WO2024022266A1 - Heteroaryl compounds as inhibitors of usp1 - Google Patents
Heteroaryl compounds as inhibitors of usp1 Download PDFInfo
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- WO2024022266A1 WO2024022266A1 PCT/CN2023/108789 CN2023108789W WO2024022266A1 WO 2024022266 A1 WO2024022266 A1 WO 2024022266A1 CN 2023108789 W CN2023108789 W CN 2023108789W WO 2024022266 A1 WO2024022266 A1 WO 2024022266A1
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- Prior art keywords
- alkyl
- membered
- ring
- formula
- substituted
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D498/14—Ortho-condensed systems
Definitions
- the invention is directed to a series of novel heteroaryl derivatives as USP1 inhibitors useful for the treatment of diseases or conditions, such as cancers, especially cancers with BRCA mutations or HR deficiencies.
- Pharmaceutical compositions and methods of use are also included.
- This invention relates to heteroaryl derivatives, or their pharmaceutically acceptable salts, pharmaceutical acceptable prodrugs, pharmaceutical compositions containing them, and their medical uses.
- the compounds of this invention have activity as ubiquitin-specific protease 1 (USP1) inhibitors and are useful in the treatment or alleviation of diseases associated with USP1 enzyme, such as cancers and other disorders.
- USP1 ubiquitin-specific protease 1
- USP1 due to the important role of USP1 in regulating DNA damage response (DDR) pathways, inhibition of USP1 has the potential to be a treatment for cancers with BRCA (BReast CAncer) gene mutations or deficiency for homologous recombination (HR) .
- Ubiquitin is a small 76-amino-acids protein which can be conjugated to specific target proteins via polyubiquitination and monoubiquitination.
- Deubiquitination is a reversible process which involves a family of deubiquitinating enzymes (DUBs) that catalyze the removal of ubiquitin moieties from ubiquitinated substrates.
- Ubiquitylation plays a regulatory role in protein interactions, localization and function, thereby affecting cellular processes, including gene expression, DNA damage signaling and DNA repair, cell cycle progression, apoptosis and cell motility, and so forth.
- USP1 plays an important role in the regulation of DNA repair processes. USP1 forms a heterodimeric complex with UAF1 (USP1-associated factor 1) , which is required for deubiquitinase activity.
- UAF1 USP1-associated factor 1
- the mono-ubiquitinated PCNA proliferating cell nuclear antigen
- PCNA monoubiquitylation facilitates the recruitment of specific TLS (translesion synthesis) polymerases, which can bypass the DNA lesions.
- TLS translesion synthesis
- the invention encompasses a genus of compounds of Formula I as USP1 inhibitors or a pharmaceutically acceptable salt thereof,
- R d is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cyclolkyl, C 3-6 fluorocycloalkyl, C 1-6 fluoroalkyl, C 0-6 alkylene-aryl, C 0-6 alkylene-heteroaryl, C (O) C 1-6 alkyl, C (O) aryl, S (O) 2 C 1-6 alkyl, S (O) 2 C 3-6 cycloalkyl, S (O) 2 aryl; each of X 0 , X 1 , X 2 , X 3 and X 4 is independently selected from N or CR 1 ;
- X 5 , X 8 is independently selected from C (R 2 ) r , O, S, SO, SO 2 , or NR 2 ;
- X 7 is N or CH
- X a , X b and X c are independently N or CR 2 ;
- X d is C (O) , O, S, S (O) 2 , O or NR d ;
- R 1 is independently selected from the group consisting of hydrogen, halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 halogenated alkyl, C 1 -C 6 alkoxy, C 1-6 alkylthio, hydroxyl, amino, nitro, formyl, -CF 3 , -CN, -SF 5 , NR a R b , carboxyl, -COR a , -CO 2 C 1 -C 6 alkyl, -CONR a R b , -SO 2 R e , -SO 2 NR a R b , -P (O) Me 2 and -P (O) (OMe) 2 ;
- R 2 is independently selected from the group consisting of hydrogen, OH, oxo, CF 2 CH 2 OH, C 1 -C 6 alkanol, C 1 -C 6 halogenated alkanol, halogen, C 1 -C 6 alkyl, C 1 -C 6 halogenated alkyl, C 1 -C 6 alkoxy, nitro, formyl, -CF 3 , -CN, -SF 5 , NR a R b , carboxyl, -COR a , -CO 2 C 1 -C 6 alkyl, -CONR a R b , -SO 2 R c , -SO 2 NR a R b , -P (O) Me 2 and -P (O) (OMe) 2 ;
- Two R 2 on the same carbon atom or adjacent carbon atoms together with carbon atom (s) can form a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which is optionally substituted with R 4 or a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which contains one, two or three heteroatom (s) such as S, O or NR d ;
- R a and R b are independently hydrogen, CH 2 CH 2 OH, CH 2 CMe 2 OH, C 1 -C 6 alkanol, C 1 -C 6 halogenated alkanol, substituted/non-substituted C 1 -C 10 alkyl, substituted/non-substituted C 3 -C 10 cycloalkyl, substituted/non-substituted C 2 -C 10 alkenyl, substituted/non-substituted C 6 -C 20 aryl, or substituted/non-substituted C 3 -C 14 heteroaryl respectively;
- R a and R b can form 3-8 membered rings or 4-8 membered heterocyclic rings, which contain sulfur, oxygen, NH or NR d ;
- Two R 1 on the adjacent carbon atoms together with carbon atoms can form a four-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which is optionally substituted with R 4 or a four-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which contains one, two or three heteroatom (s) such as S, O or NR d ;
- R 1 and R 2 together with the carbon atoms to which they are attached to, can form 3-8 membered cabocyclic rings or 4-8 membered heterocyclic rings, which contain sulfur, oxygen, NH or NR d ;
- R 3 represents C 6 -C 20 aryl and C 1 -C 20 heteroaryl; R 3 can be substituted by one or more groups selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkanol, C 1 -C 6 halogenated alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkoxy, C 1 -C 6 alkoxy, hydroxyl, amino, nitro, formyl, -CF 3 , -CN, -SF 5 , NR a R b , carboxyl, -COR a , -CO 2 C 1 -C 6 alkyl, -CONR a R b , -SO 2 R c , -SO 2 NR a R b , -P (O) Me 2 and -P (O) (OMe) 2 ;
- R 4 and R 5 is independently absent or selected from the group consisting of H, NRb2, C 1 -C 6 alkoxy, C 1-6 alkylthio, halogen, CN, C 1-6 alkyl, C 3 -C 6 cyclolkyl, C 3 -C 6 fluorocycloalkyl, C 1 -C 6 fluoroalkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 halogenated alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkoxy, C 1 -C 6 alkoxy, hydroxyl, amino, nitro, formyl, -CF 3 , -CN, -SF 5
- R c represents C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, or C 3 -C 14 heteroaryl; R c can be substituted by one or more radical groups selected from halogen, hydroxyl, amino, nitro, cyano, formyl, carboxyl, alkoxy, -CF 3 and -SF 5 ;
- Y is selected from B, C, CO, N, NH, NMe, O, Si, P, S, SO, SO 2 , POH, PO (OH) ;
- R 6 represents optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, , optionally substituted C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, CN, halogen, SO 2 NH 2 , -COR a , -COOR a , -NR b R b , -NR a COR b , -NR a CONR a R a , -CONR a R b , -SO 2 NR a R b , -NR a SO 2 R b , optionally C 6 -C 10 aryl and C 1 -C 10 heteroaryl; R 6 can be substituted by one or more groups selected from: halogen, C 1 -C 6 alkyl, C
- X 0 in Formula I represents CH.
- At least one of X 1 and X 2 in Formula I represents N.
- X 3 in Formula I represents N.
- X 3 in Formula I represents CH.
- X 4 in Formula I represents N.
- Y in Formula I represents C, O, N or S.
- in Formula I represents a single bond.
- in Formula I represents a double bond.
- in Formula I is selected from the group consisting of
- in Formula I is selected from the group consisting of
- R 3 in Formula I is selected from the group consisting of
- R 6 in Formula I is
- Each V 1 , V 2 , V 3 , and V 4 are independently selected from C (R 2 ) , NR d , O and S; V 5 is C, or N; V 1 , V 2 , V 3 , V 4 and V 5 together form a 5-membered heteroaryl ring.
- R 2 , R d are defined as in Formula I.
- R 6 in Formula I is selected from the group consisting of
- the invention further provides a compound of Formula IA and IB or a pharmaceutically acceptable salt thereof:
- R 4a is C 1 -C 6 alkyl, C 3 -C 6 cyclolkyl, C 3 -C 6 fluorocycloalkyl, C 1 -C 6 fluoroalkyl.
- the invention further provides a compound of Formula II or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula IV or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula V or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula VI or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula VII or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula VIII or a pharmaceutically acceptable salt thereof:
- R 1 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula IX or a pharmaceutically acceptable salt thereof:
- R 1 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula X or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula XI or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula XII or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula XIII or a pharmaceutically acceptable salt thereof:
- Y 1 is a bond, O, CH 2 or NR b ; Y 2 is C (O) or CH 2 ; X 2 is N or CH; r, R b , R 2 , R 3 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof:
- Y 1 is a bond, O, CH 2 or NR b ;
- R b , R 2 , R 3 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula XVA or XVB or a pharmaceutically acceptable salt thereof:
- R 1 , r, R 2 , R 3 and R 6 are defined as in Formula I.
- R 4a is C 1 -C 6 alkyl, C 3 -C 6 cyclolkyl, C 3 -C 6 fluorocycloalkyl, C 1 -C 6 fluoroalkyl.
- the invention further provides a compound of Formula XVI or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula XVII or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula XVIII or a pharmaceutically acceptable salt thereof:
- Y 1 is a bond, O, S, CH 2 or NR b ;
- Y 2 is a bond, C (O) or CH 2 ;
- r, R b , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula XIX or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula XX or a pharmaceutically acceptable salt thereof:
- R d , R 1 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I. is a 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, which contain sulfur, oxygen, NH or NR d ; is a single or double bond such that all valences are satisfied.
- the invention further provides a compound of Formula XXI or a pharmaceutically acceptable salt thereof:
- R d , R 1 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I. is a saturated or unsaturated 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, which contain sulfur, oxygen, NH or NR d ; is a single or double bond such that all valences are satisfied.
- the invention further provides a compound of Formula XXII or a pharmaceutically acceptable salt thereof:
- R d , R 1 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I. is a 4-8 membered heterocyclic ring, which may contain additional S, O, NH or NR d .
- the invention further provides a compound of Formula XXIII or a pharmaceutically acceptable salt thereof:
- R a , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula XXIV or a pharmaceutically acceptable salt thereof:
- R a , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula XXV or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I.
- the invention further provides a compound of Formula XXVI or a pharmaceutically acceptable salt thereof:
- R a , R 1 , R 3 , R 4 , R 5 and R 6 are defined as in Formula I.
- a compound of Formula I to XXVI is selected from the group consisting of the compounds below or a pharmaceutically acceptable salt thereof:
- the invention also encompasses a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula I to XXVI in admixture with one or more physiologically acceptable carriers or excipients.
- the invention also encompasses a compound of Formula I to XXVI or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.
- the invention also encompasses a method of treating a human or animal subject suffering from a condition which is mediated by the action of ubiquitin-specific protease 1 (USP1) , which method comprises administering to said subject an effective amount of a compound of Formula I to XXVI.
- USP1 ubiquitin-specific protease 1
- the invention also encompasses the use of a compound of Formula I to XXVI for the manufacture of a therapeutic agent for the treatment of a condition which is mediated by the action of USP1.
- alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono-or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated (i.e. C1-10 means one to ten carbons) .
- saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
- An unsaturated alkyl group is one having one or more double bonds or triple bonds.
- alkyl groups examples include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) , ethynyl, 1-and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
- Alkyl groups which are limited to hydrocarbon groups are termed “homoalkyl” .
- the alkyl is optionally substituted with one or more halogen atom (s) .
- halogenated alkyl means alkyl as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.
- the alkylene radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z”orientations.
- an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
- a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
- the alkylene is optionally substituted with one or more halogen atom (s) .
- alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. The alkynyl is optionally substituted with one or more halogen atom (s) .
- alkylamino refers to an amino substituent which is further substituted with one or two alkyl groups.
- aminoalkyl refers to an alkyl substituent which is further substituted with one or more amino groups.
- hydroxyalkyl refers to an alkyl substituent which is further substituted with one or more hydroxyl groups.
- the alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.
- cycloalkyl or “carbococyclyl” means mono-, bicyclic or spiro-bicyclic carbocyclic rings, each of which has from 3 to 10 carbon atoms.
- a “fused analog” of cycloalkyl means a monocyclic ring fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
- the spiro-bicyclic carbocyclic rings are bicyclic (having just two rings) or have a bicyclic portion as part of the larger ring system, in either case with the two rings connected through the defining single common carbon atom.
- the cycloalkyl is optionally substituted with one or more halogen atom (s) .
- alkoxy means alkoxy groups of a straight or branched having the indicated number of carbon atoms.
- C 1-6 alkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
- heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom (s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
- heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 -and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
- heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like) .
- chain termini e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like.
- no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
- heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C (O) R’, -C (O) NR’, -NR’R”, -OR’, -SR’, and/or -SO 2 R’.
- heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR’R” or the like, it will be understood that the terms heteroalkyl and -NR’R” are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR’R” or the like.
- cycloalkoxy means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy.
- halogenated alkoxy means alkoxy as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.
- aryl means mono-or bicyclic aromatic rings containing only carbon atoms.
- a “fused analog” of aryl means an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2, 3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1, 4-benzodioxanyl, and the like.
- heteroaryl means a mono-or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
- a “fused analog” of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion.
- heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo (2, 3-b) pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
- heterocyclyl means mono-, bicyclic, tricyclic, spirocyclic, fused or bridged saturated ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
- a “heterocyclyl” includes a “fused analog” which means a monocyclic heterocycle fused to a heterocycle, a carbocycle, an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion.
- heterocyclyl and fused analogs thereof include azeridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dioxolanyl, oxazolodinyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorphonulyl 1, 1-dioxide, morpholinyl, azapanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyl, azabycyclononanyl, azaspiroheptanyl, dihydro-1H, 3H, 5H-oxazolo [3, 4-c] oxazolyl, tetroxazolyl,
- the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2-or 4-pyridones attached through the nitrogen or N-substituted- (1H, 3H) -pyrimidine-2, 4-diones (N-substituted uracils) .
- alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups referred to in the definitions are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents.
- the substituents are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent-x groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfony
- halo or “halogen, ” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl, ” or “halogenated alkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo (C 1 -C 4 ) alkyl” is meant to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
- prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug.
- An example, without limitation, of a prodrug would be a compound of any of Formula I, which is administered as an ester (the “prodrug” ) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
- a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
- Compounds of the present invention may contain one or more asymmetric centers and may thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
- the present invention is meant to comprehend all such isomeric forms of the compounds.
- Some of the compounds of described herein may contain one or more than one cyclic ring systems and may thus exist in cis-and trans-isomers.
- the present invention is meant to include all such cis-and trans-isomers.
- tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of the present invention.
- any enantiomer of a compound described herein may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
- One or more than one of the protons (hydrogen atoms) in compounds of the present invention can be replaced with deuterium atom (s) , thus providing deuterated analogs that may have improved pharmacokinetic properties or pharmacological activities.
- the compounds described herein can be useful as the free base or as a salt.
- salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N’-dibenzyl-ethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tris (hydroxymethyl) aminomethane, tromethamine, and the like.
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include acetic, benzenesulfonic, benzoic, 2, 5-dihydroxybenzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like.
- Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- an oil medium for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorb
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
- preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- flavoring agents such as sucrose, saccharin or aspartame.
- sweetening agents such as sucrose, saccharin or aspartame.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
- the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavouring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butane diol.
- Suitable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono-or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an I atomiser using electrohydrodynamics to produce a fine mist) , or nebuliser, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane.
- the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
- the pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate oroleic acid.
- a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate oroleic acid.
- the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns) .
- This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
- Capsules (made, for example, from gelatin or HPMC) , blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
- the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
- Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
- a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from l mg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 L to 100 L.
- a typical formulation may comprise a compound of Formula (A) propylene glycol, sterile water, ethanol and sodium chloride.
- Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
- Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
- Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly (DL-lactic-coglycolic acid (PGLA) .
- Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
- the dosage unit is determined by means of a valve which delivers a metered amount.
- Units in accordance with the invention are typically arranged to administer a metered dose or “puff” containing from 1 pg to 1 mg of the compound of the present invention.
- the overall daily dose will typically be in the range 1 pg to 1 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
- compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- creams, ointments, jellies, solutions or suspensions, etc., containing the compound of the present invention are employed.
- topical application shall include mouth washes and gargles.
- Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
- a condition may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
- Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
- the compounds of the invention are inhibitors of USP1 and are useful in treating a USP1 associated disease or condition such as cancer.
- the invention also encompasses a method of treating cancer with an effective amount of a compound of the present invention or using a combination of an effective amount of a compound of the present invention with an effective amount of radiation, chemotherapies, PARP inhibitors, endocrine/hormone therapeutics, FAK inhibitors, immunotherapies such as antibodies against programmed cell death protein 1 (PD-1) , programmed death ligand 1 (PD-Ll) , or cytotoxic t-lymphocyte antigen 4 (CTLA4) .
- PD-1 programmed cell death protein 1
- PD-Ll programmed death ligand 1
- CTLA4 cytotoxic t-lymphocyte antigen 4
- the cancer treated is selected from ovarian cancers, breast cancers, pancreatic cancers, prostate cancers, gastric cancers, liver cancers, lung cancers, bladder cancers, skin cancers and other cancers.
- the compounds of the present invention can be prepared according to the following synthetic schemes:
- Deubiquitination assay for USP1/UAF1 compounds described here were tested for their ability to inhibit USP1 deubiquitinase activity in this assay using ubiquitin-rhodamine 110 as the substrate.
- the assay was conducted in 20 ul total volume of assay buffer (50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.1mg/ml Bovine Serum Albumin, 1 mM DTT, 0.01%Tween-20) in 384 well plates.
- 0.5 nM USP1/UAF1 (R&D Systems) was incubated with compounds in dose response format for 10 minutes at room temperature.
- Table 1 shows the activities of selected compounds of this invention in the USP1/UAF1 deubiquitination assay.
- the IC 50 value was determined as the concentration for 50%inhibition of the USP1/UAF1 activity compared to DMSO control (A: IC 50 ⁇ 100 nM; B: IC 50 between 100 nM and 1,000 nM; C: IC 50 ⁇ 1,000 nM) .
- EA means ethyl acetate
- CIP means 2-chloro-1, 3-dimethylimidazolidium hexafluorophosphate
- DBU means l, 8-diazabicyclo [5.4.0] undec-7-ene
- DIAD means diisopropyl azodicarboxylate
- DIBAL means diisobutylaluminum hydride
- DCM means dichloromethane
- DDQ means 1, 2-dichloro-4, 5-dicyanobenzoquinone
- DIEA means N, N-diisopropylethylamine
- DMAP means N, N-dimethylaminopyridine
- DME means 1, 2-dimethoxyethane
- DMF means N, N-dimethylformamide
- dmpe means l, 2-bis(dimethyl ⁇ hosphino) ethane
- DMSO means dimethylsulfoxide
- dppb means l, 4-bis (dip
- RT room temperature
- sat. means saturated
- T3P means propylphosphonic anhydride
- TCFH means N, N, N’, N’-tetramethylchloroformaidinium hexafluorophosphate
- MCPBA means 3-chloroperbenzoic acid
- MTBE means methyl tert-butyl ether
- NBS means N-Bromosuccinimide
- DMA means N, N-Dimethylacetamide, *in structures means undetermined R or S chiral center.
- MS instrument Waters UPLC-PDA-3100 (SQD3100) single-quadrupole mass spectrometer.
- Step 1 1-isopropyl-4- (trifluoromethyl) -1H-imidazole
- Step 3 4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzaldehyde
- Step 4 (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol
- Step 1 The product of Step 1 (1.5 g) was dissolved in methanol (80 mL) .
- Sodium borohydride (303 mg) was added at 0°C.
- the mixture was warmed to r.t. for 2 h.
- the mixture was then treated with ammonium chloride (1N, 30 mL) and extracted with dichloromethane (3 x 50 mL) .
- the organic layer was concentrated in vacuum.
- LCMS (ESI) 285.4 [M+1] + .
- Step 5 2- (4- (chloromethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole
- Step 7 4-cyclopropyl-6-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine
- Step 9 ethyl 3- (4-amino-4'-cyclopropyl-6'-methoxy- [2, 5'-bipyrimidin] -5-yl) propanoate
- Step 10 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 8-dihydropyrido [2, 3-d] pyrimidin-7 (6H) -one
- Step 11 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5, 8-dihydropyrido [2, 3-d] pyrimidin-7 (6H) -one acid
- Step 2 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 1 di-tert-butyl 1- (1- (4-bromophenyl) cyclopropyl) hydrazine-1, 2-dicarboxylate
- a 40 mL screw-top vial was charged with 1- (4-bromophenyl) cyclopropane-1-carboxylic acid (2.00 mmol, 1.0 equiv. ) , di-tert-butyl azodicarboxylate (461 mg, 4.00 mmol, ) , cerous chloride heptahydrate (photocatalyst, 74.6 mg, 0.10 mmol) , and cesium carbonate (130.4 mg, 0.40 mmol) .
- the vial was evacuated and back-filled with N 2 followed by addition of acetonitrile (20 mL, 0.10 M) .
- Step 2 di-tert-butyl 1- (1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) cyclopropyl) hydrazine-1, 2-dicarboxylate
- Step 1 the product of Step 1 (600 mg, 1.4 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (711 mg, 2.8 mmol) , bis (diphenylphosphino) ferrocene-palladium (II) dichloride (85 mg, 0.14 mmol) , potassium acetate (550 mg) were dissolved in 1, 4-dioxane (5 mL) , and the reaction was stirred for 4 h at 90 °C. To the reaction mixture was treated with 50 mL water and the mixture was extracted 3 x 60 mL ethyl acetate.
- Step 3 di-tert-butyl 1- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) cyclopropyl) hydrazine-1, 2-dicarboxylate
- Step 2 the product of Step 2 (400 mg, 0.8 mmol) , 2-bromo-1-isopropyl-4- (trifluoromethyl) -1H-imidazole (411 mg, 1.6 mmol) , xphos-Pd-G2 (60 mg, 0.08 mmol) and potassium phosphate (340 mg) were dissolved in 1, 4-dioxane/water (5 mL) , and the reaction mixture was stirred for 12 h at 90°C. To the reaction mixture was treated with 50 mL water and the reaction mixture was extracted 3 x 60 mL ethyl acetate.
- Step 4 2- (4- (1-hydrazineylcyclopropyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole hydrochloride
- Step 5 6-chloro-1- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) cyclopropyl) -1H-pyrazolo [3, 4-d] pyrimidine
- Step 6 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) cyclopropyl) -1H-pyrazolo [3, 4-d] pyrimidine
- Step 4 2- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6-methyl-1, 3, 6, 2-dioxazaborocane-4, 8-dione
- Step 5 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2- yl) benzyl) pyrrolo [2, 1-f] [1, 2, 4] triazine
- Step 1 6- (2-isopropylphenyl) -1, 6-dihydro-7H-pyrazolo [69yridazineidazin-7-one
- Step 2 1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (2-isopropylphenyl) -1, 6-dihydro-7H-pyrazolo [69yridazineidazin-7-one
- Step 1 2- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (2-isopropylphenyl) -2H-pyrazolo [3, 4-d] pyridazin-7 (6H) -one
- Step 1 4- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-b] pyridine
- Step 2 4- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (2-isopropylphenyl) -4, 5, 6, 7-tetrahydro -2H-pyrazolo [4, 3-b] pyridine
- Step 1 ( ⁇ ) 1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethan-1-ol
- Example 24 was resolved by the following conditions to provide EXAMPLE 25 and EXAMPLE 26: column type: IG column 5 ⁇ m, 10 mm I.D. *250 mm.
- Mobile phase 25%ethanol, 75%hexane, flow rate, 2 mL/min.
- EXAMPLE 25 retention time at 37 min
- EXAMPLE 26 retention time at 51 min.
- Step 4 (8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (2-isopropylphenyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 1 6- (5-amino-2-chloropyrimidin-4-yl) hex-5-yn-1-ol
- Step 2 4- (2-chloro-5H-pyrrolo [3, 2-d] pyrimidin-6-yl) butan-1-ol
- Step 4 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6, 7, 8, 9-tetrahydropyrimido [4, 5-b] indolizine
- Step 5 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -10-iodo-6, 7, 8, 9-tetrahydropyrimido [4, 5-b] indolizine
- Step 6 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -10- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6, 7, 8, 9-tetrahydropyrimido [4, 5-b] indolizine
- Step 2 (R) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 3 (R) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 1 (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanamine
- Step 2 5- (benzyloxy) -2-chloro-N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrimidin-4-amine
- Step 4 4'-cyclopropyl-4- ( (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) -6'-methoxy- [2, 5'-bipyrimidin] -5-ol
- step 1 To the reaction mixture of step 1 was added potassium carbonate (2.5 g) , followed by 4- (1-isopropyl-4-ea (trifluoromethyl) -1H-imidazol-2-yl) benzaldehyde (1.0 g) . The reaction mixture was stirred at 50°C for 1 h. NaBH (OAc) 3 (11.3 g) was then added and the reaction mixture was stirred for additional 0.5 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 2: 8) to afford the title compound as a yellow solid (0.86 g) . LCMS (ESI) : 398.3 [M+1] + .
- Step 4 3- ( (5-bromo-2-chloropyrimidin-4-yl) (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) cyclobutan-1-one
- Step 6 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7, 8-dihydro-5, 7-methanopyrido [2, 3-d] pyrimidin-5 (6H) -ol
- Step 1 methyl 4- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzoate
- Step 2 (4- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) methanol
- Step 3 (4- (chloromethyl) phenyl) -5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazole
- Step 4 (8- (4- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
- Step 5 ( ⁇ ) 5- (4- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] -pyrido [2, 3-d] pyrimidin-6-one
- Step 2 methyl 4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate
- Step 3 (4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol
- Step 4 2- (4- (chloromethyl) phenyl) -1-cyclopropyl-4- (trifluoromethyl) -1H-imidazole
- Step 5 ( ⁇ ) 5- (4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
- Example 45 was resolved by the following conditions to provide EXAMPLE 47 and EXAMPLE 48: Column type: IE column 5 ⁇ m, 4.6 mm I.D. *250 mm.
- Mobile phase 40%isopropanol, 60%hexane, flow rate, 1 mL/min.
- EXAMPLE 47 retention time at 16.8 min; EXAMPLE 48: retention time at 17.3 min.
Abstract
The disclosure is related to a series of novel heteroaryl derivatives as USP1 inhibitors useful for the treatment of diseases or conditions, such as cancers, especially cancers with BRCA mutations or HR deficiencies. Specifically, provided are the compounds of any of formula (I) to (XXII), pharmaceutically acceptable salts or pharmaceutical compositions. Definition of each group in the formula can be found in the specification for details.
Description
The invention is directed to a series of novel heteroaryl derivatives as USP1 inhibitors useful for the treatment of diseases or conditions, such as cancers, especially cancers with BRCA mutations or HR deficiencies. Pharmaceutical compositions and methods of use are also included.
This invention relates to heteroaryl derivatives, or their pharmaceutically acceptable salts, pharmaceutical acceptable prodrugs, pharmaceutical compositions containing them, and their medical uses.
The compounds of this invention have activity as ubiquitin-specific protease 1 (USP1) inhibitors and are useful in the treatment or alleviation of diseases associated with USP1 enzyme, such as cancers and other disorders. In particular, due to the important role of USP1 in regulating DNA damage response (DDR) pathways, inhibition of USP1 has the potential to be a treatment for cancers with BRCA (BReast CAncer) gene mutations or deficiency for homologous recombination (HR) .
Ubiquitin is a small 76-amino-acids protein which can be conjugated to specific target proteins via polyubiquitination and monoubiquitination. Deubiquitination is a reversible process which involves a family of deubiquitinating enzymes (DUBs) that catalyze the removal of ubiquitin moieties from ubiquitinated substrates. Ubiquitylation plays a regulatory role in protein interactions, localization and function, thereby affecting cellular processes, including gene expression, DNA damage signaling and DNA repair, cell cycle progression, apoptosis and cell motility, and so forth.
As a member of the DUBs, USP1 plays an important role in the regulation of DNA repair processes. USP1 forms a heterodimeric complex with UAF1 (USP1-associated factor 1) , which is required for deubiquitinase activity. The mono-ubiquitinated PCNA (proliferating cell nuclear antigen) is a critical substrate of USP1-UAF1. During DNA replication, PCNA monoubiquitylation facilitates the recruitment of specific TLS (translesion synthesis) polymerases, which can bypass the DNA lesions. Inhibition of USP1 leads to replication fork destabilization due to persistent TLS polymerase loading and accumulation of toxic mono-ubiquitinated PCNA. Replication fork instability can cause double strand breaks (DSBs) , which require BRCA-mediated HR repair. Therefore, like Poly- (ADP) -ribose polymerase (PARP) inhibitors, USP1 inhibition is synthetic lethal with BRCA mutations or deficiency for HR. Another DNA repair-related process, Fanconi anemia (FA) pathway that repair DNA inter-strand crosslink (ICL) lesions, is also regulated by USP1/UAF1. The critical USP1 substrate in FA pathway is FANCD2 (Fanconi anemia group complementation group D2) and FANCI (Fanconi anemia complementation group I) . Besides these DNA repair-related functions, USP1 has been reported to deubiquitinate and stabilize inhibitors of DNA binding proteins to maintain stem-cell characteristics in osteosarcoma cells.
The invention encompasses a genus of compounds of Formula I as USP1 inhibitors or a pharmaceutically acceptable salt thereof,
whereinis the selected from the follow moieties:
with the proviso that whenisR4 and R5, together with the carbon atom to which they are both attached to, complete a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which is optionally substituted with Rd or a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which contains one, two or three heteroatom (s) such as S, O or NRd;
Rd is selected from the group consisting of hydrogen, C1-6alkyl, C3-6cyclolkyl, C3-6fluorocycloalkyl, C1-6fluoroalkyl, C0-6alkylene-aryl, C0-6alkylene-heteroaryl, C (O) C1-6alkyl, C (O) aryl, S (O) 2C1-6alkyl, S (O) 2C3-6cycloalkyl, S (O) 2aryl; each of X0, X1, X2, X3 and X4 is independently selected from N or CR1;
X5, X8 is independently selected from C (R2) r, O, S, SO, SO2, or NR2;
r, q = 0, 1, 2, 3 or 4;
X6 is NRb, C=O, CRaRb;
X7 is N or CH;
Xa, Xb and Xc are independently N or CR2;
Xd is C (O) , O, S, S (O) 2, O or NRd;
R1 is independently selected from the group consisting of hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, C1-6 alkylthio, hydroxyl, amino, nitro, formyl, -CF3, -CN, -SF5, NRaRb, carboxyl, -CORa, -CO2C1-C6 alkyl, -CONRaRb, -SO2Re, -SO2NRaRb, -P (O) Me2 and -P (O) (OMe) 2;
R2 is independently selected from the group consisting of hydrogen, OH, oxo, CF2CH2OH, C1-C6 alkanol, C1-C6 halogenated alkanol, halogen, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, nitro, formyl, -CF3, -CN, -SF5, NRaRb, carboxyl, -CORa, -CO2C1-C6 alkyl, -CONRaRb, -SO2Rc, -SO2NRaRb, -P (O) Me2 and -P (O) (OMe) 2;
Two R2 on the same carbon atom or adjacent carbon atoms together with carbon atom (s) can form a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which is optionally substituted with R4 or a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which contains one, two or three heteroatom (s) such as S, O or NRd;
Ra and Rb are independently hydrogen, CH2CH2OH, CH2CMe2OH, C1-C6 alkanol, C1-C6 halogenated alkanol, substituted/non-substituted C1-C10 alkyl, substituted/non-substituted C3-C10 cycloalkyl, substituted/non-substituted C2-C10 alkenyl, substituted/non-substituted C6-C20 aryl, or substituted/non-substituted C3-C14 heteroaryl respectively; Ra and Rb can form 3-8 membered rings or 4-8 membered heterocyclic rings, which contain sulfur, oxygen, NH or NRd;
Two R1 on the adjacent carbon atoms together with carbon atoms can form a four-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which is optionally substituted with R4 or a four-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which contains one, two or three heteroatom (s) such as S, O or NRd;
R1 and R2, together with the carbon atoms to which they are attached to, can form 3-8 membered cabocyclic rings or 4-8 membered heterocyclic rings, which contain sulfur, oxygen, NH or NRd;
R3 represents C6-C20 aryl and C1-C20 heteroaryl; R3 can be substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkanol, C1-C6 halogenated alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C1-C6 alkoxy, hydroxyl, amino, nitro, formyl, -CF3, -CN, -SF5, NRaRb, carboxyl, -CORa, -CO2C1-C6 alkyl, -CONRaRb, -SO2Rc, -SO2NRaRb, -P (O) Me2 and -P (O) (OMe) 2;
Each of R4 and R5 is independently absent or selected from the group consisting of H, NRb2, C1-C6 alkoxy, C1-6 alkylthio, halogen, CN, C1-6alkyl, C3-C6cyclolkyl, C3-C6fluorocycloalkyl, C1-C6fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents selected from halogen, C1-C6alkyl, C1-C6halogenated alkyl, C3-C10cycloalkyl, C3-C10 cycloalkoxy, C1-C6alkoxy, hydroxyl, amino, nitro, formyl, -CF3, -CN, -SF5, NRaRb, carboxyl, -CORa, -CO2C1-C6 alkyl, -CONRaRb, -SO2Rc, -SO2NRaRb, -P (O) Me2 and -P (O) (OMe) 2; R4 and R5, together with the carbon atom to which they are both attached to, complete a three-to six-membered carbocyclic ring, four-to ten-membered bicyclic ring or five-to ten-membered spirocyclic ring which is optionally substituted with Rd or a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which contains one, two or three heteroatom (s) such as S, O or NRd;
Rc represents C1-C10 alkyl, C3-C10 cycloalkyl, C6-C20 aryl, or C3-C14 heteroaryl; Rc can be substituted by one or more radical groups selected from halogen, hydroxyl, amino, nitro, cyano, formyl, carboxyl, alkoxy, -CF3 and -SF5;
is selected from a single bond or double bond;
Y is selected from B, C, CO, N, NH, NMe, O, Si, P, S, SO, SO2, POH, PO (OH) ;
is C5-C14aryl, C3-C14cycloalkyl, C4-C14bicycloalkyl, C5-C14tricycloalkyl, C5-C14spiroalkyl, C5-C14 heteroaryl, C4-C14heterocycloalkyl, C4-C14heterobicycloalkyl, C5-C14heterotricycloalkyl, C5-C14heterospiroalkyl with 0-5 O, N or S atoms independently, wherein the aryl, cycloalkyl, bicycloalkyl, tricycloalkyl, spiroalkyl, heteroaryl, heterocycloalkyl, heterobicycloalkyl, heterotricycloalkyl, heterospiroalkyl are substituted with one or more R6;
R6 represents optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, , optionally substituted C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6hydroxyalkyl, CN, halogen, SO2NH2, -CORa, -COORa, -NRbRb, -NRaCORb, -NRaCONRaRa, -CONRaRb, -SO2NRaRb, -NRaSO2Rb, optionally C6-C10 aryl and C1-C10heteroaryl; R6 can be substituted by one or more groups selected from: halogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6 halogenated cycloalkyl, C1-C6halogenated alkyl, C1-C6alkoxy, hydroxyl, amino, nitro, formyl, -CF3, -CN, -SF5, NRaRb, carboxyl, -CORa, -CO2C1-C6 alkyl, -CONRaRb, -SO2Rc, -SO2NRaRb, -P (O) Me2 and -P (O) (OMe) 2;
In another preferred embodiment, X0 in Formula I represents CH.
In another preferred embodiment, at least one of X1 and X2 in Formula I represents N.
In another preferred embodiment, X3 in Formula I represents N.
In another preferred embodiment, X3 in Formula I represents CH.
In another preferred embodiment, X4 in Formula I represents N.
In another preferred embodiment, Y in Formula I represents C, O, N or S.
In another preferred embodiment, in Formula I represents a single bond.
In another preferred embodiment, in Formula I represents a double bond.
In another preferred embodiment, in Formula I represents CH2, CHR4, NH, NR4, Me2Si, O, S, CO, SO, SO2, S (O) =NH, CF2,
In another preferred embodiment, in Formula I is selected from the group consisting of
In another preferred embodiment, in Formula I is selected from the group consisting of
In another preferred embodiment, R3 in Formula I is selected from the group consisting of
In another preferred embodiment, R6 in Formula I is
Each V1, V2, V3, and V4 are independently selected from C (R2) , NRd, O and S; V5 is C, or N; V1, V2, V3, V4 and V5 together form a 5-membered heteroaryl ring. R2, Rd are defined as in Formula I.
In another preferred embodiment, R6 in Formula I is selected from the group consisting of
In one embodiment, the invention further provides a compound of Formula IA and IB or a pharmaceutically acceptable salt thereof:
where Z, W, ring A and ring B are defined as in Formula I. R4a is C1-C6alkyl, C3-C6cyclolkyl, C3-C6fluorocycloalkyl, C1-C6fluoroalkyl.
In one embodiment, the invention further provides a compound of Formula II or a pharmaceutically acceptable salt thereof:
wherein X0, X1, X2, X3, X4, R3 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula IV or a pharmaceutically acceptable salt thereof:
wherein X0, X1, X2, X5, R3 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula V or a pharmaceutically acceptable salt thereof:
wherein X1, X2, X3, X4, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula VI or a pharmaceutically acceptable salt thereof:
wherein X0, X1, X2, X3, X4, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula VII or a pharmaceutically acceptable salt thereof:
wherein X0, X1, X2, X3, X4, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula VIII or a pharmaceutically acceptable salt thereof:
wherein R1, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula IX or a pharmaceutically acceptable salt thereof:
wherein R1, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula X or a pharmaceutically acceptable salt thereof:
wherein r, R1, R2, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XI or a pharmaceutically acceptable salt thereof:
wherein r, R1, R2, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XII or a pharmaceutically acceptable salt thereof:
wherein r, R1, R2, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XIII or a pharmaceutically acceptable salt thereof:
wherein Y1 is a bond, O, CH2 or NRb; Y2 is C (O) or CH2; X2 is N or CH; r, Rb, R2, R3 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof:
wherein Y1 is a bond, O, CH2 or NRb; Rb, R2, R3 and R6 are defined as in Formula I.
In one embodiment, the invention further provides a compound of Formula XVA or XVB or a pharmaceutically acceptable salt thereof:
wherein R1, r, R2, R3 and R6 are defined as in Formula I. R4a is C1-C6alkyl, C3-C6cyclolkyl, C3-C6fluorocycloalkyl, C1-C6fluoroalkyl.
In an embodiment, the invention further provides a compound of Formula XVI or a pharmaceutically acceptable salt thereof:
wherein X0, X1, X2, q, r, R2, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XVII or a pharmaceutically acceptable salt thereof:
wherein X0, X1, X2, q, r, R2, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XVIII or a pharmaceutically acceptable salt thereof:
wherein Y1 is a bond, O, S, CH2 or NRb; Y2 is a bond, C (O) or CH2; r, Rb, R2, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XIX or a pharmaceutically acceptable salt thereof:
wherein X0, X1, X2, q, r, R2, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XX or a pharmaceutically acceptable salt thereof:
wherein Rd, R1, R3, R4, R5 and R6 are defined as in Formula I. is a 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, which contain sulfur, oxygen, NH or NRd; is a single or double bond such that all valences are satisfied.
In an embodiment, the invention further provides a compound of Formula XXI or a pharmaceutically acceptable salt thereof:
wherein Rd, R1, R3, R4, R5 and R6 are defined as in Formula I. is a saturated or unsaturated 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, which contain sulfur, oxygen, NH or NRd; is a single or double bond such that all valences are satisfied.
In an embodiment, the invention further provides a compound of Formula XXII or a pharmaceutically acceptable salt thereof:
wherein Rd, R1, R3, R4, R5 and R6 are defined as in Formula I. is a 4-8 membered heterocyclic ring, which may contain additional S, O, NH or NRd.
In an embodiment, the invention further provides a compound of Formula XXIII or a pharmaceutically acceptable salt thereof:
wherein Ra, R1, R2, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XXIV or a pharmaceutically acceptable salt thereof:
wherein Ra, R1, R2, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XXV or a pharmaceutically acceptable salt thereof:
wherein R1, R2, R3, R4, R5 and R6 are defined as in Formula I.
In an embodiment, the invention further provides a compound of Formula XXVI or a pharmaceutically acceptable salt thereof:
wherein Ra, R1, R3, R4, R5 and R6 are defined as in Formula I.
In some embodiments, a compound of Formula I to XXVI is selected from the group consisting of the compounds below or a pharmaceutically acceptable salt thereof:
The invention also encompasses a pharmaceutical composition comprising a compound of Formula I to XXVI in admixture with one or more physiologically acceptable carriers or excipients.
The invention also encompasses a compound of Formula I to XXVI or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.
The invention also encompasses a method of treating a human or animal subject suffering from a condition which is mediated by the action of ubiquitin-specific protease 1 (USP1) , which method comprises administering to said subject an effective amount of a compound of Formula I to XXVI.
The invention also encompasses the use of a compound of Formula I to XXVI for the manufacture of a therapeutic agent for the treatment of a condition which is mediated by the action of USP1.
Definitions
The term “alkyl” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono-or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated (i.e. C1-10 means one to ten carbons) . Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) , ethynyl, 1-and 3-propynyl, 3-butynyl, and the higher homologs and isomers. Alkyl groups which are limited to hydrocarbon groups are termed “homoalkyl” . The alkyl is optionally substituted with one or more halogen atom (s) .
The term “halogenated alkyl” means alkyl as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.
The term “alkenyl” means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, Z-or E-, or combinations thereof. Examples of alkenyl are CH3CH=CH-, CH2=CHCH2-and CH (CH3) 2CH=CH-.
The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH2CH2CH2CH2-, -CH=CH-, -CH2CH=CHCH2-, -CH2C≡CCH2-, -CH2CH2CH (CH2CH2CH3) CH2-. The alkylene radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The alkylene is optionally substituted with one or more halogen atom (s) .
The term “alkynyl” means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. The alkynyl is optionally substituted with one or more halogen atom (s) .
The term “alkylamino” refers to an amino substituent which is further substituted with one or two alkyl groups.
The term “aminoalkyl” refers to an alkyl substituent which is further substituted with one or more amino groups.
The term “hydroxyalkyl” refers to an alkyl substituent which is further substituted with one or more hydroxyl groups. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.
The term “cycloalkyl” or “carbococyclyl” means mono-, bicyclic or spiro-bicyclic carbocyclic rings, each of which has from 3 to 10 carbon atoms. A “fused analog” of cycloalkyl means a monocyclic ring fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like. The spiro-bicyclic carbocyclic rings are bicyclic (having just two rings) or have a bicyclic portion as part of the larger ring system, in either case with the two rings connected through the defining single common carbon atom. The cycloalkyl is optionally substituted with one or more halogen atom (s) .
The term “alkoxy” means alkoxy groups of a straight or branched having the indicated number of carbon atoms. C1-6alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
The term “heteroalkyl, ” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom (s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S (O) -CH3, -CH2-CH2-S (O) 2-CH3, -CH=CH-O-CH3, -Si (CH3) 3, -CH2-CH=N-OCH3, -CH=CH-N (CH3) -CH3, -O-CH3, -O-CH2-CH 3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si (CH3) 3. Similarly, the term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2 -CH2-S-CH2-CH2-and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C (O) OR’-represents both-C (O) OR’-and -R’ OC (O) -. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C (O) R’, -C (O) NR’, -NR’R”, -OR’, -SR’, and/or -SO2R’. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR’R” or the like, it will be understood that the terms heteroalkyl and -NR’R” are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR’R” or the like.
The term “cycloalkoxy” means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy.
The term “halogenated alkoxy” means alkoxy as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.
The term “aryl” means mono-or bicyclic aromatic rings containing only carbon atoms. A “fused analog” of aryl means an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2, 3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1, 4-benzodioxanyl, and the like.
The term “heteroaryl” means a mono-or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms. A “fused analog” of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo (2, 3-b) pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
The term “heterocyclyl” means mono-, bicyclic, tricyclic, spirocyclic, fused or bridged saturated ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. A “heterocyclyl” includes a “fused analog” which means a monocyclic heterocycle fused to a heterocycle, a carbocycle, an aryl or heteroaryl group in which the point of
attachment is on the non-aromatic portion. Examples of “heterocyclyl” and fused analogs thereof include azeridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dioxolanyl, oxazolodinyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorphonulyl 1, 1-dioxide, morpholinyl, azapanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyl, azabycyclononanyl, azaspiroheptanyl, dihydro-1H, 3H, 5H-oxazolo [3, 4-c] oxazolyl, tetrohydro-1’H3’ Hspiro [cyclopropane-1, 2’-pyrrolizinyl, hexahydro-1H-pyrralizinyl, hexahydro-1H-pyrrolo [2, 1-c] [1, 4] oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazspirooctanyls, diazaspirononanyls, oxaazabicycloheptanyls, hexahydropyrrolidinyl 4 (1H-oxide, tetrohydro-2H-thiopyranyl 1-oxide, tetrohydro-2H-thiopyranyl 1, 1-dioxide, bicycloheptanyl, 2, 3-dihydrofuro (2, 3-b) pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, hexahydro-1H-pyrrolizine, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2-or 4-pyridones attached through the nitrogen or N-substituted- (1H, 3H) -pyrimidine-2, 4-diones (N-substituted uracils) .
The said alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups referred to in the definitions are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents. The substituents are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent-x groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxy groups, -SF5, -P (O) Me2, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl (alkyl) amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and alkyl part, alkanoyl (alkyl) aminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono-or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono-or di-alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono-or di alkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono-or di-alkylamino groups having from 1 to 6 carbon atoms, mono-or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbon atoms.
The terms “halo” or “halogen, ” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl, ” or “halogenated alkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo (C1-C4) alkyl” is meant to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of any of Formula I, which is administered as an ester (the “prodrug” ) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
Optical Isomers –Diastereomers –Geometric Isomers –Tautomers
Compounds of the present invention may contain one or more asymmetric centers and may thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Some of the compounds of described herein may contain one or more than one cyclic ring systems and may thus exist in cis-and trans-isomers. The present invention is meant to include all such cis-and trans-isomers.
Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of the present invention.
Compounds described herein may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or EtOAc or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine or acid as a resolving agent or on a chiral HPLC column.
Alternatively, any enantiomer of a compound described herein may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
Stable Isotope-Labeled Analogs
One or more than one of the protons (hydrogen atoms) in compounds of the present invention can be replaced with deuterium atom (s) , thus providing deuterated analogs that may have improved pharmacokinetic properties or pharmacological activities.
Salts and Formulations
The compounds described herein can be useful as the free base or as a salt.
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N’-dibenzyl-ethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tris (hydroxymethyl) aminomethane, tromethamine, and the like.
When the compound of the present invention is alkaline, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, 2, 5-dihydroxybenzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an I atomiser using electrohydrodynamics to produce a fine mist) , or nebuliser, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate oroleic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns) .
This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
Capsules (made, for example, from gelatin or HPMC) , blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from l mg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from
1 L to 100 L. A typical formulation may comprise a compound of Formula (A) propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly (DL-lactic-coglycolic acid (PGLA) . Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or “puff” containing from 1 pg to 1 mg of the compound of the present invention. The overall daily dose will typically be in the range 1 pg to 1 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
Compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of the present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles. )
Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, a condition may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Utilities
The compounds of the invention are inhibitors of USP1 and are useful in treating a USP1 associated disease or condition such as cancer.
The invention also encompasses a method of treating cancer with an effective amount of a compound of the present invention or using a combination of an effective amount of a compound of the present invention with an effective amount of radiation, chemotherapies, PARP inhibitors, endocrine/hormone therapeutics, FAK inhibitors, immunotherapies such as antibodies against programmed cell death protein 1 (PD-1) , programmed death ligand 1 (PD-Ll) , or cytotoxic t-lymphocyte antigen 4 (CTLA4) .
In yet another aspect of the invention, the cancer treated is selected from ovarian cancers, breast cancers, pancreatic cancers, prostate cancers, gastric cancers, liver cancers, lung cancers, bladder cancers, skin cancers and other cancers.
Synthesis
The compounds of the present invention can be prepared according to the following synthetic schemes:
Evaluation of Biological Activity
Deubiquitination assay for USP1/UAF1: compounds described here were tested for their ability to inhibit USP1 deubiquitinase activity in this assay using ubiquitin-rhodamine 110 as the substrate. The assay was conducted in 20 ul total volume of assay buffer (50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.1mg/ml Bovine Serum Albumin, 1 mM DTT, 0.01%Tween-20) in 384 well plates. 0.5 nM USP1/UAF1 (R&D Systems) was incubated with compounds in dose response format for 10 minutes at room temperature. Then the reaction was initiated by addition of 150 nM ubiquitin-rhodamine (R&D Systems) . The fluorescence intensity was read after 45 minutes at Ex488/Em535 by CLARIOstar (BMG Labtech) . IC50 response curves were plotted.
Table 1 shows the activities of selected compounds of this invention in the USP1/UAF1 deubiquitination assay. The IC50 value was determined as the concentration for 50%inhibition of the USP1/UAF1 activity compared to DMSO control (A: IC50 ≤ 100 nM; B: IC50 between 100 nM and 1,000 nM; C: IC50 ≥ 1,000 nM) .
Table 1 Activities in USP1/UAF1 deubiquitination assay
Abbreviations
The following abbreviations have the meanings indicated. EA means ethyl acetate; CIP means 2-chloro-1, 3-dimethylimidazolidium hexafluorophosphate; DBU means l, 8-diazabicyclo [5.4.0] undec-7-ene; DIAD means diisopropyl azodicarboxylate; DIBAL means diisobutylaluminum hydride; DCM means dichloromethane; DDQ means 1, 2-dichloro-4, 5-dicyanobenzoquinone; DIEA means N, N-diisopropylethylamine; DMAP means N, N-dimethylaminopyridine; DME means 1, 2-dimethoxyethane; DMF means N, N-dimethylformamide; dmpe means l, 2-bis(dimethylρhosphino) ethane; DMSO means dimethylsulfoxide; dppb means l, 4-bis (diphenylphosphino) butane; dppe means 1, 2-bis (diphenylphosphino) ethane; dppf means 1, 1’-bis (diphenylphosphino) ferrocene; dppm means 1, 1’-bis (diphenylphosphino) methane; DIAD means diisopropylazodicarboxylate; EDCI means 1- (3-
dimethylaminopropyl) -3-ethylcarbodiimide; HATU means 2- (7-Aza-1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphorarnide; IPA means isopropyl alcohol; LDA means lithium diisopropylamide; LHMDS means lithium bis (hexamethyldisilylamide) ; LAH means lithium aluminum hydride; NCS means N-chlorosuccinimide; PE means petroleum ether; PyBOP means benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; SGC means silica gel chromatography; TDA means tris (2- (2-methoxyethoxy) ethyl) amine; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMI means 1-methylimidazole; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh3 means triphenylphosphine; rt, r.t. or RT means room temperature; sat. means saturated; T3P means propylphosphonic anhydride; TCFH means N, N, N’, N’-tetramethylchloroformaidinium hexafluorophosphate; MCPBA means 3-chloroperbenzoic acid; MTBE means methyl tert-butyl ether; NBS means N-Bromosuccinimide; DMA means N, N-Dimethylacetamide, *in structures means undetermined R or S chiral center.
LCMS conditions:
Column: Xtimate C18, 3 mm, 4.6 x 50 mm.
Mobile phase: 0.03%TFA in water and 0.03%TFA in CH3CN;
Gradient: 5%CH3CN to 95%CH3CN in 6.5 min;
Flow rate: 1mL/min.;
MS instrument: Waters UPLC-PDA-3100 (SQD3100) single-quadrupole mass spectrometer.
The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.
EXAMPLE 1
2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5, 8-dihydropyrido [2, 3-d] pyrimidin-7 (6H) -one
Step 1 1-isopropyl-4- (trifluoromethyl) -1H-imidazole
To a mixture of 4- (trifluoromethyl) -1H-imidazole (5.0 g) and cesium carbonate (13.2 g) in anhydrous DMF (100 mL) at 0℃ was added 2-iodopropane (6.8 g) . The reaction mixture was then warmed to rt and stirred overnight. The reaction mixture was poured into 100 mL ice-water, extracted by 3 x 50 mL ethyl acetate. The combined organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 10: 1) to afford the title compound as white solids (4.2 g) . LCMS (ESI) : 179.3 [M+1] +.
Step 2 2-bromo-1-isopropyl-4- (trifluoromethyl) -1H-imidazole
To a stirred solution of the product of Step 1 (500 mg, 2.806 mmol) in THF (25 mL) at -78℃, was added n-butyllithium (2.5 M in hexane, 1.5 mL) dropwise. The resulting mixture was stirred for 30 min at -78℃ and was then treated with a solution of carbon tetrabromide (691 mg, 4.210 mmol) in dry THF (10 mL) . The reaction mixture was allowed to warm room temperature and then stirred for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3 x 50 mL) . The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography eluted with 0-10%ethyl acetate in hexane to afford the title compound (368
mg) . LCMS (ESI) : 258.3 [M+1] +.
Step 3 4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzaldehyde
A mixture of the product of Step 2 (15 g) , (4-formylphenyl) boronic acid (9.6 g) , [2’- (amino-κN) [1, 1’-biphenyl] -2-yl-κC] chloro [dicyclohexyl [2’, 4’, 6’-tris (1-methylethyl) [1, 1’-biphenyl] -2-yl] phosphine] palladium (917 mg) , 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl-1, 1'-biphenyl (1.1 g) and potassium phosphate (37.1 g) in 1, 4-dioxane/water (200 mL/10 mL) was stirred for 16 h at 100℃ under nitrogen. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1) to afford the title compound as a yellow solid (14.0 g) . LCMS (ESI) : 283.4 [M+1] +.
Step 4 (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol
The product of Step 1 (1.5 g) was dissolved in methanol (80 mL) . Sodium borohydride (303 mg) was added at 0℃. The mixture was warmed to r.t. for 2 h. The mixture was then treated with ammonium chloride (1N, 30 mL) and extracted with dichloromethane (3 x 50 mL) . The organic layer was concentrated in vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the product as a yellow solid (1.2 g) . LCMS (ESI) : 285.4 [M+1] +.
Step 5 2- (4- (chloromethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole
The product of Step 4 (1.5 g) was dissolved in dichloromethane (50 mL) . Thionyl chloride (15 mL) was added at 0℃. After stirring at r.t. for 2 h, the mixture was then concentrated in vacuo to give the product as a yellow solid (1.8 g) . LCMS (ESI) : 303.5 [M+1] +.
Step 6 ethyl (E) -3- (4-amino-2-chloropyrimidin-5-yl) acrylate
To a mixture of 4-amino-2-chloro-5-iodopyrimidine (500 mg, 1.96 mmol) and ethyl acrylate (235 mg, 2.35 mmol) in acetonitrile (30 mL) at r.t. were added palladium acetate (44 mg, 0.196 mmol) and triethylamine (396 mg, 3.92 mmol) . After stirring at 90 ℃ for 18 h, the reaction mixture was poured into 100 mL ice-water, extracted 3 x 50 mL ethyl acetate. The combined organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 10: 1) to afford the title compound as a yellow solid (350 mg) . LCMS (ESI) : 228.1 [M+1] +.
Step 7 4-cyclopropyl-6-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine
A mixture of 5-bromo-4-cyclopropyl-6-methoxypyrimidine (10.0 g) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (33.26 g) , potassium acetate (12.85 g) and dichlorobis (triphenylphosphin) palladium (1.53 g) in 1, 4-dioxane (150 mL) was heated to reflux for 4 h under Ar. The reaction mixture was then concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 1: 20) to afford the title compound as a white solid (15 g) . LCMS (ESI) : 277.5 [M+1] +.
Step 8 ethyl (E) -3- (4-amino-4'-cyclopropyl-6'-methoxy- [2, 5'-bipyrimidin] -5-yl) acrylate
To a mixture of the product of Step 6 (200 mg, 0.881 mmol) and the product of Step 7 (486 mg, 1.76 mmol) in 1, 2-dioxane/water (5/0.5 mL) at RT was added 1, 1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (71 mg, 0.088 mmol) and potassium acetate (259 mg, 2.64 mmol) . After stirring at 100℃for 18 h, the reaction mixture was then poured into 100 mL ice-water, extracted 3 x 50 mL ethyl acetate. The combined organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 10: 1) to afford the title compound as a yellow solid (41 mg) . LCMS (ESI) : 342.2 [M+1] +.
Step 9 ethyl 3- (4-amino-4'-cyclopropyl-6'-methoxy- [2, 5'-bipyrimidin] -5-yl) propanoate
The mixture of the product of Step 8 (41 mg, 0.12 mmol) and palladium on active carbon (10 mg) in methanol (10 mL) under hydrogen was stirred at rt for 1 h. The reaction mixture was quenched with 10 mL water and extracted 3 x 100 mL ethyl acetate. The combined organic layer was washed with 100 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 5: 1) to afford the title compound as a yellow solid (40 mg) . LCMS (ESI) : 344.5 [M+1] +.
Step 10 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 8-dihydropyrido [2, 3-d] pyrimidin-7 (6H) -one
A mixture of the product of Step 9 (40 mg, 0.12 mmol) , sodium methoxide (127 mg, 2.34 mmol) in methanol (5 mL) was stirred for 1 h at 50℃. The reaction mixture was then concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1) to afford the title compound as a yellow solid (30 mg) . LCMS (ESI) : 298.4 [M+1] +.
Step 11 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5, 8-dihydropyrido [2, 3-d] pyrimidin-7 (6H) -one acid
A mixture of the product of Step 10 (30 mg, 0.10 mmol) , the product of Step 5 (49 mg, 0.162 mmol) and cesium carbonate (132 mg, 0.40 mmol) in DMF (5 mL) was stirred for 1 h at 60 ℃. The reaction mixture was then concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1) to afford the title compound as a white solid (26 mg) . LCMS (ESI) : 564.6 [M+1] +. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H) , 8.65 (s, 1H) , 8.21-8.13 (m, 1H) , 7.48 (d, J = 8.2 Hz, 2H) , 7.41 (d, J = 8.0 Hz, 2H) , 5.27 (s, 2H) , 4.49-4.38 (m, 1H) , 3.81 (s, 3H) , 3.13-3.05 (m, 2H) , 2.94-2.85 (m, 2H) , 1.71 –1.60 (m, 1H) , 1.41 (d, J = 6.6 Hz, 6H) , 1.05 –0.97 (m, 2H) , 0.80 –0.69 (m, 2H) .
EXAMPLE 2
2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of the product of Step 8 in Example 1 (40 mg, 0.12 mmol) , sodium methoxide (127 mg, 2.34 mmol) in methanol (5 mL) was stirred for 1 h at 50℃. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1) to afford the title compound as a yellow solid (30 mg) . LCMS (ESI) : 296.3 [M+1] +.
Step 2 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of the product of Step 1 (30 mg, 0.10 mmol) , the product of Step 5 in Example 1 (49 mg, 0.162 mmol) and cesium carbonate (132 mg, 0.40 mmol) in DMF (5 mL) was stirred for 1 h at 60 ℃. The reaction mixture was then concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1) to afford the title compound as a white solid (26 mg) . LCMS (ESI) : 562.6 [M+1] +.
EXAMPLE 6
6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) cyclopropyl) -1H-pyrazolo [3, 4-d] pyrimidine
Step 1 di-tert-butyl 1- (1- (4-bromophenyl) cyclopropyl) hydrazine-1, 2-dicarboxylate
A 40 mL screw-top vial was charged with 1- (4-bromophenyl) cyclopropane-1-carboxylic acid (2.00 mmol, 1.0 equiv. ) , di-tert-butyl azodicarboxylate (461 mg, 4.00 mmol, ) , cerous chloride heptahydrate (photocatalyst, 74.6 mg, 0.10 mmol) , and cesium carbonate (130.4 mg, 0.40 mmol) . The vial was evacuated and back-filled with N2 followed by addition of acetonitrile (20 mL, 0.10 M) . The solution was degassed for 5 min with N2, sealed off with parafilm and irradiated with 34 W Blue LED at room temperature for 24 h. On completion, solvents were removed under reduced pressure and the crude mixture was purified by silica gel column chromatography (gradient from 0 to 15%petroleum ether/ethyl acetate) afforded 600 mg (70%) of the title compound as a colorless oil. LCMS (ESI) : 429.5 [M+1] +.
Step 2 di-tert-butyl 1- (1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) cyclopropyl) hydrazine-1, 2-dicarboxylate
Under nitrogen atmosphere, the product of Step 1 (600 mg, 1.4 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (711 mg, 2.8 mmol) , bis (diphenylphosphino) ferrocene-palladium (II) dichloride (85 mg, 0.14 mmol) , potassium acetate (550 mg) were dissolved in 1, 4-dioxane (5 mL) , and the reaction was stirred for 4 h at 90 ℃. To the reaction mixture was treated with 50 mL water and the mixture was extracted 3 x 60 mL ethyl acetate.
The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (gradient from 0 to 10%petroleum ether: ethyl acetate) to afford product (620 mg, 98%) . LCMS (ESI) : 475.6 [M+1] +.
Step 3 di-tert-butyl 1- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) cyclopropyl) hydrazine-1, 2-dicarboxylate
Under Nitrogen atmosphere, the product of Step 2 (400 mg, 0.8 mmol) , 2-bromo-1-isopropyl-4- (trifluoromethyl) -1H-imidazole (411 mg, 1.6 mmol) , xphos-Pd-G2 (60 mg, 0.08 mmol) and potassium phosphate (340 mg) were dissolved in 1, 4-dioxane/water (5 mL) , and the reaction mixture was stirred for 12 h at 90℃. To the reaction mixture was treated with 50 mL water and the reaction mixture was extracted 3 x 60 mL ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered, the crude residue was purified by silica gel column chromatography (gradient from 0 to 25%petroleum ether: ethyl acetate) to afford product (400 mg, 95%) . LCMS (ESI) : 525.6 [M+1] +.
Step 4 2- (4- (1-hydrazineylcyclopropyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole hydrochloride
The product of Step 3 (400 mg, 0.75 mmol) was dissolved in 4.0 mL 4.0 M hydrochloride (in 1, 4-dioxane) and the reaction mixture was stirred 16 h at rt. The reaction mixture was directly concentrated in vacuo to afford the title product as a white solid (250 mg, 92%) . LCMS (ESI) : 325.4 [M+1] +.
Step 5 6-chloro-1- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) cyclopropyl) -1H-pyrazolo [3, 4-d] pyrimidine
The product of Step 4 (200 mg, 0.56 mmol) and 2, 4-dichloropyrimidine-5-carbaldehyde (110 mg, 0.62 mmol) were dissolved in anhydrous N-methylpyrrolidone (5 mL) . After the reaction mixture was stirred 1h at RT, DIEA (145 mg) was added. The reaction mixture was stirred for 1.5 h at 150℃. To the reaction mixture was added 50 mL water and the reaction mixture was extracted 3 x 60 mL ethyl acetate. The combined organic layer was washed with sat. brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (gradient from 10 to 60%petroleum ether: ethyl acetate) to afford the title product (70 mg, 28%) . LCMS (ESI) : 447.4 [M+1] +.
Step 6 6- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) cyclopropyl) -1H-pyrazolo [3, 4-d] pyrimidine
A mixture of the product of Step 5 (70 mg) , the product of Step 7 in Example 1 (132 mg) , bis (diphenylphosphino) ferrocene-palladium (II) dichloride (11 mg) , and potassium phosphate (64 mg) in 1, 4-dioxane/water (5 mL/0.5 mL) was stirred for 16 h at 90℃ under nitrogen. The reaction mixture was then concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1) to afford the title compound as a pale yellow solid (20 mg) . LCMS (ESI) : 561.6 [M+1] +.
EXAMPLE 18
2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-
yl) benzyl) pyrrolo [2, 1-f] [1, 2, 4] triazine
Step 1 2-chloropyrrolo [2, 1-f] [1, 2, 4] triazine
A mixture of 2, 4-dichloropyrrolo [2, 1-f] [1, 2, 4] triazine (1.0 g) and sodium borohydride (305 mg) in methanol (30 mL) was stirred at r.t. for 18h. The reaction mixture was then poured into 100 mL ethyl acetate and washed with 3 x 100 mL ammonium chloride (aq. ) . The organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. To the crude product was diluted with DCM (30 mL) followed by addition of DDQ (1.8 g) . The reaction mixture was then stirred at r.t. for 18 h. The reaction mixture was poured into 100 mL ice-water, wash with potassium bicarbonate (aq. ) and extracted 3 x 50 mL ethyl acetate. The combined organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 10: 1) to afford the title compound as a yellow solid (540 mg) . LCMS (ESI) : 154.2 [M+1] +.
Step 2 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrrolo [2, 1-f] [1, 2, 4] triazine
To a mixture of the product of Step 1 (540 mg, 3.53 mmol) and the product of Step 7 in Example 1 (1.02 g) in 1, 2-dioxane/water (20/2 mL) at r.t. was added tris (dibenzylideneacetone) dipalladium (323 mg) and 2- (dicyclohexylphosphino) -2, 4, 6-triisopropylbiphenyl (337 mg) and CsF (2.6 g) . The reaction mixture was then stirred at 100 ℃ for 18 h. The reaction mixture was poured into 100 mL ice-water, and extracted 3 x 50 mL ethyl acetate. The combined organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 10: 1) to afford the title compound as a yellow solid (690 mg) . LCMS (ESI) : 268.4 [M+1] +.
Step 3 7-bromo-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrrolo [2, 1-f] [1, 2, 4] triazine
A mixture of the product of Step 2 (650 mg) and NBS (477 mg) in acetonitrile (10 mL) was stirred at r.t. for 18h. The reaction mixture was quenched with 10 mL water and extracted 3 x 100 mL ethyl acetate. The combined organic layer was washed with 100 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 5: 1) to afford the title compound as a yellow solid (350 mg) . LCMS (ESI) : 346.3 [M+1] +.
Step 4 2- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6-methyl-1, 3, 6, 2-dioxazaborocane-4, 8-dione
A mixture of the product of Step 4 in Example 11 (100 mg) and 2, 2'- (methylazanediyl) diacetic acid (94 mg) in DMF (10 mL) was stirred at 120℃ for 1h. The reaction mixture was quenched with 100 mL water and extracted 3 x 50 mL ethyl acetate. The combined organic layer was washed with 100 mL saturated brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a colorless solid (100 mg) . LCMS (ESI) : 424.5 [M+1] +.
Step 5 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-
yl) benzyl) pyrrolo [2, 1-f] [1, 2, 4] triazine
To a mixture of the product of Step 3 (10 mg) and the product of Step 4 (12 mg) in 1, 2-dioxane/water (2/0.2 mL) at r.t. were added tris (dibenzylideneacetone) dipalladium (3 mg) and 2- (dicyclohexylphosphino) -2, 4, 6-triisopropylbiphenyl (3 mg) and CsF (13 mg) . The reaction mixture was then stirred at 100℃ for 18h. The reaction mixture was poured into 100 mL ice-water, extracted 3 x 50 mL ethyl acetate. The combined organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 10: 1) to afford the title compound as a yellow solid (10 mg) . LCMS (ESI) : 534.6 [M+1] +.
EXAMPLE 19
1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (2-isopropylphenyl) -1, 6-dihydro-7H-pyrazolo [69yridazineidazin-7-one
Step 1 6- (2-isopropylphenyl) -1, 6-dihydro-7H-pyrazolo [69yridazineidazin-7-one
The mixture of ethyl 4-formyl-1H-pyrazole-3-carboxylate (200 mg, 1.0 eq) and (2-isopropylphenyl) hydrazine (221 mg, 1.0 eq) in ethanol (2 ml) was stirred at 60℃ overnight under Ar. Water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE =1: 1) to give 36 mg of product as a yellow solid. MS (ESI) : 255.1 [M+1] +.
Step 2 1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (2-isopropylphenyl) -1, 6-dihydro-7H-pyrazolo [69yridazineidazin-7-one
The mixture of the product of Step 1 (30 mg, 1.0 eq) and potassium carbonate (84 mg, 5.0 eq) in DMF (3 ml) was stirred at 0℃ for 5 minutes. Then 2- (4- (chloromethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (18 mg, 1.5 eq ) was added at 0℃. The mixture was heat to 100℃ and stirred overnight. Water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE =1: 1) to give 11.84 mg of product (the first peak) as a white solid. MS (ESI) : 520.7 [M+1] +.
1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H) , 8.17 (s, 1H) , 7.89 (d, J = 1.4 Hz, 1H) , 7.56 –7.45 (m, 6H) , 7.33 (ddd, J = 8.7, 6.7, 2.0 Hz, 1H) , 7.26 (dd, J = 7.8, 1.4 Hz, 1H) , 6.01 (s, 2H) , 4.51 –4.45 (m, 1H) , 2.69 –2.59 (m, 1H) , 1.42 (d, J = 6.7 Hz, 6H) , 1.15 (dd, J = 15.4, 6.8 Hz, 6H) .
EXAMPLE 20
2- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (2-isopropylphenyl) -2H-pyrazolo [3, 4-d] pyridazin-7 (6H) -one
Step 1 2- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (2-isopropylphenyl) -2H-pyrazolo [3, 4-d] pyridazin-7 (6H) -one
The mixture of 6- (2-isopropylphenyl) -1, 6-dihydro-7H-pyrazolo [3, 4-d] pyridazin-7-one (30 mg, 1.0 eq) and potassium carbonate (84 mg, 5.0 eq) in DMF (3 ml) was stirred at 0℃ for 5 minutes. Then 2- (4- (chloromethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (18 mg, 1.5 eq ) was added at 0℃. The mixture was heat to 100 ℃ and stirred overnight. Water was added and extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (EA: PE =1: 1) to give 8.12 mg of product (the second peak) as a white solid. MS (ESI) : 520.7 [M+1] +.
EXAMPLE 21
4- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (2-isopropylphenyl) -4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-b] pyridine
Step 1 4- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-b] pyridine
To a stirred solution of 4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-b] pyridine HCl (50 mg, 1.0 eq) in DCM (2.5 ml) were added 4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzaldehyde (85 mg, 1.5 eq) , acetic acid (57 mg, 3.0 eq) and NaBH (OAc) 3 (332 mg, 5.0 eq) at 0℃ under Ar. The mixture was stirred at 0℃ for 2 h. Water was added and extracted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC to give 30 mg of product as a yellow solid. MS (ESI) 389.4 [M+1] + .
Step 2 4- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (2-isopropylphenyl) -4, 5, 6, 7-tetrahydro -2H-pyrazolo [4, 3-b] pyridine
The mixture of the product of Step 1 (66 mg, 1.0 eq) , 2-isopropylphenylboronic acid (33 mg, 1.1 eq) and
copper (II) acetate (33 mg, 1.1 eq) in pyridine (11 ml) was stirred at 115 ℃ for 1 h under Ar. Water was added and adjusted pH=6 with 1N HCl , then extracted with EA. The organic layer was washed with 0.1N HCl and brine, dried over anhydrous Na2SO4 and filtered. The residue was purified by Prep-HPLC (Column: Green ODS-A, 21.2*250mm, 10um; Mobile A: water with 0.05%HCOOH, Mobile B: ACN; Gradient: 70%B over 2 min, 85%B over 15 min; Flow: 35 mL/min) to give 9.47 mg of product as a white solid. MS (ESI) 507.8 [M+1] + .
1H NMR (400 MHz, Methanol-d4) δ 7.89 (d, J = 1.5 Hz, 1H) , 7.59 (d, J = 8.0 Hz, 2H) , 7.52 (d, J = 8.0 Hz, 2H) , 7.45 –7.36 (m, 2H) , 7.24 (td, J = 7.4, 6.9, 1.8 Hz, 1H) , 7.18 (dd, J = 7.9, 1.5 Hz, 1H) , 6.94 (s, 1H) , 4.56 –4.49 (m, 1H) , 4.22 (s, 2H) , 3.04 (dd, J = 6.2, 4.2 Hz, 2H) , 2.87 –2.81 (m, 1H) , 2.77 (t, J = 6.6 Hz, 2H) , 2.16 –2.03 (m, 2H) , 1.43 (d, J = 6.7 Hz, 6H) , 1.13 (d, J = 6.9 Hz, 6H) .
EXAMPLE 22
(±) 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) -5, 8-dihydropyrido [2, 3-d] pyrimidin-7 (6H) -one
Step 1 (±) 1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethan-1-ol
A mixture of 1- (4-bromophenyl) ethan-1-ol (1.0 g) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (1.9 g) , potassium acetate (0.98 g) , bis (diphenylphosphino) ferrocene-palladium (II) dichloride (200 mg) in 1, 4-dioxane (30 mL) was stirred at 90℃ overnight under Ar. The reaction solution was poured into water and extracted with ethyl acetate (3 x 50 mL) . The combined organic layer was washed with water (20 mL) and dried over sodium sulfate. The combined organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 5: 1) to afford product as pale-yellow oil (1.1g, 88%) . LCMS (ESI) : 231.4 [M+1] +.
Step 2 (±) 1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethan-1-ol
A mixture of the product of Step 1 (500 mg) , 2-bromo-1-isopropyl-4- (trifluoromethyl) -1H-imidazole (780 mg) , xphos-Pd-G2 (158 mg) , potassium phosphate (840 mg) , 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl-1, 1'-biphenyl (96 mg) were dissolved in 1, 4-dioxane/water (15 mL) , and the reaction mixture was stirred for 12 h at 90℃. To the reaction mixture was treated with 50 mL water and the reaction mixture was extracted ethyl acetate (3 x 50 mL) . The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 5: 1) to afford product (500 mg) . LCMS (ESI) : 299.4 [M+1] +.
Step 3 (±) 2- (4- (1-chloroethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole
The product of Step 2 (400 mg) was dissolved in DCM (20 mL) . Phosphorus tribromide (270 mg) was added at 0℃. After stirring at r.t. for 2 h, the reaction mixture was quenched with a saturate sodium bicarbonate solution (50 mL) , extracted by DCM (3 x 20 mL) . The combined organic layer was washed with 50 mL saturated brine, dried
over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 2: 1) to afford the compound as yellow solids (500 mg) . LCMS (ESI) : 361.3 [M+1] +.
Step 4 ethyl 3- (4-amino-4'-cyclopropyl-6'-methoxy- [2, 5'-bipyrimidin] -5-yl) propanoate
The mixture of ethyl (E) -3- (4-amino-4'-cyclopropyl-6'-methoxy- [2, 5'-bipyrimidin] -5-yl) acrylate (41 mg) and palladium on active carbon (10 mg) in methanol (10 mL) under hydrogen was stirred at rt for 1 h. The reaction mixture was quenched with 10 mL water and extracted 3 x 100 mL ethyl acetate. The combined organic layer was washed with 100 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 5: 1) to afford the title compound as a yellow solid (40 mg) . LCMS (ESI) : 344.5 [M+1] +.
Step 5 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 8-dihydropyrido [2, 3-d] pyrimidin-7 (6H) -one
A mixture of the product of Step 4 (40 mg, 0.12 mmol) , sodium methoxide (127 mg, 2.34 mmol) in methanol (5 mL) was stirred for 1 h at 50℃. The reaction mixture was then concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1) to afford the title compound as a yellow solid (30 mg) . LCMS (ESI) : 298.4 [M+1] +.
Step 6 (±) 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) -5, 8-dihydropyrido [2, 3-d] pyrimidin-7 (6H) -one
A mixture of the product of Step 3 (123 mg) , the product of Step 5 (50 mg) and cesium carbonate (98 mg) in DMF (5 mL) was stirred for 4 h at 45℃. The reaction mixture was then concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 1: 1) to afford the title compound as a white solid (25 mg) . LCMS (ESI) : 578.6 [M+1] +. 1H NMR (400 MHz, DMSO) δ 8.67 (s, 1H) , 8.65 (s, 1H) , 8.16 (d, J = 1.4 Hz, 1H) , 7.44 (d, J = 1.8 Hz, 4H) , 6.40 –6.30 (m, 1H) , 4.49 –4.38 (m, 1H) , 3.83 (s, 3H) , 3.11 –2.98 (m, 2H) , 2.88-2.76 (m, 2H) , 1.86 (d, J = 7.0 Hz, 3H) , 1.73-1.62 (m, 1H) 1.41 (t, J = 6.6 Hz, 6H) , 1.04 –0.97 (m, 2H) , 0.83 –0.77 (m, 2H) .
EXAMPLE 23
(±) 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
To a mixture of the product of Step 2 in Example 22 (60 mg) , the product of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (50 mg) and tributyl phosphine (103 mg) in tetrahydrofuran (4 mL) at 0℃, was added DIAD (103 mg in 1 mL tetrahydrofuran) over 5 min. The mixture reaction warmed to r.t. and stirred 4h. The reaction mixture was then concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 1: 1) to afford the title compound as a white solid (20 mg) . LCMS (ESI) : 576.6 [M+1] +. 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H) , 8.70 (s, 1H) , 8.16 (s, 1H) , 8.13 (d,
1H) , 7.47 (d, J = 7.9 Hz, 2H) , 7.40 (d, J = 8.1 Hz, 2H) , 6.98 –6.71 (m, 2H) , 4.51 –4.36 (m, 1H) , 3.85 (s, 3H) , 1.97 (d, J = 7.0 Hz, 3H) , 1.80 –1.68 (m, 1H) , 1.44 –1.36 (m, 6H) , 1.06 –1.01 (m, 2H) , 0.85 –0.78 (m, 2H) .
EXAMPLE 24
(±) 3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
To a solution of trimethylsulfoxonium iodide (22 mg) in dry DMSO (1.0 mL) was added potassium tert-butoxide (1M solution in THF, 0.13 mL) under nitrogen. The reaction was stirred at r.t. for 1 h, then 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (50 mg) in dry DMSO (1.0 mL) was added and the solution was heated at 60℃ for 3 h. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3: 7) to afford the title compound as a yellow solid (20 mg) . LCMS (ESI) : 576.5 [M+1] +. 1H NMR (500 MHz, DMSO-d6) δ8.90 (s, 1H) , 8.62 (s, 1H) , 8.15 (s, 1H) , 7.46 (d, J = 7.9 Hz, 2H) , 7.31 (d, J = 7.9 Hz, 2H) , 5.36 –5.15 (m, 2H) , 4.52 –4.38 (m, 1H) , 3.78 (s, 3H) , 3.43-3.36 (m, 1H) , 2.86 –2.77 (m, 1H) , 2.50 –2.45 (m, 1H) , 1.84 –1.76 (m, 1H) , 1.68 –1.59 (m, 1H) , 1.39 (d, J = 6.6 Hz, 6H) , 0.96 –0.94 (m, 2H) , 0.76 –0.62 (m, 2H) .
EXAMPLE 25 and EXAMPLE 26
(6aR, 7aS) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
(6aS, 7aR) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
Example 24 was resolved by the following conditions to provide EXAMPLE 25 and EXAMPLE 26: column type: IG column 5 μm, 10 mm I.D. *250 mm.
Mobile phase: 25%ethanol, 75%hexane, flow rate, 2 mL/min.
EXAMPLE 25: retention time at 37 min; EXAMPLE 26: retention time at 51 min.
EXAMPLE 27
(±) 5- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -3- (2-isopropylphenyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
Step 1 ethyl (E) -3- (4-amino-2-chloropyrimidin-5-yl) acrylate
To a mixture of 4-amino-2-chloro-5-iodopyrimidine (500 mg) and ethyl acrylate (235 mg) in acetonitrile (30 mL) at r.t. were added palladium acetate (44 mg) and TEA (396 mg) . After stirring at 90 ℃ for 18 h, the reaction mixture was poured into 100 mL ice-water, extracted 3 x 50 mL ethyl acetate. The combined organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 10: 1) to afford the title compound as a yellow solid (350 mg) . LCMS (ESI) : 228.1 [M+1] +.
Step 2 ethyl (E) -3- (4-amino-2- (2-isopropylphenyl) pyrimidin-5-yl) acrylate
To a mixture of (2-isopropylphenyl) boronic acid (287 mg) and the product of Step 1 (200 mg) in 1, 2-dioxane/water (5/0.5 mL) at r.t. was added 1, 1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride complex (71 mg) and potassium acetate (259 mg) . After stirring at 100℃ for 18 h, the reaction mixture was then poured into 100 mL ice-water, extracted 3 x 50 mL ethyl acetate. The combined organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 10: 1) to afford the title compound as a yellow solid (40 mg) . LCMS (ESI) : 312.2 [M+1] +.
Step 3 2- (2-isopropylphenyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of the product of Step 2 (40 mg) , sodium methoxide (127 mg) in methanol (5 mL) was stirred for 1 h at 50℃. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1) to afford the title compound as a yellow solid (30 mg) . LCMS (ESI) : 266.3 [M+1] +.
Step 4 8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (2-isopropylphenyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of the product of Step 3 (30 mg) , 2- (4- (chloromethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H-imidazole (49 mg) and cesium carbonate (132 mg) in DMF (5 mL) was stirred for 1 h at 60 ℃. The reaction mixture was then concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1) to afford the title compound as a white solid (25 mg) . LCMS (ESI) : 532.5 [M+1] +.
Step 5 (±) 5- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -3- (2-isopropylphenyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
Starting with the product of Step 4, the title product was obtained as a yellow solid by following the same procedures described in Example 24. LCMS (ESI) : 546.6 [M+1] +. 1H NMR (500 MHz, DMSO-d6) δ 8.88 (s, 1H) , 8.16 (s, 1H) , 7.50 –7.46 (m, 2H) , 7.46 –7.42 (m, 1H) , 7.38 (d, J = 4.0 Hz, 2H) , 7.29 (d, J = 8.2 Hz, 2H) , 7.24 –7.19 (m, 1H) , 5.34-5.29 (m, 2H) , 4.47 –4.40 (m, 1H) , 3.49 –3.40 (m, 1H) , 2.85 –2.78 (m, 1H) , 2.50-2.46 (m, 1H) , 2.04-1.96 (m, 1H) , 1.83 –1.77 (m, 1H) , 1.38 (d, J = 6.6 Hz, 6H) , 0.99 –0.93 (m, 6H) .
EXAMPLE 28
5-chloro-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl)
benzyl) pyrrolo [2, 1-f] [1, 2, 4] triazine
Step 1 5-chloro-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrrolo [2, 1-f] [1, 2, 4] triazine
A mixture of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrrolo [2, 1-f] [1, 2, 4] triazine (60 mg) and NBS (25 mg) in acetonitrile (10 mL) was stirred at r.t. for 2h. The reaction mixture was quenched with saturate sodium thiosulfate solution (10 mL) and extracted (3 x 15) mL ethyl acetate. The combined organic layer was washed with 100 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 2: 1) to afford the title compound as a yellow solid (30 mg) . LCMS (ESI) : 614.4 [M+1] +. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H) , 8.72 (s, 1H) , 8.16 (s, 1H) , 7.49 (d, J = 8.2 Hz, 2H) , 7.42 (d, J = 8.2 Hz, 2H) , 7.26 (s, 1H) , 4.48 –4.39 (m, 3H) , 3.88 (s, 3H) , 1.88 –1.80 (m, 1H) , 1.39 (d, J = 6.7 Hz, 6H) , 1.09 –1.02 (m, 2H) , 0.90 –0.81 (m, 2H) .
EXAMPLE 29
5-chloro-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrrolo [2, 1-f] [1, 2, 4] triazine
A mixture of step 4 in Example 28 (60 mg) and NCS (20 mg) in acetonitrile (10 mL) was stirred at r.t. for 2h. The reaction mixture was quenched with saturate sodium thiosulfate solution (10 mL) and extracted (3 x 15) mL ethyl acetate. The combined organic layer was washed with 100 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 2: 1) to afford the title compound as a yellow solid (30 mg) . LCMS (ESI) : 568.5 [M+1] +. 1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H) , 8.72 (s, 1H) , 8.16 (s, 1H) , 7.49 (d, J = 8.3 Hz, 2H) , 7.42 (d, J = 8.2 Hz, 2H) , 7.20 (s, 1H) , 4.48 –4.38 (m, 3H) , 3.88 (s, 3H) , 1.88 –1.80 (m, 1H) , 1.39 (d, J = 6.6 Hz, 6H) , 1.09 –1.01 (m, 2H) , 0.90 –0.83 (m, 2H) .
EXAMPLE 30
2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -5-methylpyrrolo [2, 1-f] [1, 2, 4] triazine
To a mixture of step 5 in Example 28 (60 mg) , Pd (PPh3) 4 (11 mg) in THF (4 mL) , was added trimethylaluminum (0.3 mL, 1M sol. in n-pentane) . The mixture reaction stirred 4 h at 75℃. The reaction mixture was quenched with a
saturate ammonium chloride solution (10 mL) , extracted with ethyl acetate (3 x 15) . The combined organic layer was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 2: 1) to afford the title compound as a yellow solid (10 mg) . LCMS (ESI) : 548.5 [M+1] +. 1H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H) , 8.70 (s, 1H) , 8.18 –8.12 (m, 1H) , 7.48 (d, J = 8.2 Hz, 2H) , 7.40 (d, J = 7.9 Hz, 2H) , 6.86 (s, 1H) , 4.48 –4.42 (m, 1H) , 4.39 (s, 2H) , 3.88 (s, 3H) , 2.46 (s, 3H) , 1.85 –1.76 (m, 1H) , 1.39 (d, J = 6.6 Hz, 6H) , 1.08 –1.01 (m, 2H) , 0.90 –0.82 (m, 2H) .
EXAMPLE 34
2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -10- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6, 7, 8, 9-tetrahydropyrimido [4, 5-b] indolizine
Step 1 6- (5-amino-2-chloropyrimidin-4-yl) hex-5-yn-1-ol
A mixture of 2, 4-dichloropyrimidin-5-amine (1.0 g) , copper (I) iodide (116 mg) and bis (triphenylphosphine) palladium (II) dichloride (214 mg) in THF/TEA (15.0 mL, 3/1) under nitrogen. Hex-5-yn-1-ol (658 mg) was added and the mixture was then heated at 65℃ for 3 h. The reaction mixture was concentrated under vacuum and purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (0%to 100%ethyl acetate) to afford the title product as a pale-yellow solid (500 mg) . LCMS (ESI) : 226.38 [M+1] +.
Step 2 4- (2-chloro-5H-pyrrolo [3, 2-d] pyrimidin-6-yl) butan-1-ol
A mixture of the product of Step 1 (180 mg) and copper (I) iodide (15 mg) in N, N-dimethylformamide (5.0 mL) was degassed and refilled with Ar for three times. The resulting was stirred at 110℃ for 3h. The reaction solution was cooled to room temperature and filtered through a filter paper then washed by DMF (1.0 mL) . The organic layer was used to the next step reaction without other purification. LCMS (ESI) : 226.38 [M+1] +.
Step 3 2-chloro-6, 7, 8, 9-tetrahydropyrimido [4, 5-b] indolizine
A solution of the product of Step 2 (200 mg) and triphenylphosphine (418 mg) was degassed and refilled with Ar for three times. To the above mixture was added THF (7.0 mL) and dropwise DIAD (269 mg) at rt. The resulting was stirred at rt for 2h. The reaction solution was concentrated and the residue was poured into water (20.0 mL) and extracted with ethyl acetate (30 mL x 3) . The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum and then purified using silica gel column chromatography eluted with ethyl acetate/petroleum ether (0%to 100%ethyl acetate) to afford the title product as a white solid (100 mg) . LCMS (ESI) : 208.56 [M+1] +.
Step 4 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -6, 7, 8, 9-tetrahydropyrimido [4, 5-b] indolizine
A mixture of the product of Step 3 (200 mg) , (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (374 mg) , cesium fluoride (439 mg) , tris (dibenzylideneacetone) dipalladium (0) (441 mg) , 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl-1, 1'-biphenyl (459 mg) in 1, 4-dioxane/water (4.0 mL, 8/1) was degassed under vacuum and purged with Ar three times. The resulting mixture was stirred at 90℃ overnight. The reaction solution was evaporated under
reduced pressure and purified using silica gel column chromatography eluted with ethyl acetate/petroleum ether (0%to 100%ethyl acetate) to afford the title product as a white solid (230 mg) . LCMS (ESI) : 322.38 [M+1] +.
Step 5 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -10-iodo-6, 7, 8, 9-tetrahydropyrimido [4, 5-b] indolizine
To a mixture of the product of Step 4 (230 mg) in methanol (6.0 mL) was added N-iodosuccinimide (242 mg) at rt. The mixture was stirred at rt for 0.5 h. The suspension was filtered through a filter paper and washed with methanol (5.0 mL) to afford the title product as a white solid (280 mg) . LCMS (ESI) : 448.32 [M+1] +.
Step 6 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -10- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6, 7, 8, 9-tetrahydropyrimido [4, 5-b] indolizine
A mixture of the product of Step 5 (80 mg) , methyl 3- ( (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) sulfonyl) propanoate (112 mg) , potassium carbonate (49 mg) , di-tert-b-butylmethylphosphonium tetrafluoroborate (9 mg) and palladium (II) acetate (4 mg) in dry- (methylsulfinyl) methane (1.5 mL) was added to the above mixture at rt. The resulting mixture was stirred at 120℃ for 6h. The mixture was cooled to rt and then extracted with water (15.0 mL) and ethyl acetate (15.0 mL x 3) . The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum and then purified using silica gel column chromatography eluted with ethyl acetate/petroleum ether (0%to 100%ethyl acetate) to afford the title product as a white solid (15.0 mg) . LCMS (ESI) : 587.59 [M+1] +. 1H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 1H) , 8.66 (s, 1H) , 8.14 (s, 1H) , 7.47 -7.39 (m, 4H) , 4.45 -4.39 (m, 1H) , 4.24 (t, J = 6.0 Hz, 2H) , 4.11 (s, 2H) , 3.83 (s, 3H) , 3.00 (t, J = 6.4 Hz, 2H) , 2.08 -2.02 (m, 2H) , 1.93 -1.87 (m, 2H) , 1.65 -1.58 (m, 1H) , 1.37 (d, J = 6.7 Hz, 6H) , 1.06 -1.00 (m, 2H) , 0.84 -0.79 (m, 2H) .
EXAMPLE 35
(R) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6- (trifluoromethyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Step 1 (R) -8- (1- (4-bromophenyl) ethyl) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A solution of (S) -1- (4-bromophenyl) ethan-1-ol (202 mg) , 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (200 mg) , and tributylphosphane (411 mg) was stirred in dry THF (20 mL) at 0℃ under a nitrogen atmosphere. To this mixture was added dropwise DIAD (274 mg) over a period of 5 min. After complete disappearance of starting material, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 10: 1) . The title compound was obtained as a yellow solid (250 mg) . LCMS (ESI) : 478.12 [M+1] +.
Step 2 (R) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of the product of Step 1 (150 mg) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (96 mg) , potassium acetate (92 mg) , bis (diphenylphosphino) ferrocene-palladium (II) dichloride (23 mg) in 1, 4-dioxane (20 mL) was stirred at 90℃ overnight under Ar. The reaction solution was poured into water and extracted with ethyl acetate (3 x 50 mL) . The combined organic layer was washed with water (20 mL) and dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 5: 1) to afford product as pale yellow oil (159 g) . LCMS (ESI) : 526.5 [M+1] +.
Step 3 (R) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of the product of Step 2 (159 mg) , 2-bromo-1-isopropyl-4- (trifluoromethyl) -1H-imidazole (123 mg) , xphos-Pd-G2 (49 mg) and potassium phosphate (393 mg) were dissolved in 1, 4-dioxane/water (15 mL/2 mL) , and the reaction mixture was stirred for 12 h at 90℃. To the reaction mixture was added 50 mL water and the reaction mixture was extracted ethyl acetate (3 x 50 mL) . The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 5: 1) to afford product (50 mg) . LCMS (ESI) : 576.8 [M+1] +. 1H NMR (500 MHz, DMSO-d6) δ 9.27 (s, 1H) , 8.68 (s, 1H) , 8.15 (s, 1H) , 8.12 (d, J = 9.5 Hz, 1H) , 7.51 –7.34 (m, 4H) , 6.94 –6.75 (m, 2H) , 4.48 -4.34 (m, 1H) , 3.92 –3.72 (m, 3H) , 1.95 (d, J = 7.0 Hz, 3H) , 1.84-1.68 (m, 1H) , 1.41-1.37 (m, 6H) , 1.09-0.96 (m, 2H) , 0.88-0.73 (m, 2H) .
EXAMPLE 36
(S) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
Starting with (R) -1- (4-bromophenyl) ethanol (50 mg) , the title product was obtained as a yellow solid (15 mg) by following the same procedures as described in Example 35. LCMS (ESI+) : 576.55 [M+1] +. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H) , 8.69 (s, 1H) , 8.15 (s, 1H) , 8.12 (d, J = 9.5 Hz, 1H) , 7.46 (d, J = 8.0 Hz, 2H) , 7.39 (d, J = 8.0 Hz, 2H) , 6.98 –6.76 (m, 2H) , 4.47 –4.37 (m, 1H) , 3.83 (s, 3H) , 1.95 (d, J = 7.0 Hz, 3H) , 1.81 –1.68 (m, 1H) , 1.39 (t, J = 6.8 Hz, 6H) , 1.05 –0.97 (m, 2H) , 0.85 –0.77 (m, 2H) .
EXAMPLE 38
2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6, 7, 8, 9-tetrahydropyrimido [5, 4-b] [1, 4] oxazepane
Step 1 (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanamine
To a mixture of 2- (4- (chloromethyl) phenyl) -1-isopropyl-4- (trifluoromethyl) -1H -imidazole (3.0 g) and ammonia (70 mL, 7M in MeOH) was added KI (2.47 g) . The reaction mixture was stirred at rt for 48 h. The mixture was then concentrated under vacuum and the residue was suspended in DCM (100 mL) . The mixture was filtered and washed with DCM (20 mL) . The filtrate was concentrated under vacuum to afford the title product as a yellow solid (2.0 g, crude) . LCMS (ESI) : 284.45 [M+1] +
Step 2 5- (benzyloxy) -2-chloro-N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrimidin-4-amine
A solution of the product of Step 1 (944 mg) , 5- (benzyloxy) -2, 4-dichloropyrimidine (500 mg) and DIEA (861 mg) in 1, 4-dioxane (5 mL) was stirred at 80℃ overnight. The mixture was cooled and concentrated under vacuum. The residue was purified using silica gel chromatography column with ethyl acetate/petroleum ether (0%to 100%ethyl acetate) to afford the title product (800 mg) as a yellow solid. LCMS (ESI) : 502.68 [M+1] +.
Step 3 5- (benzyloxy) -4'-cyclopropyl-N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6'-methoxy- [2, 5'-bipyrimidin] -4-amine
A mixture of the product of Step 2 (600 mg) , (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (464 mg) , cesium fluoride (545 mg) , tris (dibenzylideneacetone) dipalladium (0) (547 mg) , 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl-1, 1'-biphenyl (570 mg) in 1, 4-dioxane/water (12 mL, 8/1) was degassed under vacuum and purged with Ar. The resulting mixture was stirred at 90℃ overnight. The reaction mixture was concentrated under reduced pressure and purified using silica gel column chromatography eluted with ethyl acetate/petroleum ether (0%to 100%ethyl acetate) to afford the title product as a white solid (500 mg) . LCMS (ESI) : 616.66 [M+1] +.
Step 4 4'-cyclopropyl-4- ( (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) -6'-methoxy- [2, 5'-bipyrimidin] -5-ol
A mixture of the product of Step 3 (220 mg) and Pd/C (23 mg, 10%on carbon 55%wet) in methanol (6.0 mL) was degassed under vacuum and purged with hydrogen three times. The mixture was stirred at rt for 1h. The mixture was filtered through celite pad and washed with methanol (20.0 mL) . The filtrate was concentrated to afford the title product as a white solid (160 mg) . LCMS (ESI) : 526.53 [M+1] +.
Step 5 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -9- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol -2-
yl) benzyl) -6, 7, 8, 9-tetrahydropyrimido [5, 4-b] [1, 4] oxazepine
A mixture of the product of Step 4 (20 mg) , cesium carbonate (62 mg) in DMF (0.5 mL) was added 1, 3-diiodopropane (71 mg) in one portion. The mixture was stirred at rt for 1h and then heated to 65℃ for 1h. The reaction mixture was poured into water and extracted with ethyl acetate (10 mL x 2) . The combine organic layer was washed with brine (10 mL) and dried over sodium sulfate and concentrated under vacuum. The residue was purified using Prep-TLC with ethyl acetate/petroleum ether (1/1) to afford the title product as a white solid (6.3 mg) . LCMS (ESI) : 566.57 [M+1] +. 1H NMR (500 MHz, DMSO-d6) δ 8.58 (s, 1H) , 8.17 (s, 1H) , 8.04 (s, 1H) , 7.52 (d, J = 7.9 Hz, 2H) , 7.44 (d, J = 8.0 Hz, 2H) , 4.86 (s, 2H) , 4.49-4.42 (m, 1H) , 4.28 (t, J = 6.7 Hz, 2H) , 3.83 (s, 3H) , 3.72 -3.67 (m, 2H) , 2.16 -2.11 (m, 2H) , 1.78 -1.74 (m, 1H) , 1.41 (d, J = 6.6 Hz, 6H) , 0.99 -0.93 (m, 2H) , 0.84 -0.77 (m, 2H) .
EXAMPLE 39
(±) 3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- ( (R) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
( (6aR, 7aS) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- ( (R) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one and (6aS, 7aR) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- ( (R) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one)
Starting with (R) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (80 mg) , the title product (amixture of two diastereomers) was obtained as a yellow solid (45 mg) by following the same procedures as described in Example 25. LCMS (ESI) : 590.4 [M+1] +.
EXAMPLE 40
(±) 3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- ( (S) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
( (6aR, 7aS) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- ( (S) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one and (6aS, 7aR) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- ( (S) -1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one)
Starting with (S) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (1- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) ethyl) pyrido [2, 3-d] pyrimidin-7 (8H) -one, the title product (amixture of two diastereomers) was obtained as a yellow solid by following the same procedures as described in Example 25. LCMS (ESI) : 590.4
[M+1] +.
EXAMPLE 42
2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7, 8-dihydro-5, 7-methanopyrido [2, 3-d] pyrimidin-5 (6H) -ol
Step 1 3, 3-dimethoxycyclobutan-1-amine
A solution of 3-aminocyclobutanonehydrochloride (0.5 g) in methanol/sulfuric acid (20mL/0.5 mL) was stirred at 50℃ for 1 h. The reaction mixture was used directly in the next step without purification. LCMS (ESI) : 132.3 [M+1] +.
Step 2 N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -3, 3-dimethoxycyclobutan-1-amine
To the reaction mixture of step 1 was added potassium carbonate (2.5 g) , followed by 4- (1-isopropyl-4-ea (trifluoromethyl) -1H-imidazol-2-yl) benzaldehyde (1.0 g) . The reaction mixture was stirred at 50℃ for 1 h. NaBH (OAc) 3 (11.3 g) was then added and the reaction mixture was stirred for additional 0.5 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 2: 8) to afford the title compound as a yellow solid (0.86 g) . LCMS (ESI) : 398.3 [M+1] +.
Step 3 5-bromo-2-chloro-N- (3, 3-dimethoxycyclobutyl) -N- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyrimidin-4-amine
A solution of the product of step 2 (0.8 g) and DIEA (1.4 g) in THF (15 mL) was added 5-bromo-2, 4-dichloropyrimidine (0.6 g) and stirred at 50℃ for 18 h. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 7: 3) to afford the title compound as a yellow oil (1.0 g) . LCMS (ESI) : 588.2 [M+1] +.
Step 4 3- ( (5-bromo-2-chloropyrimidin-4-yl) (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) amino) cyclobutan-1-one
A solution of the product of step 3 (1.0 g) in ACN/6 M HCl (10/10 mL) was stirred at r.t. for 0.5 h. The solution was adjusted pH to 8 with potassium carbonate and extracted with EA (50 mL) . The organic layer was concentrated to afford the title compound as a yellow solid (0.7 g) . LCMS (ESI) : 542.4 [M+1] +.
Step 5 2-chloro-8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7, 8-dihydro-5, 7-methanopyrido [2, 3-d] pyrimidin-5 (6H) -ol
A solution of the product of step 4 (0.4 g) in dry THF (8 mL) was treated with n-BuLi (2.5 M, in hexane) at -78℃ under nitrogen. The mixture was stirred for 1h and then warmed to 0℃ and quenched with saturated aqueous ammonium chloride (0.5 mL) . The mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 3: 7) to afford the title compound as a yellow oil (0.09 g) . LCMS (ESI) : 464.3 [M+1] +.
Step 6 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -8- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -7, 8-dihydro-5, 7-methanopyrido [2, 3-d] pyrimidin-5 (6H) -ol
A solution of the product of step 5 (0.09 g) , (4-cyclopropyl-6-methoxypyrimidin-5-yl) boronic acid (0.05 g) , tris (dibenzylideneacetone) dipalladium (0.09 g) , 2- (dicyclohexylphosphino) -2', 4', 6'-tri-i-propyl-1, 1'-biphenyl (0.09 g) and CsF (0.15 g) in 1, 4-dioxane/H2O (1.5/0.15 mL) was stirred at 100℃ for 1 h. The mixture was then concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 3: 7) to afford the title compound as a yellow oil (0.02 g) . LCMS (ESI) : 578.3 [M+1] +.
1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H) , 8.17 (s, 1H) , 7.55 (d, J = 8.0 Hz, 2H) , 7.39 (d, J = 8.0 Hz, 2H) , 6.77 (s, 1H) , 5.05 (s, 2H) , 4.88 –4.81 (m, 1H) , 4.60 (s, 1H) , 4.49 –4.44 (m, 1H) , 3.84 (s, 3H) , 3.48 –3.40 (m, 2H) , 3.31 –3.26 (m, 2H) , 1.83 –1.76 (m, 1H) , 1.41 (d, J = 6.7 Hz, 6H) , 1.01 –0.98 (m, 2H) , 0.87 –0.83 (m, 2H) .
EXAMPLE 43
(±) 5- (4- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] -pyrido [2, 3-d] pyrimidin-6-one
Step 1 methyl 4- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzoate
A mixture of methyl 4-hydrazineylbenzoate hydrochloride (1.1 g) and 1-cyclopropyl-4, 4, 4-trifluorobutane-1, 3-dione (1.0 g) in acetic acid (10 mL) was stirred at 100℃ for 4h. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate (60 mL) . The solution was washed with saturated sodium bicarbonate (50 mL) , water (50 mL) , brine (50 mL) and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified using silica gel column chromatography eluted with ethyl acetate /petroleum ether (0 to 80%ethyl acetate) to afford the title product (1.5 g) as a white solid. LCMS (ESI) : 311.5 [M+1] +.
Step 2 (4- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) methanol
To a solution of the product of step 1 (1.5 g) in THF (30 mL) was added dropwise a solution of DIBAL (9.7 mL, 1M in n-hexane) at 0℃ over 30 min. After stirring at 0℃ for 1h, the reaction mixture was quenched with sodium sulfate decahydrate (10 g) at 0℃. The mixture was filtered through a Celite pad and washed with THF (50 mL) and DCM (50 mL) . The filtrate was concentrated under vacuum to afford the title product (1.2 g) as a colorless oil. LCMS (ESI) : 283.3 [M+1] +.
Step 3 1- (4- (chloromethyl) phenyl) -5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazole
A stirred solution of the product of step 2 (1.0 g) in DCM/thionyl chloride (10 mL, 2/1) was stirred at rt for 30 min. The reaction mixture was concentrated under vacuum to afford the title product (1.1 g) as a yellow solid. LCMS (ESI) : 301.6 [M+1] +.
Step 4 8- (4- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one
A mixture of the product of Step 3 (100 mg) , 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one (88 mg) and cesium carbonate (195 mg) in DMF (5 mL) was stirred at 60℃ for 2h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 2: 1) to afford the title compound as a white solid (134 mg) . LCMS (ESI) : 560.5 [M+1] +.
Step 5 (± ) 5- (4- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] -pyrido [2, 3-d] pyrimidin-6-one
To a solution of trimethylsulfoxonium iodide (66 mg) in DMSO (2.0 mL) was added KOtBu (0.3 mL, 1M solution in THF) under nitrogen. After stirring at rt for 1h, the reaction mixture was treated with the product of Step 4 (80 mg) in DMSO (3.0 mL) . The reaction mixture was heated at 60℃ for 3h and then quenched with water (10 mL) and extracted with ethyl acetate (3x10 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: from 100: 0 to 2: 1) to afford the title compound as a white solid (60 mg) . LCMS (ESI) : 574.6 [M+1] +.
EXAMPLE 44
(±) 5- (4- (3, 5-bis (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
Starting with 1, 1, 1, 5, 5, 5-hexafluoropentane-2, 4-dione and methyl 4-hydrazineylbenzoate hydrochloride to obtain the title product as a yellow solid following the same procedures as described in Step 1, Step 2, Step 3, Step 4 and step 5 of EXAMPLE 43. LCMS (ESI) : 602.5 [M+1] +.
EXAMPLE 45
(±) 3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (5-isopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
Starting with 1, 1, 1-trifluoro-5-methylhexane-2, 4-dione and methyl 4-hydrazineylbenzoate hydrochloride to obtain the title product as a yellow solid following the same procedures as described in Step 1, Step 2, Step 3, Step 4 and step 5 of EXAMPLE 43. LCMS (ESI) : 576.7 [M+1] +.
EXAMPLE 46
(±) 5- (4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
Step 1 methyl 4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate
To a stirred mixture of the 3, 3-dibromo-1, 1, 1-trifluoropropan-2-one (31 g) in 60 mL water, potassium acetate (11.5 g) was added. After stirring at 100 ℃ for 1 h, the reaction mixture was treated with a solution of methyl 4-formylbenzoate (17.2 g) in methanol (470 mL) , followed by ammonia (110 mL) at rt. The mixture was stirred at rt for 1 h and then stirred at 100℃ for 2 hrs. After being cooled to rt, 1L water was added and the precipitate appeared. After stirring at rt for 2 h, the solid was collected by filtration to give the title compound (21 g) . LCMS (ESI) : 271.1 [M+1] +.
Step 2 methyl 4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzoate
A mixture of the product of Step 1 (13.0 g) , cyclopropyl boronic acid (8.50 g) , cupric acetate (8.50 g) , bipyridine (8.0 g) and sodium carbonate (10.6 g) in 100 mL dichloroethane was stirred at 70℃ for 16 hours under the oxygen atmosphere. The resulting mixture was cooled to rt, adjusted to pH 4 by 1 N hydrochloric acid and extracted with DCM (3 x 100 ml) . The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0-50%ethyl acetate in hexane to afford the title compound (10.0 g) . LCMS (ESI) : 311.3 [M+1] +.
Step 3 (4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) phenyl) methanol
To a stirred solution of the product of Step 2 (7.0 g) in 50 mL of THF was added DIBAL (45 ml, 1 M) dropwise at 0℃. After stirring at 25℃ for 2 hr, the mixture was poured into ice water and the pH of the mixture was adjusted to 3 with 6 N hydrochloric acid solution. The mixture was extracted with ethyl acetate (100mL) . The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by
silica gel column chromatography eluted with 0-100%ethyl acetate in hexane to afford the title compound (6.3 g) . LCMS (ESI) : 283.3 [M+1] +.
Step 4 2- (4- (chloromethyl) phenyl) -1-cyclopropyl-4- (trifluoromethyl) -1H-imidazole
To a stirred solution of the product of Step 3 (6.3 g) in DCM (50 ml) , was added thionyl chloride (5.0 mL) at 0℃ under the nitrogen atmosphere. After stirring at 0℃ for 30 min and at 25℃ for 1 hr, the reaction mixture was concentrated. The residue was partitioned between DCM (50 mL) and sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with 0-30%ethyl acetate in hexane to afford the title compound (6.5 g) . LCMS (ESI) : 301.6 [M+1] +.
Step 5 (± ) 5- (4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
Starting with 2- (4- (chloromethyl) phenyl) -1-cyclopropyl-4- (trifluoromethyl) -1H-imidazole and 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) pyrido [2, 3-d] pyrimidin-7 (8H) -one the title product was obtained as a yellow solid following the same procedures as described in Step 4 and step 5 of EXAMPLE 43. LCMS (ESI) : 574.6 [M+1] +.
1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H) , 8.63 (s, 1H) , 7.91 (s, 1H) , 7.79 (d, 2H) , 7.29 (d, 2H) , 5.26 (d, 1H) , 5.20 (d, 1H) , 3.78 (s, 3H) , 3.72-3.66 (m, 1H) , 2.84-2.78 (m, 1H) , 2.49-2.45 (m, 1H) , 1.83-1.76 (m, 1H) , 1.68-1.60 (m, 1H) , 1.0-0.88 (m, 7H) , 0.76-0.65 (m, 2H) .
EXAMPLE 47 and EXAMPLE 48
(6aR, 7aS) -5- (4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
(6aS, 7aR) -5- (4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5, 6a, 7, 7a-tetrahydro-6H-cyclopropa [4, 5] pyrido [2, 3-d] pyrimidin-6-one
Example 45 was resolved by the following conditions to provide EXAMPLE 47 and EXAMPLE 48: Column type: IE column 5 μm, 4.6 mm I.D. *250 mm.
Mobile phase: 40%isopropanol, 60%hexane, flow rate, 1 mL/min.
EXAMPLE 47: retention time at 16.8 min; EXAMPLE 48: retention time at 17.3 min.
Claims (14)
- A compound of Formula I or a pharmaceutically acceptable salt thereof:
whereinis the selected from the follow moieties:
with the proviso that whenisR4 and R5, together with the carbon atom to which they are both attached to, complete a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which is optionally substituted with Rd or a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which contains one, two or three heteroatom (s) such as S, O or NRd;Rd is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cyclolkyl, C3-C6fluorocycloalkyl, C1-C6fluoroalkyl, C0-C6alkylene-aryl, C0-C6alkylene-heteroaryl, C (O) C1-6alkyl, C (O) aryl, S (O) 2C1-C6alkyl, S (O) 2C3- 6cycloalkyl, S (O) 2aryl,;each of X0, X1, X2, X3 and X4 is independently selected from N or CR1;X5, X8 is independently selected from C (R2) r, O, S, SO, SO2, or NR2;r, q = 0, 1, 2, 3 or 4;X6 is NRb, C=O, CRaRb;X7 is N or CH;Xa, Xb and Xc are independently N or CR2;Xd is S, S (O) 2, O or NRd;R1 is independently selected from the group consisting of hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, C1-6 alkylthio, hydroxyl, amino, nitro, formyl, -CF3, -CN, -SF5, NRaRb, carboxyl, -CORa, -CO2C1-C6 alkyl, -CONRaRb, -SO2Re, -SO2NRaRb, -P (O) Me2 and -P (O) (OMe) 2;R2 is independently selected from the group consisting of hydrogen, OH, oxo, CF2CH2OH, C1-C6 alkanol, C1-C6 halogenated alkanol, halogen, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, nitro, formyl, -CF3, -CN, -SF5, NRaRb, carboxyl, -CORa, -CO2C1-C6 alkyl, -CONRaRb, -SO2Rc, -SO2NRaRb, -P (O) Me2 and -P (O) (OMe) 2;Two R2 on the same carbon atom or adjacent carbon atoms together with carbon atom (s) can form a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which is optionally substituted with R4 or a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which contains one, two or three heteroatom (s) such as S, O or NRd;Ra and Rb are independently hydrogen, CH2CH2OH, CH2CMe2OH, C1-C6 alkanol, C1-C6 halogenated alkanol, substituted/non-substituted C1-C10 alkyl, substituted/non-substituted C3-C10 cycloalkyl, substituted/non-substituted C2-C10 alkenyl, substituted/non-substituted C6-C20 aryl, or substituted/non-substituted C3-C14 heteroaryl respectively; Ra and Rb can form 3-8 membered rings or 4-8 membered heterocyclic rings, which contain sulfur, oxygen, NH or NRd;Two R1 on the adjacent carbon atoms together with carbon atom (s) can form a four-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which is optionally substituted with R4 or a four-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which contains one, two or three heteroatom (s) such as S, O or NRd;R1 and R2, together with the carbon atoms to which they are attached to, can form 3-8 membered cabocyclic rings or 4-8 membered heterocyclic rings, which contain sulfur, oxygen, NH or NRd;R3 represents C6-C20 aryl and C1-C20 heteroaryl; R3 can be substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkanol, C1-C6 halogenated alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C1-C6 alkoxy, hydroxyl, amino, nitro, formyl, -CF3, -CN, -SF5, NRaRb, carboxyl, -CORa, -CO2C1-C6 alkyl, -CONRaRb, -SO2Rc, -SO2NRaRb, -P (O) Me2 and -P (O) (OMe) 2;Each of R4 and R5 is independently absent or selected from the group consisting of H, NRb 2, C1-C6 alkoxy, C1-C6 alkylthio, halogen, CN, C1-C6alkyl, C3-6cyclolkyl, C3-6fluorocycloalkyl, C1-C6fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 halogenated alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C1-C6 alkoxy, hydroxyl, amino, nitro, formyl, -CF3, -CN, -SF5, NRaRb, carboxyl, -CORa, -CO2C1-C6 alkyl, -CONRaRb, -SO2Rc, -SO2NRaRb, -P (O) Me2 and -P (O) (OMe) 2; R4 and R5, together with the carbon atom to which they are both attached to, complete a three-to six-membered carbocyclic ring, four-to ten-membered bicyclic ring or five-to ten-membered spirocyclic ring which is optionally substituted with Rd or a three-to six-membered carbocyclic ring, four-to eight-membered bicyclic ring or five-to eight-membered spirocyclic ring which contains one, two or three heteroatom (s) such as S, O or NRd;Rc represents C1-C10 alkyl, C3-C10 cycloalkyl, C6-C20 aryl, or C3-C14 heteroaryl; Rc can be substituted by one or more radical groups selected from halogen, hydroxyl, amino, nitro, cyano, formyl, carboxyl, alkoxy, -CF3 and -SF5;is selected from a single bond or double bond;Y is selected from C;is C5-C14 aryl, C3-C14 cycloalkyl, C4-C14 bicycloalkyl, C5-C14 tricycloalkyl, C5-C14 spiroalkyl, C5-C14 heteroaryl, C4-C14 heterocycloalkyl, C4-C14 heterobicycloalkyl, C5-C14 heterotricycloalkyl, C5-C14 heterospiroalkyl with 0-5 O, N or S atoms independently, wherein the aryl, cycloalkyl, bicycloalkyl, tricycloalkyl, spiroalkyl, heteroaryl, heterocycloalkyl, heterobicycloalkyl, heterotricycloalkyl, heterospiroalkyl are substituted with one or more R6;R6 represents optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, CN, halogen, SO2NH2, -CORa, -COORa, -NRbRb, -NRaCORb, -NRaCONRaRa, -CONRaRb, -SO2NRaRb, -NRaSO2Rb, optionally C6-C10 aryl and C1-C10 heteroaryl; R6 can be substituted by one or more groups selected from: halogen, C1-C6 alkyl, C3-C6cycloalkyl, C3-C6 halogenated cycloalkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, hydroxyl, amino, nitro, formyl, -CF3, -CN, -SF5, NRaRb, carboxyl, -CORa, -CO2C1-C6 alkyl, -CONRaRb, -SO2Rc, -SO2NRaRb, -P (O) Me2 and -P (O) (OMe) 2. - A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein the said compound is represented by Formula IA and IB
where Z, W, ring A and ring B are defined as in Formula I. R4a is C1-C6 alkyl, C3-C6 cyclolkyl, C3-C6 fluorocycloalkyl, C1-C6 fluoroalkyl. - A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, whereinis selected from:
- A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, whereinis selected from:
- A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from:
- A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein R6 is independently selected from the group consisting of:
Each V1, V2, V3, and V4 are independently selected from (C (R2) , NRd, O and S; V5 is C, or N; V1, V2, V3, V4 and V5 together form a 5-membered heteroaryl ring. R2 and Rd are defined as in Claim 1. - A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein R6 is independently selected from the group consisting of:
- A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula I is selected from the formulae in the following table:
wherein X0, X1, X2, X3, X4, q, r, Rb, R1, R2, R3, R4, R5 and R6 are defined as in Formula I; Y1 is a bond, O, S, CH2 or NRb; Y2 is a bond, C (O) or CH2; R4a is C1-C6 alkyl, C3-C6 cyclolkyl, C3-C6 fluorocycloalkyl, C1-C6 fluoroalkyl; X2 is N or CH; r, Rb, R2, R3 and R6 are defined as in Formula I. - A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula I is:
wherein Rd, R1, R3, R4, R5 and R6 are defined as in Formula I. is a 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, which contain S, O, NH or NRd; is a single bond or double bond such that all valences are satisfied. - A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula I is:
wherein Rd, R1, R3, R4, R5 and R6 are defined as in Formula I. is a saturated or unsaturated 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, which contain S, O, NH or NRd; is a single bond or double bond such that all valences are satisfied. - A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula I is:
wherein Rd, R1, R3, R4, R5 and R6 are defined as in Formula I. is a 4-8 membered heterocyclic ring, which may contain additional S, O, NH or NRd. - The compound of Claim 1 wherein the compound is selected from the compounds described in “Description” and Examples of the invention.
- A method of treating a human suffering from a condition or disease, via administering to said subject an effective amount of a compound according to Claim 1-12, wherein said disease or pathological condition is cancer or others.
- A method of treating cancer in a subject in need thereof comprising administering to said subject with an effective amount of a compound according to Claim 1-12 in combination with PARP inhibitors, chemotherapeutic agents, radiation therapy, immunotherapies such as antibodies against PD-1, PD-L1, or CTLA4, or in combination with a small molecule drug such as kinase inhibitors, endocrine/hormone therapeutics, or ADC therapeutic agents.
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