
Or a pharmaceutically acceptable salt thereof, wherein ring A, L, Z, R 2、R4、Ra and R x are as defined herein.
In some embodiments, the present disclosure provides compounds of formula IV
Or a pharmaceutically acceptable salt thereof, wherein ring A, L, Z, R', R 2、Ra, and R x are as defined herein.
Detailed Description
Compounds and definitions
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 shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to Periodic Table of THE ELEMENTS, CAS version, handbook of CHEMISTRY AND PHYSICS, 75 th edition. Furthermore, 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.
Unless otherwise indicated, structures depicted herein are intended to include all stereoisomeric (e.g., enantiomeric or diastereoisomeric) forms of the structures, as well as all geometric or conformational isomeric forms of the structures. For example, the R and S configurations of each stereocenter are considered to be part of the present disclosure. Thus, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) isomer mixtures of the provided compounds are within the scope of the disclosure. For example, in some cases, table 1 shows one or more stereoisomers of a compound, and table 1 represents each stereoisomer alone and/or as a mixture, unless otherwise indicated. Unless otherwise indicated, all tautomeric forms of the provided compounds are within the scope of the disclosure.
Unless otherwise indicated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention (including hydrogen replaced with deuterium or tritium or carbon replaced with 13 C or 14 C enriched carbon) are within the scope of the present disclosure.
Aliphatic: the term "aliphatic" refers to a straight (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a mono-or bicyclic hydrocarbon (also referred to herein as "carbocycle" or "alicyclic") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise indicated, aliphatic groups contain 1 to 12 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-6 aliphatic carbon atoms (e.g., C 1-6). In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms (e.g., C 1-5). In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms (e.g., C 1-4). In still other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms (e.g., C 1-3), and in still other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms (e.g., C 1-2). Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof. In some embodiments, "aliphatic" refers to a straight (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, having a single point of attachment to the rest of the molecule.
Alkyl: the term "alkyl" as used alone or as part of a larger moiety refers to a saturated, optionally substituted, straight or branched chain hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C 1-12、C1-10、C1-8、C1-6、C1-4、C1-3 or C 1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.
Carbocyclyl: the term "carbocyclyl", "carbocycle (carbocycle)" or "carbocycle (carbocyclic ring)" as used herein refers to a saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic or polycyclic ring system having 3 to 14 members as described herein, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, "carbocyclyl" (or "cycloaliphatic") refers to an optionally substituted monocyclic C 3-C8 hydrocarbon or an optionally substituted C 7-C10 bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule. The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3-6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic mono-or polycyclic ring system containing at least one carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.
Alkenyl: the term "alkenyl" used alone or as part of a larger moiety refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12、C2-10、C2-8、C2-6、C2-4 or C 2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
Alkynyl: the term "alkynyl", used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12、C2-10、C2-8、C2-6、C2-4 or C 2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
Aryl: the term "aryl" refers to mono-and bi-cyclic ring systems having a total of six to fourteen ring members (e.g., C 6-14), 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, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, naphthyl, anthracenyl, and the like, which may bear one or more substituents. Unless otherwise indicated, "aryl" is a hydrocarbon.
Heteroaryl group: the terms "heteroaryl" and "heteroaryl (heteroar-)" used alone or as part of a larger moiety (e.g., a "heteroaralkyl" or "heteroarylalkoxy") refer to a monocyclic heteroaryl group having 5 to 10 ring atoms (e.g., 5 to 6 membered or 9 to 10 membered bicyclic heteroaryl groups); having 6, 10 or 14 pi electrons shared in a ring array; and a monocyclic or bicyclic ring group having one to five heteroatoms in addition to carbon atoms. Exemplary heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl (pyridonyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo [1,2-a ] pyrimidinyl, imidazo [1,2-a ] pyridyl, thienopyrimidinyl, triazolopyridinyl, and benzisoxazolyl. The terms "heteroaryl" and "heteroaryl-" as used herein also include groups in which the heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, wherein the linking group or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido [2,3-b ] -1, 4-oxazin-3 (4H) -one, and benzisoxazolyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which include an optionally substituted ring.
Heteroatom(s): the term "heteroatom" as used herein refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen.
Heterocycles: as used herein, the terms "heterocycle (heterocycle)", "heterocyclyl" and "heterocycle (heterocyclic ring)" are used interchangeably and refer to a stable 3-to 8-membered monocyclic or 7-to 10-membered bicyclic heterocyclic moiety, which may be saturated or partially unsaturated, and which has one or more (such as one to four) heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used in reference to a ring atom of a heterocycle includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring 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 heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazanyl, oxazazepinyl, thiazazepinyl, morpholinyl, and thiamorpholinyl. The heterocyclyl group may be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or bicyclic. Bicyclic heterocycles also include groups in which the heterocycle is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1, 3-dihydroisobenzofuranyl, 2, 3-dihydrobenzofuranyl, and tetrahydroquinolinyl. The bicyclic heterocycle may also be a spiro ring system (e.g., a 7 to 11 membered spiro ring fused heterocycle having one or more heteroatoms (e.g., one, two, three, or four heteroatoms) as defined above in addition to a carbon atom).
Partially unsaturated: as used herein, the term "partially unsaturated" when referring to a ring moiety means a ring moiety that contains at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties as defined herein.
Patient or subject: as used herein, the term "patient" or "subject" refers to any organism to which the provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, the patient is a human. In some embodiments, the patient or subject has or is susceptible to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of the disorder or condition. In some embodiments, the patient or subject has been diagnosed as having one or more conditions or disorders. In some embodiments, the patient or subject is receiving or has received certain therapies to diagnose and/or treat a disease, disorder, or condition.
Substituted or optionally substituted: as described herein, the compounds of the present disclosure may contain an "optionally substituted" moiety. Generally, the term "substituted" means that one or more hydrogens of the designated moiety are replaced with a suitable substituent (i.e., an optionally substituted group as described below), whether or not the term "optionally" is present. "substituted" applies to one or more hydrogens either explicitly or implicitly in the structure (e.g.,At least refer to/>And/>At least means). 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 viable compounds. The term "stable" as used herein refers to a compound that does not substantially change when subjected to conditions that allow for its production, detection, and in some embodiments its recovery, purification, and use for one or more of the purposes provided herein. The group described as "substituted" preferably has 1to 4 substituents, more preferably 1 or 2 substituents. The groups described as "optionally substituted" may be unsubstituted or "substituted" as described above.
Suitable monovalent substituents on the substitutable carbon atom of an "optionally substituted" group are independently halogen ;-(CH2)0-4Ro;-(CH2)0-4ORo;-O(CH2)0-4Ro、-O-(CH2)0-4C(O)ORo;-(CH2)0-4CH(ORo)2;-(CH2)0- 4SRo;-(CH2)0-4Ph, which may be substituted with R o; - (CH 2)0-4O(CH2)0-1 Ph, which may be substituted by R o, -CH=CHPh, which may be substituted by R o, -CH 2)0-4O(CH2)0-1 -pyridyl, which may be substituted by R o for ;-NO2;-CN;-N3;-(CH2)0-4N(Ro)2;-(CH2)0-4N(Ro)C(O)Ro;-N(Ro)C(S)Ro;-(CH2)0-4N(Ro)C(O)NRo 2;-N(Ro)C(S)NRo 2;-(CH2)0-4N(Ro)C(O)ORo;-N(Ro)N(Ro)C(O)Ro;-N(Ro)N(Ro)C(O)NRo 2;-N(Ro)N(Ro)C(O)ORo;-(CH2)0-4C(O)Ro;C(S)Ro;-(CH2)0-4C(O)ORo;-(CH2)0-4C(O)SRo;-(CH2)0-4C(O)OSiRo 3;-(CH2)0-4OC(O)Ro;-OC(O)(CH2)0-4SRo;-(CH2)0-4SC(O)Ro;-(CH2)0-4C(O)NRo 2;-C(S)NRo 2;-C(S)SRo;-SC(S)SRo、-(CH2)0- 4OC(O)NRo 2;-C(O)N(ORo)Ro;-C(O)C(O)Ro;-C(O)CH2C(O)Ro;-C(NORo)Ro;-(CH2)0-4SSRo;-(CH2)0-4S(O)2Ro;-(CH2)0-4S(O)2ORo;-(CH2)0-4OS(O)2Ro;-S(O)2NRo 2;-(CH2)0-4S(O)Ro;-N(Ro)S(O)2NRo 2;-N(Ro)S(O)2Ro;-N(ORo)Ro;-C(NH)NRo 2;-P(O)2Ro;-P(O)Ro 2;-OP(O)Ro 2;-OP(O)(ORo)2;SiRo 3;-(C1-4 straight or branched chain alkylene) O-N (R o)2, or- (C 1-4 straight or branched chain alkylene) C (O) O-N (R o)2, wherein each R o may be substituted as defined below and is independently hydrogen, C 1-6 aliphatic, -CH 2Ph、-O(CH2)0- 1Ph、-CH2 - (5-to 6-membered heteroaryl ring), or a 3-to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, although defined above, two independently occurring R 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.
Suitable monovalent substituents on R o (OR the ring formed by two independently occurring R o with its intervening atoms) are independently halogen, - (CH 2)0-2R·, - (halo R·)、-(CH2)0-2OH、-(CH2)0-2OR·、-(CH2)0-2CH(OR·)2、-O( halo R·)、-CN、-N3、-(CH2)0-2C(O)R·、-(CH2)0-2C(O)OH、-(CH2)0-2C(O)OR·、-(CH2)0-2SR·、-(CH2)0- 2SH、-(CH2)0-2NH2、-(CH2)0-2NHR·、-(CH2)0-2NR· 2、-NO2、-SiR· 3、-OSiR· 3、-C(O)SR·、-(C1-4 linear OR branched alkylene) C (O) OR · OR-SSR ·, wherein each R · is unsubstituted OR substituted with only one OR more halogen with "halo" added in front, and are independently selected from C 1-4 aliphatic, -CH 2Ph、-O(CH2)0-1 Ph, OR 3 to 6 membered saturated, partially unsaturated, OR aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, OR sulfur suitable divalent substituents on the saturated carbon atoms of R o include =o and =s.
Suitable divalent substituents on saturated carbon atoms of an "optionally substituted" group include the following: =o ("oxo ")、＝S、＝NNR* 2、＝NNHC(O)R*、＝NNHC(O)OR*、＝NNHS(O)2R*、＝NR*、＝NOR*、-O(C(R* 2))2-3O- or-S (C (R * 2))2-3 S-, wherein each independently occurring R * is selected from hydrogen, a C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 3 to 6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur suitable divalent substituents bonded to the ortho-substitutable carbon of the" optionally substituted "group include: -O (CR * 2)2-3 O-, wherein each independently occurring R * is selected from hydrogen, a C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5 to 6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur).
Suitable substituents on the aliphatic group of R * include halogen, -R ·, - (halo R ·)、-OH、-OR·, -O (halo R ·)、-CN、-C(O)OH、-C(O)OR·、-NH2、-NHR·、-NR· 2 or-NO 2, wherein each R · is unsubstituted or substituted with only one or more halogens with "halo" in the preceding case, and are independently C 1-4 aliphatic, -CH 2Ph、-O(CH2)0-1 Ph, or a 3-to 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/>Wherein each/>Independently is hydrogen, a C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 3 to 6 membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently occur/>, despite the above definitionTogether with the intervening atoms, form an unsubstituted 3 to 12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.
Suitable substituents on the aliphatic radical of (a) are independently halogen, -R ·, - (halo R ·)、-OH、-OR·, -O (halo R ·)、-CN、-C(O)OH、-C(O)OR·、-NH2、-NHR·、-NR· 2 or-NO 2, wherein each R · is unsubstituted or substituted with only one or more halogen if preceded by "halo"), and are independently C 1-4 aliphatic, -CH 2Ph、-O(CH2)0-1 Ph, or a 3-to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.
Treatment: as used herein, the term "treatment" (and also "treatment") or "treatment") refers to any administration of a therapy 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. In some embodiments, such treatment may be directed to subjects that do not exhibit signs of the associated disease, disorder, and/or condition and/or to 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 determined signs of the associated disease, disorder, and/or condition. In some embodiments, the treatment may be directed to a subject that has been diagnosed as suffering from a related disease, disorder, and/or condition.
The provided compounds
In some embodiments, the present disclosure provides compounds of formula I:
Or a pharmaceutically acceptable salt thereof, wherein:
W is CR w or N;
X is CR x or N;
Y is CR y or N;
Z is-O-or-NR z -;
R w、Rx and R y are each independently hydrogen, halogen, -OR 3、-N(R3)2、-SR3, optionally substituted C 1-6 aliphatic OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
R 1 is-N (R) 2、-N(R)C(O)R'、-C(O)N(R)2、-N(R)C(O)N(R)2 OR-N (R) C (O) OR;
Each R c is independently selected from halogen, -CN, -CO 2R、-C(O)N(R)2、-NO2、-N(R)2, -OR, -SR, OR optionally substituted C 1-6 aliphatic;
N is 0, 1,2 or 3, provided that when R 1 is-N (R) 2, -N (R) C (O) R' or-C (O) N (R) 2, N is 1,2 or 3;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
Ring a is optionally substituted phenyl, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
l is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;
R a is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
Each R is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's taken together when attached to the same nitrogen atom form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
Each R' is independently optionally substituted C 1-6 aliphatic or optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl.
In some embodiments, the present disclosure provides compounds of formula I-a:
Or a pharmaceutically acceptable salt thereof, wherein ring A, n, L, Z, R 1、R2、Ra、Rc、Rx and R y, either alone or in combination, are as defined above for formula I and are described in the classes and subclasses herein.
In some embodiments, the present disclosure provides compounds of formula I-B:
Or a pharmaceutically acceptable salt thereof, wherein ring A, n, L, Z, R 1、R2、Ra、Rc and R y, either alone or in combination, are as defined above for formula I and are described in the classes and subclasses herein.
In some embodiments, the present disclosure provides compounds of formula I-C:
Or a pharmaceutically acceptable salt thereof, wherein ring A, n, L, Z, R 1、R2、Ra、Rc and R x, either alone or in combination, are as defined above for formula I and are described in the classes and subclasses herein.
In some embodiments, the present disclosure provides compounds of formula I-D:
Or a pharmaceutically acceptable salt thereof, wherein ring A, n, L, W, X, Y, Z, R 1、R2、Ra and R c, either alone or in combination, are as defined above for formula I and are described in the classes and subclasses herein; and
R b is hydrogen, halogen 、-CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R'、-SO2N(R)2、-SO3R'、 optionally substituted C 1-6 aliphatic, optionally substituted 3 to 6 membered saturated or partially unsaturated carbocyclyl, optionally substituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
M is 1, 2 or 3.
In some embodiments, the present disclosure provides compounds of formula I-E:
Or a pharmaceutically acceptable salt thereof, wherein ring A, L, W, X, Y, Z, R 1、R2 and R a, either alone or in combination, are as defined above for formula I and are described in the classes and subclasses herein.
In some embodiments, the present disclosure provides compounds of formula II:
Or a pharmaceutically acceptable salt thereof, wherein:
W is CR w or N;
X is CR x or N;
Y is CR y or N;
Z is-O-or-NR z -;
R w、Rx and R y are each independently hydrogen, halogen, -OR 3、-N(R3)2、-SR3, optionally substituted C 1-6 aliphatic OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
R 1 is-N (R) 2、-N(R)C(O)R'、-C(O)N(R)2、-N(R)C(O)N(R)2 OR-N (R) C (O) OR;
Each R c is independently selected from halogen, -CN, -CO 2R、-C(O)N(R)2、-NO2、-N(R)2, -OR, -SR, OR optionally substituted C 1-6 aliphatic;
n is 0,1, 2 or 3;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
Ring a is an optionally substituted 9-to 16-membered bicyclic or tricyclic aryl, an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 10-to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 7-to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 10-to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's taken together when attached to the same nitrogen atom form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
Each R' is independently optionally substituted C 1-6 aliphatic or optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl.
In some embodiments, the present disclosure provides compounds of formula II-A:
Or a pharmaceutically acceptable salt thereof, wherein ring A, n, Z, R 1、R2、Rc、Rx and R y, either alone or in combination, are as defined above for formula II and are described in the classes and subclasses herein.
In some embodiments, the present disclosure provides compounds of formula II-B:
Or a pharmaceutically acceptable salt thereof, wherein ring A, n, Z, R 1、R2、Rc and R y, either alone or in combination, are as defined above for formula II and are described in the classes and subclasses herein.
In some embodiments, the present disclosure provides compounds of formula II-C:
Or a pharmaceutically acceptable salt thereof, wherein ring A, n, Z, R 1、R2、Rc and R x, either alone or in combination, are as defined above for formula II and are described in the classes and subclasses herein.
In some embodiments, the present disclosure provides compounds of formulas II-D:
Or a pharmaceutically acceptable salt thereof, wherein ring A, W, X, Y, Z, R 1 and R 2, either alone or in combination, are as defined above for formula II and are described in the classes and subclasses herein.
In some embodiments, the present disclosure provides compounds of formula II-E:
Or a pharmaceutically acceptable salt thereof, wherein n, W, X, Y, Z, R 1、R2 and R c, either alone or in combination, are as defined above for formula II and are described in the classes and subclasses herein; and
Ring A1 is an optionally substituted ring selected from phenyl, a 5 to 6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl group, and a 5 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
wherein ring A1 is fused to ring A2;
Ring A2 is an optionally substituted ring selected from phenyl, a 5 to 6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl group, and a 5 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
wherein ring A2 is optionally (i) further fused to ring A3,
Or (ii) ring A2 and ring A3 combine to form a spiro ring; and
When present, ring A3 is an optionally substituted ring selected from phenyl, a 5-to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, A3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl group, and A3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
In some embodiments, the present disclosure provides compounds of formulas II-F:
Or a pharmaceutically acceptable salt thereof, wherein rings A2, n, W, X, Y, Z, R 1、R2 and R c, either alone or in combination, are as defined above for formula II and are described in the classes and subclasses herein.
In some embodiments, the present disclosure provides compounds of formula III:
Or a pharmaceutically acceptable salt thereof, wherein:
Z is-O-or-NR z -;
R x is hydrogen, halogen, -OR 3、-N(R3)2、-SR3, optionally substituted C 1-6 aliphatic OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
r 4 is halogen, -OR, -N (R) 2 OR an optionally substituted 3-to 7-membered saturated OR partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
Ring a is optionally substituted phenyl, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
l is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;
R a is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
Each R is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's taken together when attached to the same nitrogen atom form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, the present disclosure provides compounds of formula IV:
Or a pharmaceutically acceptable salt thereof, wherein:
Z is-O-or-NR z -;
R x is hydrogen, halogen, OR 3, OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
Selected from (i) or (ii):
(i) Or (b)
(ii)Wherein ring a is further substituted at least once and at least one substituent on ring a is C 1-6 haloalkyl;
l is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;
R a is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
R' is C 1-6 aliphatic or a 3-to 7-membered saturated or partially unsaturated carbocyclyl.
In some embodiments of any of formulas I, I-D, I-E, II-D, II-E, and II-F, W is CR w. In some embodiments, W is N.
In some embodiments of any of formulas I, I-D, I-E, II-D, II-E, and II-F, X is CR x. In some embodiments, X is N.
In some embodiments of any of formulas I, I-D, I-E, II-D, II-E, and II-F, Y is CR y. In some embodiments, Y is N.
In some embodiments of any of formulas I, I-D, I-E, II-D, II-E, and II-F, W is CR w or N, X is CR x or N, and Y is CR y or N, and no more than one of W, X and Y is N. In some embodiments of any of formulas I, I-D, I-E, II-D, II-E, and II-F, W is CR w or N, X is CR x or N, and Y is CR y or N, and no more than two of W, X and Y are N.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, Z is-O-. In some embodiments, Z is-NR z -. In some embodiments, Z is-NH-.
In some embodiments of any of formulas I, I-D, I-E, II-D, II-E, and II-F, R w is hydrogen, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R w is hydrogen. In some embodiments, R w is halogen. In some embodiments, R w is fluoro. In some embodiments, R w is chloro. In some embodiments, R w is-OR 2. In some embodiments, R w is-OR 2, wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, Y is N, W is CR w, and R w is-OR 2, wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, R w is-N (R 2)2. In some embodiments, R w is-SR 2. In some embodiments, R w is-SR 2, wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, Y is N, W is CR w, and R w is-SR 2, wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, R w is optionally substituted C 1-6 aliphatic. In some embodiments, R w is an optionally substituted straight or branched chain C 1-6 aliphatic (i.e., an optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R w is optionally substituted C 1-6 alkyl. In some embodiments, R w is optionally substituted C 1-4 alkyl. In some embodiments, R w is optionally substituted C 1-2 alkyl. In some embodiments, R w is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, R w is —cn.
In some embodiments of any of formulas I, I-A, I-C, I-D, I-E, II-A, II-C, II-D, II-E, II-F, III, and IV, R x is hydrogen, halogen, -CN, -OR 2, OR optionally substituted C 1-6 aliphatic. In some embodiments, R x is hydrogen, halogen, -CN, -O (C 1-4 alkyl) or C 1-4 alkyl optionally substituted with one or more halogens. In some embodiments, R x is hydrogen, halogen, -OR 2, OR optionally substituted C 1-6 aliphatic. In some embodiments, R x is hydrogen, halogen, -O (C 1-4 alkyl), or C 1-4 alkyl optionally substituted with one or more halogens. In some embodiments, R x is hydrogen, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R x is hydrogen, halogen, -CN, OR 2. In some embodiments, R x is hydrogen, halogen, -CN, or O (C 1-4 alkyl). In some embodiments, R x is halogen or —cn. In some embodiments, R x is hydrogen. In some embodiments, R x is halogen. In some embodiments, R x is fluoro. In some embodiments, R x is hydrogen. In some embodiments, R x is-OR 2. In some embodiments, R x is-OR 2, where R 2 is optionally substituted C 1-6 aliphatic (e.g., optionally substituted C 1-6 alkyl). In some embodiments, R x is-O (C 1-4 alkyl). In some embodiments, R x is-OCH 3. In some embodiments, R x is-N (R 2)2. In some embodiments, R x is-SR 2. In some embodiments, R x is-SR 2, wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, R x is optionally substituted C 1-6 aliphatic. In some embodiments, R x is an optionally substituted straight or branched chain C 1-6 aliphatic (i.e., an optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R x is optionally substituted C 1-6 alkyl (e.g., C 1-6 alkyl optionally substituted with one or more fluoro). In some embodiments, R x is optionally substituted C 1-4 alkyl (e.g., C 1-4 alkyl optionally substituted with one or more fluoro). In some embodiments, R x is optionally substituted C 1-2 alkyl (e.g., C 1-2 alkyl optionally substituted with one or more fluoro). In some embodiments, R x is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro, such as-CHF 2). In some embodiments, R x is —cn.
In some embodiments of any of formulas I, I-A, I-B, I-D, I-E, II-A, II-B, II-D, II-E, II-F, R y is hydrogen, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R y is hydrogen. In some embodiments, R y is halogen. In some embodiments, R y is fluoro. In some embodiments, R y is chloro. In some embodiments, R y is-OR 2. In some embodiments, R y is-OR 2, wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, W is N, Y is CR y, and R y is-OR 2, wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, R y is-N (R 2)2, in some embodiments, R y is-SR 2. In some embodiments, R y is-SR 2, wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, W is N, Y is CR y, and R y is-SR 2, wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, R y is optionally substituted C 1-6 aliphatic. In some embodiments, R y is an optionally substituted straight or branched chain C 1-6 aliphatic (i.e., an optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R y is optionally substituted C 1-6 alkyl. In some embodiments, R y is optionally substituted C 1-4 alkyl. In some embodiments, R y is optionally substituted C 1-2 alkyl. In some embodiments, R y is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, R y is —cn.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, R z is hydrogen. In some embodiments, R z is optionally substituted C 1-6 aliphatic. In some embodiments, R z is an optionally substituted straight or branched chain C 1-6 aliphatic (i.e., an optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R z is optionally substituted C 1-6 alkyl. In some embodiments, R z is optionally substituted C 1-4 alkyl. In some embodiments, R z is unsubstituted C 1-4 alkyl. In some embodiments, R z is optionally substituted C 1-2 alkyl. In some embodiments, R z is unsubstituted C 1-2 alkyl.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, and II-F, R 1 is-N (R) C (R) N (R) 2 OR-N (R) C (O) OR. In some embodiments, R 1 is-N (R) 2, -N (R) C (O) R', or-C (O) N (R) 2. In some embodiments, R 1 is-N (R) C (O) R' or-C (O) N (R) 2. In some embodiments, R 1 is-N (R) C (O) R', -C (O) N (R) 2、-N(R)C(O)N(R)2 OR-N (R) C (O) OR.
In some embodiments, when R 1 is-N (R) 2, -N (R) C (O) R', or-C (O) N (R) 2, then N is 1, 2, or 3. In some embodiments, when N is 0, then R 1 is-N (R) C (O) N (R) 2 OR-N (R) C (O) OR.
In some embodiments, R 1 is-N (R) 2. In some embodiments, R 1 is-N (H) (R). In some embodiments, R 1 is-NH 2. In some embodiments, when R 1 is-N (R) 2, then N is 1,2, or 3.
In some embodiments, R 1 is-N (R) C (O) R'. In some embodiments, R 1 is-N (H) C (O) R'. In some embodiments, R 1 is-N (R) C (O) (optionally substituted C 1-6 aliphatic). In some embodiments, R 1 is-N (H) C (O) (optionally substituted C 1-6 aliphatic). In some embodiments, R 1 is-N (R) C (O) (C 1-6 aliphatic). In some embodiments, R 1 is-N (H) C (O) (C 1-6 aliphatic). In some embodiments, R 1 is-N (R) C (O) (straight or branched C 1-6 aliphatic). In some embodiments, R 1 is-N (H) C (O) (straight or branched C 1-6 aliphatic). In some embodiments, R 1 is-N (R) C (O) (optionally substituted C 1-6 alkyl). In some embodiments, R 1 is-N (H) C (O) (optionally substituted C 1-6 alkyl). In some embodiments, R 1 is-N (R) C (O) R ', wherein R' of R 1 is C 1-6 alkyl optionally substituted with halogen, -OH, -O (C 1-6 alkyl), -NH (CH 2)2O(C1-6 alkyl), -NH (C 1-4 haloalkyl) or optionally substituted 3-to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is-N (H) C (O) R ', wherein R' of R 1 is C 1-6 alkyl optionally substituted with halogen, -OH, -O (C 1-6 alkyl), -NH (CH 2)2O(C1-6 alkyl), -NH (C 1-4 haloalkyl) or optionally substituted 3-to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is-N (R) C (O) (C 1-6 alkyl). In some embodiments, R 1 is-N (H) C (O) (C 1-6 alkyl). In some embodiments, R 1 is-N (R) C (O) (optionally substituted C 1-4 alkyl). In some embodiments, R 1 is-N (H) C (O) (optionally substituted C 1-4 alkyl). In some embodiments, R 1 is-N (R) C (O) R ', wherein R' of R 1 is C 1-4 alkyl optionally substituted with halogen, -OH, -O (C 1-6 alkyl), -NH (CH 2)2O(C1-6 alkyl), -NH (C 1-4 haloalkyl) or optionally substituted 3-to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is-N (H) C (O) R ', wherein R' of R 1 is C 1-4 alkyl optionally substituted with halogen, -OH, -O (C 1-6 alkyl), -NH (CH 2)2O(C1-6 alkyl), -NH (C 1-4 haloalkyl) or optionally substituted 3-to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is-N (R) C (O) (C 1-4 alkyl). In some embodiments, R 1 is-N (H) C (O) (C 1-4 alkyl). In some embodiments, R 1 is-N (R) C (O) (C 1-2 alkyl). In some embodiments, R 1 is-N (H) C (O) (C 1-2 alkyl). In some embodiments, R 1 is-N (R) C (O) CH 3. In some embodiments, R 1 is-N (H) C (O) CH 3. In some embodiments, R 1 is-N (R) C (O) (optionally substituted C 3-7 cycloalkyl). In some embodiments, R 1 is-N (H) C (O) (optionally substituted C 3-7 cycloalkyl). In some embodiments, R 1 is-N (R) C (O) (optionally substituted cyclopropyl). In some embodiments, R 1 is-N (H) C (O) (optionally substituted cyclopropyl). In some embodiments, when R 1 is-N (R) C (O) R', then N is 1, 2, or 3.
In some embodiments, R 1 is-C (O) N (R) 2. In some embodiments, R 1 is-C (O) N (R) (C 1-6 aliphatic). In some embodiments, R 1 is-C (O) N (H) (C 1-6 aliphatic). In some embodiments, R 1 is-C (O) N (R) (straight or branched C 1-6 aliphatic). In some embodiments, R 1 is-C (O) N (H) (straight or branched C 1-6 aliphatic). In some embodiments, R 1 is-C (O) N (R) (C 1-6 alkyl). In some embodiments, R 1 is-C (O) N (H) (C 1-6 alkyl). In some embodiments, R 1 is-C (O) N (R) (C 1-4 alkyl). In some embodiments, R 1 is-C (O) N (H) (C 1-4 alkyl). In some embodiments, R 1 is-C (O) N (R) (C 1-2 alkyl). In some embodiments, R 1 is-C (O) N (H) (C 1-2 alkyl). In some embodiments, R 1 is-C (O) N (R) CH 3. In some embodiments, R 1 is-C (O) N (H) (R). In some embodiments, when R 1 is-C (O) N (R) 2, then N is 1, 2, or 3.
In some embodiments, R 1 is-N (R) C (O) N (R) 2. In some embodiments, R 1 is-N (H) C (O) N (R) 2. In some embodiments, R 1 is-N (H) C (O) N (optionally substituted C 1-6 aliphatic) 2. In some embodiments, R 1 is-N (H) C (O) N (optionally substituted C 1-6 alkyl) 2. In some embodiments, R 1 is-N (H) C (O) N (optionally substituted C 1-4 alkyl) 2. In some embodiments, R 1 is-N (H) C (O) N (optionally substituted C 1-2 alkyl) 2. In some embodiments, R 1 is-N (R) C (O) NH (R). In some embodiments, R 1 is-N (H) C (O) NH (R). In some embodiments, R 1 is-N (H) C (O) NH (optionally substituted C 1-6 aliphatic). In some embodiments, R 1 is-N (H) C (O) NH (optionally substituted C 1-6 alkyl). In some embodiments, R 1 is-N (H) C (O) NH (optionally substituted C 1-4 alkyl). In some embodiments, R 1 is-N (H) C (O) NH (optionally substituted C 1-2 alkyl). In some embodiments, R 1 is-N (H) C (O) NH (optionally substituted C 3-7 cycloaliphatic). In some embodiments, R 1 is-N (H) C (O) NH (optionally substituted C 3-7 cycloalkyl). In some embodiments, R 1 is-N (H) C (O) NH (optionally substituted cyclopropyl). In some embodiments, R 1 is-N (H) C (O) NH (optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is-N (H) C (O) NH (optionally substituted 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is-N (H) C (O) NH (optionally substituted oxetanyl). In some embodiments, R 1 is-N (R) C (O) N (R) 2, wherein two R groups attached to the same nitrogen together form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is-N (H) C (O) N (R) 2, wherein two R groups attached to the same nitrogen together form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is-N (H) C (O) N (R) 2, wherein two R groups attached to the same nitrogen together form a 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more halogens, C 1-6 alkyl, -OH, and-O (C 1-6 alkyl). In some embodiments, R 1 is-N (H) C (O) N (R) 2, wherein two R groups attached to the same nitrogen together form an optionally substituted 4-to 6-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is-N (H) C (O) N (R) 2, wherein two R groups attached to the same nitrogen together form a 4-to 6-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more halo, C 1-6 alkyl, -OH, and-O (C 1-6 alkyl). In some embodiments, R 1 is selected from: In some embodiments, R 1 is not/> In some embodiments, when X is CH, then R 1 is not/>
In some embodiments, R 1 is-N (R) C (O) OR. In some embodiments, R 1 is-N (H) C (O) OR. In some embodiments, R 1 is-N (H) C (O) OR, wherein R of R 1 is optionally substituted C 1-6 aliphatic OR an optionally substituted 3-to 7-membered saturated OR partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is-N (H) C (O) OR, wherein R of R 1 is optionally substituted C 1-6 alkyl OR optionally substituted 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is-N (H) C (O) OR, wherein R of R 1 is C 1-6 alkyl optionally substituted with one OR more-OH, -O (C 1-6 alkyl), -N (C 1-6 alkyl) 2, OR a 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is-N (H) C (O) OR, wherein R of R 1 is a 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one OR more C 1-6 alkyl groups. In some embodiments, R 1 is selected from:/>
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, R 2 is an optionally substituted straight or branched chain C 1-6 aliphatic (i.e., an optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R 2 is optionally substituted C 1-6 alkyl. In some embodiments, R 2 is optionally substituted C 1-4 alkyl. In some embodiments, R 2 is unsubstituted C 1-4 alkyl. In some embodiments, R 2 is optionally substituted C 1-2 alkyl. In some embodiments, R 2 is unsubstituted C 1-2 alkyl. In some embodiments, R 2 is methyl.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, each R 3 is independently hydrogen or optionally substituted C 1-4 aliphatic. In some embodiments, each R 3 is independently hydrogen or an optionally substituted C 1-2 aliphatic. In some embodiments, each R 3 is hydrogen. In some embodiments, each R 3 is independently optionally substituted C 1-6 aliphatic. In some embodiments, each R 3 is independently an optionally substituted straight or branched chain C 1-6 aliphatic (i.e., an optionally substituted acyclic C 1-6 aliphatic). In some embodiments, each R 3 is independently optionally substituted C 1-4 aliphatic. In some embodiments, each R 3 is independently an optionally substituted straight or branched chain C 1-4 aliphatic (i.e., an optionally substituted acyclic C 1-4 aliphatic). In some embodiments, each R 3 is independently optionally substituted C 1-2 aliphatic. In some embodiments, each R 3 is independently hydrogen or C 1-6 alkyl. In some embodiments, each R 3 is independently hydrogen or C 1-4 alkyl. In some embodiments, each R 3 is independently hydrogen or C 1-2 alkyl.
In some embodiments of formula III, R 4 is halo. In some embodiments, R 4 is fluoro. In some embodiments, R 4 is chloro. In some embodiments, R 4 is-OR. In some embodiments, R 4 is-OH or-O (optionally substituted C 1-6 alkyl). In some embodiments, R 4 is-OH or-O (C 1-6 alkyl). In some embodiments, R 4 is-OH or-OCH 3. In some embodiments, R 4 is-N (R) 2. In some embodiments, R 4 is-NH (R). In some embodiments, R 4 is —nh (optionally substituted C 1-6 alkyl). In some embodiments, R 4 is-NH (R), wherein R of R 4 is C 1-6 alkyl optionally substituted with one or more halogens or-O (C 1-6 alkyl). In some embodiments, R 4 is-NH (CH 2)2 F or-NH (CH 2)2OCH3). In some embodiments, R 4 is an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is an optionally substituted 4-to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is a 4-to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more C 1-6 alkyl groups. In some embodiments, R 4 is tetrahydropyranyl or morpholinyl optionally substituted with one or more C 1-6 alkyl groups.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, II-A, II-B, II-C, II-E, and II-F, each R c is independently selected from halogen, -CN, -CO 2R、-C(O)N(R)2、-NO2、-N(R)2, -OR, -SR, OR optionally substituted C 1-6 alkyl, wherein each R of R c is independently hydrogen OR C 1-6 alkyl. In some embodiments, R c is halogen (e.g., fluorine). In some embodiments, R c is-CN, -CO 2R、-C(O)N(R)2, or-NO 2. In some embodiments, R c is-N (R) 2, -OR, OR-SR. In some embodiments, R c is optionally substituted C 1-6 aliphatic (e.g., C 1-6 alkyl).
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, II-A, II-B, II-C, II-E, and II-F, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E and III, ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, ring a is optionally substituted phenyl. In some embodiments, ring a is not optionally substituted phenyl.
In some embodiments, ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is an optionally substituted 5 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is optionally substituted pyrazolyl. In some embodiments, ring a is an optionally substituted 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is optionally substituted pyridinyl.
In some embodiments, ring a is an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is an optionally substituted 8 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is an optionally substituted 9 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is optionally substituted tetrahydropyrazolo [1,5-a ] pyridinyl or dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazinyl. In some embodiments, ring a is an optionally substituted 10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, ring a is an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring a is an optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring a is an optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring a is an optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring a is an optionally substituted 6 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring a is not an optionally substituted 6 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring a is an optionally substituted 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
In some embodiments, ring a is an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 3-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
In some embodiments, ring a is an optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 7 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 8 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 9 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
In some embodiments, ring a is
In some embodiments of any of formulas II, II-A, II-B, II-C, II-D, II-E and II-F, ring a is an optionally substituted 8-to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted 10-to 16-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted 7-to 10-membered bicyclic heterocyclyl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 10-to 16-membered polycyclic heterocyclyl group having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 10-to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is an optionally substituted 7-to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms selected independently from nitrogen, oxygen and sulfur or an optionally substituted 10-to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms selected independently from nitrogen, oxygen and sulfur.
In some embodiments, each ring in the bicyclic or polycyclic ring system of ring a contains at least one heteroatom. In some embodiments, one and only one ring of the bicyclic or polycyclic ring system of ring a contains no heteroatoms.
In some embodiments, each ring in the bicyclic or polycyclic ring system of ring a is aromatic. In some embodiments, one and only one ring of the bicyclic or polycyclic ring system of ring a is aromatic. In some embodiments, no ring in the bicyclic or polycyclic ring system of ring a is aromatic.
In some embodiments, ring a is an optionally substituted 9-to 16-membered bicyclic or tricyclic aryl. In some embodiments, ring a is an optionally substituted 9-to 10-membered bicyclic aryl. In some embodiments, ring a is an optionally substituted 9-membered bicyclic aryl (e.g., a 5-membered carbocyclic ring fused to a benzene ring). In some embodiments, ring a is not a substituted indanyl (e.g., an indanyl substituted with one or more halogens). In some embodiments, ring a is an optionally substituted 10 membered bicyclic aryl (e.g., naphthyl or a 6 membered carbocyclic ring fused to a benzene ring).
In some embodiments, ring a is an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is an 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more oxo, halogen, or C 1-6 alkyl groups. In some embodiments, ring a is an optionally substituted 8 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is optionally substituted dihydro-1H-imidazo [1,2-b ] pyrazolyl. In some embodiments, ring a is an optionally substituted 9 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is a 9 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more oxo, halogen, or C 1-6 alkyl groups. In some embodiments, ring A is optionally substituted tetrahydropyrazolo [1,5-a ] pyridinyl, dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -onyl, tetrahydropyrazino [1,5-a ] pyrimidinyl, or dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazinyl. In some embodiments, ring a is an optionally substituted 10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is a 10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more C 1-6 alkyl groups. In some embodiments, ring a is optionally substituted tetrahydro-4H-pyrazolo [1,5-a ] [1,4] diazepinyl, tetrahydro-4H-pyrazolo [1,5-d ] [1,4] diazepinyl, tetrahydropyrazolo [1,5-d ] [1,4] oxaazepinyl, or tetrahydro-4H-pyrazolo [1,5-a ] azepinyl.
In some embodiments, ring a is an optionally substituted 10-to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is an optionally substituted 11 membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring a is optionally substituted dihydrospiro [ cyclobutane-1, 4' -pyrrolo [1,2-b ] pyrazolyl ], dihydro-5 ' h-spiro [ cyclopropane-1, 4' -pyrazolo [1,5-a ] pyridinyl ], dihydro-5 ' h-spiro [ cyclopropane-1, 4' -pyrazolo [1,5-a ] pyrazin ] or dihydro-4'H-spiro [ cyclopropane-1, 5' -pyrazolo [1,5-a ] pyrimidinyl ].
In some embodiments, ring a is an optionally substituted 7-to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms selected independently from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 7-to 10-membered fused bicyclic heterocyclyl having 1-4 heteroatoms selected independently from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 7 membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 8-membered bicyclic heterocyclyl having 1-3 heteroatoms selected independently from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 9 membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring a is an optionally substituted 10 membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
In some embodiments, ring a is an optionally substituted 10-to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, ring a is selected from:
In some embodiments, ring a is Wherein ring A1 and ring A2, either alone or in combination, are as defined in formulas II-E and described in the classes and subclasses herein; and ring A1 is fused to ring A2; ring A2 is optionally (i) further fused to ring A3 or (ii) ring A2 and ring A3 combine to form a spiro ring.
In some embodiments, ring A1 is an optionally substituted ring selected from 5-to 6-membered monocyclic heteroaryl groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, ring A1 is optionally substituted phenyl. In some embodiments, when ring A1 is phenyl, ring A2 contains at least one heteroatom.
In some embodiments, ring A1 is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is an unsubstituted 5-to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is an optionally substituted 5 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is optionally substituted pyrazole. In some embodiments, ring A1 is an optionally substituted 6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, ring A1 is an optionally substituted 5-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when ring A1 is an optionally substituted 5-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, ring A2 contains at least one heteroatom. In some embodiments, when ring A2 is not aromatic, ring A1 is an optionally substituted 5-to 7-membered saturated monocyclic carbocyclyl. In some embodiments, ring A1 is an optionally substituted 5-to 7-membered partially saturated monocyclic carbocyclyl.
In some embodiments, ring A1 is an optionally substituted 5-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, when ring A2 is not aromatic, ring A1 is an optionally substituted 5-to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms selected independently from nitrogen, oxygen and sulfur. In some embodiments, ring A1 is an optionally substituted 5-to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
In some embodiments, optionally substituted ring A1 fused to ring A2 is
In some embodiments, ring A2 is an optionally substituted ring selected from 5-to 6-membered monocyclic heteroaryl groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, ring A2 is optionally substituted phenyl. In some embodiments, when ring A2 is phenyl, ring A1 contains at least one heteroatom.
In some embodiments, ring A2 is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is an optionally substituted 5 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is an optionally substituted 6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, ring A2 is an optionally substituted 5-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when ring A2 is an optionally substituted 5-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, ring A1 contains at least one heteroatom. In some embodiments, when ring A1 is not aromatic, ring A2 is an optionally substituted 5-to 7-membered saturated monocyclic carbocyclyl. In some embodiments, ring A2 is an optionally substituted 5-to 7-membered partially saturated monocyclic carbocyclyl.
In some embodiments, ring A2 is an optionally substituted 5-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, when ring A1 (and ring A3, if present) is not aromatic, ring A2 is an optionally substituted 5-to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms selected independently from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is an optionally substituted 5-to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring A2 is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring A2 is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more C 1-6 alkyl groups. In some embodiments, ring A2 is optionally substituted pyrrolidine or imidazolidine. In some embodiments, ring A2 is an optionally substituted 6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring A2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more oxo, halogen, and C 1-6 alkyl groups. In some embodiments, ring A2 is an optionally substituted piperidine, hexahydropyrimidine, morpholine, or piperazinone. In some embodiments, ring A2 is an optionally substituted 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring A2 is a 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more C 1-6 alkyl groups. In some embodiments, ring A2 is azepane, diazepane, or oxaazepane.
In some embodiments, optionally substituted ring A2 fused to ring A1 is selected from the group consisting of:
in some embodiments, ring A1 is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring A2 is an optionally substituted 5-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring A2 is an optionally substituted 5-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring A2 is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring A2 is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring A2 is an optionally substituted 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, ring A2 is further fused with ring A3. In some embodiments, ring A2 and ring A3 combine to form a spiro ring. In some embodiments, when ring A2 and ring A3 combine to form a spiro ring, ring A3 is an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl or an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, ring A3 (when present) is optionally substituted phenyl. In some embodiments, ring A3 (when present) is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A3 (when present) is an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring A3 (when not fused to aromatic ring A2) is A3-to 7-membered saturated monocyclic carbocyclyl. In some embodiments, ring A3 is A3-to 7-membered partially saturated monocyclic carbocyclyl. In some embodiments, ring A3 is an optionally substituted C 3-C7 cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some embodiments, ring A3 is A3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A3 (when not fused to aromatic ring A2) is A3-to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring A3 is A3-to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, optionally substituted ring A2 fused to ring A1 and combined with ring A3 to form a spiro ring is selected from:
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, ring a is optionally substituted on the substitutable carbon atom with one or more groups independently selected from: oxo, halogen 、Ro、-CN、-ORo、-O(CH2)1-4Ro、-SRo、-N(Ro)2、-NO2、-C(O)Ro、-C(O)OR、-C(O)NRo 2、-OC(O)Ro、-OC(O)NRo 2、-OC(O)OR、-OS(O)2Ro、-OS(O)2NRo 2、-N(Ro)C(O)Ro、-N(Ro)S(O)2Ro、-S(O)2Ro、-SO2NRo 2, and-S (O) 2ORo, and (ii) optionally substituted on the substitutable nitrogen atom with one or more groups selected from: And/> In some embodiments, ring A (i) is optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, R o、-ORo, and-O (CH 2)1-4Ro), and (ii) is optionally substituted on a substitutable nitrogen atom with one or more groups selected from/>Is substituted with a group of (a). In some embodiments, ring a (i) is optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, and R o, and (ii) is optionally substituted on a substitutable nitrogen atom with one or more groups selected from/>Is substituted with a group of (a).
In some embodiments, ring a is optionally substituted (e.g., except by-L-R a (when present)) with one or more R b, wherein R b is as defined in formulas I-D above and described in the classes and subclasses herein. In some embodiments, ring a is substituted with zero, one, two, three, four, or five R b, where valence permits.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, III and IV, L is a covalent bond. In some embodiments, L is a divalent C 1-3 straight or branched hydrocarbon chain. In some embodiments, L is a divalent C 1-2 straight or branched hydrocarbon chain. In some embodiments, L is methylene (i.e., -CH 2 -). In some embodiments, L is-CH 2CH2 -. In some embodiments, L is-CH 2CH2CH2 -. In some embodiments, L is-C (CH 3)2 -. In some embodiments, L is a covalent bond or-CH 2 -.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, III and IV, R a is halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R a is optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, R a is hydrogen. In some embodiments, R a is not hydrogen.
In some embodiments, R a is halogen. In some embodiments, R a is fluoro, chloro, bromo, or iodo. In some embodiments, R a is fluoro. In some embodiments, R a is chloro.
In some embodiments, R a is optionally substituted C 1-6 aliphatic. In some embodiments, R a is an optionally substituted straight or branched chain C 1-6 aliphatic (i.e., an optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R a is C 1-6 aliphatic optionally substituted with one or more halogens, -N (C 1-6 alkyl) 2, -OH, or-O (an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl). In some embodiments, R a is optionally substituted C 1-6 alkyl. In some embodiments, R a is C 1-6 alkyl optionally substituted with one or more halo, -N (C 1-6 alkyl) 2, -OH, or-O (optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl). In some embodiments, R a is optionally substituted C 1-4 alkyl. In some embodiments, R a is C 1-4 alkyl optionally substituted with one or more halo, -N (C 1-6 alkyl) 2, -OH, or-O (optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl). In some embodiments, R a is -CH3、-CD3、-CF3、-CH2N(CH3)2、-CH2CH2OH or
In some embodiments, R a is optionally substituted phenyl.
In some embodiments, R a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
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 3-to 6-membered saturated monocyclic carbocyclyl. In some embodiments, R a is an optionally substituted 3-membered saturated monocyclic carbocyclyl. In some embodiments, R a is an optionally substituted 4-membered saturated monocyclic carbocyclyl. In some embodiments, R a is an optionally substituted 5 membered saturated monocyclic carbocyclyl. In some embodiments, R a is an optionally substituted 6 membered saturated monocyclic carbocyclyl. In some embodiments, R a is an optionally substituted 7-membered saturated monocyclic carbocyclyl.
In some embodiments, R a is an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 4-to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 3-membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 4-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 5-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted pyrrolidinyl or tetrahydrofuranyl. In some embodiments, R a is an optionally substituted 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, R a is an optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 7-to 10-membered saturated spirocyclic bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 7-to 9-membered saturated spirocyclic bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 7-membered saturated spirocyclic bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 2-oxaspiro [3.3] heptyl. In some embodiments, R a is an optionally substituted 8-membered saturated spirocyclic bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 9-membered saturated spirocyclic bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 7-oxaspiro [3.5] nonyl. In some embodiments, R a is an optionally substituted 10 membered saturated spirocyclic bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, III and IV,Is-R a (i.e., L is a covalent bond). In some embodiments,/>Is- (C 1-3 alkylene) -R a (i.e., L is a C 1-3 straight or branched hydrocarbon chain). In some embodiments,/>Is- (C 1-2 alkylene) -R a (i.e., L is a C 1-2 straight or branched hydrocarbon chain). In some embodiments,/>Is-CH 2-Ra (i.e., L is a C 1 hydrocarbon chain). In some embodiments,/>Is-CH 2CH2-Ra (i.e., L is a C 2 straight hydrocarbon chain). In some embodiments,/>Is-CH 2CH2CH2-Ra (i.e., L is a C 3 straight hydrocarbon chain). In some embodiments,/>Is-C (CH 3)2-Ra) (i.e., L is a C 3 branched hydrocarbon chain).
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, R b occurs up to five times if valence rules allow, and each is independently a halogen 、-CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R'、-SO2N(R)2、-SO3R'、 optionally substituted C 1-6 aliphatic, an optionally substituted 3-to 6-membered saturated or partially unsaturated carbocyclyl, an optionally substituted 3-to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is independently at each occurrence a halogen, an optionally substituted C 1-6 aliphatic, -OR, OR-O (CH 2)m R. In some embodiments, R b is independently at each occurrence a halogen, an optionally substituted C 1-6 alkyl, -OR, OR-OCH 2 R, wherein R of R b is an optionally substituted 3-to 6-membered saturated OR partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, R b occurs once. In some embodiments, R b occurs twice. In some embodiments, R b occurs three times. In some embodiments, R b occurs four times. In some embodiments, R b occurs five times. In some embodiments, R b is absent. In some embodiments, R b occurs 1-4 times. In some embodiments, R b occurs once or twice.
In some embodiments, R b is hydrogen.
In some embodiments, R b is halogen. In some embodiments, R b is fluoro, chloro, bromo, or iodo. In some embodiments, R b is fluoro. In some embodiments, R b is chloro.
In some embodiments, R b is -CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R、-SO2N(R)2 or-SO 3 R'. In some embodiments, R b is —cn. In some embodiments, R b is-N (R) 2. In some embodiments, R b is-C (O) N (R) 2.
In some embodiments, R b is-OR. In some embodiments, R b is —or, wherein R is an optionally substituted 3-to 7-membered saturated OR partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is —or, wherein R is an optionally substituted 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is-OR, wherein R is a 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which is optionally substituted with one OR more C 1-6 alkyl (e.g., methyl). In some embodiments, R b is-OR, wherein R is optionally substituted azetidinyl OR pyrrolidinyl. In some embodiments, R b is-OR, wherein R is azetidinyl OR pyrrolidinyl optionally substituted with one OR more C 1-6 alkyl (e.g., methyl). In some embodiments, R b is
In some embodiments, R b is-O (CH 2)m R. In some embodiments, R b is-OCH 2 R. In some embodiments, R b is-O (CH 2)m R, wherein R is an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R b is-O (CH 2)m R, wherein R is a 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which is optionally substituted with one or more C 1-6 alkyl groups (e.g., methyl): in some embodiments, R b is-O (CH 2)m R, wherein R is optionally substituted pyrrolidinyl): in some embodiments, R b is-O (CH 2)m R, wherein R is pyrrolidinyl optionally substituted with one or more C 1-6 alkyl groups (e.g., methyl). In some embodiments, R b is
In some embodiments, R b is optionally substituted C 1-6 aliphatic. In some embodiments, R b is an optionally substituted straight or branched chain C 1-6 aliphatic (i.e., an optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R b is optionally substituted C 1-6 alkyl. In some embodiments, R b is optionally substituted C 1-4 alkyl. In some embodiments, R b is C 1-4 alkyl optionally substituted with one or more halogens. In some embodiments, R b is-CH 3、-CF3 or-C (CH 3)3).
In some embodiments, R b is an optionally substituted 3-to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R b is optionally substituted C 3-C6 cycloalkyl.
In some embodiments, R b is an optionally substituted 3-to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is an optionally substituted 3-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, R b is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E and III, optionally substitutedIs/>In some embodiments, optionally substituted/>Is optionally substituted/> In some embodiments,/>Is/>In some embodiments,/>/>In some embodiments,/>Selected from the group consisting of:
in some embodiments of the formula IV, Selected from the group consisting of: In some embodiments,/> Selected from the group consisting of: /(I) In some embodiments, when/>Is thatWhen-L-R a is C 1-6 haloalkyl. In some embodiments,/>Is thatWherein ring a is further substituted at least once and at least one substituent on ring a is C 1-6 haloalkyl (e.g., -CF 3). In some embodiments, when/>Is thatWhen ring a is further substituted with R b as defined and described in the classes and subclasses herein, and at least one substituent on ring a (i.e., R b or-L-R a) is C 1-6 haloalkyl (e.g., -CF 3). In some embodiments,/>Selected from the group consisting of: /(I)
In some embodiments of any of formulas II, II-A, II-B, II-C, II-D, II-E and II-F, optionally substitutedIs/>In some embodiments, optionally substituted/>Is that />
In some embodiments, optionally substituted/>Selected from the group consisting of: /(I)
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's together when attached to the same nitrogen atom form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen or an optionally substituted C 1-6 aliphatic. In some embodiments, each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently an optionally substituted C 1-6 aliphatic or an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen, optionally substituted C 1-6 alkyl, or optionally substituted 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, R is hydrogen.
In some embodiments, R is an optionally substituted C 1-6 aliphatic. In some embodiments, R is an optionally substituted straight or branched chain C 1-6 aliphatic (i.e., an optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R is optionally substituted C 1-6 alkyl. In some embodiments, R is C 1-6 alkyl optionally substituted with one or more-OH, -O (C 1-6 alkyl), -N (C 1-6 alkyl) 2, or a 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted C 1-4 alkyl. In some embodiments, R is optionally substituted C 1-2 alkyl.
In some embodiments, R is an optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R is optionally substituted C 3-7 cycloalkyl.
In some embodiments, R is an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 4-to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more C 1-6 alkyl groups. In some embodiments, R is optionally substituted oxetanyl.
In some embodiments, two R groups when attached to the same nitrogen atom together form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups attached to the same nitrogen together form a 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which is optionally substituted with one or more halogens, C 1-6 alkyl, -OH, or-O (C 1-6 alkyl). In some embodiments, two R groups attached to the same nitrogen together form an optionally substituted 4-to 6-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, two R groups attached to the same nitrogen together form a 4-to 6-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more halogen, C 1-6 alkyl, -OH, and-O (C 1-6 alkyl).
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, each R' is independently optionally substituted C 1-6 alkyl or optionally substituted C 3-7 cycloalkyl. In some embodiments, R' is an optionally substituted C 1-6 aliphatic. In some embodiments, R' is an optionally substituted straight or branched chain C 1-6 aliphatic (i.e., an optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R' is optionally substituted C 1-6 alkyl. In some embodiments, R' is C 1-6 alkyl optionally substituted with halogen, -OH, -O (C 1-6 alkyl), -NH (CH 2)2O(C1-6 alkyl), -NH (C 1-4 haloalkyl), or an optionally substituted 3-to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R' is optionally substituted C 1-4 alkyl. In some embodiments, R' is optionally substituted C 1-2 alkyl. In some embodiments, R' is methyl. In some embodiments, R' is an optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R' is optionally substituted C 3-7 cycloalkyl. In some embodiments, R' is optionally substituted cyclopropyl. In some embodiments, R' is cyclopropyl.
In some embodiments of any of the formulae described herein, the compound is not:
in some embodiments, the compound is not:
/>
in some embodiments, the compound is not:
in some embodiments, the compound is not:
/>
In some embodiments of any of formulas I, I-A, I-B, I-C, I-D and I-E, when R 1 is And Y is N, then R x is not hydrogen. In some embodiments, when R 1 is/>When ring a is not pyrazolyl. In some embodiments, when ring a is pyrazolyl, then R 1 is not-N (R) C (O) N (R) 2. In some embodiments, when ring a is pyrazolyl and Y is N, then R x is not hydrogen.
In some embodiments of any of formulas II, II-A, II-B, II-C, II-D, II-E and II-F, ring A is notIn some embodiments, when ring A is/>When R 1 is not-N (H) C (O) CH 3. In some embodiments, when ring A is/>When X is not N and R x is not-CN.
In some embodiments of formula III, R 4 is not tetrahydropyranyl. In some embodiments, when R 4 is tetrahydropyranyl and Y is N, then R x is not chloro.
In some embodiments of formula IV, when Y is N and R x is not hydrogen, then-L-R a is not-CH 3 or
In some embodiments, the present disclosure provides a compound selected from table 1:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
Or a pharmaceutically acceptable salt thereof.
In some embodiments, the present disclosure encompasses the recognition that: the provided compounds exhibit certain desirable characteristics (e.g., as compared to other known compounds). For example, in some embodiments, the provided compounds are more effective in one or more biochemical or cellular assays (e.g., JAK2 binding assays, SET2-pSTAT5 cell assays, hPBMC-GMCSF-STAT5 assays, hPBMC-IL12-STAT4 assays, or hPBMC-IL2-STAT5 assays) as described herein, and/or have one or more other characteristics that make them more suitable for drug development, such as better selectivity and/or better ADME (absorption, distribution, metabolism, and excretion) properties than other kinases, including, but not limited to, better permeability, cytotoxicity, hepatocyte stability, solubility, and/or plasma protein binding profile (e.g., based on assays described in the examples that follow). In some embodiments, for example, the provided compounds exhibit certain desirable characteristics in one or more of the assays described herein, as compared to other known compounds. Without being bound by any particular theory, the present disclosure encompasses the recognition that: the 6-heteroaryloxy benzimidazoles and azabenzimidazoles (e.g., the compounds described herein) exhibit certain more desirable characteristics (such as better characteristics in one or more of the assays described herein) than the corresponding 5-heteroaryloxy benzimidazoles and azabenzimidazoles.
In some embodiments, the provided compounds are provided and/or used in salt form (e.g., pharmaceutically acceptable salt form). Unless otherwise indicated, references to compounds provided herein should be understood to include references to salts thereof. Pharmaceutically acceptable salt forms are known in the art. For example, pharmaceutically acceptable salts are described in detail in J.pharmaceutical Sciences,66:1-19 (1977) by S.M. Bere et al.
It is to be understood that throughout this disclosure, reference to compounds of formula I is also intended to include formulas I, I-A, I-B, I-C, I-D and I-E, as well as the classes of compounds of such formulas disclosed herein, unless otherwise indicated; reference to compounds of formula II is also intended to include the classes of compounds of formulae II, II-A, II-B, II-C, II-D, II-E and II-F, as disclosed herein; references to compounds of formula III are also intended to include classes of compounds of such formulas disclosed herein; and reference to compounds of formula IV is also intended to include the class of compounds of such formula disclosed herein.
Preparation of the provided Compounds
The compounds provided can generally be prepared by the methods described in the schemes and examples that follow. In some embodiments, the provided compounds are prepared according to the following schemes:
Wherein PG is a suitable protecting group (e.g., p-methoxybenzyl, acetyl, methyl carbamate, etc.), and rings A, n, L, W, X, Y, R, R 2、Ra and R c, either alone or in combination, are as defined above for formula I and described in the classes and subclasses herein. Thus, in some embodiments, intermediate a.3 is prepared by a process comprising contacting intermediate a.1 with intermediate a.2 in the presence of a suitable coupling agent and/or a suitable base (e.g., potassium tert-butoxide). In some embodiments, the process for preparing intermediate a.3 further comprises a deprotection step and/or a functionalization step (e.g., cyanidation) under suitable conditions. In some embodiments, intermediate a.4 is prepared by a process comprising contacting intermediate a.3 with phenyl chloroformate in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound a-1 is prepared by a process comprising contacting intermediate a.4 with RO-H, optionally in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound a-1 is prepared by a process comprising contacting intermediate a.3 with RO-C (O) -Cl in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound a-2 is prepared by a process comprising contacting intermediate a.4 with R 2 N-H, optionally in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound a-2 is prepared by a process comprising contacting intermediate a.3 with R 2 N-C (O) -Cl in the presence of a suitable base (e.g., triethylamine).
In some embodiments, the provided compounds are prepared according to the following schemes:
Where PG is a suitable protecting group (e.g., p-methoxybenzyl, acetyl, methyl carbamate, etc.), and rings A, n, W, X, Y, R, R 2 and R c, either alone or in combination, are as defined above for formula II and described in the classes and subclasses herein. Thus, in some embodiments, intermediate a.6 is prepared by a process comprising contacting intermediate a.5 with intermediate a.2 in the presence of a suitable coupling agent and/or a suitable base (e.g., potassium tert-butoxide). In some embodiments, the process for preparing intermediate a.6 further comprises a deprotection step and/or a functionalization step (e.g., cyanidation) under suitable conditions. In some embodiments, intermediate a.7 is prepared by a process comprising contacting intermediate a.6 with phenyl chloroformate in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound a-3 is prepared by a process comprising contacting intermediate a.7 with RO-H, optionally in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound a-3 is prepared by a process comprising contacting intermediate a.6 with RO-C (O) -Cl in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound a-4 is prepared by a process comprising contacting intermediate a.7 with R 2 N-H, optionally in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound a-4 is prepared by a process comprising contacting intermediate a.6 with R 2 N-C (O) -Cl in the presence of a suitable base (e.g., triethylamine).
In some embodiments, the provided compounds are prepared according to the following schemes:
Wherein LG is a suitable leaving group (e.g., halogen, such as chlorine or bromine), and rings A, n, L, W, X, Y, Z, R 1、R2、Ra and R c, either alone or in combination, are as defined above for formulas I and/or II and are described in the classes and subclasses herein. Thus, in some embodiments, compound B-1 is prepared by a process comprising contacting intermediate b.1 with intermediate b.2 in the presence of a suitable base (e.g., K 3PO4、K2CO3 or Cs 2CO3), and optionally in the presence of a suitable metal complex (e.g., a palladium complex such as tris (dibenzylideneacetone) dipalladium (0)) and/or a suitable ligand (e.g., 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene). In some embodiments, compound B-2 is prepared by a process comprising contacting intermediate b.1 with intermediate b.3 in the presence of a suitable base (e.g., K 3PO4、K2CO3 or Cs 2CO3), and optionally in the presence of a suitable metal complex (e.g., a palladium complex such as tris (dibenzylideneacetone) dipalladium (0)) and/or a suitable ligand (e.g., 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene). In some embodiments, the process for preparing compound B-1 or B-2 further comprises a deprotection step under suitable conditions. In some embodiments, the process for preparing compound B-1 or B-2 further comprises a functionalization step (e.g., cyanidation) under suitable conditions.
In some embodiments, the provided compounds are prepared according to the following schemes:
Wherein rings A, n, L, W, X, Y, R 1、R2、Ra and R c, either alone or in combination, are as defined above for formula I and are described in the classes and subclasses herein. Thus, in some embodiments, compound C-1 is prepared by a process comprising contacting intermediate c.1 with intermediate c.2 in the presence of a suitable coupling agent and/or a suitable base (e.g., potassium tert-butoxide). In some embodiments, the process for preparing compound C-1 further comprises a deprotection and/or functionalization (e.g., cyanation) step under suitable conditions.
In some embodiments, the provided compounds are prepared according to the following schemes:
Wherein rings A, n, W, X, Y, R 1、R2 and R c, either alone or in combination, are as defined above for formula II and are described in the classes and subclasses herein. Thus, in some embodiments, compound C-2 is prepared by a process comprising contacting intermediate c.3 with intermediate c.2 in the presence of a suitable coupling agent and/or a suitable base (e.g., potassium tert-butoxide). In some embodiments, the process for preparing compound C-2 further comprises a deprotection and/or functionalization (e.g., cyanation) step under suitable conditions.
Composition and method for producing the same
The present disclosure also provides compositions comprising a compound provided herein and one or more other components. In some embodiments, provided compositions comprise and/or deliver compounds described herein (e.g., compounds of formulas I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV).
In some embodiments, provided compositions are pharmaceutical compositions comprising and/or delivering a compound provided herein (e.g., a compound of formula I, I-A, I-B, I-C, I-D, I-E, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV), and further comprising a pharmaceutically acceptable carrier. The pharmaceutical compositions generally contain an effective amount of an active agent (e.g., a compound described herein) to achieve the desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and/or antistatic agents, and the like. The pharmaceutical compositions provided may be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppositories, nasal sprays and/or inhalants, eye drops, intraocular injection forms, depot forms, and injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art.
In some embodiments, the provided compounds are formulated in unit dosage form to facilitate administration and achieve dose uniformity. The expression "unit dosage form" as used herein refers to physically discrete units of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, the unit dosage form contains a complete single dose of the agent. In some embodiments, more than one unit dosage form is administered to obtain a total single dose. In some embodiments, it is desirable or contemplated that multiple unit dosage forms be administered to achieve the desired effect. The unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined amount of one or more active agents, a solid pharmaceutical composition (e.g., tablet, capsule, etc.) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined amount of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.
The provided compositions may be administered using any amount and any route of administration effective to treat or reduce the severity of any of the diseases or disorders described herein.
Use of the same
The present disclosure provides for the use of the compounds and compositions described herein. In some embodiments, the provided compounds and compositions are useful in medicine (e.g., as therapies). In some embodiments, the provided compounds and compositions are useful for research, for example, as analytical tools and/or control compounds in bioassays.
In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering a provided compound or composition to a subject suffering from or susceptible to a disease, disorder, or condition associated with JAK 2.
In some embodiments, the provided compounds are useful as JAK2 inhibitors. In some embodiments, compounds provided are useful as type II JAK2 inhibitors. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides a method of inhibiting JAK2 in a biological sample comprising contacting the sample with a provided compound or composition.
JAK (e.g., JAK 2) is associated with a variety of diseases, disorders and conditions such as myeloproliferative neoplasms (Vainchenker, w. Et al, F1000Resear ch 2018,7 (F1000 Faculty Rev): 82), atopic dermatitis (Rodrigues, m.a. and Torres, t.j. Derm. Treat.2019,31 (1), 33-40) and acute respiratory syndrome, excessive inflammation and/or cytokine storm syndrome (The Lancet. Doi:10.1016/S0140-6736 (20) 30688-0). Thus, in some embodiments, the present disclosure provides methods of treating a JAK 2-associated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a provided compound or composition. In some embodiments, the disease, disorder, or condition is associated with overexpression of JAK 2.
In some embodiments, the present disclosure provides methods of treating cancer comprising administering to a subject in need thereof a provided compound or composition. In some embodiments, the present disclosure provides methods of treating a proliferative disease comprising administering to a subject in need thereof a provided compound or composition.
In some embodiments, the present disclosure provides methods of treating hematological malignancies comprising administering to a subject in need thereof a provided compound or composition. In some embodiments, the hematological malignancy is leukemia (e.g., chronic lymphocytic leukemia, acute lymphocytic leukemia, T-cell acute lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or acute monocytic leukemia). In some embodiments, the hematological malignancy is a lymphoma (e.g., burkitt's lymphoma), hodgkin's lymphoma, or non-Hodgkin's lymphoma). In some embodiments, the non-hodgkin's lymphoma is B-cell lymphoma. In some embodiments, the non-hodgkin's lymphoma is NK/T cell lymphoma (e.g., cutaneous T cell lymphoma). In some embodiments, the hematological malignancy is myeloma (e.g., multiple myeloma). In some embodiments, the hematological malignancy is a myeloproliferative neoplasm (e.g., polycythemia vera, primary thrombocytopenia, or myelofibrosis). In some embodiments, the hematological malignancy is myelodysplastic syndrome.
In some embodiments, the present disclosure provides methods of treating an inflammatory disease, disorder, or condition (e.g., acute respiratory syndrome, excessive inflammation, and/or cytokine storm syndrome (including those associated with COVID-19) or atopic dermatitis) comprising administering to a subject in need thereof a provided compound or composition.
In some embodiments, the provided compounds or compositions are administered as part of a combination therapy. As used herein, the term "combination therapy" refers to those situations in which a subject is exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents) simultaneously. In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of the first regimen are administered prior to any doses of the second regimen); in some embodiments, such agents are administered in an overlapping dosing regimen. In some embodiments, "administering" of a combination therapy may involve administering one or more agents or modes to a subject who is receiving the other one or more agents or modes in the combination. For clarity, combination therapy does not require that separate agents be administered together in a single composition (or even must be administered simultaneously), although in some embodiments, two or more agents or active portions thereof may be administered together in a combination composition.
For example, in some embodiments, the provided compounds or compositions are administered to a subject who is receiving or has received one or more additional therapies (e.g., anti-cancer therapies and/or therapies that address one or more side effects of such anti-cancer therapies, or other therapies that provide palliative treatment). Exemplary additional therapies include BCL2 inhibitors (e.g., valnemulin (venetoclax)), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mi Weibu plug (mivebresib)), proteasome inhibitors (e.g., bortezomib (bor tezomib)), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors. Useful combinations of JAK2 inhibitors with BCL2, HDAC, BET and proteasome inhibitors have been demonstrated in cells derived from cutaneous T cell lymphoma patients (Yumeen, s. Et al, blood adv.2020,4 (10), 2213-2226). The combination of a JAK2 inhibitor with a LSD1 inhibitor shows good efficacy in a myeloproliferative neoplasm mouse model (Jutzi, J.S. et al, HEMASPHERE 2018,2 (3), http:// dx.doi.org/10.1097/HS 9.0000000000000054). CXCR2 activity has been shown to modulate signaling pathways involved in tumor growth, angiogenesis and/or metastasis, including the JAK-STAT3 pathway (Jaffer, T., ma, D.Transl.cancer Res.2016,5 (supplement 4), S616-S628).
Exemplary embodiments
The following numbered embodiments (although non-limiting) are examples of certain aspects of the present disclosure:
1. A compound of formula I:
Or a pharmaceutically acceptable salt thereof, wherein:
W is CR w or N;
X is CR x or N;
Y is CR y or N;
Z is-O-or-NR z -;
R w、Rx and R y are each independently hydrogen, halogen, -OR 3、-N(R3)2、-SR3, optionally substituted C 1-6 aliphatic OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
R 1 is-N (R) 2、-N(R)C(O)R'、-C(O)N(R)2、-N(R)C(O)N(R)2 OR-N (R) C (O) OR;
Each R c is independently selected from halogen, -CN, -CO 2R、-C(O)N(R)2、-NO2、-N(R)2, -OR, -SR, OR optionally substituted C 1-6 aliphatic;
N is 0, 1,2 or 3, provided that when R 1 is-N (R) 2, -N (R) C (O) R' or-C (O) N (R) 2, N is 1,2 or 3;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
Ring a is optionally substituted phenyl, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
l is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;
R a is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
Each R is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's taken together when attached to the same nitrogen atom form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
Each R' is independently optionally substituted C 1-6 aliphatic or optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl.
2. The compound of embodiment 1, wherein the compound is not:
3. The compound of embodiment 1 or embodiment 2 wherein ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
4. The compound of any of the preceding embodiments, wherein ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
5. The compound of any of the preceding embodiments, wherein ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
6. The compound of any of the preceding embodiments, wherein R a is halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
7. The compound of any of the preceding embodiments, wherein R a is optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
8. The compound of any of the preceding embodiments, wherein R a is optionally substituted C 1-6 aliphatic or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
9. The compound of any one of the preceding embodiments, wherein:
In the case where the valence allows, the reaction proceeds, Substituted with 1-5R b; and
Each R b is independently hydrogen, halogen 、-CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R'、-SO2N(R)2、-SO3R'、 optionally substituted C 1-6 aliphatic, optionally substituted 3 to 6 membered saturated or partially unsaturated carbocyclyl, optionally substituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
M is 1, 2 or 3.
10. The compound of embodiment 9 wherein each R b is independently halogen 、-CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R'、-SO2N(R)2、-SO3R'、 optionally substituted C 1-6 aliphatic, optionally substituted 3-to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3-to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
11. The compound of embodiment 9 or 10 wherein each R b is independently halogen or optionally substituted C 1-6 aliphatic.
12. The compound of any one of embodiments 9-11, whereinIs that
13. The compound of any one of the preceding embodiments, wherein L is a covalent bond.
14. The compound of any of embodiments 1-12 wherein L is-CH 2 -.
15. The compound of any one of the preceding embodiments, wherein the compound has formula I-C:
Or a pharmaceutically acceptable salt thereof.
16. The compound of any one of the preceding embodiments, wherein the compound has formula I-D:
Or a pharmaceutically acceptable salt thereof, wherein:
R b is hydrogen, halogen 、-CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R'、-SO2N(R)2、-SO3R'、 optionally substituted C 1-6 aliphatic, optionally substituted 3 to 6 membered saturated or partially unsaturated carbocyclyl, optionally substituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
M is 1, 2 or 3.
17. The compound of any one of the preceding embodiments, wherein the compound has formula I-E:
Or a pharmaceutically acceptable salt thereof.
18. A compound of formula II:
Or a pharmaceutically acceptable salt thereof, wherein:
W is CR w or N;
X is CR x or N;
Y is CR y or N;
Z is-O-or-NR z -;
R w、Rx and R y are each independently hydrogen, halogen, -OR 3、-N(R3)2、-SR3, optionally substituted C 1-6 aliphatic OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
R 1 is-N (R) 2、-N(R)C(O)R'、-C(O)N(R)2、-N(R)C(O)N(R)2 OR-N (R) C (O) OR;
Each R c is independently selected from halogen, -CN, -CO 2R、-C(O)N(R)2、-NO2、-N(R)2, -OR, -SR, OR optionally substituted C 1-6 aliphatic;
n is 0,1, 2 or 3;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
Ring a is an optionally substituted 9-to 16-membered bicyclic or tricyclic aryl, an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 10-to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 7-to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 10-to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's taken together when attached to the same nitrogen atom form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
Each R' is independently optionally substituted C 1-6 aliphatic or optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl.
19. The compound of embodiment 18, wherein the compound is not:
/>
20. The compound of embodiment 18 or 19 wherein ring a is an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted 10-to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted 7-to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 10-to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.
21. The compound of any of embodiments 18-20 wherein ring a is an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or an optionally substituted 10-to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.
22. The compound of any of embodiments 18-21 wherein ring a is an 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more oxo, halo, or C 1-6 alkyl groups.
23. The compound of any of embodiments 18-22 wherein ring a is an optionally substituted 10-to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.
24. The compound of any one of embodiments 18-23, wherein:
Ring A is
Ring A1 is an optionally substituted ring selected from phenyl, a 5 to 6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl group, and a 5 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
wherein ring A1 is fused to ring A2;
Ring A2 is an optionally substituted ring selected from phenyl, a 5 to 6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl group, and a 5 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
wherein ring A2 is optionally (i) further fused to ring A3,
Or (ii) ring A2 and ring A3 combine to form a spiro ring; and
When present, ring A3 is an optionally substituted ring selected from phenyl, a 5-to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, A3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl group, and A3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
25. The compound of embodiment 24 wherein ring A1 is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
26. The compound of embodiment 24 or 25 wherein optionally substituted ring a is
27. The compound of any of embodiments 24-26 wherein ring A2 is an optionally substituted 5-to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
28. The compound of any one of embodiments 24-27, wherein optionally substituted ring a is selected from the group consisting of:
29. the compound of any one of embodiments 24-27, wherein optionally substituted ring a is selected from the group consisting of:
30. The compound of any one of embodiments 18-29, wherein:
In the case where the valence allows, the reaction proceeds, Substituted with 1-5R b; and
Each R b is independently hydrogen, halogen 、-CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R'、-SO2N(R)2、-SO3R'、 optionally substituted C 1-6 aliphatic, optionally substituted 3 to 6 membered saturated or partially unsaturated carbocyclyl, optionally substituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
M is 1, 2 or 3.
31. The compound of embodiment 30 wherein each R b is independently halogen 、-CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R'、-SO2N(R)2、-SO3R'、 optionally substituted C 1-6 aliphatic, optionally substituted 3-to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3-to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
32. The compound of embodiment 30 OR embodiment 31 wherein each R b is independently halogen, optionally substituted C 1-6 aliphatic, -OR, OR-O (CH 2)m R.
33. The compound of any of embodiments 30-32 whereinSelected from the group consisting of:
34. The compound of any of embodiments 30-32 wherein Selected from the group consisting of: /(I)
35. The compound of any of embodiments 18-34, wherein the compound has formula II-C:
Or a pharmaceutically acceptable salt thereof.
36. The compound of any of embodiments 18-35, wherein the compound has formula II-D:
Or a pharmaceutically acceptable salt thereof.
37. The compound of any of embodiments 18-36, wherein the compound has formula II-E:
Or a pharmaceutically acceptable salt thereof, wherein:
Ring A1 is an optionally substituted ring selected from phenyl, a 5 to 6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl group, and a 5 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
wherein ring A1 is fused to ring A2;
Ring A2 is an optionally substituted ring selected from phenyl, a 5 to 6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl group, and a 5 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
wherein ring A2 is optionally (i) further fused to ring A3,
Or (ii) ring A2 and ring A3 combine to form a spiro ring; and
When present, ring A3 is an optionally substituted ring selected from phenyl, a 5-to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, A3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl group, and A3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
38. The compound of any one of the preceding embodiments, wherein W is CR w.
39. The compound of embodiment 38 wherein R w is hydrogen.
40. The compound of any one of embodiments 1-37, wherein W is N.
41. The compound of any one of the preceding embodiments, wherein X is CR x.
42. The compound of any one of the preceding embodiments, wherein R x is hydrogen, halogen, -CN, -OR 3, OR optionally substituted C 1-6 aliphatic.
43. The compound of any of embodiments 1-40 wherein X is N.
44. The compound of any one of the preceding embodiments, wherein Y is CR y.
45. The compound of embodiment 44 wherein R y is hydrogen.
46. The compound of any of embodiments 1-43 wherein Y is N.
47. The compound of any one of the preceding embodiments, wherein R 1 is-N (R) C (O) N (R) 2 OR-N (R) C (O) OR.
48. The compound of any one of the preceding embodiments, wherein R 1 is-N (R) C (O) N (R) 2.
49. The compound of any of the preceding embodiments, wherein R 1 is-N (H) C (O) N (R) 2, and each R of R 1 is independently hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl, or two R groups attached to the same nitrogen together form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
50. The compound of any of embodiments 1-47 wherein R 1 is-N (R) C (O) OR.
51. The compound of any of embodiments 1-47 wherein R 1 is-N (H) C (O) OR and R of R 1 is optionally substituted C 1-6 aliphatic OR an optionally substituted 3-to 7-membered saturated OR partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.
52. The compound of any of embodiments 1-46 wherein R 1 is-N (R) C (O) R'.
53. The compound of any of embodiments 1-46 wherein R 1 is-N (H) C (O) (optionally substituted C 1-6 aliphatic).
54. The compound of any one of the preceding embodiments, wherein each R c is independently halogen.
55. The compound of any one of the preceding embodiments, wherein n is 0.
56. A compound of formula III:
Or a pharmaceutically acceptable salt thereof, wherein:
Z is-O-or-NR z -;
R x is hydrogen, halogen, -OR 3、-N(R3)2、-SR3, optionally substituted C 1-6 aliphatic OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
r 4 is halogen, -OR, -N (R) 2 OR an optionally substituted 3-to 7-membered saturated OR partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
Ring a is optionally substituted phenyl, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
l is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;
R a is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
Each R is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's taken together when attached to the same nitrogen atom form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
57. The compound of embodiment 56, wherein the compound is not:
58. The compound of embodiment 56 OR embodiment 57 wherein R 4 is halogen, -OR, -N (R) 2 OR optionally substituted 3-to 7-membered saturated OR partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and each R of R 4 is independently hydrogen OR optionally substituted C 1-6 aliphatic.
59. The compound of any of embodiments 56-58 wherein ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
60. The compound of any of embodiments 56-59 wherein ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
61. The compound of any of embodiments 56-60 wherein ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
62. The compound of any of embodiments 56-61 wherein R a is halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
63. The compound of any of embodiments 56-62 wherein R a is optionally substituted C 1-6 aliphatic.
64. The compound of any of embodiments 56-63 wherein:
In the case where the valence allows, the reaction proceeds, Substituted with 1-5R b; and
Each R b is independently hydrogen, halogen 、-CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R'、-SO2N(R)2、-SO3R'、 optionally substituted C 1-6 aliphatic, optionally substituted 3 to 6 membered saturated or partially unsaturated carbocyclyl, optionally substituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
M is 1, 2 or 3.
65. The compound of embodiment 64 wherein each R b is independently halogen 、-CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R'、-SO2N(R)2、-SO3R'、 optionally substituted C 1-6 aliphatic, optionally substituted 3-to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3-to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
66. The compound of embodiment 64 or 65 wherein each R b is independently optionally substituted C 1-6 aliphatic.
67. The compound of any of embodiments 64-66 whereinIs that
68. The compound of any of embodiments 56-67 wherein L is a covalent bond.
69. The compound of any of embodiments 56-67 wherein L is-CH 2 -.
70. The compound of any of the preceding embodiments, wherein each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's when attached to the same nitrogen atom together form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
71. The compound of any one of the preceding embodiments, wherein each R is independently hydrogen or optionally substituted C 1-6 aliphatic.
72. The compound of any one of the preceding embodiments, wherein each R' is independently optionally substituted C 1-6 alkyl or optionally substituted C 3-7 cycloalkyl.
73. The compound of any one of the preceding embodiments, wherein each R' is independently optionally substituted C 1-6 aliphatic.
74. A compound of formula IV:
Or a pharmaceutically acceptable salt thereof, wherein:
Z is-O-or-NR z -;
R x is hydrogen, halogen, OR 3, OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
Selected from (i) or (ii):
(i) Or (b)
(ii)Wherein ring a is further substituted at least once and at least one substituent on ring a is C 1-6 haloalkyl;
l is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;
R a is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
R' is C 1-6 aliphatic or a 3-to 7-membered saturated or partially unsaturated carbocyclyl.
75. The compound of embodiment 74, wherein the compound is not:
/>
76. The compound of embodiment 74 or 75 wherein R a is halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
77. The compound of any of embodiments 74-76 wherein R a is optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
78. The compound of any of embodiments 74-77, wherein L is a covalent bond.
79. The compound of any of embodiments 74-77, wherein L is-CH 2 -.
80. The compound of any of embodiments 74-79 wherein R' is methyl or cyclopropyl.
81. The compound of any of embodiments 56-80 wherein R x is hydrogen, halogen, -CN, -OR 3, OR optionally substituted C 1-6 aliphatic.
82. The compound of any of embodiments 56-81 wherein R x is hydrogen, halogen, -OR 3, OR-CN.
83. The compound of any of embodiments 56-82 wherein R x is halogen or-CN.
84. The compound of any one of the preceding embodiments, wherein R 2 is C 1-4 alkyl.
85. The compound of any one of the preceding embodiments, wherein Z is-O-.
86. The compound of any of embodiments 1-84 wherein Z is-NR z -.
87. The compound of embodiment 86 wherein R z is hydrogen.
88. A compound selected from table 1, or a pharmaceutically acceptable salt thereof.
89. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
90. A method of inhibiting JAK2 in a subject, the method comprising administering a compound of any one of embodiments 1-88 or a composition of embodiment 89.
91. A method of treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof a compound of any one of embodiments 1-88 or a composition of embodiment 89.
92. A method of treating cancer, the method comprising administering to a subject in need thereof a compound of any one of embodiments 1-88 or a composition of embodiment 89.
93. A method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a compound of any one of embodiments 1-88 or a composition of embodiment 89.
94. The method of embodiment 93, wherein the hematological malignancy is leukemia or lymphoma.
95. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of embodiments 1-88 or the composition of embodiment 89.
96. The method of embodiment 95, wherein the myeloproliferative neoplasm is polycythemia vera, primary thrombocytopenia, or myelofibrosis.
Examples
As described in the examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. It should be understood that while the general methods describe the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to those of ordinary skill in the art may be applied to all compounds and subclasses and species of each of these compounds as described herein.
Preparation of intermediates
Preparation of intermediate Int-1: 5-fluoro-N-methyl-2-nitropyridin-3-amine
Synthesis of Compound Int-1.1 Hydrogen peroxide (30 wt%, 31 mL) was added dropwise to concentrated sulfuric acid (60 mL) at 0deg.C. To this solution was added dropwise a solution of 3, 5-difluoropyridin-2-amine (5.0 g,38.43mmol,1.0 eq.) in concentrated sulfuric acid (60 mL) at 0 ℃. The reaction mixture was stirred at room temperature for 48h. Carefully pour it over crushed ice and stir. The aqueous mixture was basified with saturated aqueous sodium bicarbonate. The precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-1.1. 1H NMR(CDCl3 400 MHz): delta 8.35 (bs, 1H), 7.62-7.58 (m, 1H).
Synthesis of Compound Int-1. To a solution of Int-1.1 (2.3 g,14.37mmol,1.0 eq.) in acetonitrile (20 mL) was added dropwise aqueous methylamine (40%, 1.1mL,14.37mmol,1.0 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 1h. It was poured onto ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-1. 1H NMR(CDCl3 400 MHz): delta 7.93 (bs, 1H), 7.78-7.75 (d, 1H), 7.02-6.99 (m, 1H), 3.06 (s, 3H).
Preparation of intermediate Int-2: 4-chloro-5-fluoro-N-methyl-2-nitropyridin-3-amine
Synthesis of Compound Int-2.1. To a solution of 3, 5-difluoropyridin-2-amine (10 g,76.87mmol,1.0 eq.) in THF (200 mL) was added n-butyllithium (2.5 m in hexane, 61.4mL,153.7mmol,2.0 eq.). The reaction mixture was stirred at-78 ℃ for 40min. Hexachloroethane (36.3 g,153.7mmol,2.0 eq.) was added and the reaction mixture stirred at-78 ℃ for 30-40min. A saturated ammonium chloride solution was carefully added to quench the reaction. The mixture was warmed to room temperature and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography12% Ethyl acetate in hexanes) to give Int-2.1. 1H NMR(DMSO-d6 400 MHz): delta 7.98-7.94 (m, 1H), 6.48 (bs, 2H).
Synthesis of Compound Int-2.2. Concentrated sulfuric acid (3 mL,6 volumes) was added dropwise to potassium persulfate (2.05 g,7.6mmol,2.5 eq.) at room temperature and stirred for 15min. To the mixture was added Int-2.1 (0.5 g,3.04mmol,1.0 eq.) in small portions, maintaining the temperature at 30-40 ℃. The reaction mixture was stirred at room temperature for 3-4h. It was poured onto crushed ice, stirred, basified with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2-3% Ethyl acetate in hexane) to give Int-2.2. 1H NMR(DMSO-d6 400 MHz): delta 8.78 (s, 1H).
Synthesis of Compound Int-2. To a solution of Int-2.2 (0.970 g,4.99mmol,1.0 eq.) in acetonitrile (10 mL) was added dropwise aqueous methylamine (40%, 0.8mL,9.98mmol,2.0 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 10-20min. It was poured onto ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography10% Ethyl acetate in hexanes) to give Int-2. 1H NMR(DMSO-d6 400 MHz): delta 7.98 (s, 1H), 7.05 (bs, 1H), 2.79 (d, 3H).
Preparation of intermediate Int-3: (S) -5- (tert-butyl) -3-isothiocyanato-1- (tetrahydrofuran-3-yl) -1H-pyrazole
Synthesis of Compound Int-3.1. To a round bottom flask equipped with a Dean-Stark apparatus and condenser was added 5- (tert-butyl) -1H-pyrazol-3-amine (5.0 g,35.92mmol,1.0 eq.), 2, 5-hexanedione (4.09 g,35.92mmol,1.0 eq.), toluene (100 mL) and a few drops of acetic acid. The reaction mixture was heated to reflux for 3 hours. It was cooled to room temperature and concentrated under reduced pressure. Through silica gel fast column chromatography12% Ethyl acetate in hexanes as eluent) to afford Int-3.1.MS (ES) m/z 218.3[ M+H ] +.
Synthesis of Compounds Int-3.2 and Int-3.3. A mixture of Int-3.1 (2.5 g,11.50mmol,1.0 eq.) and (R) -tetrahydrofuran-3-ylmethane sulfonate (1.91 g,11.50mmol,1.0 eq.) and cesium carbonate (7.49 g,23mmol,2.0 eq.) in DMF (15 mL) was stirred under nitrogen at 70℃for 12h. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2% Ethyl acetate in hexanes as eluent) to afford Int-3.2.MS (ES) m/z 287.4[ M+H ] + and Int-3.3.MS (ES) m/z 248.3[ M+H ] +.
Synthesis of Compound Int-3.4. To a solution of Int-3.3 (0.120 g,0.417mmol,1.0 eq.) in ethanol-water (2:1, 2 mL) was added hydroxylamine hydrochloride (0.287 g,4.17mmol,10 eq.). The reaction mixture was stirred in a microwave reactor at 120 ℃ for 1h. It was poured onto ice water, basified with 2N sodium hydroxide and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-3.4.MS (ES) m/z 210.3[ M+H ] +.
Synthesis of Compound Int-3. To a solution of Int-3.4 (0.070 g,0.334mmol,1.0 eq.) in dichloromethane (2 mL) was added a solution of sodium bicarbonate (0.140 g,1.67mmol,5.0 eq.) in water (1 mL) at 0deg.C followed by thiophosgene (0.096 g,0.835mmol,2.5 eq.). The reaction mixture was stirred at room temperature for 2h. It was poured onto ice water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-3.MS (ES) m/z 252.3[ M+H ] +.
Preparation of intermediate Int-4: (R) -5- (tert-butyl) -3-isothiocyanato-1- (tetrahydrofuran-3-yl) -1H-pyrazole
Synthesis of Compound Int-4. Compound Int-4 was prepared from Int-3.2 following the procedure described in the synthesis of Int-3. MS (ES) m/z 252.3[ M+H ] +.
Preparation of intermediate Int-5: 3-isothiocyanato-1-methyl-5- (trifluoromethyl) pyridin-2 (1H) -one
Synthesis of Compound Int-5.1. A mixture of 3-nitro-5- (trifluoromethyl) pyridin-2 (1H) -one (1.0 g,4.81mmol,1.0 eq.) and potassium carbonate (1.3 g,9.62mmol,2.0 eq.) in DMF (15 mL) was stirred for 15min, then methyl iodide (1.0 g,7.21mmol,1.5 eq.) was added. The reaction mixture was stirred at 70℃for 2h. It was transferred to ice water and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography40% Ethyl acetate in hexane) to give Int-5.1.MS (ES) m/z 223.12[ M+H ] -.
Synthesis of Compound Int-5.2. A mixture of compound Int-5.1 (0.57 g,2.57mmol,1.0 eq.) and 10% palladium on carbon (0.3 g) in methanol (18 mL) was stirred under hydrogen (1 atm) for 1h. Passing it throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to obtain Int-5.2.MS (ES) m/z 193.14[ M+H ] +.
Synthesis of Compound Int-5. To a solution of Int-5.2 (0.200 g,1.04mmol,1.0 eq.) and triethylamine (0.4 mL,2.49mmol,2.4 eq.) in THF (6 mL) was added thiophosgene (0.143 g,1.25mmol,1.2 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 30min. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-5.MS (ES) m/z 192.15[ M+H ] +.
Preparation of intermediate Int-6: 1- (2-oxaspiro [3.3] heptan-6-yl) -5- (trifluoromethyl) -1H-pyrazol-3-amine
Synthesis of Compound Int-6.1. To a solution of 2-oxaspiro [3.3] heptane-6-one (0.600 g,5.35mmol,1.0 eq.) in methanol (10 mL) was added sodium borohydride (0.203 g,5.35mmol,1.0 eq.) in portions at 0 ℃. The reaction mixture was stirred for 2h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-6.1.MS (ES) m/z 115.2[ M+H ] +.
Synthesis of Compound Int-6.2. To a solution of Int-6.1 (0.540 g,4.73mmol,1.0 eq.) in dichloromethane (10 mL) was added triethylamine (1.64 mL,11.82mmol,2.5 eq.) followed by methanesulfonyl chloride (0.71 mL,9.46mmol,2.0 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 12h. It was transferred to ice water, stirred, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography40% Ethyl acetate in hexane) to give Int-6.2.MS (ES) m/z 193.2[ M+H ] +.
Synthesis of Compound Int-6. To a solution of Int-6.2 (0.4 g,2.08mmol,1.0 eq.) and 5- (trifluoromethyl) -1H-pyrazol-3-amine (0.314 g,2.08mmol,1.0 eq.) in DMF (7 mL) was added cesium carbonate (1.352 g,4.16mmol,2.0 eq.). The reaction mixture was heated at 80℃for 5h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Int-6.MS (ES) m/z 248.2[ M+H ] +.
Preparation of intermediate Int-7: 4, 4-difluoro-2-isothiocyanato-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridine
Synthesis of Compound Int-7.1. To a solution of diethyl 1H-pyrazole-3, 5-carboxylate (100 g,471mmol,1.0 eq) and ethyl 4-bromobutyrate (91.92 g,471mmol,1.0 eq) in acetonitrile (1000 mL) was added potassium carbonate (64.99 g,471mmol,1.0 eq) and the reaction mixture was stirred at 80℃for 4H. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to give Int-7.1.MS (ES) m/z 327.2[ M+H ] +.
Synthesis of Compound Int-7.2. To a solution of Int-7.1 (120 g,367mmol,1.0 eq.) in toluene (1000 mL) was added potassium tert-butoxide (1M in THF) (403 mL,403.7mmol,1.1 eq.) at room temperature. The reaction mixture was stirred at 90℃for 3h. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to give Int-7.2.m/z 281.2[ M+H ] +.
Synthesis of Compound Int-7.3. Hydrochloric acid: water (2:1,600 mL) was added to Int-7.2 (65 g,231mmol 1.0 eq.) and the reaction mixture was heated to 100deg.C for 6h. It was concentrated under reduced pressure. The residue was dissolved in acetonitrile-THF (1:4, 250 mL) and the solution was concentrated under reduced pressure to give Int-7.3.MS (ES) m/z 181.1[ M+H ] +.
Synthesis of Compound Int-7.4. To a solution of Int-7.3 (38 g,210mmol,1.0 eq.) in DMF (4000 mL) was added potassium carbonate (57.96 g,420mmol,2.0 eq.) followed by methyl iodide (15.7 mL,252mmol,1.2 eq.) and the reaction mixture was stirred at room temperature for 4h. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography25% Ethyl acetate in hexane) to give Int-7.4.MS (ES) m/z 195.0[ M+H ] +.
Synthesis of Compound Int-7.5. To a solution of Int-7.4 (22 g,113.29mmol,1.0 eq.) in 1, 2-dichloroethane (130 mL) was added diethylaminosulfur trifluoride (150 mL,1132.9mmol,10.0 eq.) and the reaction mixture was stirred at room temperature for 5 days. It was transferred to ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography20% Ethyl acetate in hexanes) to give Int-7.5.MS (ES) m/z 217.1[ M+H ] +.
Synthesis of Compound Int-7.6. To a solution of Int-7.5 (11.2 g,51.81mmol,1.0 eq.) in THF (110 mL) was added lithium hydroxide (4.35 g,103.62mmol,2.0 eq.) and water (11 mL). The reaction mixture was stirred at room temperature for 16h. It was poured into ice water and the pH was adjusted to 5 by addition of 2M hydrochloric acid. The product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-7.6.MS (ES) m/z 203.0[ M+H ] +.
Synthesis of Compound Int-7.7. To a suspension of Int-7.6 (8.0 g,39.57mmol,1.0 eq.) in toluene (100 mL) was added triethylamine (11 mL,79.14mmol,2.0 eq.) followed by benzyl alcohol (21.4 g,197.85mmol,5.0 eq.) and diphenyl azide phosphate (21.77 g,79.14mmol,2.0 eq.). The reaction mixture was stirred at 90℃for 16h. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the starting material. Passing through silica gel flash column chromatography15% Ethyl acetate in hexane) to give Int-7.7.MS (ES) m/z 308.2[ M+H ] +.
Synthesis of Compound Int-7.8. A mixture of Int-7.7 (5.4 g,17.57mmol,1.0 eq.) and 10% palladium on charcoal (2.0 g) in methanol (100 mL) was stirred under hydrogen (1 atm) for 2h. Passing it throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give Int-7.8.MS (ES) m/z 174.1[ M+H ] +.
Synthesis of Compound Int-7. Compound Int-7 was prepared from Int-7.8 following the procedure described in the synthesis of Int-3. It was used without purification. MS (ES) m/z 216.2[ M+H ] +.
Preparation of intermediate Int-8: 2-isothiocyanato-5-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one
Synthesis of Compound Int-8.1. To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (2.0 g,12.73mmol,1.0 eq.) and 2- (methylamino) ethan-1-ol (1.43 g,19.10mmol,1.5 eq.) in DCM (20 mL) was added thionyl chloride (4.6 mL,63.65mmol,5.0 eq.) and one drop of DMF dropwise at-5 ℃. The reaction mixture was stirred 10 and heated at 50 ℃ for 16h. It was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DMF (20 mL) and triethylamine (5.3 mL,38.19mmol,3.0 eq.) was added and stirred for 16h. It was poured into ice water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography1.0% Methanol in DCM) to give Int-8.1.MS (ES) m/z 197.1[ M+H ] +.
Synthesis of Compound Int-8.2. A mixture of Int-8.1 (1.3 g,6.63mmol,1.0 eq.), ammonium chloride (1.79 g,33.15mmol,5.0 eq.) and iron powder (1.85g,33.15mmol 5.0 eq.) in ethanol (20 mL) and water (7 mL) was stirred at 80℃for 4h. Cool it to room temperature and passIs filtered through a pad of (a). The filtrate was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)1.5% Methanol in DCM) to give Int-8.2.MS (ES) m/z 167.0[ M+H ] +.
Synthesis of Compound Int-8. Compound Int-8 was prepared from Int-8.2 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatography0.5% Methanol in DCM). MS (ES) m/z 209.1[ M+H ] +.
Preparation of intermediate Int-9: 2-isothiocyanato-4, 4-dimethyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazine
Synthesis of Compound Int-9.1. To a solution of 5-amino-1H-pyrazole-3-carboxylic acid ethyl ester (15.0 g,96.68mmol,1.0 eq.) and hexane-2, 5-dione (16.55 g,145.01mmol,1.5 eq.) in toluene (150 mL) was added p-toluene sulfonic acid (0.919 g,4.83mmol,0.05 eq.). The reaction mixture was heated to reflux with a Dean-Stark trap to remove water for 2h. It was cooled to room temperature and concentrated under reduced pressure. Through silica gel fast column chromatography10% Ethyl acetate in hexanes) to give Int-9.1.MS (ES) m/z 234.2[ M+H ] +.
Synthesis of Compound Int-9.2. A mixture of Int-9.1 (10 g,42.87mmol,1.0 eq.) of (2-bromoethoxy) (tert-butyl) dimethylsilane (15.38 g,64.30mmol,1.0 eq.) and potassium carbonate (17.74 g,128.61mmol,3.0 eq.) in acetonitrile (100 mL) was stirred at 80℃for 1h. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography15% Ethyl acetate in hexanes) to give Int-9.2.MS (ES) m/z 392.2[ M+H ] +.
Synthesis of Compound Int-9.3. To a solution of Int-9.2 (7.2 g,18.39mmol,1.0 eq.) in THF (70 mL) was added methyl magnesium bromide (3M in diethyl ether, 18.4mL,55.17mmol,3.0 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 1h. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography18% Ethyl acetate in hexanes) to give Int-9.3.m/z 378.5[ M+H ] +.
Synthesis of Compound Int-9.4. To a solution of Int-9.3 (5.3 g,14.04mmol,1.0 eq.) in THF (50 mL) was added tetrabutylammonium fluoride solution (1M in THF, 35mL,35.1mmol,2.5 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 1h. It was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography25% Ethyl acetate in hexanes) to give Int-9.4.m/z 264.2[ M+H ] +.
Synthesis of Compound Int-9.5. To a solution of Int-9.4 (2.3 g,8.73mmol,1.0 eq.) and 4-dimethylaminopyridine (0.0107 mmol, 0.087mmol,0.01 eq.) in DCM (25 mL) was added a solution of 4-toluenesulfonyl chloride (2.16 g,11.34mmol,1.3 eq.) in DCM (5 mL) and triethylamine (3.7 mL,26.19mmol,3.0 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 1h. It was poured into ice water and the product extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a material. To a solution of this material in THF (50 mL) was added sodium hydride (1.05 g,26.19mmol,3.0 eq.) at 0 ℃. The reaction mixture was stirred at room temperature for 30min. It was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography30% Ethyl acetate in hexanes) to give Int-9.5.m/z 246.2[ M+H ] +.
Synthesis of Compound Int-9.6. To a solution of Int-9.5 (0.900 g,3.67mmol,1.0 eq.) in ethanol-water (2:1, 20 mL) was added hydroxylamine hydrochloride (12.75 g,183.5mmol,50 eq.). The reaction mixture was stirred at 120℃for 1h. It was poured into ice water and neutralized with 2N sodium hydroxide. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2% Methanol in DCM) to give Int-9.6.MS (ES) m/z 168.1[ M+H ] +.
Synthesis of Compound Int-9. Compound Int-9 was prepared from Int-9.6 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatographyDCM) purified product. MS (ES) m/z 210.1[ M+H ] +.
Preparation of intermediate Int-10: 2 '-isothiocyanato-5', 6 '-dihydrospiro [ cyclobutane-1, 4' -pyrrolo [1,2-b ] pyrazole ]
Synthesis of Compound Int-10.1. To a solution of lithium bis (trimethylsilyl) amide (1M in THF, 17.4mL,17.44mmol,2.2 eq.) in anhydrous tetrahydrofuran (25 mL) was added a solution of 6-oxaspiro [3.4] octan-5-one (1.0 g,7.93mmol,1.0 eq.) and acetonitrile (0.83 mL,15.86mmol,2.0 eq.) in tetrahydrofuran (8 mL) at-78deg.C. The reaction mixture was stirred at-78 ℃ for 30min and allowed to warm to room temperature, stirred for 2h. It was transferred to saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue which was purified by flash column chromatography on silica gel20% Ethyl acetate in hexane) to give Int-10.1.1H NMR(DMSO-d6,400MHz):δ4.01(s,1H),3.76(m,1H),3.66-3.62(m,1H),2.84(bs,2H),2.10(bs,2H),1.99(bs,2H),1.87-1.82(m,2H),1.67(bs,2H).
Synthesis of Compound Int-10.2. To a solution of Int-10.1 (0.800 g,4.78mmol,1.0 eq.) in ethanol (10 mL) was added hydrazine monohydrate (0.178 g,7.17mmol,1.5 eq.). The reaction mixture was heated at 60℃for 72h. The reaction mixture was cooled to room temperature and carbon dioxide was bubbled through it for 1h. It was concentrated under reduced pressure. Methanol (15 mL) was added to the residue and stirred for a while. The precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure to obtain Int-10.2.MS (ES) m/z 182.1[ M+H ] +.
Synthesis of Compound Int-10.3. To a solution of Int-10.2 (0.610 g,3.37mmol,1.0 eq.) in THF (10 mL) was added thionyl chloride (1.22 mL,16.85mmol,5.0 eq.). The reaction mixture was stirred at room temperature for 3h. It was slowly transferred to a (1:1) mixture of aqueous ammonium hydroxide and ice, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue which was purified by flash column chromatography on silica gel2% Methanol in dichloromethane) to yield Int-10.3.MS (ES) m/z 164.1[ M+H ] +.
Synthesis of Compound Int-10. The compound Int-10 was prepared from Int-10.3 according to the procedure described in the synthesis of Int-3. Through silica gel fast column chromatographyDichloromethane) purified product. MS (ES) m/z 205.9[ M+H ] +.
Preparation of intermediate Int-11: 2' -isothiocyanato-6 ',7' -dihydro-5 ' H-spiro [ cyclopropane-1, 4' -pyrazolo [1,5-a ] pyridine ]
Synthesis of Compound Int-11.1. To a solution of LiHMDS (35 mL,35mmol,2.2 eq.) in THF (40 mL) was added acetonitrile (1.3 g,32mmol,2 eq.) dropwise at-78deg.C. The resulting solution was stirred for 1h, and a solution of 5-oxaspiro [2.5] octan-4-one (2 g,15.85mmol,1 eq.) in THF (10 mL) was added dropwise. The reaction mixture was stirred at-78 ℃ for a further 2h. It was allowed to warm to room temperature, quenched by saturated ammonium chloride solution and extracted by DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-11.1.MS (ES) m/z 167.21[ M+H ] +.
Synthesis of Compound Int-11.2. To a solution of Int-11.1 (1.7 g,10.17mmol,1 eq.) in methanol (50 mL) was added hydrazine hydrate (1.52 g,30.51mmol,3 eq.). The reaction mixture was stirred in the autoclave at 120 ℃ for 16h. The reaction mixture was cooled to room temperature and dry ice was slowly added over a period of 15 min. The solution was decanted and the solvent was removed under reduced pressure. Flash column chromatography on silica gel6.0% Methanol in DCM) to give Int-11.2.MS (ES) m/z 181.24[ M+H ] +.
Synthesis of Compound Int-11.3. To a stirred solution of Int-11.2 (1.2 g,6.62mmol,1 eq.) in dichloroethane (24 mL) was added thionyl chloride (0.937 g,7.94mmol,1.2 eq.) at room temperature. The reaction mixture was stirred at 90℃for 1h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous potassium carbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-11.3.MS (ES) m/z 199.68[ M+H ] +.
Synthesis of Compound Int-11.4. A mixture of Int-11.3 (1 g,5.01mmol,1 eq.) and K 2CO3 (1.38 g,10.02mmol,2 eq.) in acetonitrile (20 mL) was stirred at 80℃for 16h. It was cooled to room temperature, poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography5.0% Methanol in DCM) to give Int-11.4.MS (ES) m/z 163.22[ M+H ] +.
Synthesis of Compound Int-11. Compound Int-11 was prepared from Int-11.4 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatography40% Ethyl acetate in hexanes) was purified. MS (ES) m/z 205.28[ M+H ] +.
Preparation of intermediate Int-12: 2-isothiocyanato-4, 4-dimethyl-4, 5,7, 8-tetrahydropyrazolo [1,5-d ] [1,4] oxaazepine
/>
Synthesis of Compound Int-12.1. A mixture of Int-9.1 (40 g,171.67mmol,1.0 eq.) and ((2-bromoethoxy) methyl) benzene (46.13 g,214.59mmol,1.25 eq.) and potassium carbonate (71.07 g,515.02mmol,3.0 eq.) in acetonitrile (100 mL) was stirred at 80℃for 1h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography15% Ethyl acetate in hexanes) to give Int-12.1.MS (ES) m/z 369.2[ M+H ] +.
Synthesis of Compound Int-12.2. To a solution of Int-12.1 (34.8 g,94.56mmol,1.0 eq.) in THF (350 mL) was added lithium aluminum hydride (1M in THF, 60.0mL,94.56mmol,1.0 eq.) and stirred for 30min at 0deg.C. Pour it into ethyl acetate and passIs filtered to remove the precipitate. The filtrate was concentrated under reduced pressure to give Int-12.2.MS (ES) m/z 326.1[ M+H ] +.
Synthesis of Compound Int-12.3. To a solution of Int-12.2 (30.6 g,94.15mmol,1.0 eq.) and triethylamine (23.77 g,235.38mmol,2.5 eq.) in DCM (300 mL) was added methanesulfonyl chloride (16.1 g,141.23mmol,1.5 eq.) and stirred for 20min at 0deg.C. It was transferred to ice water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Acetonitrile was added to the residue followed by tetrabutylammonium cyanide (55.59 g,207.38mmol,2.0 eq.) was added. The mixture was stirred at 80℃for 1h. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography28% Ethyl acetate in hexanes) to give Int-12.3.MS (ES) m/z 335.3[ M+H ] +.
Synthesis of Compound Int-12.4. To a solution of Int-12.3 (20.8 g,62.27mmol,1.0 eq.) in DMF (220 mL) was added sodium hydride (60%, 7.47g,186.82mmol,3.0 eq.) followed by methyl iodide (44.21 g,311.37mmol,5.0 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 1h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography17% Ethyl acetate in hexane) to give Int-12.4.MS (ES) m/z 363.61[ M+H ] +.
Synthesis of Compound Int-12.5. To a solution of Int-12.4 (2.0 g,5.52mmol,1.0 eq.) in DCM (25 mL) was added diisobutylaluminum hydride (1.0M in hexane, 10.0 mL) and stirred for 30min at-78deg.C. The reaction mixture was poured into a saturated aqueous solution of sodium potassium tartrate and stirred for 1h. Passing it throughIs added to the solution, and the filtrate is extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)20% Ethyl acetate in hexanes) to give Int-12.5.MS (ES) m/z 366.61[ M+H ] +.
Synthesis of Compound Int-12.6. To a solution of Int-12.5 (11.4 g,31.23mmol,1.0 eq.) in methanol (125 mL) was added sodium borohydride (11.4 g,62.46mmol,2.0 eq.) and stirred for 1h at 0deg.C. It was poured into dilute hydrochloric acid (30 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography40% Ethyl acetate in hexane) to give Int-12.6.MS (ES) m/z 368.41[ M+H ] +.
Synthesis of Compound Int-12.7. To a solution of Int-12.6 (9.75 g,26.56mmol,1.0 eq.) and triethylamine (10.7 g,106.26mmol,4.0 eq.) in DCM (130 mL) was added methanesulfonyl chloride (6.05 g,53.13mmol,2.0 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 30min, transferred to water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography28% Ethyl acetate in hexanes) to give Int-12.7.MS (ES) m/z 446.81[ M+H ] +.
Synthesis of Compound Int-12.8. To a solution of Int-12.7 (7.8 g,17.52mmol,1.0 eq.) in DCM (150 mL) was added trifluoromethanesulfonic acid (20.0 mL) and stirred for 15min at 0deg.C. It was poured into saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2% Methanol in DCM) to give Int-12.8.MS (ES) m/z 356.36[ M+H ] +.
Synthesis of Compound Int-12.9. To a solution of Int-12.8 (4.1 g,11.54mmol,1.0 eq.) in dimethyl sulfoxide (60 mL) was added sodium hydride (60%, 2.30g,57.74mmol,5.0 eq.) and stirred for 2h at room temperature. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography25% Ethyl acetate in hexanes) to give Int-12.9.MS (ES) m/z 260.26[ M+H ] +.
Synthesis of Compound Int-12.10. To a solution of Int-12.9 (1.9 g,7.33mmol,1.0 eq.) in ethanol and water (1:1, 25 mL) was added hydroxylamine hydrochloride (20.24 g,293.43mmol,40.0 eq.) at room temperature. The reaction mixture was stirred at 120℃for 4h. It was poured into saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography4.2% Methanol in DCM) to give Int-12.10.MS (ES) m/z 182.27[ M+H ] +.
Synthesis of Compound Int-12. Compound Int-12 was prepared from Int-12.10 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatographyDCM) purified product. MS (ES) m/z 224.1[ M+H ] +.
Preparation of intermediate Int-13: 1- (tert-butyl) -6-isothiocyano-2, 3-dihydro-1H-imidazo [1,2-b ] pyrazole
Synthesis of Compound Int-13.1. A mixture of dimethyl 1H-pyrazole-3, 5-dicarboxylate (25 g,135.76mmol,1.0 eq.) potassium carbonate (28.10 g,203.64mmol,1.5 eq.) and ((2-bromoethoxy) methyl) benzene (37.96 g,176.49mmol,1.3 eq.) in acetonitrile (250 mL) was stirred at 80℃for 4H. It was cooled to room temperature, transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-13.1.MS (ES) m/z 319.1[ M+H ] +.
Synthesis of Compound Int-13.2. A solution of Int-13.1 (32.5 g,102.10mmol,1.0 eq.) and potassium hydroxide (5.61 g,102.10mmol,1.0 eq.) in methanol (200 mL) was stirred at room temperature under nitrogen for 16h. It was concentrated under reduced pressure. The residue was added to water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-13.2.MS (ES) M/z305.2[ M+H ] +.
Synthesis of Compound Int-13.3. To a solution of compound Int-13.2 (28.50 g,93.66mmol,1.0 eq.) and triethylamine (16.2 mL,112.39mmol,1.2 eq.) in t-butanol (40 mL) under nitrogen was added diphenyl azide phosphate (30.9 g,112.39mmol,1.2 eq.) at room temperature. The reaction mixture was stirred at 80℃for 3h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography25-30% Ethyl acetate in hexane) to give Int-13.3.MS (ES) m/z 376.7[ M+H ] +.
Synthesis of Compound Int-13.4. A mixture of compound Int-13.3 (21.0 g,55.94mmol,1.0 eq.) and 20% palladium hydroxide (5.25 g) in methanol (210 mL) was stirred under hydrogen for 8h. Passing it throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give Int-13.4.MS (ES) m/z 286[ M+H ] +.
Synthesis of Compound Int-13.5. To a solution of compound Int-13.4 (15 g,52.58mmol,1.0 eq.) in THF (300 mL) was added tri-tert-butylphosphine (15.93, 78.87mmol,1.5 eq.) followed by diethyl azodicarboxylate (19.87 g,78.87mmol,1.5 eq.) at 0 ℃. The reaction mixture was stirred at room temperature for 2h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography50-55% Ethyl acetate in hexane) to give Int-13.5.MS (ES) m/z 268.7[ M+H ] +.
Synthesis of Compound Int-13.6. To a solution of Int-13.5 (13.0 g,48.64mmol,1.0 eq.) in a mixture of THF and methanol (100 mL, 5:1) was added an aqueous solution of lithium hydroxide (6.1 g,145.92mmol,3.0 eq.) and stirred at room temperature for 2h. The reaction mixture was concentrated under reduced pressure. To the residue was added water and the pH was adjusted to 3-4 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-13.6.MS (ES) m/z 254.5[ M+H ] +.
Synthesis of Compound Int-13.7. To a suspension of compound Int-13.6 (9.5 g,37.51mmol,1.0 eq.) in toluene (20 mL) was added benzyl alcohol (4.8 g,45.01mmol,1.2 eq.), diphenyl azide phosphate (12.33 g,45.01mmol,1.2 eq.) and triethylamine (6.8 mL,48.76mmol,1.3 eq.) at room temperature. The reaction mixture was stirred at 100℃for 6h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration in a mixture of ethyl acetate: methanol (1:1) to give Int-13.7.MS (ES) m/z 359.7[ M+H ] +.
Synthesis of Compound Int-13.8. To a solution of Int-13.7 (8.2 g,22.88mmol,1.0 eq.) in DCM (5 mL) was added trifluoroacetic acid (82 mL) at room temperature. The reaction mixture was stirred for 3h. It was transferred to a mixture of ice and saturated aqueous sodium bicarbonate and extracted with 10% methanol in DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-13.8.MS (ES) m/z 259[ M+H ] +.
Synthesis of Compound Int-13.9. To a solution of Int-13.8 (7.0 g,27.10mmol,1.0 eq.) in a mixture of DCM: toluene (1:1, 350 mL) was added boron trifluoride diethyl ether (7 mL) followed by tert-butyl 2, 2-trichloroacetimide (11.84 g,54.20mmol,2.0 eq.) at room temperature. The reaction mixture was stirred for 16h. It was transferred to aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.3-2.5% Methanol in DCM) to give Int-13.9.MS (ES) m/z 315.2[ M+H ] +.
Synthesis of Compound Int-13.10. A mixture of compound Int-13.9 (2.8 g,8.91mmol,1.0 eq.) and 20% palladium hydroxide (0.700 g) in methanol (42 mL) was stirred under hydrogen (1 atm) for 3h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure. Through silica gel fast column chromatography3-3.5% Methanol in DCM) to give Int-13.10.MS (ES) m/z 181.6[ M+H ] +.
Synthesis of Compound Int-13. To a solution of Int-13.10 (1.0 g,5.55mmol,1.0 eq.) in acetonitrile (15 mL) was added imidazole (0.096 g,1.66mmol,0.3 eq.) followed by thiocarbonyldiimidazole (1.9 g,11.1mmol,2.0 eq.) and stirred at room temperature for 1h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography100% Dcm) to give Int-13.MS (ES) m/z 223[ M+H ] +. /(I)
Preparation of intermediate Int-14: 2-isothiocyanato-6, 6-dimethyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazine
Synthesis of Compound Int-14.1. To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (5.0 g,8.51mmol,1.0 eq.) in THF (100 mL) was added dropwise DMF (0.1 mL) and oxalyl chloride (3.58 mL,9.50mmol,1.3 eq.) at 0deg.C and stirred at room temperature for 2H. Most of the solvent was removed under reduced pressure, and the residue was dissolved in THF and lithium borohydride (24 ml,4.70mmol,1.3 eq.) was added. The mixture was stirred at room temperature for 16h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give Int-14.1.MS (ES) m/z 143.10[ M+H ] +.
Synthesis of Compound Int-14.2. A mixture of Int-14.1 (1.7 g,11.77mmol,1.0 eq.) and cesium carbonate (0.772 g,2.377mmol,0.2 eq.) in 2, 2-dimethyloxirane (30 mL) was stirred at 70℃for 3h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography1.2% Methanol in DCM) to give Int-14.2.MS (ES) m/z 216.81[ M+H ] +.
Synthesis of Compound Int-14.3. A solution of Int-14.2 (0.5 g,2.32mmol,1.0 eq.) in sulfuric acid (10 mL) was stirred at 45℃for 16h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography0.5% Methanol in DCM) to give Int-14.3.MS (ES) m/z 198.19[ M+H ] +.
Synthesis of Compound Int-14.4. A mixture of palladium on carbon (10%; 0.200 g) and compound Int-14.3 (350 g,5.72mmol,1.0 eq.) in methanol (5 mL) was stirred under hydrogen for 2h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give Int-14.4.MS (ES) m/z 168.21[ M+H ] +.
Synthesis of Compound Int-14. Compound Int-14 was prepared from Int-14.4 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatography1.5% Methanol in DCM). MS (ES) m/z 210.27[ M+H ] +.
Preparation of intermediate Int-15: 1- (2- (benzyloxy) ethyl) -3-isothiocyanato-5- (trifluoromethyl) pyridin-2 (1H) -one
Synthesis of Compound Int-15.1. To a solution of 5- (trifluoromethyl) pyridin-2 (1H) -one (5.0 g,30.66mmol,1.0 eq.) in concentrated sulfuric acid (25 mL) at 0deg.C was added fuming nitric acid (8 mL). The reaction mixture was stirred at 65℃for 6h. It was transferred to crushed ice, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give Int-15.1.MS (ES) m/z 209.10[ M+H ] +.
Synthesis of Compound Int-15.2. A mixture of Int-15.1 (0.5 g,2.4mmol,1.0 eq.) and potassium carbonate (0.662 g,4.8mmol,2.0 eq.) in DMF (7 mL) was stirred for 15min. ((2-bromoethoxy) methyl) benzene (0.775 g,3.6mmol,1.5 eq.) was added to the mixture and stirred at 110℃for 2h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography30% Ethyl acetate in hexanes) to give Int-15.2.MS (ES) m/z 343.2[ M+H ] +.
Synthesis of Compound Int-15.3. A mixture of Int-15.2 (0.322 g,0.940mmol,1.0 eq.), iron powder (0.263 g,4.7mmol,5.0 eq.) and ammonium chloride (0.803 g,4.7mmol,5.0 eq.) in ethanol to water (2:1, 10 mL) was stirred at 80℃for 2h. It was transferred to ice water, filtered, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give Int-15.3.MS (ES) m/z 313.3[ M+H ] +.
Synthesis of Compound Int-15. Compound Int-15 was prepared from Int-15.3 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatography1.5% Methanol in DCM). MS (ES) m/z 355.3[ M+H ] +.
Preparation of intermediate Int-16: 3-isothiocyanato-1- (methyl d 3) -5- (trifluoromethyl) pyridin-2 (1H) -one
Synthesis of Compound Int-16.1. A mixture of Int-15.1 (12 g,57.67mmol,1.0 eq.) and potassium carbonate (23.87 g,173.01mmol,3.0 eq.) in DMF (140 mL) was stirred for 15min, then methyl iodide-d 3 (10.03 g,69.20mmol,1.2 eq.) was added. The reaction mixture was stirred at 70℃for 1h. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-16.1.MS (ES) m/z 226.1[ M+H ] +.
Synthesis of Compound Int-16.2. A mixture of Int-16.1 (10 g,44.42mmol,1.0 eq.), iron powder (12.43 g,222.1mmol,5.0 eq.), acetic acid (17.76 g,222.1mmol,5.0 eq.) in ethanol (100 mL) and water (20 mL) was stirred at 80℃for 3h. The reaction mixture was concentrated under reduced pressure. The residue was transferred to saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give Int-16.2.MS (ES) m/z 196.2[ M+H ] +.
Synthesis of Compound Int-16. Compound Int-16 was prepared from Int-16.2 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatography30% Ethyl acetate in hexanes) was purified. MS (ES) m/z 238.1[ M+H ] +.
Preparation of intermediate (+ -) -Int-17: 2- (tetrahydrofuran-3-yl) -6- (trifluoromethyl) pyridin-4-amine
Synthesis of Compound Int-17.1. A mixture of 2-chloro-6- (trifluoromethyl) pyridin-4-amine (0.600 g,3.05mmol,1.0 eq), 2- (4, 5-dihydrofuran-3-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (0.898 g,4.58mmol,1.5 eq) and potassium carbonate (1.26 g,9.15mmol,3.0 eq) in 1, 4-dioxane (10 mL) and water (1 mL) was degassed by bubbling an argon stream for 10 min. [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride-DCM complex (0.125 g,0.152mmol,0.05 eq.) was added and degassed for 5min. The reaction mixture was stirred at 120℃for 3h. It was cooled to room temperature byIs filtered through a pad of (a). The filtrate was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)1% Methanol in DCM) to give Int-17.1.MS (ES) m/z 231.19[ M+H ] +.
Synthesis of compound (+ -) -Int-17. A mixture of palladium on carbon (10%, 0.2 g) and compound Int-17.1 (0.308 g,1.34mmol,1.0 eq.) in methanol (5 mL) was stirred under hydrogen (1 atm) for 12h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give (+ -) -Int-17.MS (ES) m/z 233.21[ M+H ] -.
Preparation of intermediate Int-18: 1- (4-isothiocyanato-2- (trifluoromethyl) phenyl) -N, N-dimethylmethylamine
Synthesis of Compound Int-18.1. A solution of 4-nitro-2- (trifluoromethyl) benzoic acid (2.0 g,8.51mmol,1.0 eq.), HATU (1.2 g,2.92mmol,1.1 eq.) and triethylamine (3.5 g,2.92mmol,3.0 eq.) in DCM (30 mL) was stirred at room temperature for 30min. Dimethylamine (4.1 mL,2.9mmol,2.5 eq.) was added and stirred for 16h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.4 Methanol in DCM) to give Int-18.1.MS (ES) m/z 262.19[ M+H ] +.
Synthesis of Compound Int-18.2. A mixture of palladium on carbon (10%, 0.800 g) and compound Int-18.1 (1.5 g,5.72mmol,1.0 eq.) in methanol (5 mL) was stirred under hydrogen (1 atm) for 2h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give Int-18.2.MS (ES) m/z 233.21[ M+H ] +.
Synthesis of Compound Int-18.3. To a solution of Int-18.2 (0.900 g,4.58mmol,1.0 eq.) in THF (15 mL) was added lithium aluminum hydride (1.088 g,13.76mmol,5.0 eq.). The mixture was heated to reflux for 1h. It was cooled to room temperature and quenched by stirring with hydrated sodium sulfate powder. It was filtered and washed with ethyl acetate. The organic layer was concentrated under reduced pressure. Through silica gel fast column chromatography2.8% Methanol in DCM) to give Int-18.3.MS (ES) m/z 219.22M+H +.
Synthesis of Compound Int-18. Compound Int-18 was prepared from Int-18.3 following the procedure described in the synthesis of Int-13. Through silica gel fast column chromatography2.4% Methanol in DCM). MS (ES) m/z 261.28[ M+H ] +.
Preparation of intermediate Int-19: (S) -2- ((3-isothiocyanato-5- (trifluoromethyl) phenoxy) methyl) -1-methylpyrrolidine
Synthesis of Compound Int-19.1. To a solution of 1-fluoro-3-nitro-5- (trifluoromethyl) benzene (0.7 g,3.35mmol,1.0 eq.) and tert-butyl (S) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (0.806 g,4.02mmol,1.2 eq.) in DMF (12 mL) was added sodium hydride (0.201 g,5.025mmol,1.5 eq.) and the reaction mixture stirred at room temperature for 30min. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Through silica gel fast column chromatography15-17% Ethyl acetate in hexanes) to give Int-19.1.MS (ES) m/z 391.0[ M+H ] +.
Synthesis of Compound Int-19.2. A mixture of compound Int-19.1 (0.420 g,1.08mmol,1.0 eq.) and 10% palladium on carbon (0.200 g) in methanol (10 mL) was stirred under hydrogen (1 atm) for 2h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure. Through silica gel fast column chromatography20-23% Ethyl acetate in hexanes) to give Int-19.2.MS (ES) m/z 361.2[ M+H ] +.
Synthesis of Compound Int-19.3. To a solution of Int-19.2 (0.270 g,0.749mmol,1.0 eq.) in THF (5 mL) was added lithium aluminum hydride (1M in THF, 5.2mL,5.243mmol,7.0 eq.) at 0deg.C. The reaction mixture was heated to reflux for 30min. It was cooled to room temperature, transferred to ice, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography60-65% Ethyl acetate in hexane) to give Int-19.3.MS (ES) m/z 275.1[ M+H ] +.
Synthesis of Compound Int-19. Compound Int-19 was prepared from Int-19.3 following the procedure described in the synthesis of Int-13. Through silica gel fast column chromatography1.5% Methanol in DCM). MS (ES) m/z 317.2[ M+H ] +.
Preparation of intermediate Int-20: (R) -2- ((3-isothiocyanato-5- (trifluoromethyl) phenoxy) methyl) -1-methylpyrrolidine
Synthesis of Compound Int-20. Compound Int-20 was prepared by following the procedure described in the synthesis of Int-19. Through silica gel fast column chromatography1.5% Methanol in DCM). MS (ES) m/z 317.3[ M+H ] +.
Preparation of intermediate Int-21: (S) -3- (3-isothiocyanato-5- (trifluoromethyl) phenoxy) -1-methylpyrrolidine
Synthesis of Compound Int-21.1. To a solution of 1-fluoro-3-nitro-5- (trifluoromethyl) benzene (1.0 g,4.78mmol,1.0 eq.) and (S) -1-methylpyrrolidin-3-ol (0.580 g,5.74mmol,1.2 eq.) in DMF (10 mL) was added sodium hydride (0.382 g,9.56mmol,2.0 eq.) at 0deg.C and stirred at room temperature for 30min. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Through silica gel fast column chromatography3.0% Methanol in DCM) to give Int-21.1.MS (ES) m/z 291.2[ M+H ] +.
Synthesis of Compound Int-21.2. A mixture of compound Int-21.1 (0.670 g,2.31mmol,1.0 eq.) and 10% palladium on carbon (0.350 g) in methanol (5 mL) was stirred under hydrogen (1 atm) for 1h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give Int-21.1.MS (ES) m/z 261.1[ M+H ] +.
Synthesis of Compound Int-21. Compound Int-21 was prepared from Int-21.2 following the procedure described in the synthesis of Int-13. Through silica gel fast column chromatography2.0% Methanol in DCM). MS (ES) m/z 303.2[ M+H ] +.
Preparation of Compound Int-22: (S) -3- (3-isothiocyanato-5- (trifluoromethyl) phenoxy) -1-methylpyrrolidine
Synthesis of Compound Int-22. The compound Int-22 was prepared by following the procedure described in the synthesis of Int-21. Through silica gel fast column chromatography2.0% Methanol in DCM). MS (ES) m/z 303.2[ M+H ] +.
Preparation of intermediate Int-23: 3- ((3-amino-5- (trifluoromethyl) benzyl) oxy) azetidine-1-carboxylic acid tert-butyl ester
Synthesis of Compound Int-23.1. To a solution of (3-nitro-5- (trifluoromethyl) phenyl) methanol (2.0 g,9.04mmol,1.0 eq.) in THF (30 mL) at 0deg.C was added triphenylphosphine (4.74 g,18.09mmol,2.0 eq.) followed by N-bromosuccinimide (3.22 g,18.09mmol,2.0 eq.). The reaction mixture was stirred at room temperature for 16h. It was transferred to saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography15% Ethyl acetate in hexanes) to give Int-23.1.MS (ES) m/z 285.32[ M+H ] +. /(I)
Synthesis of Compound Int-23.2. To a solution of Int-23.1 (0.800 g,4.62mmol,1.0 eq.) in THF (10 mL) was added NaH (60%, 0.277g,6.93mmol,1.5 eq.) in portions at 0deg.C and stirred for 20min. A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.6 g,5.54mmol,1.2 eq.) in THF (5 mL) was added dropwise at 0deg.C. The reaction mixture was stirred at room temperature for 16h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography20% Ethyl acetate in hexanes) to give Int-23.2.MS (ES) m/z 377.62[ M+H ] +.
Synthesis of Compound Int-23. A mixture of Int-23.2 (0.850 g,2.26mmol,1.0 eq.) and 10% palladium on carbon (0.450 g) in methanol (15 mL) was stirred under hydrogen (1 atm) for 2h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give Int-23.MS (ES) m/z 347.51[ M+H ] +.
Preparation of intermediates Int-24-a and I-24-b: (R) -2- (3-isothiocyanato-5- (trifluoromethyl) phenyl) -1-methylpyrrolidine and (S) -2- (3-isothiocyanato-5- (trifluoromethyl) phenyl) -1-methylpyrrolidine
Synthesis of Compound Int-24.1. A mixture of 3-bromo-5- (trifluoromethyl) aniline (2.5 g,10.42mmol,1.0 eq), (1- (tert-butoxycarbonyl) -1H-pyrrol-2-yl) boronic acid (4.4 g,20.83mmol,2.0 eq) and sodium carbonate (3.31 g,31.26mmol,3.0 eq) in ethylene glycol dimethyl ether (25 mL) was degassed by bubbling a stream of argon for 10 min. Tetrakis (triphenylphosphine) palladium (0) (1.2 g,1.042mmol,0.1 eq.) was added and degassed for 5min. The reaction mixture was stirred at 80℃for 5h. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give Int-24.1.MS (ES) m/z 327.2[ M+H ] +.
Synthesis of compound (+ -) -Int-24.2. A mixture of compound Int-24.1 (2.1 g,6.44mmol,1.0 eq.) and 20% palladium hydroxide (1.0 g) in methanol (20 mL) was stirred under hydrogen (1 atm) for 1h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give (+ -) -Int-24.2.MS (ES) m/z 331.1[ M+H ] +.
Synthesis of compound (+ -) -Int-24.3. To a solution of (+ -) -Int-24.2 (1.37 g,4.15mmol,1.0 eq.) in THF (10 mL) was added lithium aluminum hydride (1M in THF, 29mL,29.05mmol,7.0 eq.) at 0deg.C. The reaction mixture was heated to reflux for 30min. It was cooled to room temperature, transferred to ice, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (+ -) -Int-24.3.MS (ES) m/z 245.1[ M+H ] +. The racemate was subjected to chiral HPLC separation (chromatographic column CHIRALPAK AD-H (250 mm x 21mm,5 μm); mobile phase (a) 0.1% dea in n-hexane (B) 0.1% dea in isopropanol; flow rate = 30 mL/min) to give a first eluted fraction (Int-24.3-a) and a second eluted fraction (Int-24.3-B). MS (ES) m/z 245.1[ M+H ] +.
Synthesis of the Compounds Int-24-a and Int-24-b. The compounds Int-24-a and Int-24-b were prepared from Int-24.3-a and Int-24.4-b, respectively, according to the procedure described in the synthesis of Int-13. Through silica gel fast column chromatography12% Ethyl acetate in hexanes) was purified. MS (ES) m/z 287.2[ M+H ] +.
Preparation of intermediate Int-25: 3- (3-amino-5- (trifluoromethyl) phenoxy) azetidine-1-carboxylic acid tert-butyl ester
Synthesis of Compound Int-25.1. To a solution of 1-fluoro-3-nitro-5- (trifluoromethyl) benzene (1.0 g,4.78mmol,1.0 eq.) in DMF (10 mL) was added sodium hydride (0.313 g,7.17mmol,1.5 eq.) and stirred for 1h at 0deg.C. To the mixture was added 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (1.24 g,7.17mmol,1.5 eq.). The reaction mixture was stirred at room temperature for 2h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography38% Ethyl acetate in hexanes) to give Int-25.1.MS (ES) m/z 363.31[ M+H ] +.
Synthesis of Compound Int-25. A mixture of Int-25.1 (0.700 g,1.93mmol,1.0 eq.) iron powder (0.541 g,9.66mmol,5.0 eq.) and ammonium chloride (0.512 g,9.66mmol,5.0 eq.) in ethanol to water (8:2, 6 mL) was stirred at 80℃for 2h. Passing the reaction mixture throughIs filtered and rinsed with ethanol. The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)63% Ethyl acetate in hexanes) to give Int-25.MS (ES) m/z 333.32[ M+H ] +.
Preparation of intermediate Int-26: 3-isothiocyanato-1- (7-oxaspiro [3.5] nonan-2-yl) -5- (trifluoromethyl) -1H-pyrazole
Synthesis of Compound Int-26.1. To a solution of 4-methylenetetrahydro-2H-pyran (5.0 g,50.95mmol,1.0 eq.) in t-butyl methyl ether (100 mL) was added zinc copper pair (71.73 g,560.45mmol,11.0 eq.) followed by diphosgene (37.10 g,204.08mmol,4.0 eq.) in ethylene glycol dimethyl ether (40 mL) at 0deg.C. The mixture was stirred at room temperature for 18h. Passing it throughIs added to the solution, and the filtrate is washed with sodium bicarbonate solution and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-26.1.MS (ES) m/z 210.0[ M+H ] +.
Synthesis of Compound Int-26.2. A mixture of Int-26.1 (8.9 g,42.58mmol,1.0 eq.) in methanol (200 mL), saturated aqueous ammonium chloride and zinc (27.67 g,425.8mmol,10.0 eq.) was stirred at room temperature for 16h. Passing the reaction mixture throughIs washed with diethyl ether and concentrated under reduced pressure. Through silica gel fast column chromatography30% Ethyl acetate in hexanes) to give Int-26.2.MS (ES) m/z 141.1[ M+H ] +.
Synthesis of Compound Int-26.3. To a solution of Int-26.2 (3.9 g,27.82mmol,1.0 eq.) in methanol (40 mL) was added sodium borohydride (0.308 g,8.34mmol,0.3 eq.) at 0deg.C and stirred at room temperature for 16h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-26.3.MS (ES) m/z 143.1[ M+H ] +.
Synthesis of Compound Int-26.4. To a solution of Int-26.3 (3.0 g,21.1mmol,1.0 eq.) and triethylamine (8.8 mL,63.3mmol,3.0 eq.) in DCM (30 mL) was added methanesulfonyl chloride (2.4 mL,31.65mmol,1.5 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 30min. It was transferred to ice water, stirred, and extracted with DCM. The combined organic layers were washed with saturated sodium bicarbonate, then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-26.4.MS (ES) m/z 221.0[ M+H ] +.
Synthesis of Compound Int-26.5. A mixture of Int-26.4 (2.8 g,12.22mmol,1.0 eq.) 3- (2, 5-dimethyl-1H-pyrrol-1-yl) -5- (trifluoromethyl) -1H-pyrazole (4.04 g,18.32mmol,1.3 eq.) and cesium carbonate (7.94 g,24.44mmol,2.0 eq.) in DMF (15 mL) was stirred at 90℃for 4H. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography4.0% Ethyl acetate in hexane) to give Int-26.5.MS (ES) m/z 354.2[ M+H ] +.
Synthesis of Compound Int-26.6. A solution of Int-26.5 (1.5 g,4.24mmol,1.0 eq.) and hydroxylamine hydrochloride (11.4 g,169.6mmol,40 eq.) in ethanol in water (2:1, 50 mL) was heated at reflux for 3h. It was transferred to ice water and 2N sodium hydroxide was added to adjust the pH to 10. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give Int-26.6.MS (ES) m/z 276.0[ M+H ] +.
Synthesis of Compound Int-26. Compound Int-26 was prepared from Int-26.6 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatographyDCM) purified product. MS (ES) m/z 318.2[ M+H ] +.
Preparation of intermediates Int-27-a and Int-27-b: (R) -2- (4-isothiocyanato-2- (trifluoromethyl) phenyl) -1-methylpyrrolidine and (S) -2- (4-isothiocyanato-2- (trifluoromethyl) phenyl) -1-methylpyrrolidine
Synthesis of Compound Int-27.1. A mixture of 4-bromo-3- (trifluoromethyl) aniline (3.0 g,12.5mmol,1.0 eq), (1- (tert-butoxycarbonyl) -1H-pyrrol-2-yl) boronic acid (3.9 g,18.7mmol,1.5 eq) and sodium carbonate (5.2 g,50.02mmol,4.0 eq) in ethylene glycol dimethyl ether (40 mL) was degassed by bubbling argon for 10 min. Tetrakis (triphenylphosphine) palladium (0) (1.2 g,1.3mmol,0.9 eq.) was added and degassed for 5min. The reaction mixture was stirred at 80℃for 5h. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography8.0% Methanol in DCM) to give Int-27.1.MS (ES) m/z 327.32[ M+H ] +.
Synthesis of compound (+ -) -Int-27.2. A mixture of compound Int-27.1 (1.4 g,4.29mmol,1.0 eq.) and 20% palladium hydroxide (1.0 g) in methanol (38 mL) was stirred under hydrogen (1 atm) for 7h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give (+ -) -Int-27.2.MS (ES) m/z 331.35[ M+H ] +. The racemate was subjected to chiral SFC separation (chromatographic column CHIRALPAK AD-H (250 mm. Times.4.6 mm,5 μm; mobile phase (A) CO 2 (B) 0.1% diethylamine in isopropanol: acetonitrile (50:50; flow rate = 75 mL/min) to give a first eluted fraction (Int-27.2-a) and a second eluted fraction (Int-27.2-B).
Synthesis of Compounds Int-27.3-a and Int-27.3-b. To a solution of Int-27.2-a (0.410 g,1.24mmol,1.0 eq.) in THF (10 mL) was added lithium aluminum hydride (1M in THF, 8.6mL,8.69mmol,7.0 eq.) at 0deg.C. The reaction mixture was heated to reflux for 30min. It was cooled to room temperature and stirred with sodium sulfate decahydrate. The solid was removed by filtration and rinsed with ethyl acetate. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-27.2-a. MS (ES) M/z245.26[ M+H ] +. Int-27.3-b was prepared from Int-27.2-b following the same procedure.
Synthesis of Compounds Int-27-a and Int-27-b. The compound Int-27-a was prepared from Int-27.3-a according to the procedure described in the synthesis of Int-13. Through silica gel fast column chromatography2.1% Methanol in DCM). MS (ES) M/z287.32[ M+H ] +. Int-27-b was prepared from Int-27.3-b in the same manner.
Preparation of intermediate Int-28: 4-isothiocyanato-2- (pyrrolidin-1-yl) -6- (trifluoromethyl) pyridine
Synthesis of Compound Int-28.1. A mixture of 2-chloro-6- (trifluoromethyl) pyridin-4-amine (0.500 g,2.54mmol,1.0 eq.) pyrrolidine (0.271 g,3.82mmol,1.5 eq.) and potassium carbonate (1.05 g,7.62mmol,3.0 eq.) in DMF (5 mL) was stirred at 150℃for 18h. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography20-30% Ethyl acetate in hexanes) to give Int-28.1.MS (ES) m/z 232.5[ M+H ] +.
Synthesis of Compound Int-28. Compound Int-28 was prepared from Int-28.1 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatography5-10% Ethyl acetate in hexane). MS (ES) m/z 274.5[ M+H ] +.
Preparation of intermediate Int-29: 2 '-isothiocyanato-5', 6 '-dihydrospiro [ cyclobutane-1, 4' -pyrrolo [1,2-b ] pyrazole ]
/>
Synthesis of Compound Int-29.1. To a solution of lithium bis (trimethylsilyl) amide (1M in THF, 17.4mL,17.44mmol,2.2 eq.) in anhydrous THF (25 mL) was added a solution of 6-oxaspiro [3.4] octan-5-one (1.0 g,7.93mmol,1.0 eq.) and acetonitrile (0.83 mL,15.86mmol,2.0 eq.) in THF (8 mL) at-78deg.C. The reaction mixture was stirred at-78 ℃ for 30min and allowed to warm to room temperature, stirred for 2h. It was transferred to saturated aqueous ammonium chloride and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel20% Ethyl acetate in hexanes) to give Int-29.1.
Synthesis of Compound Int-29.2. To a solution of Int-29.1 (0.800 g,4.78mmol,1.0 eq.) in ethanol (10 mL) was added hydrazine monohydrate (0.178 g,7.17mmol,1.5 eq.). The reaction mixture was stirred at 60℃for 72h. The reaction mixture was cooled to room temperature and carbon dioxide was bubbled through it for 1h. The reaction mixture was concentrated under reduced pressure. Methanol (15 mL) was added to the residue, stirred, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure to give Int-29.2.MS (ES) m/z 182.1[ M+H ] +.
Synthesis of Compound Int-29.3. To a solution of Int-29.2 (0.610 g,3.37mmol,1.0 eq.) in THF (10 mL) was added thionyl chloride (1.22 mL,16.85mmol,5.0 eq.). The reaction mixture was stirred at room temperature for 3h. It was slowly transferred to a mixture of aqueous ammonium hydroxide and ice, stirred and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel2% Methanol in DCM) to give Int-29.3.MS (ES) m/z 164.1[ M+H ] +.
Synthesis of Compound Int-29. Compound Int-29 was prepared from Int-29.3 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatographyDCM) purified product. MS (ES) m/z 205.9[ M+H ] +.
Preparation of intermediate Int-30: 2 '-isothiocyanato-5' -methyl-6 ',7' -dihydro-5 'H-spiro [ cyclopropane-1, 4' -pyrazolo [1,5-a ] pyrazin ]
Synthesis of Compound Int-30.1. To a solution of Int-8.2 (0.600 g,4.81mmol,1.0 eq.) in toluene (6 mL) was added hexane-2, 5-dione (0.618 g,5.41mmol,1.5 eq.) followed by acetic acid (catalysis) at room temperature. The reaction mixture was stirred at 130℃for 3 hours. It was cooled to room temperature and concentrated under reduced pressure. Through silica gel fast column chromatography0.5% Methanol in DCM) to give Int-30.1.MS (ES) m/z 245[ M+H ] +.
Synthesis of Compound Int-30.2. To a solution of Int-30.2 (0.500 g,2.55mmol,1.0 eq.) in THF (10 mL) was added titanium isopropoxide (1.45 g,5.102mmol,2.0 eq.) followed by ethyl magnesium bromide (1M in THF, 3.4mL,10.2mmol,4.0 eq.) at 80deg.C. The reaction mixture was stirred for 30min. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a material. Through silica gel fast column chromatography15% Ethyl acetate in hexanes) to give Int-30.2.MS (ES) m/z 257[ M+H ] +.
Synthesis of Compound Int-30.3. To a solution of Int-30.3 (0.450 g,1.75mmol,1.0 eq.) in ethanol (8 mL) and water (2 mL) was added hydroxylamine hydrochloride (3.65 g,52.5mmol,30.0 eq.). The reaction mixture was stirred at 60℃for 1h. It was transferred to ice-cold saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to give Int-30.3.MS (ES) m/z 179[ M+H ] +.
Synthesis of Compound Int-30. Compound Int-30 was prepared from Int-30.3 following the procedure described in the synthesis of Int-3. Through silica gel fast column chromatography0.5% Methanol in DCM). MS (ES) m/z 221[ M+H ] +.
Preparation of the provided Compounds
Example 1: (R) -N- (4- ((2- ((5- (tert-butyl) -1- (tetrahydrofuran-3-yl) -1H-pyrazol-3-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methoxyazetidine-1-carboxamide
Synthesis of Compound 1.1. To a solution of benzyl alcohol (17.05 g,157.69mmol,1.0 eq.) in THF (250 mL) at 0deg.C was added sodium hydride (12.61 g,315.38mmol,2.0 eq.). The mixture was stirred for 1h and 2-chloro-4-nitropyridine (25 g,157.69mmol,1.0 eq.) was added in portions. The reaction mixture was stirred at 0 ℃ for 2h. It was poured onto ice, stirred, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography10% Ethyl acetate in hexane as eluent) to give 1.1.MS (ES) m/z 220.13[ M+H ] +.
Synthesis of Compound 1.2. A solution of compound 1.1 (20 g,91.05mmol,1.0 eq.) in THF (200 mL) was degassed by bubbling argon through for 10 min. 2-dicyclohexylphosphino-2 ',4',6' -triisopropylbiphenyl (4.34 g,9.105mmol,0.1 eq.) and tris (dibenzylideneacetone) dipalladium (4.17 g,4.55mmol,0.05 eq.) were added under argon and degassed by bubbling through a stream of argon for 5 min. To the mixture was added a solution of lithium bis (trimethylsilyl) amide (1M in THF, 182.1mmol,2.0 eq.) and stirred at 60 ℃ for 1h. The reaction mixture was cooled to room temperature, poured onto ice water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3% Methanol in DCM as eluent) to give 1.2.MS (ES) m/z 201.2[ M+H ] +.
Synthesis of Compound 1.3. To a solution of 1.2 (2.0 g,9.99mmol,1.0 eq.) and triethylamine (4.2 mL,29.97mmol,3.0 eq.) in THF (20 mL) was added dropwise phenyl chloroformate (4.67 g,29.97mmol,3.0 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 3h. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.1.MS (ES) M/z321.3[ M+H ] +. It was used in the next step without further purification.
Synthesis of Compound 1.4. To a solution of 1.3 (3.0 g,9.36mmol,1.0 eq.) and triethylamine (12.5 mL,84.24mmol,9.0 eq.) in DMF (20 mL) was added dropwise 3-methoxyazetidine (1.06 g,12.17mmol,1.3 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 16h. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give 1.4.MS (ES) m/z 314.3[ M+H ] +.
Synthesis of Compound 1.5. A mixture of compound 1.4 (1.1 g,3.51mmol,1.0 eq.) and 10% palladium on carbon (0.5 g) in methanol (10 mL) was stirred under hydrogen (1 atm) for 3h. Passing it throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 1.5.MS (ES) m/z 224.2[ M+H ] +.
Synthesis of Compound 1.6. A mixture of 1.5 (0.760 g,3.4mmol,1.0 eq.) in DMF (10 mL), int-1 (0.699 g,4.09mmol,1.2 eq.) and sodium carbonate (0.720 g,6.8mmol,2.0 eq.) was stirred at 90℃for 12h. It was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.8% Methanol in DCM) to give 1.6.MS (ES) m/z 375.3[ M+H ] +.
Synthesis of Compound 1.7. To a solution of 1.6 (0.700 g,1.87mmol,1.0 eq.) in ethanol-water (2:1, 10 mL) was added iron powder (0.733 g,13.09mmol,7.0 eq.) followed by ammonium chloride (0.706 g,13.09mmol,7.0 eq.). The reaction mixture was stirred at 90℃for 3h. It was poured into ice water, filtered, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.5% Methanol in DCM) to give 1.6.MS (ES) m/z 345.5[ M+H ] +.
Synthesis of Compound 1.8. To a solution of 1.7 (0.400 g,1.16mmol,1.0 eq.) in THF (5 mL) was added 1,1' -thiocarbonyldiimidazole (1.03 g,5.8mmol,5.0 eq.). The reaction mixture was stirred at 70℃for 1h. It was cooled to room temperature and poured into ice water. The precipitated solid was collected by filtration and triturated with hexane to give 1.8.MS (ES) m/z 387.4[ M+H ] +.
Synthesis of Compound 1.9. To a solution of 1.8 (0.350 g, 0.015 mmol,1.0 eq.) in DCM (5 mL) was added sulfonyl chloride (2.7 mL,33.48mmol,37 eq.) and stirred for 10min at 0deg.C. It was transferred to saturated sodium bicarbonate solution, stirred, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.4% Methanol in DCM) to give 1.9.MS (ES) m/z 389.8[ M+H ] +.
Synthesis of Compound 1. 1.9 A mixture of (0.080 g,0.205mmol,1.0 eq), int-3 (0.052 g,0.246mmol,1.2 eq.) and potassium carbonate (0.070 g,0.512mmol,2.5 eq.) in 1, 4-dioxane (2 mL) was degassed by bubbling a stream of argon for 10 min. 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthine (0.023 g,0.041mmol,0.2 eq.) and tris (dibenzylideneacetone) dipalladium (0) (0.01 g,0.021mmol,0.1 eq.) were added and degassed for a further 5min. The reaction mixture was stirred at 80℃for 3h. It was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.0% Methanol in DCM) to give the compound 1.MS(ES):m/z:562.6[M+H]+,1H NMR(DMSO-d6,400MHz):δ9.89(s,1H),9.20(s,1H),8.11-8.10(d,J＝5.6Hz,1H),7.96-7.95(d,J＝2.4Hz,1H),7.63-7.62(d,J＝2.4Hz,1H),7.47(bs,1H),6.60-6.58(m,2H),5.77(s,1H),5.26(bs,1H),4.13-4.07(m,5H),3.88-3.83(m,2H),3.75-3.73(m,2H),3.68(s,3H),3.19(s,3H),2.27-2.24(m,1H),1.41(s,9H).
Example 3: (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of Compound 3.1. A mixture of benzyl alcohol (102.3 g,946.13mmol,1.0 eq.) and cesium carbonate (768.7 g,2365.3mmol,2.5 eq.) in DMF (1000 mL) was stirred at room temperature for 2h. A solution of 2-chloro-4-nitropyridine (150 g,946.13mmol,1.0 eq.) in DMF (500 mL) was added and stirred for 16h. It was poured into ice water, stirred, and the precipitated solid was collected by filtration and dried in vacuo to give 3.1.MS (ES) m/z 220.5[ M+H ] +.
Synthesis of Compound 3.2. 3.1 A solution of (150 g,682.85mmol,1.0 eq.) in THF (1500 mL) was degassed by bubbling through a stream of argon for 10min. 2-dicyclohexyl [2',4',6 '-tris (propan-2-yl) [1,1' -biphenyl ] -2-yl ] phosphine (32.55 g,68.28mmol,0.1 eq.) and tris (dibenzylideneacetone) dipalladium (0) (31.26 g,34.14mmol,0.05 eq.) were added to the solution and degassed for an additional 10min. A solution of lithium bis (trimethylsilyl) amide (1M in THF, 1365mL,1365.7mmol,2.0 eq.) was added and the reaction mixture stirred at 60℃for 1h. It was concentrated under reduced pressure. The residue was slowly added to ice and 6N hydrochloric acid (1500 mL) and extracted with ethyl acetate. The aqueous layer was separated, neutralized with solid sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3.2.MS (ES) m/z 201.2[ M+H ] +. It was used in the next step without purification.
Synthesis of Compound 3.3. To a solution of 3.2 (100 g,499mmol,1.0 eq.) in methanol (1000 mL) was added di-tert-butyl dicarbonate (130.5 g,598.8mmol,1.2 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 3h. After the reaction was completed, the precipitated solid was filtered off, washed with methanol, and dried in vacuo to give 3.3.MS (ES) m/z 259.2[ M+H ] +.
Synthesis of Compound 3.4. A mixture of 3.3 (106 g,410.4mmol,1.0 eq.) and 10% palladium on carbon (100 g) in methanol (1000 mL) was stirred under hydrogen (1 atm) for 1h. Passing it throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 3.4.MS (ES) m/z 169.1[ M+H ] +.
Synthesis of Compound 3.5. To a solution of 3.4 (66 g,392.5mmol,1.0 eq.) in DMF (660 mL) was added Int-2 (64.55 g,314mmol,0.8 eq.) followed by sodium carbonate (124.8 g,1177.5mmol,3.0 eq.). The reaction mixture was stirred at 60℃for 3h. It was poured into ice water and the precipitated solid was collected by filtration and dried in vacuo to give 3.5.MS (ES) m/z 354.5[ M+H ] +.
Synthesis of Compound 3.6. Compound 3.6 was prepared from compound 3.5 following the procedure described in the synthesis of compound 1.7. Through silica gel fast column chromatography7.0% Methanol in DCM) to give 3.6.MS (ES) m/z 324.5[ M+H ] +.
Synthesis of Compound 3.7. To a solution of 3.6 (38 g,117.38mmol,1.0 eq.) and Int-5 (41.23 g,176mmol,1.5 eq.) in THF (1300 mL) was added potassium tert-butoxide (1M in THF, 704mL,704.28mmol,6.0 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 1h. It was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography12% Methanol in DCM) to give 3.7.MS (ES) m/z 524.2[ M+H ] +.
Synthesis of Compound 3.8. To a solution of 3.7 (0.500 g,0.954mmol,1.0 eq.) in DMA (11 mL) was added zinc (0.012 g,0.190mmol,0.2 eq.) and zinc cyanide (0.056 g,0.477mmol,0.5 eq.). The reaction mixture was degassed by bubbling through a stream of argon for 10 min. Tris (dibenzylideneacetone) dipalladium (0) (0.131 g,0.143mmol,0.15 eq.) and 1,1' -bis (diphenylphosphino) ferrocene (0.158 g, 0.284 mmol,0.3 eq.) were added and degassed for 5min. The reaction mixture was stirred in a microwave reactor at 190 ℃ for 2h. It was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a material.
Synthesis of I-3. To a solution of 3.8 (9.6 g,21.03mmol,1.0 eq.) in THF (200 mL) at 0deg.C was added triethylamine (5.9 mL,42.06mmol,2.0 eq.) followed by methyl chloroformate (1.8 mL,23.13mmol,1.1 eq.). The reaction mixture was stirred at room temperature for 4h. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.4% Methanol in DCM) to give the residue I-3.MS(ES):m/z:515.2[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.41(s,1H),9.07(s,1H),8.66(s,1H),8.34(s,1H),8.23-8.21(d,J＝6.8Hz 2H),7.49(s,1H),6.76-6.75(d,J＝5.2Hz 1H),3.98(s,3H),3.68(s,3H),3.64(s,3H)./>
Example 4:3- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -1, 1-dimethylurea
Synthesis of I-4. To a solution of 3.8 (0.040 g,0.087mmol,1.0 eq.) and dimethylcarbamoyl chloride (0.010g, 0.096mmol,1.1 eq.) in THF (2 mL) was added potassium tert-butoxide (1M in THF) (0.52 mL,0.522mmol,6.0 eq.) at 0deg.C and stirred at the same temperature for 15min. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give I-4.MS(ES):m/z:528.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ9.04-9.03(d,J＝6.8Hz 2H),8.66(s,1H),8.31(s,1H),8.19(s,1H),8.17(s,1H),7.48(s,1H),6.69(bs,1H),3.97(s,3H),3.67(s,3H),2.90(s,6H).
Example 5:1- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methylurea
Synthesis of I-5. To a solution of 3.8 (0.040 g,0.087mmol,1.0 eq.) and methylcarbamoyl chloride (0.009 g,0.105mmol,1.2 eq.) in THF (2 mL) was added potassium tert-butoxide (1M in THF) (0.35 mL,0.348mmol,4.0 eq.) at 0deg.C and stirred at the same temperature for 15min. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography4.5% Methanol in DCM) to give the residue I-5.MS(ES):m/z:514.2[M+H]+.1H NMR(DMSO-d6,400MHz):δ9.21(s,1H),9.07(s,1H),8.66-8.65(d,J＝1.6Hz,1H),8.32(s,1H),8.20(s,1H),8.14-8.13(d,J＝6.0Hz,1H),7.80(bs,1H),7.09-7.07(d,J＝7.2Hz,1H),7.04(s,1H),3.98(s,3H),3.67(s,3H),2.70-2.69(d,3H).
Example 6: n- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -4-methylpiperazine-1-carboxamide
Synthesis of Compound 6.1. To a solution of 3.8 (0.025 g,0.054mmol,1.0 eq.) and triethylamine (0.016 g,0.162mmol,3.0 eq.) in THF (3 mL) at 0deg.C was added phenyl chloroformate (0.012 g,0.081mmol,1.5 eq.). The reaction mixture was stirred at 0℃for 15min. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6.1.MS (ES) m/z 577.4[ M+H ] +.
Synthesis of I-6. To a solution of 6.1 (0.030 g,0.052mmol,1.0 eq.) and triethylamine (0.015 g,0.156mmol,3.0 eq.) in dimethyl sulfoxide (3 mL) was added 1-methylpiperazine (0.008 g,0.078mmol,1.5 eq.). The reaction mixture was stirred at 80℃for 15min. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography7.0% Methanol in DCM) to give the residue I-6.MS(ES):m/z:583.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ9.37(s,1H),9.06(s,1H),8.67(s,1H),8.32(s,1H),8.20(bs,2H),7.47(s,1H),6.70(s,1H),3.98(s,3H),3.68(s,3H),3.43(bs,4H),2.45(bs,4H),2.29(s,3H).
Example 7: n- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) azetidine-1-carboxamide
Synthesis of I-7. Compound I-7 was prepared from 6.1 and azetidine hydrochloride according to the procedure described in the synthesis of I-6. Purification of the product by preparative HPLC .MS(ES):m/z:540.4[M+H]-.1H NMR(DMSO-d6,400MHz):δ9.23(s,1H),9.06(s,1H),8.66(s,1H),8.31(s,1H),8.20(bs,1H),8.18-8.17(d,J＝6Hz,1H),7.58(s,1H),6.68(s,1H),3.98(s,3H),3.95(bs,4H),3.67(s,3H),2.16-2.12(m,2H).
Example 8: n- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-hydroxyazetidine-1-carboxamide
Synthesis of I-8. Compound I-8 was prepared from 6.1 and azetidine-3-ol hydrochloride according to the procedure described in the synthesis of I-6. Through silica gel fast column chromatography3.0% Methanol in DCM) purification of the product .MS(ES):m/z:556.3[M+H]-,1H NMR(DMSO-d6,400MHz):δ9.29(s,1H),9.05(s,1H),8.66(s,1H),8.31(s,1H),8.20(bs,1H),8.18-8.17(d,J＝5.6Hz,1H),7.58(bs,1H),6.69-6.67(m,1H),5.63-5.62(d,J＝6.4Hz,1H),4.40-4.38(m,1H),4.14-4.11(m,2H),3.97(s,3H),3.67(s,3H),3.19-3.17(m,2H).
Example 9: n- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methoxyazetidine-1-carboxamide
Synthesis of I-9. Compound I-9 was prepared from 6.1 and 3-methoxyazetidine hydrochloride according to the procedure described in the synthesis of I-6. Through silica gel fast column chromatography3.0% Methanol in DCM) purification of the product .MS(ES):m/z:570.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ9.38(s,1H),9.05(s,1H),8.66(s,1H),8.32(s,1H),8.19-8.18(m,2H),7.57(bs,1H),6.69(bs,1H),4.14(bs,4H),3.98(s,3H),3.76(bs,1H),3.68(s,3H),3.20(s,3H).
Example 10: (4- ((2- ((1- (2-oxaspiro [3.3] heptan-6-yl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) amino) -7-chloro-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of Compound 10.1. To a solution of 3.6 (8.0 g,24.71mmol,1.0 eq.) in THF (80 mL) was added 1,1' -thiocarbonyldiimidazole (21.99 g,123.5mmol,5.0 eq.). The reaction mixture was stirred at 70℃for 1h. It was cooled to room temperature and poured into ice water. The precipitated solid was collected by filtration and triturated with hexane to give 10.1.MS (ES) m/z 332.2[ M+H ] +.
Synthesis of Compound 10.2. To a solution of 10.1 (2.0 g,5.47mmol,1.0 eq.) in DCM (20 mL) was added sulfonyl chloride (16.4 mL,202.39mmol,37 eq.) at 0deg.C and the reaction mixture was stirred for 10min. It was transferred to saturated sodium bicarbonate solution, stirred, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.3% Methanol in DCM) to give 10.2.MS (ES) m/z 369.1[ M+H ] +.
Synthesis of I-10. 10.2 A mixture of (0.050 g,0.135mmol,1.0 eq.) and Int-6 (0.043 g,0.176mmol,1.3 eq.) and cesium carbonate (0.131 g,0.405mmol,3.0 eq.) in 1, 4-dioxane (2 mL) was degassed by bubbling a stream of argon for 10 min. 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthine (0.015 g,0.027mmol,0.2 eq.) and tris (dibenzylideneacetone) dipalladium (0) (0.012 g,0.013mmol,0.1 eq.) were added and degassed for 5min. The reaction mixture was stirred at 110℃for 2h. It was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.0% Methanol in DCM) to give the residue I-10.MS(ES):m/z:579.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.58(s,1H),10.32(s,1H),8.15(bs,2H),7.36(s,1H),7.31(s,1H),6.65-6.64(d,J＝3.6Hz,1H),4.88-4.82(m,1H),4.70(bs,2H),4.58(bs,2H),3.96(s,3H),3.60(s,3H),2.81(bs,4H).
Example 11: n- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) pyrrolidin-1-carboxamide
Synthesis of I-11. Compound I-11 was prepared from 6.1 and pyrrolidine following the procedure described in the synthesis of I-6. Through silica gel fast column chromatography3.2% Methanol in DCM) purification of the product .MS(ES):m/z:554.3[M+H]+.1H NMR(DMSO-d6,400MHz):δ9.05(s,1H),8.85(s,1H),8.67-8.66(d,J＝2.0Hz,1H),8.32(s,1H),8.20-8.18(m,2H),7.57(bs,1H),6.70-6.69(d,J＝3.2Hz,1H),3.98(s,3H),3.68(s,3H),2.47(bs,4H),1.82(bs,4H).
Example 12: 2-methoxyethyl (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamate
Synthesis of I-12. A solution of 6.1 (0.110 g,0.190mmol,1.0 eq), 2-methoxyethane-1-ol (0.022 g, 0.284 mmol,1.5 eq) and triethylamine (0.115 g,1.14mmol,6.0 eq) in dimethyl sulfoxide (5 mL) was stirred at 100deg.C for 16h. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.5% Methanol in DCM) to give the residue I-12.MS(ES):m/z:559.2[M+H]-,1H NMR(DMSO-d6,400MHz):δ10.41(s,1H),9.06(s,1H),8.66(s,1H),8.34(s,1H),8.22-8.21(m,2H),7.47(bs,1H),6.76-6.75(d,J＝2.8Hz,1H),4.19(bs,2H),3.98(s,3H),3.68(s,3H),3.53(bs,2H),3.27(s,3H).
Example 13: (R) -N- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methoxypyrrolidine-1-carboxamide
Synthesis of I-13. Compound I-13 was prepared from 6.1 and (R) -3-methoxypyrrolidine according to the procedure described in the synthesis of I-6. Through silica gel fast column chromatography4.7% Methanol in DCM) purification of the product .MS(ES):m/z:584.3[M+H]-,1H NMR(DMSO-d6,400MHz):δ9.04(s,1H),8.94(s,1H),8.65(s,1H),8.31(s,1H),8.19-8.17(m,2H),7.55-7.54(d,J＝2.0Hz,1H),6.70-6.68(m,1H),3.96(s,3H),3.66(s,3H),3.46(bs,2H),3.38(bs,1H),3.21(s,3H),2.54(bs,2H),1.93(bs,2H).
Example 14: (S) -N- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methoxypyrrolidine-1-carboxamide
Synthesis of I-14. Compound I-14 was prepared from 6.1 and (S) -3-methoxypyrrolidine according to the procedure described in the synthesis of I-6. Through silica gel fast column chromatography4.9% Methanol in DCM) purification of the product .MS(ES):m/z:584.3[M+H]-,1H NMR(DMSO-d6,400MHz):δ9.04(s,1H),8.94(s,1H),8.65(s,1H),8.31(s,1H),8.18-8.17(m,2H),7.54(z,1H),6.69-6.68(m,1H),3.96(s,3H),3.66(s,3H),3.46(bs,2H),3.39(bs,1H),3.21(s,3H),2.54(bs,2H),1.93(bs,2H).
Example 15: (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid 2-morpholinoethyl ester
Synthesis of I-15. Compound I-15 was prepared from 6.1 and 2-morpholinoethane-1-ol following the procedure described in the synthesis of I-6. Through silica gel fast column chromatography2.5% Methanol in DCM) purification of the product .MS(ES):m/z:614.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.37(s,1H),9.06(s,1H),8.65(s,1H),8.33(s,1H),8.19(bs,2H),7.45(s,1H),6.74(s,1H),4.16(bs,2H),3.96(s,3H),3.66(s,3H),3.53(bs,4H),2.40(bs,6H).
Example 16: oxetan-3-yl (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamate
Synthesis of I-16. Compound I-16 was prepared from 6.1 and oxetan-3-ol according to the procedure described in the synthesis of I-6. Through silica gel fast column chromatography2.7% Methanol in DCM) purification of the product .MS(ES):m/z:557.2[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.63(s,1H),9.05(s,1H),8.65(s,1H),8.32(s,1H),8.23-8.22(d,J＝5.6Hz,1H),8.19(s,1H),7.40(s,1H),6.78(bs,1H),5.36(bs,1H),4.77-4.75(m,2H),4.50(bs,2H),3.96(s,3H),3.66(s,3H).
Example 17: (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid (S) -tetrahydrofuran-3-yl ester
Synthesis of I-17. Compound 6.1 (0.110 g,0.190mmol,1.0 eq.) and (S) -tetrahydrofuran-3-ol (0.084 g,0.954mmol,5.0 eq.) in triethylamine (1.0 mL) are stirred at 110℃for 6h. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.2% Methanol in DCM) to give the residue I-17.MS(ES):m/z:571.3[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.37(s,1H),9.06(s,1H),8.65(s,1H),8.33(s,1H),8.21-8.20(m,2H),7.43(s,1H),6.76-6.75(d,J＝4.0Hz,1H),5.20(bs,1H),3.96(s,3H),3.78-3.72(m,4H),3.66(s,3H),2.16-2.10(m,1H),1.92-1.89(m,1H).
Example 18: (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid (R) -tetrahydrofuran-3-yl ester
Synthesis of I-18. Compound I-18 was prepared from 6.1 and (R) -tetrahydrofuran-3-ol according to the procedure described in the synthesis of I-17. Through silica gel fast column chromatography3.2% Methanol in DCM) purification of the product .MS(ES):m/z:571.3[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.38(s,1H),9.07(s,1H),8.67(s,1H),8.34(s,1H),8.22-8.21(m,2H),7.45(s,1H),6.77(bs,1H),5.21(bs,1H),3.98(s,3H),3.79-3.70(m,4H),3.68(s,3H),2.15-2.11(m,1H),1.92(bs,1H).
Example 19: (4- ((7-chloro-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid 2- (dimethylamino) ethyl ester
Synthesis of Compound 19.1. A solution of 1.3 (0.400 g,1.25mmol,1.0 eq), triethylamine (0.87 mL,6.25mmol,5.0 eq.) and 2- (dimethylamino) ethan-1-ol (0.166 g,1.87mmol,1.5 eq.) was stirred at 70℃for 30min. It was transferred to water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.0% Methanol in DCM) to give 19.1.MS (ES) m/z 316.3[ M+H ] +.
Synthesis of Compound 19.2. A mixture of compound 19.1 (0.230 g,0.729mmol,1.0 eq.) and 10% palladium on carbon (0.200 g) in methanol (5 mL) was stirred under hydrogen (1 atm) for 30min. Passing it throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 19.2.MS (ES) m/z 226.1[ M+H ] +. /(I)
Synthesis of Compound 19.3. A mixture of 19.2 (0.150 g, 0.661mmol, 1.0 eq), int-2 (0.109 g, 0.284 mmol,0.8 eq.) and potassium carbonate (0.275 g,1.995mmol,3.0 eq.) in DMF (5 mL) was stirred at room temperature for 1.5h. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography7.0% Methanol in DCM) to give 19.3.MS (ES) m/z 411.5[ M+H ] +.
Synthesis of Compound 19.4. Compound 19.4 was prepared from 19.3 following the procedure described in the synthesis of compound 3.6. Through silica gel fast column chromatography9.0% Methanol in DCM). MS (ES) m/z 381.5[ M+H ] +.
Synthesis of I-19. To a solution of 19.4 (0.080 g,0.210mmol,1.0 eq.) in THF (3.0 mL) at 0deg.C was added Int-5 (0.098 g,0.420mmol,2.0 eq.) followed by potassium tert-butoxide (1M in THF, 0.63mL,0.630mmol,3.0 eq.). The reaction mixture was stirred at 0℃for 30min. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF (3.0 mL) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.120 g,0.630mmol,3.0 eq.) was added. The reaction mixture was stirred at 70℃for 1.5h. It was transferred to water and the product extracted with ethyl acetate. Subjecting the product to silica gel flash column chromatography10% Methanol in DCM) to yield I-19.MS(ES):m/z:581.2[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.31(s,1H),8.87(s,1H),8.63(s,1H),8.25(s,1H),8.16(bs,2H),7.36(s,1H),6.67(bs,1H),4.17(bs,2H),3.99(s,3H),3.66(s,3H),3.52-3.45(m,2H),2.30(bs,6H).
Example 20: (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid 2-hydroxyethyl ester
Synthesis of Compound 20.1. To a solution of 2- (benzyloxy) ethane-1-ol (0.063 g,0.416mmol,1.0 eq.) in DMF (5 mL) was added sodium hydride (0.049 g,1.248mmol,3.0 eq.) and stirred for 30min at 0deg.C. To the mixture was added 6.1 (0.200 g,0.346mmol,1.0 eq.) and stirred at room temperature for 30min. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a material. Passing through silica gel flash column chromatography2.2% Methanol in DCM) to give 20.1.MS (ES) m/z 635.4[ M+H ] +.
Synthesis of I-20. To a solution of 20.1 (0.040 g,0.063mmol,1.0 eq.) in DCM (3 mL) was added trifluoromethanesulfonic acid (1 mL) and stirred for 10min at 0deg.C. It was transferred to ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.0% Methanol in DCM) to give the residue I-20.MS(ES):m/z:545.2[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.63(s,1H),8.99(s,1H),8.60(s,1H),8.27(s,1H),8.14(bs,2H),7.41(s,1H),6.68(bs,1H),4.74(s,1H),4.02(bs,2H),3.91(s,3H),3.61(s,3H),3.51(bs,2H).
Example 21:3- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -1, 1-dimethylurea
Synthesis of Compound 21.1. To a solution of 3, 5-difluoropyridin-2-amine (10 g,76.87mmol,1.0 eq.) in THF (200 mL) was added n-butyllithium (2.5M in hexane) (61.4 mL,153.7mmol,2.0 eq.) and stirred for 40min at-78 ℃. Hexachloroethane (36.3 g,153.7mmol,2.0 eq.) was added and the reaction mixture stirred at-78 ℃ for 40min. Saturated aqueous ammonium chloride was carefully added to quench the reaction. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography12% Ethyl acetate in hexane) to give 21.1. 1H NMR(DMSO-d6 400 MHz): delta 7.98-7.94 (m, 1H), 6.48 (bs, 2H).
Synthesis of Compound 21.2. Concentrated sulfuric acid (3 mL) was added dropwise to potassium persulfate (2.05 g,7.6mmol,2.5 eq.) at room temperature and stirred for 15min. 21.1 (0.5 g,3.04mmol,1.0 eq.) was added in small portions to the mixture while maintaining the temperature in the range of 30-40 ℃. After the addition, the reaction mixture was stirred at room temperature for 3-4h. It was poured onto crushed ice, stirred, basified with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2-3% Ethyl acetate in hexane) to give 21.2. 1H NMR(DMSO-d6 400 MHz): delta 8.78 (s, 1H).
Synthesis of Compound 21.3. To a solution of 21.2 (0.970 g,4.99mmol,1.0 eq.) in acetonitrile (10 mL) was added dropwise aqueous methylamine (40%) (0.8 mL,9.98mmol,2.0 eq.) at 0deg.C. The reaction mixture was allowed to warm to room temperature and stirred for 20min. It was poured onto ice water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography10% Ethyl acetate in hexane) to give 21.3. 1HNMR(DMSO-d6 400 MHz): delta 7.98 (s, 1H), 7.05 (bs, 1H), 2.79 (d, 3H).
Synthesis of Compound 21.4. A mixture of 21.3 (0.930 g,4.52mmol,1.0 eq.) N- (4-hydroxypyridin-2-yl) acetamide (0.895 g,5.88mmol,1.3 eq.) and sodium carbonate (0.958 g,9.04mmol,2.0 eq.) in DMF (10 mL) was stirred at 50deg.C for 6h. The reaction mixture was cooled to room temperature and poured onto ice water. The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 21.4.MS (ES) m/z 338.7[ M+H ] +.
Synthesis of Compound 21.5. To a solution of compound 21.4 (0.850 g,2.52mmol,1.0 eq.) in ethanol-water (8:2, 10 mL) was added iron powder (0.705 g,12.6mmol,5.0 eq.) followed by ammonium chloride (0.673 g,12.6mmol,5.0 eq.). The reaction mixture was stirred at 80℃for 2h. Passing it throughIs filtered and rinsed with ethanol. The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)2.4% Methanol in dichloromethane) to give 21.5.MS (ES) m/z 308.5[ M+H ] +.
Synthesis of Compound 21.6. Compound 21.6 was prepared from 21.5 and Int-7 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatography3.0% Methanol in DCM). MS (ES) m/z 489.6[ M+H ] +.
Synthesis of Compound 21.7. To a solution of 21.6 (0.230 g,0.470mmol,1.0 eq.) in DMA (5 mL) was added zinc (0.006g, 0.094mmol,0.2 eq.) and zinc cyanide (0.275 g,2.35mmol,5.0 eq.). The reaction mixture was degassed by bubbling through a stream of argon for 10 min. Tris (dibenzylideneacetone) dipalladium (0) (0.030 g,0.032mmol,0.07 eq.) and 1,1' -bis (diphenylphosphino) ferrocene (0.039 g,0.070mmol,0.15 eq.) were added and degassed for 5min. The reaction mixture was stirred in a microwave reactor at 210 ℃ for 1h. It was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography4.5% Methanol in DCM as eluent) to give 21.7.MS (ES) m/z 438.2[ M+H ] +.
Synthesis of I-21. To a solution of 21.7 (0.050 g,0.114mmol,1.0 eq.) in THF (2 mL) was added dimethylcarbamoyl chloride (0.013 g,0.125mmol,1.1 eq.) followed by potassium tert-butoxide (1M in THF) (0.57 mL,0.57mmol,5.0 eq.) and stirred at the same temperature for 15min. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by preparative HPLC to give I-21.MS(ES):m/z:509.3[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.69(s,1H),9.01(s,1H),8.19(s,1H),8.16-8.15(d,J＝6.0Hz,1H),7.45(s,1H),7.10(s,1H),6.66-6.65(d,J＝3.6Hz,1H),4.16(bs,2H),3.92(s,3H),2.89(s,6H),2.69-2.67(m,2H),2.19(bs,2H).
Example 22: (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of I-22. To a solution of 21.7 (0.050 g,0.114mmol,1.0 eq.) and triethylamine (0.023 g,0.228mmol,2.0 eq.) in THF (2 mL) was added methyl chloroformate (0.01 g,0.125mmol,1.1 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 4h. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by preparative HPLC to give I-22.MS(ES):m/z:496.2[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.72(s,1H),10.43(s,1H),8.22-8.21(d,J＝2.4Hz,1H),8.19(s,1H),7.43(s,1H),7.08(s,1H),6.74-6.73(m,1H),4.16(bs,2H),3.92(s,3H),3.63(s,3H),2.45(bs,2H),2.19(bs,2H).
Example 23: n- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) pyrrolidine-1-carboxamide
Synthesis of I-23. To a solution of 21.7 (0.050 g,0.114mmol,1.0 eq.) and triethylamine (0.034 g, 0.348 mmol,3.0 eq.) in THF (3 mL) at 0deg.C was added phenyl chloroformate (0.027 g,0.171mmol,1.5 eq.). The reaction mixture was stirred for 15min, then pyrrolidine (0.040 g,0.57mmol,5.0 eq.) was added. The reaction mixture was stirred at 50℃for 15min. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography4.5% Methanol in DCM) to give the residue I-23.MS(ES):m/z:535.4[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.67(s,1H),8.80(s,1H),8.19(s,1H),8.16-8.15(d,J＝5.6Hz,1H),7.54(s,1H),7.09(s,1H),6.83-6.81(d,J＝7.2Hz,1H),4.16(bs,2H),3.93(s,3H),3.39-3.33(m,4H),1.92-1.84(m,4H),1.80-1.76(m,4H).
Example 24: n- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -4-methylpiperazine-1-carboxamide
Synthesis of Compound 24.1. To a solution of 21.7 (0.080 g,0.182mmol,1.0 eq.) and triethylamine (0.055 g, 0.540 mmol,3.0 eq.) in THF (3 mL) was added phenyl chloroformate (0.042 g,0.274mmol,1.5 eq.) at 0deg.C. The reaction mixture was stirred for 15min. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 24.1.MS (ES) m/z 558.4[ M+H ] +.
Synthesis of I-24. To a solution of 24.1 (0.090 g,0.161mmol,1.0 eq.) and triethylamine (0.097 g,0.966mmol,6.0 eq.) in dimethyl sulfoxide (3 mL) was added N-methylpiperazine (0.024 g,0.242mmol,1.5 eq.). The reaction mixture was stirred at 90℃for 15min. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography7.5% Methanol in DCM) to give the residue I-24.MS(ES):m/z:562.5[M-H]+.1H NMR(DMSO-d6,400MHz):δ10.67(s,1H),9.33(s,1H),8.19-8.18(d,J＝4.0Hz,1H),8.17(s,1H),7.45(s,1H),7.10(s,1H),6.84(bs,1H),4.17(bs,2H),3.93(s,3H),3.43(bs,4H),2.31(bs,4H),2.20(s,3H),1.56(bs,2H),1.25(bs,2H).
Example 25: n- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) morpholine-4-carboxamide
Synthesis of I-25. Compound I-25 was prepared from 24.1 and morpholine following the procedure for the synthesis of I-24. Through silica gel fast column chromatography3.0% Methanol in DCM) purification of the product .MS(ES):m/z:551.3[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.68(s,1H),9.36(s,1H),8.19-8.18(d,J＝4.0Hz,1H),8.16(s,1H),7.09(s,1H),7.06(s,1H),6.83(bs,1H),4.16(bs,2H),3.92(s,3H),3.55(bs,4H),3.40(bs,4H),1.55(bs,2H),1.23(bs,2H).
Example 26: n- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methoxyazetidine-1-carboxamide
Synthesis of I-26. Compound I-26 was prepared from 24.1 and 3-methoxyazetidine hydrochloride following the procedure for the synthesis of I-24. Through silica gel fast column chromatography3.2% Methanol in DCM) purification of the product .MS(ES):m/z:551.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.73(s,1H),10.05(s,1H),8.26(bs,1H),7.32(s,1H),7.08(s,1H),6.96(s,1H),6.84(s,1H),4.18(bs,4H),3.96(bs,2H),3.94(s,3H),3.82(s,3H),3.74(bs,1H),2.21(bs,2H),1.56(bs,2H).
Example 27:1- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methylurea
Synthesis of I-27. Compound I-27 was prepared from 21.7 and methylamine according to the synthetic procedure for I-23. Through silica gel fast column chromatography4.0% Methanol in DCM) purification of the product .MS(ES):m/z:495.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.67(s,1H),8.80(s,1H),8.19(s,1H),8.16-8.15(d,J＝5.6Hz,1H),7.54(s,1H),7.09(s,1H),6.83(bs,1H),6.66-6.65(d,J＝3.6Hz,1H),4.16(bs,2H),3.93(s,3H),3.38(s,3H),2.19(bs,2H),1.89-1.87(m,2H).
Example 28: (R) -N- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-hydroxypyrrolidine-1-carboxamide
Synthesis of I-28. Compound I-28 was prepared from 21.7 and (R) -pyrrolidin-3-ol following the synthetic procedure of I-23. Through silica gel fast column chromatography3.4% Methanol in DCM) purification of the product .MS(ES):m/z:551.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.68(s,1H),8.86(s,1H),8.20-8.16(m,2H),7.54(s,1H),7.10(s,1H),6.84(s,1H),5.36(s,1H),4.95(bs,2H),4.26(bs,1H),4.11(bs,2H),4.00(bs,2H),3.94(s,3H),2.20(bs,2H),1.56(bs,4H).
Example 29: (S) -N- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-hydroxypyrrolidine-1-carboxamide
Synthesis of I-29. Compound I-29 was prepared from 21.7 and (S) -pyrrolidin-3-ol following the synthetic procedure of I-23. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:551.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.69(s,1H),8.86(s,1H),8.20-8.16(m,2H),7.54(s,1H),7.11(s,1H),6.84(s,1H),5.36(s,1H),4.95(bs,2H),4.26(s,1H),4.11(bs,2H),4.00(bs,2H),3.94(s,3H),2.20(bs,2H),1.56(bs,4H).
Example 30:6- ((2-Aminopyridin-4-yl) oxy) -2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridine-7-carbonitrile
Synthesis of I-30. Compound I-30 was prepared from 21.7 and azetidine following the procedure for the synthesis of I-23. Through silica gel fast column chromatography4.0% Methanol in DCM). MS (ES) m/z 521.4[ M+H ] +. LCMS purity: 98.49% HPLC purity ：96.93％,1H NMR(DMSO-d6,400MHz):δ10.69(s,1H),9.18(s,1H),8.18(s,1H),8.15(bs,1H),7.55(s,1H),7.09(s,1H),6.23(bs,1H),4.16(bs,2H),3.95(bs,4H),3.92(s,3H),2.19-2.13(m,6H).
Example 31: (4- ((2- ((1- (2-oxaspiro [3.3] heptan-6-yl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) amino) -7-cyano-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of Compound 31.1. To a solution of 4-bromopyridin-2-amine (100 g,577.9mmol,1.0 eq.) in DMF (1300 mL) was added sodium hydride (111 g,2773.9mmol,4.8 eq.) in portions and stirred for 2h at 0deg.C. 4-methoxybenzyl chloride (433 g,2773.9mmol,4.8 eq.) was added to the mixture and stirred at 0deg.C for 30min. It was transferred to ice water, the precipitated solid was filtered, and dried in vacuo to give 1.1 (150 g, yield: 62.79%). MS (ES) m/z 414.2[ M+H ] +.
Synthesis of Compound 31.2. To a solution of 31.1 (60 g,145mmol,1.0 eq.) in DMSO (1000 mL) was added cuprous chloride (I) (1.14 g,11.6mmol,0.08 eq.) followed by N1, N2-bis (4-hydroxy-2, 6-dimethylphenyl) oxamide (3.8 g,11.6mmol,0.08 eq.). The reaction mixture was stirred at room temperature for 10min and aqueous sodium hydroxide (11.6 g,290mmol,2.0 eq.) was added. The mixture was stirred at 110℃for 48h. It was cooled to room temperature, transferred to ice-cold water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to give 31.2.MS (ES) m/z 351.2[ M+H ] +.
Synthesis of Compound 31.3. A mixture of 31.2 (39 g,111.3mmol,1.0 eq), sodium carbonate (23.59 g,222.6mmol,2.0 eq.) and Int-2 (18.3 g,89.04mmol,0.8 eq.) in DMF (390 mL) was stirred at 80℃for 1h. It was filtered, and the filtrate was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography28% Ethyl acetate in hexane) to give 31.3.MS (ES) m/z 536.6[ M+H ] +.
Synthesis of Compound 31.4. Compound 31.4 was prepared from 31.3 following the procedure described in the synthesis of compound 3.6. Through silica gel fast column chromatography70% Ethyl acetate in hexanes) was purified. MS (ES) m/z 506.9[ M+H ] +.
Synthesis of Compound 31.5. Compound 31.5 was prepared from 31.4 following the procedure described in the synthesis of compound 21.7. Through silica gel fast column chromatography1.8% Methanol in DCM) was further purified. MS (ES) m/z 497.5[ M+H ] +.
Synthesis of Compound 31.6. To a solution of 31.5 (1.0 g,2.01mmol,1.0 eq.) in THF (10 mL) was added 1,1' -thiocarbonyldiimidazole (1.788 g,10.05mmol,5.0 eq.). The reaction mixture was stirred at 80℃for 6h. It was concentrated under reduced pressure. Through silica gel fast column chromatography30% Ethyl acetate in hexane) to give 31.6.MS (ES) m/z 539.5[ M+H ] +.
Synthesis of Compound 31.7. To a solution of 31.6 (0.510 g,0.946mmol,1.0 eq.) in acetonitrile (7 mL) was added sulfonyl chloride (0.15 mL,1.892mmol,2.0 eq.) at-40 ℃ and the reaction mixture was stirred for 10min. It was transferred to saturated sodium bicarbonate solution, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography40% Ethyl acetate in hexane) to give 31.7.MS (ES) m/z 541.9[ M+H ] +.
Synthesis of Compound 31.8. To a solution of 31.7 (0.230 g,0.425mmol,1.0 eq.) in DCM (8 mL) was added trifluoromethanesulfonic acid (0.2 mL) and stirred for 5min at 0deg.C. It was transferred to ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.0% Methanol in DCM) to give 31.8.MS (ES) m/z 301.5[ M+H ] +.
Synthesis of Compound 31.9. To a solution of 31.8 (0.070 g,0.232mmol,1.0 eq.) in THF (3 mL) at 0deg.C was added triethylamine (0.070 g,0.696mmol,3.0 eq.) followed by methyl chloroformate (0.033 g,0.349mmol,1.5 eq.). The reaction mixture was stirred at room temperature for 15min. It was concentrated under reduced pressure. Through silica gel fast column chromatography2.8% Methanol in DCM) to give 31.9.MS (ES) m/z 359.5[ M+H ] +.
Synthesis of I-31. Compound I-31 was prepared from 31.9 and Int-6 following the synthetic procedure of I-10. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:570.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.59(s,1H),10.32(s,1H),8.17(bs,2H),7.37(s,1H),7.33(s,1H),6.66-6.65(d,J＝3.2Hz,1H),4.88-4.85(m,1H),4.71(bs,2H),4.61(bs,2H),3.98(s,3H),3.62(s,3H),2.82(bs,4H).
Example 32: (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid 2-methoxyethyl ester
Synthesis of I-32. Compound I-32 was prepared from 21.7 and 2-methoxyethane-1-ol following the procedure for the synthesis of I-23. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:540.2[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.70(s,1H),10.39(s,1H),8.22-8.19(m,2H),7.44(s,1H),7.10(s,1H),6.73-6.71(m,1H),4.18(bs,3H),3.93(s,3H),3.53-3.51(m,2H),3.26(bs,4H),2.46(bs,2H),2.20(bs,2H).
Example 33: (R) -N- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methoxypyrrolidine-1-carboxamide
Synthesis of I-33. Compound I-33 was prepared from 21.7 and (R) -3-methoxypyrrolidine hydrochloride following the procedure for the synthesis of I-23. Through silica gel fast column chromatography3.3% Methanol in DCM) purification of the product .MS(ES):m/z:565.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.69(s,1H),8.92(s,1H),8.19-8.17(d,J＝7.2Hz,1H),7.52(s,1H),7.08-7.07(d,J＝7.6Hz,1H),6.83-6.81(d,J＝7.2Hz,1H),6.68-6.67(d,J＝3.6Hz,1H),5.36-5.35(m,1H),4.16(bs,2H),3.99(bs,2H),3.92(s,3H),3.50(bs,2H),3.17(s,3H),2.19(bs,2H),1.93(bs,2H),1.55(bs,2H).
Example 34: (S) -N- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methoxypyrrolidine-1-carboxamide
Synthesis of I-34. Compound I-34 was prepared from 21.7 and (S) -3-methoxypyrrolidine hydrochloride following the procedure for the synthesis of I-23. Through silica gel fast column chromatography3.3% Methanol in DCM) purification of the product .MS(ES):m/z:565.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.70(s,1H),8.93(s,1H),8.19-8.17(d,J＝7.2Hz,1H),7.54(s,1H),7.11(bs,1H),6.85(bs,1H),6.69(bs,1H),5.37(bs,1H),4.17(bs,2H),4.01(bs,2H),3.94(s,3H),3.50(bs,2H),3.23(s,3H),2.21(bs,2H),1.95(bs,2H),1.57(bs,2H).
Example 35: n- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-hydroxyazetidine-1-carboxamide
Synthesis of I-35. Compound I-35 was prepared from 21.7 and azetidine-3-ol hydrochloride following the procedure for the synthesis of I-23. Through silica gel fast column chromatography4.2% Methanol in DCM) purification of the product .MS(ES):m/z:537.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.70(s,1H),9.27(s,1H),8.20(s,1H),8.17-8.16(d,J＝5.6Hz,1H),7.56(s,1H),7.11(bs,1H),6.85(bs,1H),5.64-5.62(m,1H),4.38(bs,1H),4.17-4.14(m,4H),3.94(s,3H),3.70(bs,2H),2.21(bs,2H),1.57(bs,2H).
Example 36: (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid (S) -tetrahydrofuran-3-yl ester
Synthesis of I-36. Compound I-36 was prepared according to the procedure for the synthesis of I-23 from 21.7 and (S) -tetrahydrofuran-3-ol. Through silica gel fast column chromatography4.2% Methanol in DCM) purification of the product .MS(ES):m/z:552.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.71(s,1H),10.36(s,1H),8.23(bs,2H),7.42(s,1H),7.11(s,1H),6.75(s,1H),5.21(s,1H),4.17(bs,2H),3.94(s,3H),3.77-3.71(m,4H),2.21(bs,4H),1.94(bs,2H).
Example 37: (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid (R) -tetrahydrofuran-3-yl ester
Synthesis of I-37. Compound I-37 was prepared from 21.7 and (R) -tetrahydrofuran-3-ol following the procedure for the synthesis of I-23. Through silica gel fast column chromatography4.2% Methanol in DCM) purification of the product .MS(ES):m/z:552.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.70(s,1H),10.36(s,1H),8.21-8.19(m,2H),7.41(s,1H),7.10(s,1H),6.73(s,1H),5.20(s,1H),4.16(bs,2H),3.93(s,3H),3.75-3.70(m,4H),2.20(bs,4H),1.91(bs,2H).
Example 38: (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid 2- (dimethylamino) ethyl ester
Synthesis of I-38. Compound I-38 was prepared from 21.7 and 2- (dimethylamino) ethan-1-ol following the procedure for the synthesis of I-23. Through silica gel fast column chromatography4.5% Methanol in DCM) purification of the product .MS(ES):m/z:553.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.71(s,1H),10.35(s,1H),8.22-8.20(m,2H),7.46(s,1H),7.09(s,1H),6.73(s,1H),4.16(bs,4H),3.93(s,3H),2.49(bs,2H),2.20(bs,10H).
Example 39: 1-Methylazetidin-3-yl (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamate
Synthesis of I-39. A solution of 6.1 (0.150 g,0.260mmol,1.0 eq.) N, N-diisopropylethylamine (0.100 g,0.780mmol,3.0 eq.) and 1-methylazetidin-3-ol (0.034 g,0.390mmol,1.5 eq.) in dimethyl sulfoxide (3 mL) was stirred at 80℃for 16h. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by preparative HPLC to give I-39.MS(ES):m/z:570.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ9.04(s,1H),8.66(s,1H),8.28(s,1H),8.26-8.25(d,J＝5.6Hz,1H),8.19(s,1H),7.53(s,1H),6.77(bs,1H),5.30(bs,1H),4.10(bs,1H),3.97(s,3H),3.87-3.84(m,2H),3.67(s,3H),3.52-3.50(m,2H),2.83(s,3H).
Example 40: (4- ((7-chloro-1-methyl-2- ((5-methyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of Compound 40.1. To a solution of 31.4 (0.500 g,0.988mmol,1.0 eq.) and Int-8 (0.308 g,1.48mmol,1.5 eq.) in THF (5 mL) was added potassium tert-butoxide (1M in THF, 2.96mL,2.964mmol,3.0 eq.) at 0deg.C. The reaction mixture was stirred at the same temperature for 30min. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol-THF (1:1, 10 mL) and ferric chloride (0.272 g,1.68mmol,1.5 eq.). The reaction mixture was stirred at 70℃for 1h. The reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.0% Methanol in DCM) to give 40.1.MS (ES) m/z 681.1[ M+H ] +.
Synthesis of Compound 40.2. To a solution of 40.1 (0.300 g,0.441mmol,1.0 eq.) in DCM (5 mL) was added trifluoromethanesulfonic acid (0.3 mL) and stirred for 5min at 0deg.C. It was transferred to ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to give 40.2.MS (ES) m/z 440.5[ M+H ] +.
Synthesis of Compound I-40. To a solution of 40.2 (0.060 g,0.136mmol,1.0 eq.) and triethylamine (0.041 g,0.408mmol,3.0 eq.) in THF (2 mL) at 0deg.C was added methyl chloroformate (0.015 g,0.163mmol,1.2 eq.). The reaction mixture was stirred at room temperature for 2h. It was concentrated under reduced pressure. Through silica gel fast column chromatography5.0% Methanol in DCM) to give I-40.MS(ES):m/z:498.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.28(s,1H),8.12(bs,1H),7.81(s,1H),7.36(s,1H),7.07(bs,1H),6.83(bs,1H),6.62(bs,1H),3.87(bs,2H),3.76(s,3H),3.61-3.59(m,5H),3.01(s,3H).
Example 41: (4- ((7-cyano-1-methyl-2- ((5-methyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of Compound 41.1. Compound 41.1 was prepared from 31.5 and Int-8 following the procedure described in the synthesis of 40.1. Through silica gel fast column chromatography4.5% Methanol in DCM). MS (ES) m/z 671.5[ M+H ] +.
Synthesis of Compound 41.2. Compound 41.2 was prepared from 41.1 according to the procedure described in the synthesis of 40.2. The product was purified by trituration with diethyl ether. MS (ES) m/z 431.2[ M+H ] +.
Synthesis of Compound I-41. Compound I-41 was prepared from 41.2 according to the procedure described in the synthesis of I-40. Through silica gel fast column chromatography4.0% Methanol in DCM) purification of the product .MS(ES):m/z:489.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.72(s,1H),10.39(s,1H),8.23(bs,2H),7.47(s,1H),7.26(s,1H),6.74(bs,1H),4.35(bs,2H),3.94(s,3H),3.84(bs,2H),3.64(s,3H),3.05(s,3H).
Example 42:1- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-cyclopropylurea
Synthesis of I-42. Compound I-42 was prepared from 6.1 and cyclopropylamine following the procedure described in the synthesis of I-6. Through silica gel fast column chromatography4.0% Methanol in DCM) purification of the product .MS(ES):m/z:540.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ9.06(bs,2H),8.64(s,1H),8.31(s,1H),8.19(s,1H),8.13-8.11(d,J＝6.0Hz,1H),7.83(s,1H),7.12(s,1H),6.65-6.64(d,J＝3.6Hz,1H),3.96(s,3H),3.66(s,3H),1.23(bs,1H),0.63-0.62(m,2H),0.40(bs,2H).
Example 43: (4- ((7-cyano-2- ((4, 4-dimethyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of Compound 43.1. Compound 43.1 was prepared from 31.5 and Int-9 following the procedure described in the synthesis of 40.1. Through silica gel fast column chromatography2.0% Methanol in DCM). MS (ES) m/z 672.5[ M+H ] +.
Synthesis of Compound 43.2. Compound 43.2 was prepared from 43.1 according to the procedure described in the synthesis of 40.2. The product was purified by trituration with diethyl ether. MS (ES) m/z 432.3[ M+H ] +.
Synthesis of Compound I-43. Compound I-43 was prepared from 43.2 according to the procedure described in the synthesis of I-40. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:490.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.46(s,1H),10.38(s,1H),8.18(bs,2H),7.44(s,1H),6.72-6.71(d,J＝4.0Hz,1H),6.64(s,1H),4.09(bs,2H),4.00(bs,2H),3.91(s,3H),3.62(s,3H),1.53(s,6H).
Example 44:3- (4- ((7-cyano-2- ((4, 4-dimethyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -1, 1-dimethylurea
Synthesis of I-44. Compound I-44 was prepared from 43.2 and dimethylamine following the synthetic procedure of I-23. Through silica gel fast column chromatography3.0% Methanol in DCM) purification of the product .MS(ES):m/z:503.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.45(s,1H),9.01(s,1H),8.15(bs,2H),7.44(s,1H),6.66-6.64(d,J＝5.6Hz,2H),4.09(bs,2H),4.00(bs,2H),3.90(s,3H),2.89(s,6H),1.53(s,6H).
Example 45: n- (4- ((7-cyano-2- ((4, 4-dimethyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) pyrrolidine-1-carboxamide
Synthesis of I-45. Compound I-45 was prepared from 43.2 and pyrrolidine following the procedure for the synthesis of I-23. Through silica gel fast column chromatography4.0% Methanol in DCM) purification of the product .MS(ES):m/z:529.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.45(s,1H),8.82(s,1H),8.16(bs,2H),7.53-7.52(d,J＝1.6Hz,1H),6.66-6.63(m,2H),4.09(bs,2H),4.00(bs,2H),3.90(s,3H),3.33(bs,4H),1.80(bs,4H),1.53(bs,6H).
Example 46:3- (4- ((7-chloro-1-methyl-2- ((5-methyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -1, 1-dimethylurea
Synthesis of I-46. Compound I-46 was prepared from 40.2 and dimethylamine following the synthetic procedure of I-23. Through silica gel fast column chromatography3.5% Methanol in DCM) further purifying the product .MS(ES):m/z:511.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.39(s,1H),8.93(s,1H),8.11(s,1H),7.36(s,1H),7.23(s,1H),7.07(bs,1H),6.83(bs,1H),4.32(bs,2H),3.95(s,3H),3.81(bs,2H),3.03(s,3H),2.88(s,6H).
Example 47: n- (4- ((7-cyano-2- ((4, 4-dimethyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) azetidine-1-carboxamide
Synthesis of I-47. Compound I-47 was prepared from 43.2 and azetidine following the procedure for the synthesis of I-23. Through silica gel fast column chromatography4.0% Methanol in DCM) purification of the product .MS(ES):m/z:515.2[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.45(s,1H),9.20(s,1H),8.15(bs,2H),7.54(s,1H),7.07(s,1H),6.83(bs,1H),4.10(bs,2H),4.00(bs,4H),3.94(bs,2H),3.91(s,3H),2.14-2.11(m,2H),1.53(s,6H).
Example 48: (4- ((7-cyano-2- ((4, 4-dimethyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid (R) -tetrahydrofuran-3-yl ester
Synthesis of I-48. Compound I-48 was prepared from 43.2 and (R) -tetrahydrofuran-3-ol following the procedure for the synthesis of I-23. Through silica gel fast column chromatography3.8% Methanol in DCM) purification of the product .MS(ES):m/z:546.5[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.42(s,1H),10.33(s,1H),8.21-8.18(m,2H),7.38(s,1H),6.76-6.75(d,J＝3.6Hz,1H),6.62(s,1H),5.21(s,1H),4.09(bs,2H),4.00(bs,2H),3.90(s,3H),3.78-3.70(m,4H),2.16-2.11(m,1H),1.93-1.89(m,1H),1.53(s,6H).
Example 49: (4- ((7-cyano-2- ((4, 4-dimethyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid (S) -tetrahydrofuran-3-yl ester
Synthesis of I-49. Compound I-49 was prepared from 43.2 and (S) -tetrahydrofuran-3-ol following the procedure for the synthesis of I-23. Through silica gel fast column chromatography4.0% Methanol in DCM) purification of the product .MS(ES):m/z:546.5[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.46(s,1H),10.35(s,1H),8.20-8.17(m,2H),7.40(s,1H),6.73-6.72(d,J＝3.2Hz,1H),6.63(s,1H),5.20(bs,1H),4.09(bs,2H),4.00(bs,2H),3.90(s,3H),3.77-3.69(m,4H),2.15-2.10(m,1H),1.92-1.88(m,1H),1.53(s,6H).
Example 51: n- (4- ((7-chloro-1-methyl-2- ((1- (methyl-d 3) -2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
/>
Synthesis of Compound 51.1. To a solution of 21.5 (0.150 g,0.487mmol,1.0 eq.) in THF (2 mL) was added 1,1' -thiocarbonyldiimidazole (0.433 g,2.43mmol,5.0 eq.). The reaction mixture was stirred at 80℃for 1h. It was cooled to room temperature and transferred to ice water. The precipitated solid was collected by filtration and triturated with hexane to give 51.1.MS (ES) m/z 350.7[ M+H ] +.
Synthesis of Compound 51.2. To a solution of 51.1 (0.110 g,0.314mmol,1.0 eq.) in acetic acid (5 mL) was added aqueous hydrobromoacid (0.037 g,0.471mmol,1.5 eq.) followed by bromine (0.200 g,1.25mmol,4.0 eq.) at 0deg.C. The reaction mixture was stirred for 10min. It was transferred to saturated sodium bicarbonate solution, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give 51.2.MS (ES) m/z 397.6[ M+H ] +.
Synthesis of I-82. Compound I-82 was prepared from 51.2 and Int-16.2 according to the procedure described in the synthesis of I-10. Through silica gel fast column chromatography2.3% Methanol in DCM) to give the product I-82.MS(ES):m/z:511.2[M]+,1H NMR(DMSO-d6,400MHz):δ10.59(s,1H),8.85(s,1H),8.64(d,J＝2.4Hz,1H),8.25(s,1H),8.20(d,J＝6.0Hz,1H),8.15(s,1H),7.67(s,1H),6.68-6.66(m,1H),4.00(s,3H),2.05(s,3H).
Example 52:3- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -1, 1-bis (methyl-d 3) urea
Synthesis of I-52. Compound I-52 was prepared from 6.1 and dimethylamine hydrochloride (d 6) following the procedure described in the synthesis of I-6. Through silica gel fast column chromatography4.0% Methanol in DCM) purification of the product .MS(ES):m/z:540.3[M+H]+;1H NMR(DMSO-d6,400MHz):δ9.04(d,J＝10.8Hz,2H),8.67(s,1H),8.32(s,1H),7.50(s,1H),7.10-7.09(bs,1H),6.86-6.83(bs,1H),6.71-6.696(bs,1H),4.00(s,3H),3.69(s,3H).
Example 53: (4- ((7-chloro-1-methyl-2- ((5-methyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid (R) -tetrahydrofuran-3-yl ester
Synthesis of I-53. To a solution of 40.2 (0.080 g,0.181mmol,1.0 eq.) in THF (3 mL) at 0deg.C was added triethylamine (0.055 g,0.545mmol,3.0 eq.) followed by phenyl chloroformate (0.042 g,0.272mmol,1.5 eq.). The reaction mixture was stirred at 0℃for 15min. (R) -tetrahydrofuran-3-ol (0.080 g,0.909mmol,5.0 eq.) was added and the mixture stirred at 80℃for 16h. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.5% Methanol in DCM) to give the residue I-53.MS(ES):m/z:554.4[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.41(s,1H),10.28(s,1H),8.15(d,J＝5Hz,2H),7.32(s,1H),7.23(s,1H),6.66(d,J＝5Hz,1H),5.19(bs,1H),4.34(t,J＝7.5Hz,3H),4.12-4.11(m,1H),3.96(s,4H),3.83-3.61(m,9H),3.24(m,2H),3.03(s,3H),2.17-2.09(m,2H),1.90-1.87(m,1H).
Example 54: oxetan-3-yl (4- ((7-chloro-1-methyl-2- ((5-methyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamate
Synthesis of I-54. Compound I-54 was prepared from 40.2 and oxetan-3-ol according to the procedure described in the synthesis of I-53. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:540.4[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.54(s,1H),10.41(s,1H),8.18-8.13(m,2H),7.29-7.23(m,2H),4.78-4.74(m,2H),4.49(bs,2H),4.33(bs,2H),4.13-4.11(bs,2H),3.952(s,4H),3.821(bs,2H),3.18-3.16(m,4H),3.03(s,4H),2.17-2.09(m,2H),1.55(s,1H).
Example 55: (4- ((7-chloro-1-methyl-2- ((5-methyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid (S) -tetrahydrofuran-3-yl ester
Synthesis of I-55. Compound I-55 was prepared from 40.2 and (S) -tetrahydrofuran-3-ol following the procedure described in the synthesis of I-53. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:554.4[M+H]+;H NMR(DMSO-d6,400MHz):δ10.41(s,1H),10.28(s,1H),8.15(d,J＝5Hz,2H),7.32(s,1H),7.23(s,1H),6.66(d,J＝5Hz,1H),5.19(bs,1H),4.33(t,J＝7.5Hz,3H),4.12-4.11(m,1H),3.96(s,4H),3.83-3.61(m,9H),3.24(m,2H),3.03(s,3H),2.17-2.09(m,2H),1.90-1.87(m,1H).
Example 56:3- (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -1, 1-dimethylurea
Synthesis of Compound 56.1. Compound 56.1 was prepared from 31.5 and Int-10 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatographyDCM) purified product. MS (ES) m/z 668[ M+H ] +.
Synthesis of Compound 56.2. Compound 56.2 was prepared from 56.1 following the procedure described in the synthesis of 40.2. The product was purified by trituration with diethyl ether and used in the next step without further purification. MS (ES) m/z 428[ M+H ] +.
Synthesis of I-56. Compound I-56 was prepared from 56.2 following the procedure described in the synthesis of I-21. Through silica gel fast column chromatography3.2% DCM: methanol) purification of the product .MS(ES):m/z 499.35[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.38(s,1H),9.011(s,1H),8.17(s,2H),7.44(m,2H),6.72(s,3H),4.07-4.04(m,2H),3.92(s,3H),2.91(s,3H),2.79-2.656(m,2H),2.37(m,2H),2.01(s,2H),1.25(s,2H).
Example 57: (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of I-57. Compound I-57 was prepared from 56.2 according to the procedure described in the synthesis of I-22. Through silica gel fast column chromatography2% DCM: methanol) purification of the product .MS(ES):m/z 486.35[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.38(s,1H),8.18(s,1H),7.62(s,1H),7.45(m,2H),6.72(s,2H),4.10-3.91(m,2H),3.62(s,3H),2.65(s,3H),2.50-2.35(m,2H),2.27(s,2H),2.02(s,2H),1.23(s,2H).
Example 58:1- (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methylurea
Synthesis of I-58. Compound I-58 was prepared from 56.2 and methylamine according to the procedure described in the synthesis of I-23. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:485.39[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.39(s,1H),9.19(s,1H),8.17(m,2H),7.84(bs,2H),7.07-6.98(m,2H),4.04(bs,2H),3.91(s,3H),2.68(s,3H),2.10-2.00(m,4H),1.72-1.56(m,2H),1.24(s,2H).
Example 59: (S) -N- (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methoxypyrrolidine-1-carboxamide
Synthesis of I-59. Compound I-59 was prepared from 56.2 and (S) -3-methoxypyrrolidine according to the procedure described in the synthesis of I-23. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:555.40[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.37(s,1H),8.90(s,1H),8.16(d,J＝4.8Hz,2H),7.52(s,1H)6.71(m,2H),4.05(t,J＝6.4Hz,3H),3.90(s,3H),3.36(bs,4H),3.21(s,3H),2.67(bs,2H),2.37(m,2H),2.27(bs,2H),2.03(m,2H),1.93(m,2H).
Example 60: (R) -N- (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methoxypyrrolidine-1-carboxamide
Synthesis of I-60. Compound I-60 was prepared from 56.2 and (R) -3-methoxypyrrolidine according to the procedure described in the synthesis of I-23. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:555.42[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.38(s,1H),8.91(s,1H),8.15(d,J＝4.8Hz,2H)7.51(s,1H),6.71(m,2H),4.05(m,1H),4.04(m,2H),3.90(s,3H),3.36(bs,4H),3.21(s,3H),2.67(bs,2H),2.37(m,2H),2.27(bs,2H)2.03(m,2H),1.93(m,2H)./>
Example 61: n- (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methoxyazetidine-1-carboxamide
Synthesis of I-61. Compound I-61 was prepared from 56.2 and 3-methoxyazetidine according to the procedure described in the synthesis of I-23. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:541.43[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.42(s,1H),9.39(s,1H),8.19(s,2H)7.55(m,1H),6.72(m,3H),4.16(s,2H),4.07(t,J＝6.8Hz,2H),3.93(s,3H),3.79(d,J＝5.6Hz,2H),3.21(s,3H),2.701(m,2H),2.31(m,2H),2.06(m,2H),1.26(s,2H).
Example 62: (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid 2-methoxyethyl ester
Synthesis of I-62. Compound I-62 was prepared from 56.2 and 2-methoxyethane-1-ol according to the procedure described in the synthesis of I-23. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:530.39[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.38(s,1H),8.18(s,1H),7.43(s,1H),6.71(m,2H),4.71(m,3H),4.04(m,3H),3.90(s,3H),3.52(m,2H),3.25(s,3H),2.65(bs,2H),2.50(m,2H),2.35(m,2H),2.27(bs,2H)2.03(m,2H).
Example 63: (4- ((7-cyano-2- ((6 ',7' -dihydro-5 ' H-spiro [ cyclopropane-1, 4' -pyrazolo [1,5-a ] pyridin ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of Compound 63.1. Compound 63.1 was prepared from 31.5 and Int-11 following the procedure described in the synthesis of 40.1. Through silica gel fast column chromatography2% Methanol in DCM). MS (ES) m/z 667.77[ M+H ] +.
Synthesis of Compound 63.2. Compound 63.2 was prepared from 63.1 according to the procedure described in the synthesis of 40.2. The product was triturated with diethyl ether and used in the next step without further purification. MS (ES) m/z 427.47[ M+H ] +.
Synthesis of Compound I-63. Compound I-63 was prepared from 63.1 according to the procedure described in the synthesis of I-22. Through silica gel fast column chromatography3% Methanol in DCM) purification of the product .MS(ES):m/z 485.51[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.43(s,1H),8.22-8.20(bs,1H),7.45(s,1H),7.26-7.00(bs,2H),6.75(s,1H),6.22(s,1H),4.10(bs,2H),3.91(s,3H),3.65(s,3H),2.11(bs,2H),1.74(bs,2H),1.26(bs,2H),0.96-0.87(bs,2H).
Example 64:1- (4- ((7-cyano-2- ((6 ',7' -dihydro-5 ' H-spiro [ cyclopropane-1, 4' -pyrazolo [1,5-a ] pyridin ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methylurea
Synthesis of I-64. Compound I-64 was prepared from 63.2 and methylamine according to the procedure described in the synthesis of I-23. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:484.52[M+H]+;1H NMR(DMSO-d6,400MHz):δ9.17(s,1H),8.10(bs,1H),7.82(bs,1H),7.07(bs,2H),6.83(bs,2H),6.20(s,1H),5.34(s,1H),4.09(bs,1H),3.99(s,3H),3.90(s,3H),3.10(bs,2H),1.55(s,2H),1.18(bs,2H),0.94(bs,2H).
Example 65:3- (4- ((7-cyano-2- ((6 ',7' -dihydro-5 ' H-spiro [ cyclopropane-1, 4' -pyrazolo [1,5-a ] pyridin ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -1, 1-dimethylurea
Synthesis of I-65. Compound I-65 was prepared from 63.2 and dimethylcarbonyl chloride according to the procedure described in the synthesis of I-21. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:498.55[M+H]+;1H NMR(DMSO-d6,400MHz):δ8.98(s,1H),8.16-8.08(bs,1H),7.74(s,1H),7.44-7.42(bs,1H),6.65-6.59(bs,1H),6.22(s,1H),5.67(s,1H),3.75(s,3H),3.58-3.51(bs,2H),2.89-2.87(bs,6H),2.16-2.09(bs,1H),1.93(bs,1H),1.72-1.66(bs,2H),1.23-1.24(bs,2H),1.02-0.91(bs,2H).
Example 66: oxetan-3-yl (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutan-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamate
Synthesis of I-66. Compound I-66 was prepared from 63.2 and oxetan-3-ol according to the procedure described in the synthesis of I-23. Through silica gel fast column chromatography3.5% Methanol in DCM) and then HPLC.MS(ES):m/z:528.41[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.58(s,1H),10.36(s,1H),8.20(m,2H),7.36(s,1H),6.74(m,2H),5.34(t,J＝5.6Hz,1H),4.75(t,J＝6.8Hz,2H),4.48(t,J＝5.6Hz,2H),4.02(t,J＝6.4Hz,2H),3.88(s,3H),2.65(m,2H),2.48(m,2H),2.35(m,2H),2.25(bs,2H),2.02(m,2H).
Example 67:3- (4- ((7-cyano-2- ((4, 4-dimethyl-4, 5,7, 8-tetrahydropyrazolo [1,5-d ] [1,4] oxazepin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -1, 1-dimethylurea
Synthesis of Compound 67.1. Compound 67.1 was prepared from 31.5 and Int-12 following the procedure described in the synthesis of 40.1. Through silica gel fast column chromatography4.1% Methanol in DCM). MS (ES) m/z 686.52[ M+H ] +.
Synthesis of Compound 67.2. Compound 67.2 was prepared from 67.1 according to the procedure described in the synthesis of 40.2. The product was purified by trituration with diethyl ether and used in the next step without further purification. MS (ES) m/z 446.35[ M+H ] +.
Synthesis of I-67. Compound I-67 was prepared from 67.2 according to the procedure described in the synthesis of I-21. Through silica gel fast column chromatography4.1% Methanol in DCM) purification of the product .MS(ES):m/z:517.41[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.36(s,1H),9.01(s,1H),8.17(d,J＝6.8Hz,2H),7.44(s,1H),6.67(s,2H),4.38(s,2H),3.91-3.86(m,5H),3.59(s,2H),2.91(s,6H),1.32(s,6H).
Example 68: (4- ((7-cyano-2- ((4, 4-dimethyl-4, 5,7, 8-tetrahydropyrazolo [1,5-d ] [1,4] oxazepin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of I-68. Compound I-68 was prepared from 67.2 according to the procedure described in the synthesis of I-22. Through silica gel fast column chromatography3.9% Methanol in DCM) purification of the product .MS(ES):m/z:504.36[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.66(s,1H),10.38(s,1H),8.24(d,J＝5.6Hz,1H),8.17(s,1H),7.73(s,1H),6.74(d,J＝3.2Hz,1H),6.67(s,1H),4.38(s,2H),3.90(s,3H),3.86(s,2H),3.58(s,2H),2.06(s,3H),1.31(s,6H).
Example 69:1- (4- ((7-cyano-2- ((4, 4-dimethyl-4, 5,7, 8-tetrahydropyrazolo [1,5-d ] [1,4] oxazepin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methylurea
Synthesis of I-69. Compound I-69 was prepared from 67.2 and methylamine according to the procedure described in the synthesis of I-23. Through silica gel fast column chromatography4.4% Methanol in DCM) purification of the product .MS(ES):m/z:503.38[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.38(s,1H),9.20(s,1H),8.17(s,1H),8.2(d,J＝5.6Hz,1H),7.84(bs,1H),6.99(s,1H),6.66(s,1H),6.63(d,J＝5.2Hz,1H),4.38(s,2H),3.91(s,3H),3.86(s,2H),3.58(s,2H),2.69(s,3H),1.31(s,6H).
Example 70:3- (4- ((2- ((1- (tert-butyl) -2, 3-dihydro-1H-imidazo [1,2-b ] pyrazol-6-yl) amino) -7-cyano-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -1, 1-dimethylurea
Synthesis of Compound 70.1. Compound 70.1 was prepared from 31.5 and Int-13 following the procedure described in the synthesis of 40.1. Through silica gel fast column chromatography2.0% Methanol in DCM). MS (ES) m/z 685.83[ M+H ] +.
Synthesis of Compound 70.2. Compound 70.2 was prepared from 70.1 following the procedure described in the synthesis of 40.2. The product was purified by trituration with diethyl ether and used in the next step without further purification. MS (ES) m/z 445.2[ M+H ] +.
Synthesis of I-70. Compound I-70 was prepared from 70.2 following the procedure described in the synthesis of I-21. Through silica gel fast column chromatography2.3-2.6% Methanol in DCM) purification of the product .MS(ES):m/z:516.32[M+H]+;1H NMR(DMSO-d6,400MHz):δ8.95(s,1H),8.14-8.07(m,1H),7.76(s,1H),7.41(s,1H),6.61(s,1H),6.05(s,1H),4.06-3.87(m,2H),3.74-3.65(m,3H),3.56-3.49(m,2H),2.88-2.86(m,6H),1.27(s,9H).
Example 71: (4- ((2- ((1- (tert-butyl) -2, 3-dihydro-1H-imidazo [1,2-b ] pyrazol-6-yl) amino) -7-cyano-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid methyl ester
Synthesis of I-71. To a solution of 70.2 (0.050 g,0.112mmol,1.0 eq.) in THF (5 mL) was added lithium bis (trimethylsilyl) amide (0.33 mL,0.336mmol,3.0 eq.) at 0 ℃ and stirred for 10min. It was cooled to 10℃and methyl chloroformate (0.018 g,0.168mmol,1.5 eq.) was added. The reaction mixture was stirred for 30min. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To a solution of the residue in methanol (5 mL) was added potassium carbonate (0.154 g,1.112mmol,10 eq.) and stirred at room temperature for 1h. Passing the reaction mixture throughIs filtered through a pad of (a). The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)3.5-4.1% Methanol in DCM) purification residue .MS(ES):m/z:503.53[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.34(s,1H),10.23(s,1H),8.18-8.13(m,2H),7.43(s,1H),6.69-6.68(d,J＝3.2,1H),6.04(s,1H),3.95-3.91(m,2H),3.87(s,3H),3.66-3.61(m,5H),1.26(s,9H).
Example 72:1- (4- ((2- ((1- (tert-butyl) -2, 3-dihydro-1H-imidazo [1,2-b ] pyrazol-6-yl) amino) -7-cyano-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3-methylurea
Synthesis of I-72. Compound I-72 was prepared from 70.2 and methylamine according to the procedure described in the synthesis of I-23. Purification of the product by preparative HPLC .MS(ES):m/z:502.4[M+H]+,1H NMR(DMSO-d6,400MHz):δ9.16(s,1H),8.18(s,1H),8.11-8.08(m,2H),7.80(s,1H),6.97(s,1H),6.60-6.58(m,1H),6.01(s,1H),3.95-3.91(m,2H),3.66-3.63(m,2H),3.15(s,3H),2.67-2.65(m,3H),1.26(s,9H).
Example 73:3- (4- ((7-cyano-2- ((6, 6-dimethyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -1, 1-dimethylurea
Synthesis of Compound 73.1. Compound 73.1 was prepared from 31.5 and methylamine according to the procedure described in the synthesis of 3.7. Through silica gel fast column chromatography5.2% Methanol in DCM). MS (ES) m/z 672.52[ M+H ] +.
Synthesis of Compound 73.2. Compound 73.2 was prepared from 73.1 according to the procedure described in the synthesis of 40.2. Through silica gel fast column chromatography5.8% Methanol in DCM). MS (ES) m/z 432.46[ M+H ] +.
Synthesis of I-73. Compound I-73 was prepared from 73.2 according to the procedure described in the synthesis of I-21. Through silica gel fast column chromatography2.4% Methanol in DCM) purification of the product .MS(ES):m/z:503.54[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.44(s,1H),8.99(s,1H),8.15(s,2H),7.44(s,1H),6.64(s,2H),4.83(s,2H),3.91-3.88(m,5H),2.89(s,6H),1.31(s,6H).
Example 74: (S) -N- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2- (tetrahydro-2H-pyran-2-yl) acetamide and (R) -N- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2- (tetrahydro-2H-pyran-2-yl) acetamide
Synthesis of Compound (+ -) -I-74. A mixture of (+ -) -I-50 (0.130 g,0.219mmol,1.0 eq.), zinc powder (0.002 g,0.043mmol,0.2 eq.) and zinc cyanide (0.128 g,1.09mmol,5.0 eq.) in N, N-dimethylacetamide (10 mL) was degassed by bubbling through a stream of argon for 5min. Tris (dibenzylideneacetone) dipalladium (0) (0.030 g,0.032mmol,0.15 eq.) and 1,1' -bis (diphenylphosphino) ferrocene (0.035 g,0.065mmol,0.3 eq.) were added and degassed for 5min. The reaction mixture was stirred in a microwave reactor at 170 ℃ for 2h. It was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.3% Methanol in DCM) to give (±) -I-74.MS (ES) m/z 583.54[ M+H ] +.
I-74-a and I-74-b. The racemate was subjected to chiral HPLC (CHIRALPAK OX-H (250 mm. Times.21 mm,5 μm); mobile phase (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propan-2-ol: acetonitrile (70:30; flow rate = 20 mL/min) to give a first eluted fraction (Int-74-a) and a second eluted fraction (Int-74-B).
I-74-a：MS(ES):m/z:583.54[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.59(s,1H),9.05(s,1H),8.67(s,1H),8.34(s,1H),8.26(d,J＝8.0Hz,1H),8.20(s,1H),7.78(s,1H),6.80(s,1H),3.98(s,2H),3.83-3.80(m,1H),3.68(s,3H),3.34(s,3H),2.44-2.43(bs,2H),1.74(bs,1H),1.60-1.57(m,1H),1.44(s,2H),1.22-1.19(m,2H).
I-74-b：MS(ES):m/z:583.54[M+H]-,1H NMR(DMSO-d6,400MHz):10.59(s,1H),9.05(s,1H),8.67(s,1H),8.34(s,1H),8.26(d,J＝8.0Hz,1H),8.20(s,1H),7.78(s,1H),6.80(s,1H),3.98(s,2H),3.83-3.80(m,1H),3.68(s,3H),3.39(s,3H),2.44-2.40(bs,2H),1.72(bs,1H),1.60-1.57(m,1H),1.44(bs,2H),1.22-1.12(m,2H).
Example 75: n- (4- ((7-chloro-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2-methoxyacetamide
Synthesis of Compound 75.1. A mixture of 1.1 (1.0 g,7.78mmol,1.0 eq.) and 2-methoxyacetic acid (3.5 g,38.89mmol,5 eq.) was stirred in a microwave reactor at 190℃for 2h. The reaction mixture was cooled to room temperature, transferred to methanol and concentrated under reduced pressure. To the residue was added 1N sodium hydroxide solution (5 mL) and stirred for 1h. Neutralization was performed using 1N hydrochloric acid. The precipitate was collected by filtration and dried under reduced pressure to give 75.1.MS (ES) m/z 183.3[ M+H ] +.
Synthesis of Compound 75.2. A mixture of 75.1 (0.500 g,2.74mmol,1.0 eq.) Int-2 (0.611 g,3.01mmol,1.1 eq.) and potassium carbonate (0.756 g,5.48mmol,2.0 eq.) in DMF (10 mL) was stirred at room temperature for 1h. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography30% Ethyl acetate in hexane) to give 75.2.MS (ES) m/z 368.5[ M+H ] +.
Synthesis of Compound 75.3. A mixture of 75.2 (0.350 g,0.951mmol,1.0 eq.), iron powder (0.266 g,4.775mmol,5.0 eq.) and ammonium chloride (0.256 g,4.775mmol,5.0 eq.) in ethanol to water (4:1, 7 mL) was stirred at 90℃for 1h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography1.7% Methanol in DCM) to give 75.3.MS (ES) m/z 338.5[ M+H ] +.
Synthesis of Compound I-75. Compound I-75 was prepared from 75.3 and Int-5 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatography3.1% Methanol in DCM) purification of the product .MS(ES):m/z 538.11[M+H]+.1H NMR(DMSO-d6,400MHz):δ10.136(s,1H),8.85(s,1H),8.64(s,1H),8.27(s,1H),8.23(d,J＝5.6Hz,1H),8.16(s,1H),7.66(s,1H),6.73(d,J＝3.2Hz,1H),4.03(s,2H),4.00(s,3H),3.67(s,3H),3.34(d,J＝2.4Hz,3H).
Example 76: n- (4- ((7-chloro-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2-fluoroacetamide
Synthesis of Compound 76.1. A solution of 1.2 (2.0 g,9.99mmol,0.8 eq), ethyl 2-fluoroacetate (1.32 g,12.48mmol,1.0 eq) and N, N-diisopropylethylamine (3.2 g,24.96mmol,0.5 eq) in THF (20 mL) was stirred at room temperature for 30min. Trimethylaluminum (1M solution in toluene, 50ml,50mmol,5.0 eq.) was added to the reaction and stirred for 2h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography15-20% Ethyl acetate in hexane) to give 76.1.MS (ES) m/z 261.1[ M+H ] +.
Synthesis of Compound 76.2. A mixture of compound 76.1 (0.400 g,1.54mmol,1.0 eq.) and 10% palladium on charcoal (0.100 g) in methanol (10 mL) was stirred under hydrogen (1 atm) for 1h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)12% Ethyl acetate in hexane) to give 76.2.MS (ES) m/z 171.2[ M+H ] +.
Synthesis of Compound 76.3. A mixture of 76.3 (0.260 g,1.53mmol,1.0 eq), int-2 (0.345 g,1.683mmol,1.1 eq.) and potassium carbonate (0.428 g,3.06mmol,2.0 eq.) in DMF (10 mL) was stirred at room temperature for 1h. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography38% Ethyl acetate in hexane) to give 76.3.MS (ES) m/z 356.5[ M+H ] +.
Synthesis of Compound 76.4. A mixture of 76.3 (0.350 g,0.983mmol,1.0 eq.), iron powder (0.275 g, 4.910 mmol,5.0 eq.) and ammonium chloride (0.265 g, 4.910 mmol,5.0 eq.) in ethanol to water (2:1, 8 mL) was stirred at 90℃for 1h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography1.7% Methanol in DCM) to give 76.4.MS (ES) m/z 326.5[ M+H ] +.
Synthesis of I-76. Compound I-76 was prepared from 76.4 and Int-5 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatography2.5% Methanol in DCM) purification of the product .MS(ES):m/z:526.13[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.67(s,1H),8.86(s,1H),8.64(d,J＝2Hz,1H),8.26-8.23(m,2H),8.16(s,1H),7.61(s,1H),6.75-6.73(m,1H),5.06(s,1H),4.94(s,1H),4.00(s,3H),3.67(s,3H).
Example 77: n- (4- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound 77.1. To a solution of 1.2 (11.2 g,55.93mmol,1.0 eq.) and pyridine (6.3 mL,78.30mmol,1.4 eq.) in DCM (110 mL) was added acetic anhydride (6.34 mL,67.11mmol,1.2 eq.) and stirred for 1h. It was transferred to ice, stirred, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography1% Methanol in DCM) to yield 77.1.MS (ES) m/z 243.21[ M+H ] +.
Synthesis of Compound 77.2. A mixture of compound 77.1 (6.1 g,25.18mmol,1.0 eq.) and 10% palladium on carbon (2 g) in methanol (60 mL) was stirred under hydrogen (1 atm) for 2h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)5% Methanol in DCM) to yield 77.2.MS (ES) m/z 153.2[ M+H ] +.
Synthesis of Compound 77.3. Compound 77.3 was prepared from 77.2 and Int-1 according to the procedure described in the synthesis of 1.6. Through silica gel fast column chromatography2% Methanol in DCM). MS (ES) m/z 304.3[ M+H ] +.
Synthesis of Compound 77.4. A mixture of compound 77.3 (0.960 g,3.17mmol,1.0 eq.) and 10% palladium on carbon (0.500 g) in methanol (5 mL) was stirred under hydrogen (1 atm) for 1h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 77.4.MS (ES) m/z 274.3[ M+H ] +.
Synthesis of Compound 77.5. To a solution of 77.4 (0.550 g,2.01mmol,1.0 eq.) in THF (6 mL) was added 1,1' -carbonyldiimidazole (1.041 g,6.43mmol,3.2 eq.). The reaction mixture was stirred at 70℃for 3h. It was cooled to room temperature and transferred to ice water. The precipitated solid was filtered off and triturated with hexane to give 77.5.MS (ES) m/z 300.3[ M+H ] +.
Synthesis of Compound 77.6. A solution of 77.5 (0.370 g,1.24mmol,1.0 eq.) in phosphorus oxychloride (10 mL) was stirred at 100deg.C for 8h. It was cooled and transferred to saturated sodium bicarbonate solution, stirred, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.2% Methanol in DCM) to yield 77.6.MS (ES) m/z 318.7[ M+H ] +.
Synthesis of Compound I-77. Compound I-77 was prepared according to the procedure for the synthesis of I-10 from 77.6 and Int-5. Through silica gel fast column chromatography3.8% Methanol in DCM) purification of the product .MS(ES):m/z:474.88[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.55(s,1H),8.69(s,2H),8.19(d,J＝5.2Hz,1H),8.11(s,2H),7.87(s,1H),7.67(s,1H),6.68(s,1H),3.77(s,3H),3.66(s,3H),2.03(s,3H).
Example 78: (R) -N- (4- ((7-chloro-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2- (4-methylmorpholin-2-yl) acetamide and (S) -N- (4- ((7-chloro-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2- (4-methylmorpholin-2-yl) acetamide
Synthesis of Compound (+ -) -78.1. To a solution of 2- (4- (tert-butoxycarbonyl) morpholin-2-yl) acetic acid (3 g,12.23,1.0 eq.) in DMF (30 mL) was added HATU (7.0 g,18.36mmol,1.5 eq.) and stirred for 15min at 0deg.C. To the mixture was added 1.2 (2.9 g,14.68mmol,1.2 eq.) followed by N, N-diisopropylethylamine (4.7 g,36.73mmol,3.0 eq.) and the reaction mixture was stirred at room temperature overnight. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give (±) -78.1.MS (ES) m/z 428.5[ M+H ].
Synthesis of Compound (+ -) -78.2. To a solution of (+ -) -78.1 (1.42 g,3.32mmol,1.0 eq.) in DCM (15 mL) was added HCl in dioxane (4M, 10 mL) at 0deg.C. The reaction mixture was stirred at room temperature for 1h. It was transferred to ice water, neutralized with sodium bicarbonate, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was used in the next step without purification. MS (ES) m/z 328.7[ M+H ].
Synthesis of Compound (+ -) -78.3. A solution of (+ -) -78.2 (0.910 g,2.78mmol,1.0 eq), formaldehyde solution (37% in H 2 O, 0.338g,4.1mmol,1.5 eq) and acetic acid (0.525 g,8.3mmol,3.0 eq) in 1, 2-dichloroethane (15 mL) was stirred at 0deg.C for 15min. Sodium triacetoxyborohydride (1.77 g,8.3mmol,3.0 eq.) was added to the mixture and stirred at room temperature for 16h. It was transferred to water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.2% Methanol in DCM) to give (±) -78.3.MS (ES) m/z 342.4[ M+H ].
Synthesis of Compound (+ -) -78.4. A mixture of 10% palladium on carbon (0.3 g) and (. + -.) -78.3 (0.75 g,2.20mmol,1.0 eq.) was stirred under hydrogen (1 atm) at room temperature for 2h. Passing the reaction mixture throughIs filtered through a pad of (a). The filtrate was concentrated under reduced pressure to give (±) -78.4.MS (ES) m/z 252.6[ M+H ] +.
Synthesis of Compound (+ -) -78.5. A mixture of (+ -) -78.4 (0.389 g,1.55mmol,1.0 eq.), potassium carbonate (0.641 g,4.64mmol,3.0 eq.) and Int-2 (0.318 g,1.55mmol,1.0 eq.) in DMF (10 mL) was stirred at 80℃for 2h. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3% Methanol in DCM) to give (±) -78.5.MS (ES) m/z 437.9[ M+H ] +.
Synthesis of Compound (+ -) -78.6. A mixture of (+ -) -78.5 (0.350 g,0.80 mmol,1.0 eq.), iron powder (0.224 g,4.01mmol,5.0 eq.) and acetic acid (0.240g,4.01mmol 5.0 eq.) in isopropanol (10 mL) and water (4 mL) was stirred at 90℃for 2h. Passing the reaction mixture throughIs filtered through a pad of (a). The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)3.2% Methanol in DCM) to give (±) -78.6.MS (ES) m/z 407.8[ M+H ] +.
Synthesis of Compound (+ -) -I-78. Compound (±) -I-78 was prepared from compound (±) -78.6 according to the procedure described in the synthesis of compound 3.7. Through silica gel fast column chromatography3.2% Methanol in DCM). MS (ES) m/z 608.5[ M+H ] +.
I-78-a and I-78-b. The racemate was separated by chiral HPLC (CHIRALPAK IH (250 mm x 21mm,5 μm); mobile phase (a) 0.1% dea in n-hexane (B) 0.1% dea in propan-2-ol: acetonitrile (70:30; flow rate = 20 mL/min) to give a first eluted fraction (Int-78-a) and a second eluted fraction (Int-78-B).
I-78-a：MS(ES):m/z 607.4[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.58(s,1H),8.82(bs,1H),8.63(s,1H),8.24(s,1H),8.20(d,J＝4Hz,1H),8.15(s,1H),7.66(s,1H),6.71-6.70(m,1H),4.66-4.59(m,1H),3.99(s,3H),3.78(bs,1H),3.71-3.66(m,4H),3.45-3.40(m,1H),2.67-2.64(m,1H),2.50-2.40(m,2H),2.13(s,3H),1.94-1.88(m,1H),1.71-1.66(m,1H).
I-78-b：MS(ES):m/z 607.4[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.59(s,1H),8.86(bs,1H),8.64(s,1H),8.24(s,1H),8.21(d,J＝4Hz,1H),8.15(s,1H),7.67(s,1H),6.72-6.70(m,1H),4.66-4.60(m,1H),3.99(s,3H),3.80(bs,1H),3.72-3.67(m,4H),3.43(m,1H),2.66(m,1H),2.51-2.40(m,2H),2.14(s,3H),1.92(m,1H),1.73(m,1H).
Example 79: n- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2-methoxyacetamide
Synthesis of Compound 79.1. A mixture of I-75 (0.125 g,0.232mmol,1.0 eq.), zinc (0.003g, 0.04mmol,0.2 eq.) and zinc cyanide (0.135 g,1.16mmol,5 eq.) in N, N-dimethylacetamide (3 mL) was degassed by bubbling through a stream of argon for 10 min. Tris (dibenzylideneacetone) dipalladium (0) (0.031 g,0.034mmol,0.15 eq.) and 1,1' -bis (diphenylphosphino) ferrocene (0.038 g,0.069mmol,0.3 eq.) were added and degassed for 5min. The reaction mixture was stirred in a microwave reactor at 180℃for 1h. The reaction mixture was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.6% Methanol in DCM) to yield 79.1.MS (ES) m/z 457.3[ M+H ] +.
Synthesis of I-79. To a solution of 79.1 (0.060 g,0.131mmol,1.0 eq.) and triethylamine (0.05 mL,0.393mmol,3 eq.) in DCM (6 mL) was added dropwise 2-methoxyacetyl chloride (0.060 g,0.131mmol,1.0 eq.) at 0deg.C. The reaction mixture was stirred for 2h. It was transferred to ice water, filtered, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.4% Methanol in DCM) to give the residue I-79.MS(ES):m/z 529.42[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.22(s,1H),9.04(s,1H),8.65(s,1H),8.33(s,1H),8.27(d,J＝4Hz,1H),8.19(s,1H),7.74(s,1H),6.81(d,J＝2.8Hz,1H),4.04(s,2H),3.96(s,3H),3.66(s,3H),3.36(s,3H).
Example 80: n- (4- ((2- ((1- (2-hydroxyethyl) -2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -7-methoxy-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound 80.1. A mixture of 77.2 (0.930 g,4.52mmol,1.0 eq.) Int-2 (0.895 g,5.88mmol,1.3 eq.) and sodium carbonate (0.958 g,9.04mmol,2.0 eq.) in DMF (10 mL) was stirred at 50deg.C for 6h. It was cooled to room temperature, transferred to ice water and stirred. The precipitate was collected by filtration, washed with water and dried to give 80.1.MS (ES) m/z 338.7[ M+H ] +.
Synthesis of Compound 80.2. A mixture of compound 80.1 (0.850 g,2.52mmol,1.0 eq.), iron powder (0.705 g,12.6mmol,5.0 eq.) and ammonium chloride (0.673 g,12.6mmol,5.0 eq.) in ethanol: water (8:2, 10 mL) was stirred at 80℃for 2h. Passing the reaction mixture throughIs filtered and rinsed with ethanol. The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)2.4% Methanol in DCM) to give 80.2.MS (ES) m/z 308.5[ M+H ] +.
Synthesis of Compound 80.3. A solution of 80.2 (0.150 g,0.487mmol,1.0 eq.) and 1,1' -thiocarbonyldiimidazole (0.433 g,2.43mmol,5.0 eq.) in THF (2 mL) was stirred at 80℃for 1h. It was cooled to room temperature and transferred to ice water. The precipitated solid was collected by filtration and triturated with hexane to give 80.3.MS (ES) m/z 350.7[ M+H ] +.
Synthesis of Compound 80.4. To a solution of 80.3 (1.0 g,2.86mmol,1.0 eq.) in methanol (7 mL) and NMP (15 mL) was added sodium methoxide solution (25%, 8mL,37.18mmol,13 eq.) and copper iodide (0.119 g,0.629mmol,0.22 eq.). The reaction mixture was stirred at 140℃for 4h. It was cooled to room temperature, transferred to ice water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give 80.4.MS (ES) m/z 304.3[ M+H ] +.
Synthesis of Compound 80.5. To a solution of 80.4 (0.050 g,0.164mmol,1.0 eq.) in acetonitrile (5 mL) was added sulfonyl chloride (0.49 mL,6.06mmol,37 eq.) and stirred for 15min at 0deg.C. It was transferred to saturated sodium bicarbonate solution, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.0% Methanol in DCM) to give 80.5.MS (ES) m/z 306.7[ M+H ] -.
Synthesis of Compound 80.6. To a solution of 80.5 (0.025 g,0.081mmol,1.0 eq.) and pyridine (0.03 mL) in DCM (2 mL) was added acetic anhydride (0.019 mL,0.202mmol,2.5 eq.) at 0 ℃ and the reaction mixture was stirred for 5min. It was transferred to saturated sodium bicarbonate solution, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.8% Methanol in DCM) to give 80.6.MS (ES) m/z 348.7[ M+H ] +.
Synthesis of Compound 80.7. Compound 80.7 was prepared according to the procedure for the synthesis of I-10 from 80.6 and Int-15.3. Through silica gel fast column chromatography2.0% Methanol in DCM). MS (ES) m/z 624.3[ M+H ] +.
Synthesis of I-80. Compound I-80 was prepared from 80.7 according to the procedure described in the synthesis of 40.2. Through silica gel fast column chromatography2.8% Methanol in DCM) purification of the product .MS(ES):m/z:534.45[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.58(s,1H),8.66(s,2H),8.19(d,J＝4Hz,1H),7.95(s,1H),7.69(s,1H),6.67(d,J＝4Hz,1H),5.00(d,J＝8Hz,1H),4.18(s,2H),3.95-3.90(m,6H),3.74-3.73(bs,2H),2.56(s,3H).
Example 81: (N- (4- ((7-cyano-2- ((1- (2-hydroxyethyl) -2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
/>
Synthesis of Compound 81.1. To a solution of 80.3 (30.5 g,87.19mmol,1.0 eq.) in DCM (600 mL) was added sulfuryl chloride (435.5 g,3226mmol,37 eq.) and stirred for 15min at 0deg.C. It was transferred to saturated sodium bicarbonate solution, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give 81.1.MS (ES) m/z 353.6[ M+H ] -.
Synthesis of Compound 81.2. Compound 81.2 was prepared according to the procedure for the synthesis of I-10 from 81.1 and Int-15.3. Through silica gel fast column chromatography2.1% Methanol in DCM). MS (ES) m/z 629.32[ M+H ] +.
Synthesis of Compound 81.3. Compound 81.3 was prepared from 81.2 following the synthetic procedure of (±) -I-74. Through silica gel fast column chromatography2.0% Methanol in DCM). MS (ES) m/z 619.
Synthesis of I-81. Compound I-81 was prepared from 81.3 according to the procedure described in the synthesis of 40.2. Through silica gel fast column chromatography4.0% Methanol in DCM) purification of the product .MS(ES):m/z:529.41[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.71(s,1H),8.66(s,1H),8.32(s,1H),8.25(d,J＝5.6Hz,1H),8.02(s,1H),7.71(s,1H),6.79-6.78(m,1H),4.19(m,2H),3.96(s,3H),3.17(m,2H),2.06(s,3H).
Example 82: n- (4- ((7-chloro-1-methyl-2- ((1- (methyl-d 3) -2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound 82.1. To a solution of 4-bromopyridin-2-amine (100 g,577.9mmol,1.0 eq.) in DMF (1300 mL) was added sodium hydride (111 g,2773.9mmol,4.8 eq.) in portions at 0deg.C. The reaction mixture was stirred for 2h and 4-methoxybenzyl chloride (433 g,2773.9mmol,4.8 eq.) was slowly added. After addition, it was stirred at 0 ℃ for 30min, transferred to ice water and stirred. The precipitated solid was collected by filtration and dried to give 82.1.MS (ES) m/z 414.2[ M+H ] +.
Synthesis of Compound 82.2. To a solution of 82.1 (60 g,145mmol,1.0 eq), cuprous (I) chloride (1.14 g,11.6mmol,0.08 eq.) and N, N-bis (4-hydroxy-2, 6-dimethylphenyl) oxamide (3.8 g,11.6mmol,0.08 eq.) in DMSO (1000 mL) was added sodium hydroxide (11.6 g,290mmol,2.0 eq.). The reaction mixture was stirred at 110℃for 48h. The reaction mixture was cooled to room temperature, transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to give 82.2.MS (ES) m/z 351.2[ M+H ] +.
Synthesis of Compound 82.3. A mixture of 82.2 (39 g,111.3mmol,1.0 eq), sodium carbonate (23.59 g,222.6mmol,2.0 eq.) and Int-2 (18.3 g,89.04mmol,0.8 eq.) in DMF (390 mL) was stirred at 80℃for 1h. The reaction mixture was filtered and the filtrate was transferred to water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography28% Ethyl acetate in hexane) to give 82.3.MS (ES) m/z 536.6[ M+H ] +.
Synthesis of Compound 82.4. A mixture of 82.3 (46 g,85.82mmol,1.0 eq.), ammonium chloride (23.17 g,429.1mmol,5.0 eq.) and iron powder (24.03g,429.1mmol 5.0 eq.) in ethanol (700 mL) and water (250 mL) was stirred at 90℃for 4h. Passing the reaction mixture throughIs filtered through a pad of (a). The filtrate was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)70% Ethyl acetate in hexane) to give 82.4.MS (ES) m/z 506.9[ M+H ] +.
Synthesis of Compound 82.5. Compound 82.5 was prepared from 82.4 and Int-16 according to the procedure described in the synthesis of I-19. Through silica gel fast column chromatography2.8% Methanol in DCM). MS (ES) m/z 710.1[ M+H ] +.
Synthesis of Compound 82.6. Compound 82.6 was prepared from 82.5 according to the procedure described in the synthesis of 40.2. The product was purified by trituration with diethyl ether. MS (ES) m/z 469.5[ M+H ] +.
Synthesis of I-82. To a solution of 82.6 (7.0 g,14.93mmol,1.0 eq.) and pyridine (24 mL,298.6mmol,20 eq.) in DCM (70 mL) was added acetic anhydride (56.6 mL,599.2mmol,40 eq.) and stirred at room temperature for 24h. The reaction mixture was concentrated under reduced pressure. Through silica gel fast column chromatography5-6% Methanol in DCM) to give I-82.MS(ES):m/z:511.3[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.62(bs,1H),8.86(d,J＝7.2Hz,1H),8.65(d,J＝5.2Hz,1H),8.26(d,J＝8.0Hz,1H),8.22(d,J＝6.0Hz,1H),8.17(bs,1H),7.68(bs,1H),6.70-6.68(m,1H),4.02(s,3H),2.07(s,3H).
Example 83: n- (4- ((7-cyano-1-methyl-2- ((1- (methyl-d 3) -2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-83. Compound I-83 was prepared from I-82 following the procedure described in the synthesis of (+ -) -I-74. Through silica gel fast column chromatography2.5% Methanol in DCM) purification of the product .MS(ES):m/z 501.44[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.64(s,1H),9.04(bs,1H),8.65(s,1H),8.30(s,1H),8.24(d,J＝8Hz,1H),8.17(s,1H),7.75(s,1H),6.76-6.55(t,J＝4Hz,1H),3.96(s,3H),2.06(s,3H).
Example 84: n- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2-fluoroacetamide
Synthesis of I-84. To a solution of 3.8 (0.070 g,0.153mmol,1.0 eq.) in THF (5 mL) was added HATU (0.088 g,0.229mmol,1.5 eq.) and stirred for 30min. N, N-diisopropylethylamine (0.049 g,0.382mmol,2.5 eq.) and 2-fluoroacetic acid (0.023 g,0.306mmol,1.5 eq.) were added to the mixture. The reaction mixture was stirred at room temperature for 2h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3% Methanol in DCM) to give a residue I-84.MS(ES):m/z 517.88[M+H]+;99.31％,1H NMR(DMSO-d6,400MHz):δ10.72(s,1H),9.03(s,1H),8.65(s,1H),8.33(s,1H),8.27(d,J＝1.6Hz,1H),8.19(s,1H),7.70(s,1H),6.83(d,J＝5.6Hz,1H),5.07(s,1H),4.95(s,1H),3.96(s,3H),3.36(s,3H).
Example 85: n- (4- ((7-chloro-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2- ((2-methoxyethyl) amino) acetamide
Synthesis of Compound 85.1. To a solution of 1.2 (5.00 g,25.0mmol,1.0 eq.) and trimethylamine (7.575 g,75.0mmol,3.0 eq.) in THF (50 mL) at 0deg.C was added chloroacetyl chloride (4.235 g,37.5mmol,1.5 eq.). The reaction mixture was stirred at room temperature for 2h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.8% Methanol in DCM) to give 85.1.MS (ES) m/z 277.62[ M+H ] +.
Synthesis of Compound 85.2. To a solution of 85.1 (4.0 g,14.45mmol,1.0 eq.) and N, N-diisopropylethylamine (5.60 g,43.36mmol,3.0 eq.) in THF (40 mL) was added 2-methoxyethane-1-amine (1.63 g,21.73mmol,1.5 eq.). The reaction mixture was stirred at 80℃for 1h. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography1.8% Methanol in DCM) to give 85.2.MS (ES) m/z 316.37[ M+H ] +.
Synthesis of Compound 85.3. To a solution of 85.2 (2.60 g,8.25mmol,1.0 eq.) and triethylamine (2.5 g,24.76mmol,3.0 eq.) in DCM (26 mL) was added di-tert-butyl dicarbonate (2.70 g,12.38mmol,1.5 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 2h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography1.2% Methanol in DCM) to give 85.3.MS (ES) m/z 416.49[ M+H ] +.
Synthesis of Compound 85.4. A mixture of compound 85.3 (1.6 g,25.18mmol,1.0 eq.) and 10% palladium on carbon (0.800 g) in methanol (16 mL) was stirred under hydrogen (1 atm) for 2h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 85.4.MS (ES) m/z 326.37[ M+H ] +.
Synthesis of Compound 85.5. A mixture of 85.4 (1.06 g,3.25mmol,1.0 eq), int-2 (0.802 g,3.91mmol,1.2 eq) and potassium carbonate (0.900 g,6.52mmol,2.0 eq) in DMF (10 mL) was stirred at 90℃for 2h. It was cooled to room temperature, transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2% Methanol in DCM) to give 85.5.MS (ES) m/z 511.93[ M+H ] +.
Synthesis of Compound 85.6. A mixture of compound 85.5 (0.345 g,1.28mmol,1.0 eq.), iron powder (0.358 g,6.42mmol,5.0 eq.) and ammonium chloride (0.343g, 6.42mmol,5.0 eq.) in ethanol to water (8:2, 6 mL) was stirred at 80℃for 2h. Passing the reaction mixture throughIs filtered and rinsed with ethanol. The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)2.8% Methanol in DCM) to give 85.6.MS (ES) m/z 481.95[ M+H ] +.
Synthesis of Compound 85.7. Compound 85.7 was prepared from compound 85.6 following the procedure described in the synthesis of compound 3.7. Through silica gel fast column chromatography4.1% Methanol in DCM). MS (ES) m/z 682.05[ M+H ] +.
Synthesis of I-85. To a solution of 85.7 (0.080 g,0.117mmol,1.0 eq.) in DCM (4 mL) was added trifluoroacetic acid (0.267 g,2.348mmol,20.0 eq.) at 0deg.C. The reaction mixture was stirred at room temperature for 1h. It was transferred to ice water, basified with saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography6.3% Methanol in DCM) to give the residue I-85.MS(ES):m/z:581.95[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.32(s,1H),8.85(s,1H),8.63(s,1H),8.25(s,1H),8.21(d,J＝3.7Hz,1H),8.15(s,1H),7.66(s,1H),6.73(d,J＝3.6Hz,1H),3.99(s,3H),3.66(s,3H),3.38-3.33(m,4H),3.23(s,3H),2.71-2.68(d,J＝4.8Hz,2H).
Example 86: n- (4- ((7-chloro-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2-hydroxyacetamide
Synthesis of Compound 86.1. To a solution of 1.2 (2.0 g,16.94mmol,1.0 eq), 1-hydroxybenzotriazole hydrate (2.51 g,18.64mmol,1.1 eq) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (4.88 g,25.42mmol,1.5 eq) in DCM (40 mL) was added N, N-diisopropylethylamine (5.13 g,50.84mmol,3.0 eq). The reaction mixture was stirred at 0deg.C for 15min and 2-acetoxyacetic acid (3.0 g,18.63mmol,1.5 eq.) was added. The reaction mixture was stirred for 16h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a material. Through silica gel fast column chromatography5.0% Methanol in DCM) to give 86.1.MS (ES) m/z 301.31[ M+H ] +.
Synthesis of Compound 86.2. A mixture of Pd-C (10%; 0.7 g) and 86.1 (1.45 g,4.83mmol,1.0 eq.) in methanol (40 mL) was stirred under hydrogen (1 atm) for 2h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 86.2.MS (ES) m/z 211.13[ M+H ] +.
Synthesis of Compound 86.3. A mixture of 86.2 (0.910 g,4.33mmol,1.0 eq), int-2 (0.710 g,3.46mol,0.8 eq) and potassium carbonate (1.8 g,12.99mmol,3.0 eq) in DMF (20 mL) was stirred at room temperature for 6h. It was cooled to room temperature, transferred to ice water and stirred. The precipitated solid was collected by filtration, washed with water and dried to give 86.3.MS (ES) m/z 396.76[ M+H ] +.
Synthesis of Compound 86.4. A mixture of compound 86.3 (0.330 g,0.833mmol,1.0 eq.), iron powder (0.705 g,4.16mmol,5.0 eq.) and ammonium chloride (0.225 g,4.16mmol,5.0 eq.) in ethanol: water (8:2, 10 mL) was stirred at 80℃for 2h. Passing the reaction mixture throughIs filtered and rinsed with ethanol. The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)2.4% Methanol in DCM) to give 86.4.MS (ES) m/z 366.77[ M+H ] +.
Synthesis of I-86. A mixture of 86.4 (0.155 g,0.423mmol,1.0 eq), int-5 (0.148 g,0.635mmol,1.5 eq.) and potassium tert-butoxide (1M in THF, 1.3mL,1.3mmol,3.0 eq.) in THF (5 mL) was stirred at room temperature for 1h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and potassium carbonate (0.05 g) was added at room temperature. The reaction mixture was stirred at room temperature for 30min. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.9% Methanol in DCM) to give the residue I-86.MS(ES):m/z:524.18[M+H]+;1H NMR(DMSO-d6,400MHz):δ9.83(s,1H),8.87(s,1H),8.64(s,1H),8.27(s,1H),8.23(d,J＝6.8Hz,1H),8.17(s,1H),7.68(s,1H),6.75(d,J＝4Hz,1H),5.68(t,J＝4Hz,1H),4.00(s,5H),3.67(s,3H).
Example 87: n- (4- ((7-chloro-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2- ((2-fluoroethyl) amino) acetamide
Synthesis of Compound 87.1. A solution of 85.1 (1.0 g,3.62mmol,1.0 eq.) 2-fluoroethane-1-amine (1.07 g,10.86mmol,3.0 eq.) and TEA (1.83 g,18.15mmol,5.0 eq.) in THF (15 mL) was stirred at 80℃for 20h. It was transferred to water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography48% Ethyl acetate in hexanes) to give 87.1.MS (ES) m/z 304.2[ M+H ] +.
Synthesis of Compound 87.2. A solution of 87.1 (0.910 g,3.00mmol,1.0 eq.) triethylamine (0.606 g,6.00mmol,2.0 eq.) and Boc anhydride (0.784 g,3.6mmol,1.2 eq.) in DCM (15 mL) was stirred at room temperature for 14h. It was transferred to water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography32% Ethyl acetate in hexane) to give 87.2.m/z 404.58[ M+H ] +.
Synthesis of Compound 87.3. A mixture of 87.3 (1.05 g,2.59mmol,1.0 eq.) and 10% palladium on carbon (0.800 g) in methanol (15 mL) was stirred under hydrogen (1 atm) for 1.5h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 87.3.MS (ES) m/z 314.37[ M+H ] +.
Synthesis of Compound 87.4. A mixture of 87.3 (1.05 g,3.35mmol,1.0 eq), int-5 (0.687 g,3.35mmol,1.0 eq) and potassium carbonate (0.924 g,6.7mmol,2.0 eq) in DMF (15 mL) was stirred at room temperature for 2h. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography35% Ethyl acetate in hexane) to give 87.4.MS (ES) m/z 499.52[ M+H ] +.
Synthesis of Compound 87.5. A mixture of compound 87.4 (0.820 g,1.64mmol,1.0 eq.) iron powder (0.4631 g,8.23mmol,5.0 eq.) and ammonium chloride (0.433 g,8.23mmol,5.0 eq.) in ethanol: water (8:2, 12 mL) was stirred at 80℃for 2h. Passing the reaction mixture throughIs filtered and rinsed with ethanol. The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)2.3% Methanol in DCM) to give 87.5.MS (ES) m/z 469.45[ M+H ] +.
Synthesis of Compound 87.6. Compound 87.6 was prepared from compound 87.5 following the procedure described in the synthesis of compound 3.7. Through silica gel fast column chromatography2.8% Methanol in DCM). MS (ES) m/z 670.5[ M+H ] +.
Synthesis of I-87. To a solution of 87.6 (0.120 g,0.178mmol,1.0 eq.) in DCM (6 mL) was added trifluoroacetic acid (1.0 mL) and stirred for 1.5h at 0deg.C. It was transferred to a mixture of ice and saturated aqueous sodium bicarbonate, stirred, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by trituration with diethyl ether gives I-87.MS(ES):m/z:569.82[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.39(s,1H),8.86(s,1H),8.63(s,1H),8.26(s,1H),8.22(d,J＝6.0Hz,2H),8.15(s,1H),7.65(s,1H),6.75-6.73(dd,J＝2.0Hz,1H),4.54(t,J＝4.4Hz,1H),4.42(t,J＝4.8Hz,1H),3.99(s,3H),3.66(s,3H),3.34(s,2H),2.92(t,J＝4.8Hz,1H),2.84(t,J＝4.4Hz,1H).
Example 88: n- (4- ((7-chloro-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) -5-fluoropyridin-2-yl) acetamide
Synthesis of Compound 88.1. A mixture of 2-chloro-5-fluoropyridin-4-ol, potassium carbonate (6.1 g,44.730mmol,3.0 eq.) and benzyl bromide (5.1 g, 29.630 mmol,2.0 eq.) in DMF (120 mL) was stirred at room temperature for 2h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography21% Ethyl acetate in hexane) to give 88.1.MS (ES) m/z 237.66[ M+H ] +.
Synthesis of Compound 88.2. A mixture of 88.1 (1.7 g,7.15mmol,1.0 eq), cyclopropanecarboxamide (0.608 g,7.15mmol,1.2 eq.) and potassium carbonate (1.97 g,14.30mmol,2.0 eq.) in dioxane (15 mL) was purged with argon for 5min, then 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthine (0.413 g, 0.015 mmol,0.1 eq.) and tris (dibenzylideneacetone) dipalladium (0) (0.327 g, 0.356 mmol,0.05 eq.) were added. The reaction mixture was purged with argon for another 5min and stirred at 100 ℃ for 2h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.5% Methanol in DCM). The product was dissolved in methanol and aqueous sodium hydroxide (2.0 g,5.00mmol,10 eq.) was added. The reaction mixture was stirred at 80℃for 4h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)7.0% Methanol in DCM) to give 88.2.MS (ES) m/z 218.23[ M+H ] +.
Synthesis of Compound 88.3. To a solution of 88.2 (1.0 g,4.58mmol,1.0 eq.) and pyridine (1.088 g,13.76mmol,5.0 eq.) in DCM (15 mL) was added acetic anhydride (1.40 g,13.76mmol,3.0 eq.). The reaction mixture was stirred at room temperature for 16h. It was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography26% Ethyl acetate in hexane) to give 88.3.MS (ES) m/z 260.27[ M+H ] +.
Synthesis of Compound 88.4. A mixture of palladium on carbon (10 wt%, 0.400 g) and compound 88.3 (0.700 g,2.69mmol,1.0 eq.) in methanol (20 mL) was stirred under hydrogen (1 atm) for 2h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 88.4.MS (ES) m/z 171.14[ M+H ] +.
Synthesis of Compound 88.5. A mixture of 88.4 (0.45 g,2.65mmol,1.0 eq), int-2 (0.543 g,2.65mol,1.0 eq) and potassium carbonate (1.09 g,7.94mmol,3.0 eq) in DMF (20 mL) was stirred at room temperature for 6h. It was transferred to ice water and stirred. The precipitated solid was collected by filtration, washed with water and dried to give 88.5.MS (ES) m/z 356.71[ M+H ] +.
Synthesis of Compound 88.6. A mixture of 88.5 (0.350 g,0.983mmol,1.0 eq.), iron powder (0.256 g,4.91mmol,5.0 eq.) and ammonium chloride (0.240 g,4.91mmol,5.0 eq.) in ethanol: water (8:2, 10 mL) was stirred at 80℃for 5h. Passing the reaction mixture throughIs filtered and rinsed with ethanol. The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)2.4% Methanol in DCM) to give 88.6.MS (ES) m/z 326.73[ M+H ] +.
Synthesis of I-88. Compound I-88 was prepared from compound 88.6 following the procedure described in the synthesis of compound 3.7. Through silica gel fast column chromatography3.9% Methanol in DCM) purification of the product .MS(ES):m/z:526.85[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.64(s,1H),8.88(s,1H),8.65(s,1H),8.42-8.35(bs,2H),8.17(s,1H),7.54(d,J＝5.6Hz,1H),4.01(s,3H),3.68(s,3H),1.97(s,3H).
Example 89: n- (4- ((7-cyano-2- ((1- (2-hydroxyethyl) -2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) cyclopropanecarboxamide
/>
Synthesis of Compound 89.1. To a solution of 1.2 (2.0 g,9.99mmol,1.0 eq.) and triethylamine (4.17 mL,29.97mmol,3.0 eq.) in DCM (20 mL) was added cyclopropylcarbonyl chloride (1.24 g,11.98mmol,1.2 eq.) and stirred for 1h at room temperature. It was transferred to ice, stirred, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography1.2% Methanol in DCM) to give 89.1.MS (ES) m/z 269.3[ M+H ] +.
Synthesis of Compound 89.2. A mixture of compound 89.1 (0.87 g,3.24mmol,1.0 eq.) and 10% palladium on carbon (0.4 g) in methanol (5 mL) was stirred under hydrogen (1 atm) for 2h. Passing the reaction mixture throughIs filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure. Flash column chromatography over silica gel (/ >)4.5% Methanol in DCM) to give 89.2.MS (ES) m/z 179.2[ M+H ] +.
Synthesis of Compound 89.3. A mixture of 89.2 (0.433 g,2.43mmol,1.0 eq.) Int-2 (0.500 g,2.43mmol,1.0 eq.) and potassium carbonate (0.838 g,6.07mmol,2.5 eq.) in DMF (5 mL) was stirred at 80℃for 2h. It was cooled to room temperature, transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.7% Methanol in DCM) to give 89.3.MS (ES) m/z 364.3[ M+H ] +.
Synthesis of Compound 89.4. A mixture of 89.3 (0.830 g,1.62mmol,1.0 eq.), iron powder (0.4475 g,8.1mmol,5 eq.) and ammonium chloride (0.4475 g,8.1mmol,5 eq.) in ethanol-water (2:1, 10 mL) was stirred at 80℃for 1h. It was transferred to ice water, filtered, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.3% Methanol in DCM) to give 89.4.MS (ES) m/z 334.7[ M+H ] +.
Synthesis of Compound 89.5. Compound 89.5 was prepared from compound 89.4 following the procedure described in the synthesis of compound 3.7. Through silica gel fast column chromatography2.0% Methanol in DCM). MS (ES) m/z 655.5[ M+H ] +.
Synthesis of Compound 89.6. Compound 89.6 was prepared from compound 89.5 following the procedure described in the synthesis of compound (±) -I-74. Through silica gel fast column chromatography2.3% Methanol in DCM). MS (ES) m/z 645.41[ M+H ] +.
Synthesis of I-89. Compound I-89 was prepared from 89.6 according to the procedure described in the synthesis of 40.2. Through silica gel fast column chromatography4.5% Methanol in DCM) purification of the product .MS(ES):m/z:555.26[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.97(s,1H),9.06(s,1H),8.67(s,1H),8.31(s,1H),8.25(d,J＝5.6Hz,1H),8.02(s,1H),7.72(s,1H),6.79(t,J＝2.0Hz,1H),5.00(t,J＝5.2Hz,1H),4.18(s,2H),3.96(s,3H),3.74(d,J＝4.8Hz,2H),1.97(bs,1H),0.78-0.76(m,4H).
Example 90: (R) -N- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2- (4-methylmorpholin-2-yl) acetamide and (S) -N- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2- (4-methylmorpholin-2-yl) acetamide
Synthesis of Compound (+ -) -90.1. To a solution of 2- (4- (tert-butoxycarbonyl) morpholin-2-yl) acetic acid (0.2 g,0.81mmol,1.0 eq.) in THF (8 mL) was added HATU (0.460 g,1.22mmol,1.5 eq.) and stirred for 15min at 0 ℃. To the mixture were added compound 3.8 (0.356 g,0.98mmol,1.2 eq.) and N, N-diisopropylethylamine (0.316 g,2.44mmol,3.0 eq.). The reaction mixture was stirred at 60 ℃ overnight. It was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.8% Methanol in DCM) to give (±) -90.1.MS (ES) m/z 684.2[ M+H ] +.
Synthesis of Compound (+ -) -90.2. To a solution of (+ -) -90.2 (0.15 g,0.21mmol,1.0 eq.) in DCM (5 mL) was added trifluoroacetic acid (0.8 mL) at 0deg.C. The reaction mixture was stirred at room temperature for 1h. It was concentrated under reduced pressure to give (+ -) -90.2. It was used in the next step without purification. MS (ES) m/z 584.2[ M+H ] +.
Synthesis of Compound (+ -) -I-90. To a solution of (+ -) -90.2 (0.1 g,0.17mmol,1.0 eq.) in 1, 2-dichloroethane (5 mL) was added formaldehyde solution (37% in H 2 O) (0.020g, 0.25mmol,1.5 eq.) at 0deg.C and stirred for 15min. Sodium triacetoxyborohydride (0.109 g,0.51mmol,3 eq.) was added to the mixture and stirred at room temperature for 16h. It was transferred to ice water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.2% Methanol in DCM) to give (±) -I-90.MS (ES) m/z 598.3[ M+H ] +.
I-90-a and I-90-b. The racemate was subjected to chiral HPLC separation (column: CHIRALPAK IH (250 mm x 21 mm), 5 μm; mobile phase (a) 0.1% dea in n-hexane (B) 0.1% dea in propan-2-ol: acetonitrile (70:30; flow rate = 20 mL/min) to give a first eluted fraction (Int-90-a) and a second eluted fraction (Int-90-B).
I-90-a：MS(ES):m/z 598.4[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.65(s,1H),9.05(s,1H),8.66(s,1H),8.33(s,1H),8.27-8.25,(d,J＝8Hz,1H),8.20(s,1H),7.77(s,1H),6.82-6.80(m,1H),3.97(s,3H),3.82(bs,1H),3.74-3.71(m,1H),3.67(m,3H),3.47-3.40(t,J＝8Hz,1H),2.69-2.67(d,J＝8Hz,1H),2.47-2.42(m,2H),2.16(s,3H),1.99-1.94(t,J＝12Hz,1H),1.74-1.69(t,J＝8Hz,1H).
I-90-b：MS(ES):m/z 598.4[M+H]+;1H NMR(DMSO-d6,400MHz):):δ10.65(s,1H),9.05(bs,1H),8.66(s,1H),8.33(s,1H),8.27,(d,J＝4Hz,1H),8.20(s,1H),7.77(s,1H),6.82-6.80(m,1H),4.66-4.60(m,1H),3.98(s,3H),3.81(bs,1H),3.74-3.71(m,1H),3.67(s,3H),3.45(t,J＝8Hz,1H),2.68(d,J＝8Hz,1H),2.47-2.43(m,2H),2.16(s,3H),1.94(t,J＝8Hz,1H),1.72(t,J＝8Hz,1H).
Example 91: (R) -N- (4- ((7-chloro-1-methyl-2- ((2- (tetrahydrofuran-3-yl) -6- (trifluoromethyl) pyridin-4-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide and (S) -N- (4- ((7-chloro-1-methyl-2- ((2- (tetrahydrofuran-3-yl) -6- (trifluoromethyl) pyridin-4-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of compound (+ -) -I-91. 81.1 A mixture of (0.120 g,0.516mmol,1.0 eq), (+ -) -Int-17 (0.145 g,0.413mmol,0.5 eq) and potassium carbonate (0.214 g,1.55mmol,3 eq) in 1, 4-dioxane (5 mL) was degassed by bubbling a stream of argon for 10 min. 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthine (0.059 g,0.103mmol,0.2 eq.) and tris (dibenzylideneacetone) dipalladium (0) (0.047 g,0.051mmol,0.1 eq.) were added and degassed for 5min. The reaction mixture was stirred at 120℃for 3h. It was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give (±) -I-91.MS (ES) m/z 548.92[ M+H ] +.
I-91-a and I-91-b. The racemate was subjected to chiral HPLC separation (column: CHIRALPAK IC (250 mm x 21mm,5 μm); mobile phase (a) 0.1% dea in n-hexane (B) 0.1% dea in propan-2-ol: acetonitrile (70:30; flow rate = 20 mL/min) to give a first eluted fraction (Int-91-a) and a second eluted fraction (Int-91-B).
I-91-a：MS(ES):m/z:548.25[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.59(s,1H),8.31(s,1H),8.20(s,2H),7.90(s,2H),7.67(s,1H),6.67(m,1H),4.10(m,1H),3.99(s,3H),3.37(m,3H),2.05(s,2H),1.25(m,1H),1.15(m,1H),1.12(m,1H),1.05(m,1H).
I-91-b：MS(ES):m/z:548.25[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.59(s,1H),8.31(s,1H),8.20(s,2H),7.90(s,2H),7.67(s,1H),6.67(m,1H),4.10(m,1H),3.99(s,3H),3.37(m,3H),2.05(s,2H),1.25(m,1H),1.15(m,1H),1.12(m,1H),1.05(m,1H).
Example 92: n- (4- ((7-chloro-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound I-92. Compound I-92 was prepared from 80.2 and Int-7 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatography3.0% Methanol in DCM) to give the product I-92.MS(ES):m/z:489.6[M+H]+1HNMR(DMSO-d6,400MHz):δ10.58(s,1H),10.38(s,1H),8.18(d,J＝4Hz,2H),7.65(s,1H),7.09(s,1H),6.67-6.66(m,1H),4.16(bs,2H),3.96(s,3H),2.46(m,2H),2.36(bs,2H),2.05(bs,4H).
Example 93: n- (4- ((7-cyano-2- ((4, 4-difluoro-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound I-93. Compound I-93 was prepared from I-92 following the procedure described in the synthesis of 31.5. Through silica gel fast column chromatography4.5% Methanol in DCM) purification of the product .MS(ES):m/z 438.2[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.68-10.64(d,2H),8.24-8.20(m,2H),7.73(bs,1H),7.09(s,1H),6.74-6.73(s,1H),4.16(bs,2H),3.92(s,3H),2.46(m,2H),2.36(bs,2H),2.05(bs,4H).
Example 94: n- (4- ((7-chloro-2- ((4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-94. Compound I-94 was prepared from 80.2 and Int-18 following the procedure described in the synthesis of 3.7. Through silica gel fast column chromatography3.9% Methanol in DCM) purification of the product .MS(ES):m/z:526.85[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.6(s,1H),9.67(s,1H),8.29(s,1H),8.18(t,J＝6.8Hz,3H),7.73(d,J＝8Hz,1H),7.659(s,1H),6.66(t,J＝8Hz,1H),4.00(s,3H),3.51(s,2H),2.19(s,6H),2.04(s,3H).
Example 95: (R) -N- (4- ((7-cyano-1-methyl-2- ((2- (tetrahydrofuran-3-yl) -6- (trifluoromethyl) pyridin-4-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide and (S) -N- (4- ((7-cyano-1-methyl-2- ((2- (tetrahydrofuran-3-yl) -6- (trifluoromethyl) pyridin-4-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of compound (+ -) -I-95. The compound (+ -) -I-95 was prepared from (+ -) -I-91 following the procedure described in the synthesis of (+ -) -I-74. Through silica gel fast column chromatography2.5% Methanol in DCM). MS (ES) m/z 539.49[ M+H ] +.
I-95-a and I-95-b. The racemate was subjected to chiral HPLC separation (column: CHIRALPAK IC (250 mm x 21mm,5 μm); mobile phase (a) 0.1% dea in n-hexane (B) 0.1% dea in propan-2-ol: acetonitrile (70:30; flow rate = 20 mL/min) to give a first eluted fraction (Int-95-a) and a second eluted fraction (Int-95-B).
I-95-a: MS (ES) m/z 539.22[ M+H ] +; chiral device HPLC:96.88％,1H NMR(DMSO-d6,400MHz):δ10.68(s,1H),10.28(s,1H),8.40(s,1H),8.33(s,1H),8.27(d,J＝4Hz,1H),8.05(s,1H),7.76(s,1H),6.77(s,1H),4.14(m,1H),4.00(s,3H),3.86-3.80(m,3H),2.18-2.16(m,2H),2.03(m,3H),1.42(s,1H).
I-95-b：MS(ES):m/z:539.22[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.68(s,1H),10.28(s,1H),8.40(s,1H),8.33(s,1H),8.27(d,J＝4Hz,1H),8.05(s,1H),7.76(s,1H),6.77(s,1H),4.14(m,1H),4.00(s,3H),3.86-3.80(m,3H),2.18-2.16(m,2H),2.03(m,3H),1.42(s,1H).
Example 96: (S) -N- (4- ((7-chloro-1-methyl-2- ((3- ((1-methylpyrrolidin-2-yl) methoxy) -5- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-96. Compound I-96 was prepared from 81.1 and Int-19.3 according to the procedure described in the synthesis of I-10. Through silica gel fast column chromatography5.6% Methanol in DCM) purification of the product .MS(ES):m/z:588.41[M-H]+;1H NMR(DMSO-d6,400MHz):δ10.61(s,1H),9.70(s,1H),8.21(d,J＝7.2Hz,2H),8.01(s,1H),7.90(s,1H),7.66(s,1H),6.98(s,1H),6.69-6.67(m,1H),4.186-4.130(m,1H),4.02(s,3H),3.18(s,1H),2.59(s,3H),2.05(s,5H),1.82(s,4H).
Example 97: (R) -N- (4- ((7-chloro-1-methyl-2- ((3- ((1-methylpyrrolidin-2-yl) methoxy) -5- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-97. Compound I-97 was prepared from 81.1 and Int-20.1 according to the procedure described in the synthesis of I-10. Through silica gel fast column chromatography5.6% Methanol in DCM) purification of the product .MS(ES):m/z:592.2[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.60(s,1H),9.69(s,1H),8.22-8.20(m,2H),8.00(s,1H),7.89(s,1H),7.67(s,1H),6.98(s,1H),6.69-6.67(m,1H),4.17-4.12(m,2H),4.02(s,3H),2.47(s,3H),2.05(s,4H),1.93(s,1H),1.81-1.74(m,3H),1.69(s,1H).
Example 98: n- (4- ((2- ((1- (2-oxaspiro [3.3] heptan-6-yl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) amino) -7-chloro-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound I-98. Compound I-98 was prepared from 80.2 and Int-6 following the procedure described in the synthesis of 3.7. Through silica gel fast column chromatography5.0% Methanol in DCM) purification of the product .MS(ES):m/z:539.22[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.59(s,2H),8.18(d,J＝8Hz,1H),8.14(s,1H),7.64(s,1H),7.31(s,1H),6.66(d,J＝4Hz,1H),4.85(m,1H),4.70(s,2H),4.58(s,2H),3.96(s,3H),3.17(s,3H),2.80(d,J＝8Hz,2H),2.03(s,2H).
Example 99: (S) -N- (4- ((7-chloro-1-methyl-2- ((3- ((1-methylpyrrolidin-3-yl) oxy) -5- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-99. Compound I-99 was prepared from 80.2 and Int-21 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatography3.2% Methanol in DCM) purification of the product .MS(ES):m/z:576.3[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.60(s,1H),9.69(s,1H),8.20(d,J＝4.8Hz,2H),7.98(s,1H),7.85(s,1H),7.65(s,1H),6.87(s,1H),6.79-6.65(m,1H),5.03(s,1H),4.12(s,3H),2.73-2.67(m,4H),2.45-2.41(m,5H),2.04(s,3H).
Example 100: (R) -N- (4- ((7-chloro-1-methyl-2- ((3- ((1-methylpyrrolidin-3-yl) oxy) -5- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-100. Compound I-100 was prepared from 80.2 and Int-22 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatography3.2% Methanol in DCM) to give I-100 (0.025 g, yield ：19.08％).MS(ES):m/z:574.8[M-H]+,1H NMR(DMSO-d6,400MHz):δ10.61(s,1H),9.70(s,1H),8.21-8.20(d,J＝4.4Hz,2H),7.99(s,1H),7.86(s,1H),7.67(s,1H),6.88(s,1H),6.68(d,J＝5.2,1H),5.03(s,1H),4.02(s,3H),2.97-2.86(m,3H),2.40-2.41(m,5H),2.05(s,3H),1.93(s,1H).
Example 101: n- (4- ((7-chloro-1-methyl-2- ((3- (((1-methylazetidin-3-yl) oxy) methyl) -5- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound 101.1. Compound 101.1 was prepared from 81.1 and Int-23 following the procedure described in the synthesis of I-10. Through silica gel fast column chromatography5.0% Methanol in DCM). MS (ES) m/z 663.43[ M-H ] +.
Synthesis of Compound 101.2. To a solution of 101.1 (0.145 g,0.219mmol,1.0 eq.) in DCM (5 mL) was added TFA (2.0 mL) dropwise at 0deg.C. The reaction mixture was stirred for 30min. It was transferred to saturated aqueous sodium bicarbonate and extracted with 15% methanol in DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was further triturated with diethyl ether to give 101.2.MS (ES) m/z 563.36[ M+H ] +.
Synthesis of I-101. A solution of 101.2 (0.100 g,0.177mmol,1.0 eq), formaldehyde (37% in water, 0.043g,0.533mmol,3.0 eq) and acetic acid (0.026 g,0.444mmol,2.5 eq) in 1, 2-dichloroethane (6 mL) was stirred for 10min and sodium triacetoxyborohydride (0.112 g,0.53 mmol,3.0 eq) was added. The mixture was stirred for 15min, transferred to saturated aqueous sodium bicarbonate and extracted with 15% methanol in DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography18% Methanol in DCM) to give a purified residue I-101.MS(ES):m/z:576.16[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.60(s,1H),9.80(s,1H),8.36(s,1H),8.20-8.13(m,3H),7.66(s,1H),7.34(s,1H),6.67-6.65(dd,J＝2.4Hz,1H),4.53(s,2H),4.28(t,J＝5.6Hz,1H),4.01(s,3H),3.54(s,3H),3.00(s,3H),2.32(s,2H),2.04(s,2H).
Example 102: (R) -N- (4- ((7-chloro-1-methyl-2- ((3- (1-methylpyrrolidin-2-yl) -5- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide and (S) -N- (4- ((7-chloro-1-methyl-2- ((3- (1-methylpyrrolidin-2-yl) -5- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound I-102-a. Compound I-102-a was prepared from 80.2 and Int-24-a according to the procedure described in the synthesis of 3.7. Through silica gel fast column chromatography5.0% Methanol in DCM) purification of the product .MS(ES):m/z:539.22[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.70(s,1H),9.72(s,1H),8.40(s,1H),8.21-8.20(d,J＝4Hz,2H),8.09(s,1H),7.67(s,1H),7.33(s,1H),6.67(s,1H),4.02(s,3H),3.99(m,1H),3.29-3.23(m,3H),2.34-2.30(m,2H),2.05(s,3H),1.89(m,2H),1.84(m,2H).
Synthesis of Compound I-102-b. Compound I-102-b was prepared from 80.2 and Int-24-b according to the procedure described in the synthesis of 3.7. Through silica gel fast column chromatography5.0% Methanol in DCM) purification of the product .MS(ES):m/z:539.22[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.70(s,1H),9.72(s,1H),8.40(s,1H),8.21(d,J＝4Hz,2H),8.09(s,1H),7.67(s,1H),7.33(s,1H),6.67(s,1H),4.02(s,3H),3.99(m,1H),3.29-3.23(m,3H),2.34-2.30(m,2H),2.05(s,3H),1.89(m,2H),1.84(m,2H).
Example 103: n- (4- ((7-chloro-1-methyl-2- ((3- ((1-methylazetidin-3-yl) oxy) -5- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound 103.1. Compound 103.1 was prepared from 81.1 and Int-25 according to the procedure described in the synthesis of I-10. Through silica gel fast column chromatography5.3% Methanol in DCM). MS (ES) m/z 649.04[ M-H ] +.
Synthesis of Compound 103.2. To a solution of 103.1 (0.090 g,3.32mmol,1.0 eq.) in DCM (3 mL) was added a solution of HCl in dioxane (4M, 1.0 mL) at 0deg.C. The reaction mixture was stirred at room temperature for 1h. It was transferred to ice water, neutralized with sodium bicarbonate, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 103.2. It was used in the next step without purification. MS (ES) m/z 548.92[ M+H ] +.
Synthesis of I-103. Compound I-103 was prepared from 103.2 according to the procedure described in the synthesis of I-101. Through silica gel fast column chromatography4.2% Methanol in DCM) purification of the product .MS(ES):m/z:562.95[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.60(s,1H),9.81(s,1H),8.20(d,J＝3.6Hz,2H),7.96(s,1H),7.90(s,1H),7.66(s,1H),6.79(s,1H),6.66-6.67(m,1H),4.91-4.89(m,1H),4.02(s,3H),3.92(s,2H),3.19(s,3H),2.39(s,3H),2.04(s,3H).
Example 104: n- (4- ((7-cyano-1-methyl-2- ((5- (1, 1-trifluoro-2-methylpropan-2-yl) isoxazol-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound 104.1. To a solution of 80.3 (0.110 g,0.314mmol,1.0 eq.) in acetic acid (5 mL) was added aqueous hydrobromoacid (0.037 g,0.471mmol,1.5 eq.) followed by bromine (0.200 g,1.25mmol,4.0 eq.) and the reaction mixture stirred for 10min at 0deg.C. It was transferred to saturated aqueous sodium bicarbonate, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give 104.1.MS (ES) m/z 397.6[ M+H ] +.
Synthesis of Compound 104.2. To a solution of 104.1 (0.120 g,0.320mmol,1.0 eq.) and 5- (1, 1-trifluoro-2-methylpropan-2-yl) isoxazol-3-amine (0.117 g,0.605mmol,2.0 eq.) in isopropanol (8 mL) was added hydrochloric acid in 1, 4-dioxane (4M, 0.5 mL). The reaction mixture was stirred at 80℃for 16h. It was cooled to room temperature, transferred to water, basified with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography1.9% Methanol in DCM) to give 104.2.MS (ES) m/z 510.87[ M ] +.
Synthesis of I-104. 104.2 A mixture of (0.070 g,0.137mmol,1.0 eq.), zinc powder (0.0019 g,0.027mmol,0.2 eq.) and zinc cyanide (0.080 g,0.068mmol,0.5 eq.) in dimethylacetamide (5 mL) was degassed by bubbling through a stream of argon for 10 min. 1,1' -bis (diphenylphosphino) ferrocene (0.023 g,0.041mmol,0.3 eq.) and tris (dibenzylideneacetone) dipalladium (0) (0.025 g,0.027mmol,0.2 eq.) were added and degassed for 5min. The reaction mixture was stirred in a microwave reactor at 190 ℃ for 3h. It was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.2% Methanol in DCM) to give I-104.MS(ES):m/z:499.21[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.95(s,1H),10.62(s,1H),8.19(d,J＝8Hz,2H),7.64(s,1H),7.25(bs,1H),6.66(d,J＝4Hz,1H),3.95(s,3H),2.04(s,3H),1.61(s,6H).
Example 105: n- (4- ((7-cyano-2- ((4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound 105.1. Compound 105.1 was prepared from 31.5 and Int-18 following the procedure described in the synthesis of 40.1. Through silica gel fast column chromatography3.9% Methanol in DCM). MS (ES) m/z 723.77[ M+H ] +.
Synthesis of compound 105.2. Compound 105.2 was prepared from 105.1 following the procedure described in the synthesis of 40.2. Through silica gel fast column chromatography3.9% Methanol in DCM). MS (ES) m/z 483.47[ M+H ] +.
Synthesis of I-105. To a solution of 105.2 (0.04 g,0.082mmol,1.0 eq.) in DCM (5 mL) at 0deg.C was added acetic anhydride (0.016 mg,0.16mmol,2.0 eq.) and triethylamine (0.2 mL,0.16mmol,2.0 eq.). The reaction mixture was allowed to stir at room temperature for 1h. It was transferred to water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was stirred with methanol and potassium carbonate at room temperature for 30min. It was transferred to ice water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by reverse phase column to give I-105.MS(ES):m/z 525.51[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.67(s,1H),8.31(s,1H),8.22(d,J＝8Hz,4H),7.76-7.74(d,J＝7.8Hz,2H),6.74(m,J＝8Hz,4H),3.97(s,3H),3.51(s,2H),2.20(s,6H),2.06(s,3H).
Example 106: n- (4- ((2- ((1- (2-oxaspiro [3.3] heptan-6-yl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) amino) -7-cyano-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound 106.1. Compound 106.1 was prepared from 31.8 according to the procedure described in the synthesis of I-105. Through silica gel fast column chromatography2.8% Methanol in DCM). MS (ES) m/z 343.74[ M+H ] +.
Synthesis of I-106. Compound I-106 was prepared from 106.1 and Int-6 following the procedure described in the synthesis of I-10. Through silica gel fast column chromatography3.5% Methanol in DCM) purification of the product .MS(ES):m/z:554.21[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.62(s,1H),8.21(d,J＝5.6Hz,1H),8.01(bs,2H),7.68(s,1H),7.33(s,1H),6.69-6.59(m,1H),4.69(s,4H),4.32(s,1H),3.76(bs,3H),2.73-2.69(m,4H),2.06(s,3H).
Example 107: n- (4- ((2- ((1- (7-oxaspiro [3.5] nonan-2-yl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) amino) -7-chloro-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2-methoxyacetamide
Synthesis of I-107. Compound I-107 was prepared from 75.3 and Int-26 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatography1.5-1.8% Methanol in DCM) to purify the product .MS(ES):m/z:621.31[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.53(s,1H),10.11(s,1H),8.22-8.16(m,2H),7.64(s,1H),7.34(s,1H),6.73(s,1H),4.94-4.92(d,J＝8.8Hz,1H),4.03-3.99(m,6H),3.58(s,2H),3.51(s,2H),3.33(s,3H),2.52(s,3H),1.71(s,2H),1.63(s,2H).
Example 108: (R) -N- (4- ((7-chloro-1-methyl-2- ((4- (1-methylpyrrolidin-2-yl) -3- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide and (S) -N- (4- ((7-chloro-1-methyl-2- ((4- (1-methylpyrrolidin-2-yl) -3- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-108-a. Compound I-108-a was prepared from 80.2 and Int-27-a according to the procedure described in the synthesis of 3.7. Through silica gel fast column chromatography2.8% Methanol in DCM) purification of the product .MS(ES):m/z:559.98[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.59(s,1H),9.71(s,1H),8.29(s,1H),8.21-8.18(m,3H),7.91(d,J＝8.4Hz,1H),7.67(s,1H),6.68(t,J＝5.2Hz,1H),4.01(s,3H),3.29(bs,1H),2.34-2.16(m,4H),2.05(m,4H),1.93-1.83(m,3H),1.61(bs,1H).
Synthesis of I-108-b. Compound I-108-b was prepared from 80.2 and Int-27-b according to the procedure described in the synthesis of 3.7. Through silica gel fast column chromatography2.9% Methanol in DCM) purification of the product .MS(ES):m/z:559.98[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.60(s,1H),9.69(s,1H),8.27(s,1H),8.20-8.16(m,3H),7.90(d,J＝8.4,1H),7.65(s,1H),6.68-6.65(dd,J＝2.0Hz,1H),4.00(s,3H),3.24(bs,1H),2.20-2.13(m,4H),2.04(m,4H),1.91-1.83(m,3H),1.59(bs,1H).
Example 109: (R) -N- (4- ((7-cyano-1-methyl-2- ((4- (1-methylpyrrolidin-2-yl) -3- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide and (S) -N- (4- ((7-cyano-1-methyl-2- ((4- (1-methylpyrrolidin-2-yl) -3- (trifluoromethyl) phenyl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-109-a. The compound I-109-a was prepared from I-108-a following the procedure described in the synthesis of (+ -) -I-74. Through silica gel fast column chromatography3.3% Methanol in DCM) purification of the product .MS(ES):m/z 551.4,[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.66(s,1H),9.96(s,1H),8.30(s,1H),8.26-8.21(m,3H),7.91(d,J＝8.4Hz,1H),7.76(s,1H),6.76(d,J＝3.6Hz,1H),3.98(s,3H),3.25(bs,1H),2.26-2.21(m,4H),1.97(m,4H),1.90-1.80(m,3H),1.51(bs,1H).
Synthesis of I-109-b. Compound I-109-b was prepared from I-108-b following the procedure described in the synthesis of (+ -) -I-74. Through silica gel fast column chromatography3.4% Methanol in DCM) purification of the product .MS(ES):m/z 551.3,[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.66(s,1H),9.94(s,1H),8.30(s,1H),8.26-8.21(m,3H),7.92(d,J＝8.4Hz,1H),7.76(s,1H),6.76(d,J＝3.6Hz,1H),3.98(s,3H),3.25(bs,1H),2.26-2.21(m,4H),1.97(m,4H),1.90-1.80(m,3H),1.51(bs,1H).
Example 110: n- (4- ((2- ((1- (7-oxaspiro [3.5] nonan-2-yl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) amino) -7-cyano-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -2-methoxyacetamide
Synthesis of Compound 110.1. Compound 110.1 was prepared from 31.5 and Int-26 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatography38-48% Ethyl acetate in hexanes). MS (ES) m/z 780.83[ M+H ] +.
Synthesis of Compound 110.2. Compound 110.2 was prepared from 110.1 according to the procedure described in the synthesis of 40.2. Through silica gel fast column chromatography45-55% Methanol in DCM). MS (ES) m/z 540.52[ M+H ] +.
Synthesis of I-110. To a solution of 110.2 (0.080 g,0.148mmol,1.0 eq.) and triethylamine (2.0 mL) in DCM (5 mL) was added 2-methoxyacetyl chloride (0.024 g,0.222mmol,1.5 eq.). The reaction mixture was stirred at room temperature for 30min. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography1.5-1.8% Methanol in DCM) to give I-110.MS(ES):m/z:612.41[M+H]+,1H NMR(DMSO-d6,400MHz):δ10.83(s,1H),10.21(s,1H),8.26-8.24(m,2H),7.72(s,1H),7.34(s,1H),6.79(d,J＝3.6Hz,1H),4.96-4.92(m,1H),4.04(s,3H),3.95(s,3H),3.57-3.50(m,4H),3.34(s,2H),2.50(s,4H),1.70(s,2H),1.62(s,2H).
Example 111: n- (4- ((7-chloro-1-methyl-2- ((2- (pyrrolidin-1-yl) -6- (trifluoromethyl) pyridin-4-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound I-111. Compound I-111 was prepared from 80.2 and Int-28 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatography85-90% Ethyl acetate in hexane) to purify the product .MS(ES):m/z:547.21[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.60(s,1H),9.82(s,1H),8.22-8.19(m,2H),7.66(s,1H),7.59(s,1H),7.33(s,1H),6.67(d,J＝3.6Hz,1H),4.01(s,3H),3.46(s,3H),2.50(s,4H),2.01(s,4H).
Example 112: n- (4- ((7-cyano-2- ((4, 4-dimethyl-6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-112. To a solution of 43.2 (0.050 g,0.116mmol,1.0 eq.) in DCM (3 mL) was added pyridine (0.091 g,1.16mmol,10.0 eq.) followed by acetic anhydride (0.027 g,2.32mmol,20.0 eq.). The reaction mixture was stirred at room temperature for 16h. It was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography4.0% Methanol in DCM) to give the residue I-112.MS(ES):m/z:474.5[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.65(s,1H),10.45(s,1H),8.25-8.23(d,J＝5.6Hz,1H),8.16(bs,1H),7.74(s,1H),6.75-6.74(d,J＝3.6Hz,1H),6.64(s,1H),4.11(bs,2H),4.01(bs,2H),3.91(s,3H),2.07(s,3H),1.55(s,6H).
Example 113: n- (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound 113.1. Compound 113.1 was prepared from 31.5 and Int-29 according to the procedure described in the synthesis of I-19. Through silica gel fast column chromatographyDichloromethane) to yield 113.1.MS (ES) m/z 668[ M+H ] +.
Synthesis of Compound 113.2. Compound 113.2 was prepared from 113.1 according to the procedure described in the synthesis of 40.2. The product was purified by trituration with diethyl ether. MS (ES) m/z 428[ M+H ] +.
Synthesis of I-113. Compound I-113 was prepared from 113.2 following the procedure described in the synthesis of I-112. Through silica gel fast column chromatography2.8% Methanol in DCM) purification of the product .MS(ES):m/z 470.32[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.65(s,1H),10.39(s,1H),8.19(s,1H),7.62(s,1H)7.15(d,J＝7.6Hz,2H),6.74(s,2H),4.12-3.98(m,2H),3.93(s,3H),2.70(s,3H),2.43-2.46(m,2H),2.22(s,2H),2.02(s,2H),1.58(s,2H).
Example 114: n- (4- ((7-cyano-2- ((6 ',7' -dihydro-5 ' H-spiro [ cyclopropane-1, 4' -pyrazolo [1,5-a ] pyridin ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-114. Compound I-114 was prepared from 63.2 according to the procedure described in the synthesis of I-112. Through silica gel fast column chromatography3.0% Methanol in DCM) purification of the product .MS(ES):m/z:469.51[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.66(s,1H),8.25(d,J＝4.0Hz,1H),8.16(s,1H),7.740(s,1H),6.74(bs,1H),6.24(s,1H),3.90(bs,4H),3.36(s,3H),2.07(s,3H),1.80(bs,1H),1.26(s,3H),0.97(bs,3H).
Example 115: n- (4- ((2- ((1- (tert-butyl) -2, 3-dihydro-1H-imidazo [1,2-b ] pyrazol-6-yl) amino) -7-cyano-1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of I-115. Compound I-115 was prepared from 70.2 following the procedure described in the synthesis of I-112. Through silica gel fast column chromatography3.1-3.7% Methanol in DCM) purification of the product .MS(ES):m/z:487.36[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.59(s,1H),10.22(s,1H),8.20(d,J＝6Hz,1H),8.135(s,1H),7.77-7.65(m,1H),6.70(s,1H),6.03(s,1H),3.92-3.86(m,3H),3.64(s,2H),3.84(s,2H),2.03(s,3H),1.25(s,9H).
Example 118: n- (4- ((7-cyano-2- ((4, 4-dimethyl-4, 5,7, 8-tetrahydropyrazolo [1,5-d ] [1,4] oxazepin-2-yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound I-118. Compound I-118 was prepared from 67.2 according to the procedure described in the synthesis of I-112. Through silica gel fast column chromatography4.7% Methanol in DCM) purification of the product .MS(ES):m/z:488.36[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.66(s,1H),10.38(s,1H),8.24(d,J＝5.6Hz,1H),8.17(s,1H),7.73(s,1H),6.74(d,J＝3.2Hz,1H),6.67(s,1H),4.38(s,2H),3.90(s,3H),3.86(s,2H),3.58(s,2H),2.06(s,3H),1.31(s,6H).
Example 119: n- (4- ((7-cyano-1-methyl-2- ((5 '-methyl-6', 7 '-dihydro-5' H-spiro [ cyclopropa-1, 4 '-pyrazolo [1,5-a ] pyrazin ] -2' -yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) acetamide
Synthesis of Compound 119.1. Compound 119.1 was prepared from 31.5 and Int-30 following the procedure described in the synthesis of I-19. Through silica gel fast column chromatography3.0% Methanol in DCM). MS (ES) m/z 683.7[ M+H ] +.
Synthesis of Compound 119.2. Compound 119.2 was prepared from 119.1 according to the procedure described in the synthesis of 40.2. The product was purified by trituration with diethyl ether. MS (ES) m/z 443.5[ M+H ] +.
Synthesis of Compound I-119. Compound I-119 was prepared from 119.2 according to the procedure described in the synthesis of I-118. Through silica gel fast column chromatography5.0% Methanol in DCM) purification of the product .MS(ES):m/z:485[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.62(bs,1H),10.38(bs,1H),8.23-8.14(m,2H),7.37(s,1H),6.73(bs,1H),6.30(bs,1H),4.10(bs,2H),3.90(bs,2H),3.32(s,3H),2.36(m,3H),2.06(bs,1H)1.25(m,2H),1.025(m,2H).
Example 120: (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid (S) -tetrahydrofuran-3-yl ester
Synthesis of Compound I-120. To a solution of 56.2 (0.05 g,0.116mmol,1.0 eq.) and triethylamine (0.035 g,0.348mmol,3.0 eq.) in THF (5 mL) at 0deg.C was added phenyl chloroformate (0.027 g,0.174mmol,1.5 eq.). The reaction mixture was stirred for 15min and trimethylamine (0.035 g,0.348mmol,3 eq.) and (S) -tetrahydrofuran-3-ol (0.031 g,0.35mmol,3 eq.) were added thereto. The reaction mixture was stirred at 70℃for 16h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography2.5% Methanol in DCM) to give I-120.MS(ES):m/z:541.57[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.38-10.34(bs,2H),8.20-8.17(bs,2H),7.413(s,1H),6.73-6.71(bs,2H),5.20(s,1H),4.04(t,J＝13.6Hz,2H),3.910(s,3H),3.78-3.63(bs,4H),2.67-2.60(bs,2H),2.40-2.33(bs,2H),2.27-2.25(bs,2H),2.18-2.09(bs,1H),2.04-2.02(bs,2H),1.92-1.89(bs,1H).
Example 121: (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) carbamic acid (R) -tetrahydrofuran-3-yl ester
Synthesis of Compound I-121. Compound I-121 was prepared from 56.2 and (R) -tetrahydrofuran-3-ol according to the procedure described in the synthesis of I-120. Through silica gel fast column chromatography2.5% Methanol in DCM) purification of the product .MS(ES):m/z:541.57[M+H]+;1H NMR(DMSO-d6,400MHz):δ10.38-10.35(bs,2H),8.20-8.17(bs,2H),7.414(s,1H),6.73-6.72(bs,2H),5.20(s,1H),4.04(t,J＝13.6Hz,2H),3.91(s,3H),3.78-3.67(bs,4H),2.67-2.64(bs,2H),2.40-2.33(bs,2H),2.27-2.25(bs,2H),2.16-2.08(bs,1H),2.04-2.02(bs,2H),1.93-1.91(bs,1H).
Example 122: n- (4- ((7-cyano-2- ((5 ',6' -dihydrospiro [ cyclobutane-1, 4 '-pyrrolo [1,2-b ] pyrazol ] -2' -yl) amino) -1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) cyclopropanecarboxamide
Synthesis of I-122. A solution of 56.2 (0.05 g,0.116mmol,1 eq.) and cyclopropanecarboxylic anhydride (0.238 g,2.3mmol,20 eq.) and pyridine (0.093 g,1.2mmol,10 eq.) in DCM (3 mL) was stirred at room temperature for 16h. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Through silica gel fast column chromatography3.0% Methanol in DCM) to give the residue I-122.MS(ES):m/z:495.55[M+H]+;1HNMR(DMSO-d6,400MHz):δ12.08(s,1H),10.95(s,1H),10.38(s,1H),8.24(d,J＝5.6Hz,1H),8,19(d,J＝8Hz,1H),7.71(s,1H),6.77-6.76(bs,1H),4.04(t,J＝13.6Hz,2H),3.907(s,3H),2.67-2.63(bs,1H),2.40-2.33(bs,2H),2.29-2.25(bs,2H),2.04-1.98(bs,2H),1.51-1.49(bs,1H),1.24(bs,1H),0.77(bs,4H).
Example 123:1- (4- ((7-cyano-1-methyl-2- ((1-methyl-2-oxo-5- (trifluoromethyl) -1, 2-dihydropyridin-3-yl) amino) -1H-imidazo [4,5-b ] pyridin-6-yl) oxy) pyridin-2-yl) -3- (oxetan-3-yl) urea
Synthesis of I-123. Compound I-123 was prepared from 6.1 and oxetan-3-amine following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (7.0% methanol in DCM) to give I-123.MS(ES):m/z 556.4[M+H]+;1H NMR(DMSO-d6,400MHz):δ9.25(s,1H),9.08(s,1H),8.66(d,J＝2.4Hz,1H),8.46(s,1H),8.33(s,1H),8.20(t,J＝3.6Hz,2H),7.09(d,J＝2.4Hz,2H),6.70(m,1H),4.79-4.72(m,3H),4.44(t,J＝4.8Hz,2H),3.98(s,3H),3.68(s,3H).
Reference compounds
The compound R-1 is described in WO 2020/097396 (see compound I-2 therein):
JAK2 binding assay
JAK2 (JH 1 domain catalyzed, Y1007F, Y1008F) kinase was expressed as N-terminal fusion with the DNA binding domain of NFkB in transiently transfected HEK293 cells, followed by DNA labeling for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 min at room temperature to produce an affinity resin for kinase assays. Ligand beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1%BSA,0.05%Tween 20,1mmol/L DTT) to remove unbound ligand and reduce non-specific phage binding. The binding reagents were assembled by combining the kinase, ligand affinity beads and test compound in 1x binding buffer (1x PBS,0.05%Tween 20,0.1%BSA,1mmol/L DTT). Test compounds were prepared as 111x stock in 100% dmso and diluted directly into assay wells. All reactions were performed in polypropylene 384 well plates with a final volume of 0.02mL. The assay plates were incubated for 1 hour with shaking at room temperature and the affinity beads were washed with wash buffer (1x PBS,0.05%Tween 20). The beads were then resuspended in elution buffer (1x PBS,0.05%Tween 20,0.5. Mu. Mol/L non-biotinylated affinity ligand) and incubated for 30 min at room temperature with shaking. The kinase concentration in the eluate was measured by qPCR.
The results of the JAK2 JH1 domain binding assay described above are presented in table 2. K d <10nM of the compound denoted "A"; k d of the compound denoted "B" is ≡10nM and <50nM; k d of the compound denoted "C" is ≡50nM and < 1. Mu.M; k d of the compound denoted "D" is ≡1. Mu.M and < 5. Mu.M; and K d. Gtoreq.5. Mu.M of the compound denoted "E".
Table 2.
/>
JAK family selectivity assay
The selectivity of the provided compounds was evaluated by comparing their JAK2 binding affinity (K d) in the JAK2 binding assay described above to their binding affinity (K d) for one or more other kinases. Binding affinities for other kinases were determined as follows: kinase-tagged T7 phage strains were prepared in E.coli (E.coli) hosts derived from BL21 strain. Coli was grown to log phase and infected with T7 phage and incubated with shaking at 32 ℃ until lysis. The lysate was centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently used with DNA markers for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 min at room temperature to produce an affinity resin for kinase assays. Ligand beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1%BSA,0.05%Tween 20,1mM DTT) to remove unbound ligand and reduce non-specific binding. The binding reagents were assembled by combining the kinase, ligand affinity beads and test compounds in 1x binding buffer (20%SeaBlock,0.17x PBS,0.05%Tween 20,6mM DTT). Test compounds were prepared as 111X stock in 100% dmso. Kd was determined using a 3-fold compound dilution series of 11 spots with three DMSO control spots. All compounds used for Kd measurements were distributed in 100% dmso by acoustic transfer (non-contact dispensing). The compounds were then directly diluted into the assay such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384 well plates. The final volume of each was 0.02ml. The assay plates were incubated for 1 hour with shaking at room temperature and the affinity beads were washed with wash buffer (1x PBS,0.05%Tween 20). The beads were then resuspended in elution buffer (1x PBS,0.05%Tween 20,0.5. Mu.M non-biotinylated affinity ligand) and incubated for 30 min at room temperature with shaking. The kinase concentration in the eluate was measured by qPCR. Compounds that exhibit better binding affinity for JAK2 than one or more other kinases are considered JAK2 selective compounds. In some embodiments, the provided compounds may have JAK2 selectivity over one or more of the following kinases: JAK1, JAK3 and Tyk2.
The results of the JAK2 selectivity assay described above are presented in table 3. The K d/Kd ratio of the compound denoted "A" is ≡1000; the K d/Kd ratio of the compound denoted "B" is <1000 and ≡300; the K d/Kd ratio of the compound denoted "C" is <300 and ≡100; the K d/Kd ratio of the compound denoted "D" was <100.
TABLE 3 Table 3
SET2-pSTAT5 cell assay
This assay measures JAK 2-mediated inhibition of pSTAT5 signaling in constitutively active primary thrombocytopenia cells carrying the V617F mutation. Cells were harvested from the flask into cell culture medium and the number of cells counted. Cells were diluted with medium and 100 μl of cell suspension (50000/well) was added to each well of a 96-well cell culture plate. A solution of the test compound is added to the assay plate. The plates were capped and placed in a 5% CO 2 incubator at 37℃for 4 hours. After 4 hours, the cells were spun at high speed and the cell pellet was resuspended with 100 μl cold PBS. Then, the cells were again spun at high speed at 4℃and 4000rpm for 5min. The PBS was aspirated and 25. Mu.L of lysis buffer (with protease and phosphatase inhibitor cocktail) was added to each cell pellet. The cell lysate was shaken at 4℃for 20min to lyse the cells well. The cell lysate was spun at high speed at 4℃and 4000rpm for 15min, and the supernatant was transferred to a new plate and stored at-80 ℃. Mesoscale discovery (Meso-scalediscovery) (MSD) was used for the following assay plates: standard MSD plates were coated with capture antibody (40 μl/well) in PBS and incubated overnight with shaking at 4 ℃. Washing buffer (with 0.1% of 1 XMSD at 150. Mu.L/wellTris buffered saline of 20 detergents, TBST) washed MSD plates 3 times. The MSD plates were then blocked with 150. Mu.L of blocking buffer (5% BSA in TBST) and shaken at 600rpm for 1 hour at room temperature. MSD plates were washed 3 times with 150. Mu.L/well of 1XMSD wash buffer (TBST). The sample lysate was then added to the MSD plate (25. Mu.L/well) and shaken at room temperature and 600rpm for 1h. MSD plates were washed 3 times with 150. Mu.L/well of 1XMSD wash buffer (TBST). Detection antibodies (prepared in antibody detection buffer (1% bsa in 1 xTBST)) were then added to the MSD plate and shaken at 600rpm for 1h at room temperature. MSD plates were washed 3 times with 150. Mu.L/well of 1xMSD wash buffer (TBST). A second detection antibody (prepared in antibody detection buffer (1% bsa in 1 xTBST)) was then added to the MSD plate and it was shaken at 600rpm for 1h at room temperature. MSD plates were washed 3 times with 150. Mu.L/well of 1XMSD wash buffer (TBST). MSD read buffer (1X) was added to the plate (150. Mu.L/well) and diluted from 4X with water. The plates were imaged using an MSD imaging instrument according to the manufacturer's instructions.
The results of the SET2-pSTAT5 cell assay described above are presented in Table 4. The IC 50 of the compound denoted "A" was <125nM; the compound denoted "B" has an IC 50 ≡125nM <200nM; IC 50 of the compound denoted as "C" was 200nM or more and < 1. Mu.M; IC 50 of the compound denoted "D" was ≡1. Mu.M and < 5. Mu.M.
Table 4.
Compounds of formula (I) IC50
I-3 A
I-4 A
I-7 A
I-14 A
I-15 A
I-18 A
I-26 C
I-30 B
I-48 D
I-56 B
I-57 B
I-60 A
I-61 A
I-62 A
I-75 A
I-79 A
I-88 A
I-114 C
I-118 C
I-122 A
R-1 C
HBMC-GMCSF-STAT 5 assay
This assay measures JAK2 homodimer-mediated inhibition of STAT5 signaling in human peripheral blood mononuclear cells. Thawing PBMCs with assay medium comprising:
Reagent(s) Catalog number Final concentration
RPMI+L-glutamine Gibco 21870 90％
Heat-inactivated FBS Gibco 10082-147 10％
1M HEPES Gibco 15630 10mM
2-Mercaptoethanol Gibco 21985-0231 8.6 Mu L bME/10mL of culture medium
Pen/Strep/Glut Gibco 15140 1X
Cells were then counted. Cells were diluted with medium and 120 μl of cell suspension (500000/well) was added to each well of a 96-well cell culture plate. Test compounds were diluted to 10X in assay medium and 15 μl of solution was added to the assay plate. The plates were capped and placed in a 5% CO 2 incubator at 37℃for 4 hours. After 4 hours, GM-CSF stock solution (100. Mu.g/mL) was diluted to 50ng/mL in assay medium and 15. Mu.L of the solution was added to the assay plate to give a final concentration of 5ng/mL in the assay. The plates were capped and placed in a 5% CO 2 incubator at 37℃for 5min. After 5min, the cells were spun at high speed and the medium was aspirated. Then, 50. Mu.L of lysis buffer (with protease and phosphatase inhibitor cocktail) was added to each cell pellet and the cell lysate was shaken at 4℃for 20min. The cell lysate is then spun at high speed at 4℃and 4000rpm for 5min and the supernatant is transferred to a new plate and stored at-80℃until further use. The MSD standard plates were coated with capture antibody (40. Mu.L/well) in PBS and incubated overnight with shaking at 4 ℃. The MSD plates were then washed 3 times with 150. Mu.L/well TBST. Sample lysates (50. Mu.L/well) were added to MSD plates and shaken at 600rpm for 1h at room temperature. The MSD plates were then washed 3 times with 150. Mu.L/well TBST. Detection antibody (25. Mu.L/well) was added and shaken at 600rpm for 1h at room temperature. Detection antibodies were prepared in antibody detection buffer (1% blocker a in TBST). The MSD plates were then washed 3 times with 150. Mu.L/well TBST. A second detection antibody (25. Mu.L/well) was added and the mixture was shaken at 600rpm for 1h at room temperature. The second detection antibody was prepared in antibody detection buffer (1% blocker a in TBST). The MSD plates were then washed 3 times with 150. Mu.L/well TBST. Then, MSD read buffer (2X) (150. Mu.L/well) was added and diluted from 4X with water. The plates were imaged using an MSD imaging instrument according to the manufacturer's instructions.
HBMC-IL 12-STAT4 assay
This assay measures Tyk2/JAK2 mediated inhibition of STAT4 signaling in human peripheral blood mononuclear cells. Thawing PBMCs with assay medium comprising:
Reagent(s) Catalog number Final concentration
RPMI+L-glutamine Gibco 21870 90％
Heat-inactivated FBS Gibco 10082-147 10％
1M HEPES Gibco 15630 10mM
2-Mercaptoethanol Gibco 21985-0231 8.6 Mu L bME/10mL of culture medium
Pen/Strep/Glut Gibco 15140 1X
Cells were then counted. Cells were diluted with medium and 120 μl of cell suspension (200000/well) was added to each well of a 96-well cell culture plate. Test compounds were diluted to 10X in assay medium and 15 μl of solution was added to the assay plate. The plates were capped and placed in a 5% CO 2 incubator at 37℃for 1 hour. After 1 hour, IL12 stock solution (50 ng/mL) was diluted to 50ng/mL in assay medium and 15. Mu.L of the solution was added to the assay plate to give a final concentration of 1.7ng/mL in the assay. The plates were capped and placed in a 5% CO 2 incubator at 37℃for 25min. After 25min, the cells were spun at high speed and the medium was aspirated. Then, 65 μl of lysis buffer (with protease and phosphatase inhibitor cocktail) was added to each cell pellet and the cell lysate was shaken at 4 ℃ for 30min. The cell lysate is then spun at high speed at 4℃and 4000rpm for 5min and the supernatant is transferred to a new plate and stored at-80℃until further use. The MSD standard plates were blocked with blocking buffer (3% blocking agent A in wash buffer) and shaken at 600rpm for 1h at room temperature. The MSD plates were then washed 3 times with 150. Mu.L/well of wash buffer. Sample lysates (25. Mu.L/well) were added to the MSD plates and shaken at 600rpm for 1h at room temperature. The MSD plates were then washed 3 times with 150. Mu.L/well of wash buffer. Detection antibody (25. Mu.L/well) was added and shaken at 600rpm for 1h at room temperature. Detection antibodies (150. Mu.L 2% blocking agent D-M, 30. Mu.L 10% blocking agent D-R,1mL blocking agent A solution, 1.82mL 1 Xwash buffer) were prepared in antibody detection buffer for one plate. The MSD plates were then washed 3 times with 150. Mu.L/well TBST. Then, MSD read buffer (1X) (150. Mu.L/well) was added and diluted from 4X with water. The plates were imaged using an MSD imaging instrument according to the manufacturer's instructions.
HBMC-IL 2-STAT5 assay
This assay measures JAK1/JAK3 mediated inhibition of STAT5 signaling in human peripheral blood mononuclear cells. Thawing PBMCs with assay medium comprising:
Reagent(s) Catalog number Final concentration
RPMI+L-glutamine Gibco 21870 90％
Heat-inactivated FBS Gibco 10082-147 10％
1M HEPES Gibco 15630 10mM
2-Mercaptoethanol Gibco 21985-0231 8.6 Mu L bME/10mL of culture medium
Pen/Strep/Glut Gibco 15140 1X
Cells were then counted. Cells were diluted with medium and 120 μl of cell suspension (200000/well) was added to each well of a 96-well cell culture plate. Test compounds were diluted to 10X in assay medium and 15 μl of solution was added to the assay plate. The plates were capped and placed in a 5% CO 2 incubator at 37℃for 1 hour. After 1 hour, the IL2 stock solution (100. Mu.g/mL) was diluted to 250ng/mL in the assay medium and 15. Mu.L of the solution was added to the assay plate so that the final concentration in the assay was 25ng/mL. The plates were capped and placed in a 5% CO 2 incubator at 37℃for 5min. After 5min, the cells were spun at high speed and the medium was aspirated. Then, 40. Mu.L of lysis buffer (with protease and phosphatase inhibitor cocktail) was added to each cell pellet and the cell lysate was shaken at 4℃for 20min. The cell lysate is then spun at high speed at 4℃and 4000rpm for 5min and the supernatant is transferred to a new plate and stored at-80℃until further use. The MSD standard plates were coated with capture antibody (40. Mu.L/well) in PBS and incubated overnight with shaking at 4 ℃. The MSD plates were then washed 3 times with 150. Mu.L/well TBST. The MSD plates were then blocked with blocking buffer (150. Mu.L of 3% blocking agent A in TBST) and shaken at 600rpm for 1h at room temperature. The MSD plates were then washed 3 times with 150. Mu.L/well TBST. Sample lysates (40. Mu.L/well) were added to the MSD plates and shaken at 600rpm for 1h at room temperature. The MSD plates were then washed 3 times with 150. Mu.L/well TBST. Detection antibody (25. Mu.L/well) was added and shaken at 600rpm for 1h at room temperature. Detection antibodies were prepared in antibody detection buffer (1% blocker a in TBST). The MSD plates were then washed 3 times with 150. Mu.L/well TBST. A second detection antibody (25. Mu.L/well) was added and the mixture was shaken at 600rpm for 1h at room temperature. The second detection antibody was prepared in antibody detection buffer (1% blocker a in TBST). The MSD plates were then washed 3 times with 150. Mu.L/well TBST. Then, MSD read buffer (2X) (150. Mu.L/well) was added and diluted from 4X with water. The plates were imaged using an MSD imaging instrument according to the manufacturer's instructions.
Kinase assay
Kinase assays were performed according to ANASTASSIADIS T et al Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.Nat Biotechnol.2011, 10 months 30; 29 (11) the process is carried out as described in 1039-45. Doi:10.1038/nbt.2017. Typically, the substrate is prepared in freshly prepared reaction buffer (20mM Hepes(pH 7.5),10mM MgCl2,1mM EGTA,0.01％Brij35,0.02mg/mL BSA,0.1mM Na3VO4,2mM DTT,1％DMSO). Any required cofactors are then added to the substrate solution. The kinase was then delivered to the substrate solution and gently mixed. Test compounds in 100% DMSO were then added to the kinase reaction mixture using acoustic techniques (Echo 550; nanoliter range) and incubated for 20min at room temperature. 33 P-ATP was added to the reaction mixture and incubated for 2h at room temperature. Kinase activity was detected by the P981 filter binding method.
Caco2 permeability assay
Preparation of Caco-2 cells: mu.L and 25mL of cell culture medium were added separately toAn insert and a reservoir are in each well. HTS/>, was then added to the cells prior to cell seedingPlates were incubated at 37℃for 1 hour at 5% CO 2. Caco-2 cells were diluted to 6.86 х cells/mL with medium and 50. Mu.L of cell suspension was dispensed to 96-well HTS/>In the filter holes of the plates. The cells were incubated in a cell incubator at 37℃for 14-18 days with 5% CO 2 and 95% relative humidity. Cell culture media was changed every other day, starting at the latest within 24 hours after the initial plating.
Preparation of stock solution: a 10mM stock solution of test compound was prepared in DMSO. Stock solutions of positive controls were prepared in DMSO at a concentration of 10mM. Digoxin and propranolol were used as control compounds in this assay.
Evaluation of cell monolayer integrity: from a reservoir and eachThe medium was removed from the insert and replaced with fresh medium that had been warmed up. Monolayer transepithelial resistance (TEER) was measured using a Millicell epithelial volt-ohm measurement system (Millipore, USA). Once the measurement is complete, the plate is returned to the incubator. TEER value was calculated according to the following formula: TEER measurement (ohm) x film area (cm 2) =teer value (ohm cm 2). TEER values greater than 230 ohm cm 2 indicate acceptable Caco-2 monolayers.
Measurement procedure: caco-2 plates were removed from the incubator and washed twice with pre-heated HBSS (10mM HEPES,pH 7.4) and then incubated for 30 minutes at 37 ℃. Stock solutions of control compounds were diluted in DMSO to give 1mM solutions, which were then diluted with HBSS (10mM HEPES,pH 7.4) to give 5 μm working solutions. Stock solutions of test compounds were diluted in DMSO to give 1mM solutions, which were then diluted with HBSS (10 mM HEPES and 4% bsa, ph 7.4) to give 5 μm working solutions. The final concentration of DMSO in the incubation system was 0.5%. The rate of drug transport from the apical to the basolateral direction is determined. 75. Mu.L of a working solution of 5. Mu.M test compound was added toInsert (apical compartment) and wells in receiving plate (basolateral compartment) will be filled with 235 μl HBSS (10 mM HEPES and 4% bsa, ph 7.4). The rate of drug transport from the basolateral to apical direction is determined. 235 μl of 5 μM working solution of test compound was added to the wells of the receiving plate (basolateral compartment) and then/>The insert (apical compartment) was filled with 75. Mu.L of HBSS (10 mM HEPES and 4% BSA, pH 7.4). Time 0 samples were prepared by transferring 50 μl of 5 μM working solution into wells of 96-deep well plates, followed by the addition of 200 μl of cold methanol containing the appropriate Internal Standard (IS). Plates were incubated at 37℃for 2 hours. At the end of incubation, 50 μl samples from the donor side (ap→bl flowing apical compartment and bl→ap basolateral compartment) and the receiver side (ap→bl flowing basolateral compartment and bl→ap apical compartment) were transferred to wells of a new 96-well plate, and then 4 volumes of cold acetonitrile or methanol containing the appropriate Internal Standard (IS) were added. The sample was vortexed for 5 minutes and then centrifuged at 3,220g for 40 minutes. Aliquots of 100. Mu.L of supernatant were mixed with the appropriate volumes of ultrapure water prior to LC-MS/MS analysis. To determine fluorescence Huang Xielou after 2 hours of transit, a solution of fluorescence Huang Chubei was prepared in ultrapure water and diluted with HBSS (10mM HEPES,pH 7.4) to reach a final concentration of 100 μm. 100 μl of fluorescent yellow solution was added to each/>The insert (apical compartment) was then filled with 300 μl HBSS (10mM HEPES,pH 7.4) into the wells in the receiving plate (basolateral compartment). Plates were incubated at 37℃for 30 min. 80. Mu.L of sample was taken directly from the apical and basolateral wells (using basolateral access wells) and transferred to the wells of a new 96-well plate. Fluorescent yellow fluorescence (to monitor monolayer integrity) signals were measured in a fluorescent plate reader with 485nM excitation and 530nM emission. /(I)
The results of the Caco-2 permeability assay described above are presented in Table 5. ER.ltoreq.2 for the compounds denoted "A"; ER >2 and.ltoreq.5 for the compounds denoted "B"; ER >5 and ∈10 for the compounds denoted as "C"; ER >10 and.ltoreq.30 for the compounds denoted "D".
TABLE 5
Cytotoxicity assays
HEK293T cells were harvested from flasks into cell culture medium and the cells were counted. Cells were diluted to the desired density with medium and 40 μl of cell suspension was added to each well of 384 well cell culture plates. The plates were capped and spun at 1,000RPM for 1 minute at room temperature and then transferred to a 37℃5% CO 2 incubator overnight. Test compounds were dissolved in 10mM DMSO stock solution. Then 45. Mu.L of stock solution was transferred to 384 PP-plates. Dilutions at 3-fold, 10-spots were made by transferring 15 μl of compound into 30 μl DMSO using a TECAN (EVO 200) liquid handler. The plate was rotated at 1,000rpm for 1 minute at room temperature and shaken on a plate shaker for 2 minutes. 40nL of the diluted compounds were transferred from the compound source plate into the cell plate by using a liquid processor Echo 550. After 48 hours of compound treatment, CTG assays were performed on compound-treated plates: the plates were removed from the incubator and equilibrated for 15 minutes at room temperature. Each well to be tested was added with 30. Mu. L CELLTITER-Glo reagent. The plates were then left at room temperature for 30min and then read on an EnVision. The inhibition activity was calculated using the following formula: % inhibition = 100x (LumHC-Lum samples)/(LumHC-LumLC), where HC is the reading obtained from cells treated with 0.1% dmso alone and LC is the reading obtained from cells treated with 10 μl staurosporine. IC 50 values were calculated using XLFit (equation 201).
Hepatocyte stability assay
A 10mM stock solution of test compound and positive control was prepared in DMSO. Stock solutions were diluted to 100. Mu.M by combining 198. Mu.L of 50% acetonitrile/50% water and 2. Mu.L of 10mM stock solution. Verapamil was used as a positive control in the assay. Cryopreserved hepatocyte vials were thawed in a 37 ℃ water bath with gentle shaking. The contents were poured into 50mL thawing medium conical tubes. The vials were centrifuged at 100g for 10 minutes at room temperature. The thawing medium was aspirated and the hepatocytes resuspended with serum-free incubation medium to give about 1.5X106 cells/mL. Cell viability and density were calculated using trypan blue exclusion and cells were then diluted to a working cell density of 0.5X106 viable cells/mL with serum-free incubation medium. A portion of the hepatocytes, 0.5x106 viable cells/mL, was boiled for 5min and then added to the plate as a negative control to eliminate enzyme activity so that little or no substrate turnover was observed. A 198 μl aliquot of hepatocytes was dispensed into each well of a 96-well uncoated plate. The plates were placed in an incubator for about 10 minutes. mu.L of 100. Mu.M aliquots of test compound and 2. Mu.L of positive control were added to the corresponding wells of the uncoated 96-well plate to initiate the reaction. The final concentration of the test compound was 1. Mu.M. This assay was performed in duplicate. Plates were incubated in incubators for the indicated time points. Transfer 25 μl of the contents and mix with 6 volumes (150 μl) of cold acetonitrile and internal standard (100 nM alprazolam, 200nM labetalol, 200nM caffeine and 200nM diclofenac) to terminate the reaction at time points of 0, 15, 30, 60, 90 and 120 minutes. The samples were centrifuged at 3,220g for 25 minutes and LC-MS/MS analysis was performed using 150. Mu.L aliquots of the supernatant.
The results of the above-described hepatocyte stability measurement of human or rat hepatocytes are presented in table 6. For human heps CL int: CL int of the compound denoted as "A" is 6mL/min/kg or less; CL int of the compound denoted "B" is >6mL/min/kg and.ltoreq.12 mL/min/kg; CL int of the compound denoted "C" is >12mL/min/kg and <20mL/min/kg. For rat heps CL int: CL int of the compound denoted "A" is <17mL/min/kg; CL int of the compound denoted "B" is ≡17mL/min/kg and <35mL/min/kg; CL int of the compound denoted "C" is ≡35mL/min/kg and <45mL/min/kg.
TABLE 6
N.d. =not determined
Kinetic solubility determination
Stock solutions of test compound at a concentration of 10mM were prepared in DMSO, and stock solutions of control compound at a concentration of 30mM were prepared in DMSO. Diclofenac was used as a positive control in the assay. 30 μl of stock solution of each compound was placed in a 96-well rack, and 970 μl of PBS at pH 4.0 and pH 7.4 was then added to each vial of the uncapped solubility sample plate. This study was performed in duplicate. One stir bar was added to each vial, which was then sealed using a molded PTDE/SIL 96-well plate cap. The solubility sample plate was transferred to Thermomixer comfort plate shaker and incubated at room temperature for 2 hours with shaking at 1100 rpm. After 2 hours incubation, the stirrer bar was removed using a large magnet and all samples of the solubility sample plate were transferred to the filter plate. All samples were filtered through a vacuum manifold. The filtered sample was diluted with methanol. Samples were analyzed by LC-MS/MS and quantified against standards of known concentration in DMSO using LC in combination with mass spectral peak identification and quantification. The solubility values of the test compounds were calculated as follows, where INJ VOL is the sample volume, DF is the dilution factor, and STD is the standard:
The results of the kinetic solubility assays described above are presented in table 7. The solubility of the compound denoted "A" was ≡0.1. Mu.M and < 9. Mu.M; the solubility of the compound denoted "B" is ≡9. Mu.M and < 100. Mu.M; the solubility of the compound denoted "C" was > 100. Mu.M and < 200. Mu.M.
TABLE 7
Plasma protein binding assay
Working solutions of test and control compounds were prepared in DMSO at a concentration of 200 μm and then the working solutions were incorporated into plasma. The final concentration of the compound was 1. Mu.M. The final concentration of DMSO was 0.5%. Ketoconazole was used as a positive control in the assay. The dialysis membrane was immersed in ultrapure water for 60 minutes to separate the strips, then in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes. The dialysis device is assembled according to the manufacturer's instructions. Each cell was dialyzed with 150 μl of plasma sample and an equal volume of dialysis buffer (PBS). The assay was performed in duplicate. The dialysis plates were sealed and incubated at 100rpm for 6 hours at 37℃in an incubator with 5% CO 2. At the end of incubation, 50 μl samples from the buffer and plasma chambers were transferred into wells of a 96-well plate. mu.L of plasma was added to each buffer sample, and an equal volume of PBS was added to the collected plasma samples. 400. Mu.L of precipitation buffer acetonitrile containing internal standard (IS, 100nM alprazolam, 200nM labetalol, 200nM imipramine and 2. Mu.M ketoprofen (ketoplofen)) was added to precipitate the protein and release the compound. The sample was vortexed for 2 minutes and centrifuged at 3,220g for 30 minutes. An aliquot of 50 μl of the supernatant was diluted with 150 μl of acetonitrile containing internal standard: ultrapure H 2 o=1:1 and the mixture was used for LC-MS/MS analysis.
While we have described various 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 presented by way of example.

Claims (51)

1. A compound of formula I:
Or a pharmaceutically acceptable salt thereof, wherein:
W is CR w or N;
X is CR x or N;
Y is CR y or N;
Z is-O-or-NR z -;
R w、Rx and R y are each independently hydrogen, halogen, -OR 3、-N(R3)2、-SR3, optionally substituted C 1-6 aliphatic OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
R 1 is-N (R) 2、-N(R)C(O)R'、-C(O)N(R)2、-N(R)C(O)N(R)2 OR-N (R) C (O) OR;
Each R c is independently selected from halogen, -CN, -CO 2R、-C(O)N(R)2、-NO2、-N(R)2, -OR, -SR, OR optionally substituted C 1-6 aliphatic;
N is 0, 1,2 or 3, provided that when R 1 is-N (R) 2, -N (R) C (O) R' or-C (O) N (R) 2, N is 1,2 or 3;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
Ring a is optionally substituted phenyl, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
l is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;
R a is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
Each R is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's taken together when attached to the same nitrogen atom form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
Each R' is independently optionally substituted C 1-6 aliphatic or optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl,
Wherein the compound is not:
2. The compound of claim 1, wherein R 1 is-N (R) C (O) N (R) 2 OR-N (R) C (O) OR.
3. The compound of claim 2, wherein R 1 is-N (H) C (O) N (R) 2.
4. The compound of claim 2, wherein R 1 is-N (H) C (O) OR.
5. The compound of claim 1, wherein R 1 is-N (H) C (O) R'.
6. The compound of any one of the preceding claims, wherein ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
7. The compound of claim 6, wherein ring a is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
8. The compound of any one of the preceding claims, wherein R a is optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
9. The compound of claim 8, wherein R a is optionally substituted C 1-6 aliphatic.
10. The compound of any one of the preceding claims, wherein:
In the case where the valence allows, the reaction proceeds, Substituted with 1-5R b; and
Each R b is independently hydrogen, halogen 、-CN、-OR、-O(CH2)mR、-SR、-N(R)2、-NO2、-C(O)R'、-C(O)OR、-C(O)N(R)2、-OC(O)R'、-OC(O)N(R)2、-OC(O)OR、-OSO2R、-OSO2N(R)2、-N(R)C(O)R'、-N(R)SO2R'、-SO2R'、-SO2N(R)2、-SO3R'、 optionally substituted C 1-6 aliphatic, optionally substituted 3 to 6 membered saturated or partially unsaturated carbocyclyl, optionally substituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
M is 1, 2 or 3.
11. The compound of claim 10, wherein each R b is independently halogen or optionally substituted C 1-6 aliphatic.
12. The compound of claim 10 or 11, whereinIs that
13. The compound of any one of the preceding claims, wherein L is a covalent bond.
14. The compound of any one of the preceding claims, wherein R 2 is C 1-4 alkyl.
15. The compound of any one of the preceding claims, wherein each R c is independently halogen.
16. The compound of any one of claims 1-14, wherein n is 0.
17. The compound of any one of the preceding claims, wherein W is CR w.
18. The compound of claim 17, wherein R w is hydrogen.
19. The compound of any one of claims 1-16, wherein W is N.
20. The compound of any one of the preceding claims, wherein X is CR x.
21. The compound of claim 20, wherein R x is hydrogen, halogen, -CN, -OR 3, OR optionally substituted C 1-6 aliphatic.
22. The compound of any one of claims 1-19, wherein X is N.
23. The compound of any one of the preceding claims, wherein Y is CR y.
24. The compound of claim 23, wherein R y is hydrogen.
25. The compound of any one of claims 1-22, wherein Y is N.
26. The compound of any one of claims 1-25, wherein Z is-NR z -.
27. The compound of claim 26, wherein R z is hydrogen.
28. The compound of any one of claims 1-25, wherein Z is-O-.
29. The compound of any one of the preceding claims, wherein each R is independently hydrogen or optionally substituted C 1-6 aliphatic.
30. The compound of any one of the preceding claims, wherein each R' is independently optionally substituted C 1-6 alkyl or optionally substituted C 3-7 cycloalkyl.
31. The compound of any one of the preceding claims, wherein each R' is independently optionally substituted C 1-6 aliphatic.
32. The compound of any one of the preceding claims, wherein the compound has formula I-C:
Or a pharmaceutically acceptable salt thereof.
33. A compound of formula II:
Or a pharmaceutically acceptable salt thereof, wherein:
W is CR w or N;
X is CR x or N;
Y is CR y or N;
Z is-O-or-NR z -;
R w、Rx and R y are each independently hydrogen, halogen, -OR 3、-N(R3)2、-SR3, optionally substituted C 1-6 aliphatic OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
R 1 is-N (R) 2、-N(R)C(O)R'、-C(O)N(R)2、-N(R)C(O)N(R)2 OR-N (R) C (O) OR;
Each R c is independently selected from halogen, -CN, -CO 2R、-C(O)N(R)2、-NO2、-N(R)2, -OR, -SR, OR optionally substituted C 1-6 aliphatic;
n is 0,1, 2 or 3;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
Ring a is an optionally substituted 9-to 16-membered bicyclic or tricyclic aryl, an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 10-to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 7-to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 10-to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Each R is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's taken together when attached to the same nitrogen atom form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
Each R' is independently optionally substituted C 1-6 aliphatic or optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl,
Wherein the compound is not:
34. The compound of claim 33, wherein ring a is an optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 10-to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
35. The compound of claim 33 or 34, wherein:
Ring A is
Ring A1 is an optionally substituted ring selected from phenyl, a 5 to 6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl group, and a 5 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
wherein ring A1 is fused to ring A2;
Ring A2 is an optionally substituted ring selected from phenyl, a 5 to 6 membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl group, and a 5 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
wherein ring A2 is optionally (i) further fused to ring A3,
Or (ii) ring A2 and ring A3 combine to form a spiro ring; and
When present, ring A3 is an optionally substituted ring selected from phenyl, a 5-to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, A3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl group, and A3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
36. The compound of claim 35, wherein ring A1 is an optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
37. The compound of claim 35 or 36, wherein optionally substituted ring a is
38. The compound of any one of claims 35-37, wherein ring A2 is an optionally substituted 5-to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
39. The compound of any one of claims 35-38, wherein optionally substituted ring a is selected from the group consisting of:
40. the compound of any one of claims 33-39, wherein the compound has formula II-C:
Or a pharmaceutically acceptable salt thereof.
41. A compound of formula III:
Or a pharmaceutically acceptable salt thereof, wherein:
Z is-O-or-NR z -;
R x is hydrogen, halogen, -OR 3、-N(R3)2、-SR3, optionally substituted C 1-6 aliphatic OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
r 4 is halogen, -OR, -N (R) 2 OR an optionally substituted 3-to 7-membered saturated OR partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
Ring a is optionally substituted phenyl, optionally substituted 5-to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 8-to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7-to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
l is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;
R a is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
Each R is independently hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted 3-to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's taken together when attached to the same nitrogen atom form an optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur,
Wherein the compound is not:
42. a compound of formula IV:
Or a pharmaceutically acceptable salt thereof, wherein:
Z is-O-or-NR z -;
R x is hydrogen, halogen, OR 3, OR-CN;
R z is hydrogen or optionally substituted C 1-6 aliphatic;
r 2 is optionally substituted C 1-6 aliphatic;
R 3 is hydrogen or optionally substituted C 1-6 aliphatic;
Selected from (i) or (ii):
(i) Or (b)
(ii)Wherein ring a is further substituted at least once and at least one substituent on ring a is C 1-6 haloalkyl;
l is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;
R a is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl, optionally substituted 5 to 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and
R' is C 1-6 aliphatic or 3-to 7-membered saturated or partially unsaturated carbocyclyl,
Wherein the compound is not:
43. a compound selected from table 1, or a pharmaceutically acceptable salt thereof.
44. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
45. A method of inhibiting JAK2 in a subject, the method comprising administering a compound of any one of claims 1-43 or a composition of claim 44.
46. A method of treating a disease, disorder, or condition associated with JAK2, the method comprising administering to a subject in need thereof a compound of any one of claims 1-43 or a composition of claim 44.
47. A method of treating cancer, the method comprising administering to a subject in need thereof a compound of any one of claims 1-43 or a composition of claim 44.
48. A method of treating hematological malignancies comprising administering to a subject in need thereof a compound of any one of claims 1-43 or a composition of claim 44.
49. The method of claim 48, wherein the hematological malignancy is leukemia or lymphoma.
50. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof a compound of any one of claims 1-43 or a composition of claim 44.
51. The method of claim 50, wherein the myeloproliferative neoplasm is polycythemia vera, primary thrombocytopenia, or myelofibrosis.
CN202280074285.6A 2021-11-09 2022-11-08 6-Heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors Pending CN118201928A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US63/277,343 2021-11-09
US202263354403P 2022-06-22 2022-06-22
US63/354,403 2022-06-22
PCT/US2022/049220 WO2023086319A1 (en) 2021-11-09 2022-11-08 6-he tero aryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors

Publications (1)

Publication Number Publication Date
CN118201928A true CN118201928A (en) 2024-06-14

Family

ID=91414021

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202280074285.6A Pending CN118201928A (en) 2021-11-09 2022-11-08 6-Heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors

Country Status (1)

Country Link
CN (1) CN118201928A (en)

Similar Documents

Publication Publication Date Title
JP7368369B2 (en) Heterocyclic compounds as PRMT5 inhibitors
CA3085835A1 (en) Novel benzylamino substituted pyridopyrimidinones and derivatives as sos1 inhibitors
US10662186B2 (en) Substituted pyrimidines as cyclin-dependent kinase inhibitors
US11691963B2 (en) 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
KR20130045398A (en) Pyrrolopyrimidine compounds and uses thereof
TW201605866A (en) Furo- and thieno-pyridine carboxamide compounds useful as PIM kinase inhibitors
AU2009274027A1 (en) Tri-cyclic pyrazolopyridine kinase inhibitors
TW201940483A (en) Inhibitors of tyrosine kinase 2 mediated signaling
TW202321242A (en) Heterocyclic compounds and methods of use
US20230043030A1 (en) Heteroaryl heterocyclic compounds and uses thereof
JP2023518609A (en) Novel aminopyrimidine-based EGFR inhibitor
TW202404972A (en) Spirobicyclic compounds
US11970494B2 (en) 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
WO2023041049A1 (en) Heterocyclic compound as sos1 inhibitor and uses thereof
WO2022127827A1 (en) Krasg12c protein mutation inhibitor and preparation method therefor, pharmaceutical composition and application thereof
CN118201928A (en) 6-Heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
AU2020403681A1 (en) Compound and composition as pdgf receptor kinase inhibitor
JP2023515729A (en) Polycyclic Amide Derivatives as CDK9 Inhibitors, Preparation Methods and Uses Thereof
CN112839931A (en) 1,2,3, 4-tetrahydroquinoxaline derivative and preparation method and application thereof
WO2023009712A1 (en) Heteroaryloxy thiazolo azines as jak2 inhibitors
WO2024083111A1 (en) Novel heterocyclic compounds
TW202417421A (en) Heterocyclic amide and urea compounds as jak2 inhibitors
WO2024148247A2 (en) Azaindazoles as jak2 inhibitors
WO2023009709A1 (en) Pyrazolo piperazines as jak2 inhibitors
WO2024035627A1 (en) Heterocyclic amide and urea compounds as jak2 inhibitors

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication