Patent Application
20240368169
This disclosure is in the field of medicinal chemistry. In particular, the disclosure relates to substituted tricyclic compounds, and the use of these compounds as therapeutically effective PARP inhibitors and anticancer drugs.
Poly (ADP-ribose) polymerase (PARP) is a family of proteins, which transfer negatively charged ADP-ribose groups from donor NAD+ onto target proteins. That is one of many post-transcriptional modifications. Therefore, PARP also is termed as ADP-ribose transferase.
Humans are thought to express 17 PARPs identified based on amino acid sequence homology to the catalytic domain (Vyas et al., 2013 Nature Communication, 4: 3240/1-3240/13). PARPs either catalyze the addition of a single ADP-ribose unit on target proteins or catalyze the polymerization of ADP-ribose units to form poly ADP-ribose, also known as poly (ADP-ribose) modification. As a result, the PARP family is further grouped into two subfamilies accordingly. Post-translational modification of poly (ADP-ribose) regulate many aspects of protein function and the physiological function of many PARPs have not been established.
The most characteristic member of the PARP family is PARP1, which was found to have the highest intracellular levels. PARP1 consists of 1014 amino acids (NCBI Accession P09874) with a total molecular weight of approximately 116 kDa. Structurally, this enzyme is composed of two main domains including an N-terminal DNA-binding domain and a catalytic domain. PARP1 is known to play an important role in many cellular functions, including gene expression, transcription, cell division, cell differentiation, cell apoptosis. DNA damage response and repair. PARP1 is activated when DNA damage occurs and is involved in base excision repair (BER) which is a major mechanism of DNA single-strand damage repair. PARP1 binds to the site of Single Strand Break (SSB), and subsequently repair DNA via BER. In response to DNA damage, cells also have evolved two main repair pathways: Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ), in addition to BER repair mechanisms. HR deficient tumors have been found to be sensitive to PARP inhibitors, indicating homologous recombination defects and PARP1 inhibition formed a pair of synthetic lethality, which has been validated by clinical studies. Several PARP inhibitors are currently approved for the treatment of breast, ovarian, pancreatic and prostate cancers with DNA damage repair deficient such as BRCA1/2 mutation.
PARP2 is a protein of 559 amino acids with molecular mass of approximately 62 kDa and composed of DNA binding domain and catalytic domain (Ame et al., 1999 J Biol Chem 274: 17860-17868). The catalytic domain of PARP2 is very similar to that of PARP1. PARP2 is also found to have similar functions to PARP1 and is involved in the repair of DNA damage through BER mechanism (Schreiber et al., 2002 J Biol Chem 277: 23028-23036). Marketed PARP inhibitors, such as Olaparib. Niraparib, Talazoparib and Rucaparib, not only have inhibitory activities against PARP1, but also have similar inhibitory activities against PARP2. Based on the results of clinical trials, the therapeutic effects of these marketed PARP inhibitors are comparable whereas their toxicity profiles are quite different. For example, Talazoparib has toxicity similar to chemotherapy drugs such as hair loss. Talazoparib also shows more potent inhibitory activity against TNKS1/2 (Tankyrase 1 or Tankyrase 2) than other PARP inhibitors (PARPi) in biochemical assay (Ryan et al., 2021. J Biol Chem 296:100251/1-100251/13). TNKS1 and TNKS2 share 83% sequence identity overall, and their catalytic domain sequences are 89% identical. They play roles in DNA repair, telomere maintenance, and Wnt/β-catenin signaling. Targeting PARPs other than PARP1 may be the reason why PARP inhibitors cause off-targeted toxicity, such as hair loss and diarrhea. In addition, inhibition of PARP2 activity has been found to lead to hematotoxicity (Farrés et al., 2013 Blood 122: 44-54; Farrés et al., 2015 Cell Death and Differentiation 22: 1144-1157). The toxicity of these PARP inhibitors limits their clinical application as well as in combination with other targeted drugs.
Therefore, to improve, enhance and expand the clinical application of PARP inhibitors, it is important to explore highly selective PAPR1 inhibitor to reduce mechanism—related or mechanism—independent toxicity.
Various PARP1 inhibitors have been disclosed in, for example, WO2011006803. WO2013014038. WO2021013735 and WO2021260092.
The disclosure provides compounds and analogues thereof as represented by Formula I (including Formulae II, III and IV). The compounds can be used as PARP inhibitors. In particular, the compounds of the disclosure are selective PARP1 inhibitors relative to PARP2.
The disclosure also provides pharmaceutical compositions comprising an effective amount of the compound of Formula I (including Formulae H, III and IV). The pharmaceutical compositions can be used for the treatment of cancer.
In a specific embodiment, the pharmaceutical composition may further contain one or more pharmaceutically acceptable carriers, excipients or diluents.
In a specific embodiment, the pharmaceutical composition may further contain at least one known anticancer drug or pharmaceutically acceptable salts thereof.
The disclosure is also directed to methods for the preparation of novel compounds of Formula I (including Formulae II, III and IV).
The disclosure also provides a method for treating or preventing a diseases or conditions responsive to the inhibition of PARP activity (especially PARP1 activity), comprising administering to a subject in need thereof an effective amount of the compound of Formula I (including Formulae II, III and IV) or a pharmaceutically acceptable salt thereof.
It should be understood that the characteristics of the embodiments described herein can be arbitrarily combined to form the technical solution of this disclosure. The definition of each group herein can apply to any of the embodiments described herein. For example, the definitions of the substituents of alkyl herein apply to any of the embodiments described herein unless the substituents of alkyl are clearly defined in the embodiment.
The term “hydrogen (H)” as employed herein includes its isotopes D and T.
The term “heteroatoms” as employed herein includes O, S and N.
The term “alkyl” as used herein refers to alkyl itself or a straight or branched chain radical of up to ten carbons. Useful alkyl groups include straight-chain or branched C1-10 alkyl groups, preferably C1-6 alkyl groups. In some embodiments, alkyl is C1-4 alkyl. In some embodiments, alkyl is C1-3 alkyl. In some embodiments, alkyl is deuterated C1-3 alkyl. Typical C1-10 alkyl groups include methyl, methyl-d3, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl (such as 3-pentyl), hexyl and octyl groups, which may be optionally substituted.
The term “alkenyl” as used herein refers to a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain; preferably, C2-6 alkenyl. Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.
The term “alkynyl” as used herein refers to a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain; preferably, C2-6 alkynyl. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.
Useful alkoxy groups include oxygen substituted by the above mentioned C1-10 alkyl groups, preferred C1-6 alkyl groups or C1-4 alkyl groups, e.g., methoxy, ethoxy, etc. The alkyl in the alkoxy groups may be optionally substituted. Substituents of alkoxy groups include, without limitation, halogen, morpholino, amino (including alkylamino and dialkylamino), and carboxy (including esters thereof).
Useful amino and optionally substituted amino groups are —NR′R″, wherein R′ and R″ each are independently hydrogen, an optionally substituted C1-10 alkyl, an optionally substituted C3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Preferably, R′ and R″ each are independently hydrogen, an optionally substituted C1-4 alkyl, an optionally substituted C3-6 cycloalkyl, or R′ and R″ together with the N to which they are attached form an optionally substituted 4-7 membered cyclic amino group, which optionally comprises one or more (such as 2, 3) additional heteroatoms selected from a group consisting of O, N and S. Preferred amino groups include NH2, and at least one of R′ and R″ is a C1-6 alkyl in —NR′R″.
The term “oxo” as used herein refers to ═O.
The term “aryl” as used herein by itself or as part of another group refers to monocyclic, bicyclic or tricyclic aromatic groups containing 6 to 14 carbon atoms. Aryl may be substituted by one or more substituents as described herein.
Useful aryl groups include C6-14 aryl groups, preferably C6-10 aryl groups. Typical C6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulyl, biphenyl, biphenylene and fluorenyl.
The term “carbocyclic group” as used herein include cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C3-8 cycloalkyl. In some preferred embodiments, cycloalkyl groups are C3-6 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Useful partially saturated carbocyclic groups are cycloalkenyl, such as C3-8 cycloalkenyl, which include cyclopentenyl, cycloheptenyl and cyclooctenyl. Carbocyclic group may be substituted by one or more substituents as described herein.
Useful halo or halogen groups include fluoro, chloro, bromo and iodo.
Useful acylamino (amido) groups are any C1-6 acyl (alkanoyl) attached to an amino nitrogen, e.g., acetamino, propionamido, butanoylamido, pentanoylamido and hexanoylamido, as well as aryl-substituted C1-6 acylamino groups, e.g., benzoylamido.
Useful acyl groups include C1-6 acyl groups, such as acetyl. Acyl may be optionally substituted by group selected from halo, amino and aryl, wherein the amino and aryl may be optionally substituted. When acyl is substituted by halo, the number of halogen substituents may be in the range of 1-5. Examples of substituted acyls include chloroacetyl and pentafluorobenzoyl. When acyl is substituted by amino, amino group may be substituted by one or two substituents as described herein. In some embodiments, aminoacyl is —C(O)—NR′R″, wherein R′ and R″ each are independently hydrogen, an optionally substituted C1-10 alkyl, an optionally substituted C3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Preferably, R′ and R″ each are independently hydrogen, an optionally substituted C1-4 alkyl, or an optionally substituted C3-6 cycloalkyl.
The term “heterocyclic group” as used herein refers to a saturated or partially saturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring, spirocyclic ring or bridged ring system, which consists of carbon atoms and one to four heteroatoms independently selected from a group consisting of O, N, and S, wherein the nitrogen and/or sulfur heteroatoms can be optionally oxidized and the nitrogen can be optionally quaternized, and the term also includes any bicyclic ring system in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic group can be substituted on carbon atom or nitrogen atom if the resulting compound is stable. The heterocyclic group may be substituted by one or more substituents as described herein.
Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, 1,4-diazepanyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indoline, isoindoline, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidine, pyrazolinyl, tetrahydroisoquinolyl, tetronoyl and tetramoyl, which may be optionally substituted by one or more substituents as described herein.
The term “heteroaryl” as used herein refers to a group having 5 to 14 ring atoms, preferably 5 to 10 ring atoms, with 6, 10 or 14 electrons shared in a cyclic array. Ring atoms are carbon atoms and 1-3 heteroatoms selected from a group consisting of oxygen, nitrogen and sulfur. Heteroaryl may be optionally substituted by one or more substituents as described herein.
Useful heteroaryl groups include thienyl (thiophenyl), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl, including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, tetrahydrocyclopenta[c]pyrazol-3-yl, benzoisoxazolyl such as 1,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridyl, triazolopyridazinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrrolopyrazinyl or triazolopyrazinyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
In this disclosure, unless otherwise described, when substituted, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkoxy, alkenyl, heterocycloalkenyl, alkynyl, amino, amido, acyloxy, carboxyl, hydroxyl, mercapto, alkylthio sulfonyl, sulfonyl, sulfinyl, aminoacyl, silyl, phosphinecarboxy, phosphono, carbocyclic group, heterocyclic group, aryl or heteroaryl as described in any embodiment herein may be substituted by one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from the group consisting of halogen, hydroxyl, carboxyl, amino, nitro, cyano. C1-6 amido, C1-6 acyloxy. C1-6 alkoxy, aryloxy, alkylthio. C1-6 alkyl, C1-6 acyl. C6-10 aryl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, heterocyclic or heteroaryl, methylenedioxy, urea group, mercapto group, azide group, carbonyl, alkanesulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl, etc. The substituent itself may also be optionally substituted. Preferred substituents include without limitation halogen, hydroxyl, carboxyl, amino. C1-6 amido, C1-6 acyloxy. C1-6 alkoxy, C1-6 alkyl, C1-6 acyl and alkanesulfonyl.
It should be understood that in each embodiment, when the substituent is a heterocyclic group, aryl or heteroaryl, the number thereof is usually 1.
Specifically, the disclosure provides compounds represented by Formula I:
or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, wherein:
In Formula I and each formula of the disclosure, unless otherwise described, each alkyl is independently a C1-6 alkyl, preferably a C1-4 alkyl; each alkylene is a C1-6 alkylene, preferably a C1-3 alkylene; each alkenyl is independently a C2-6 alkenyl, preferably C2-4 alkenyl; each alkynyl is independently C2-6 alkynyl, preferably C2-4 alkynyl; each alkoxy is independently C1-6 alkoxy, preferably C1-4 alkoxy. Preferably, when the alkyl, alkenyl, alkynyl and alkoxy are substituted, the substituents can be selected from a group consisting of cyano, hydroxyl, nitro, amino (—NR′R″), aryl, heterocyclic group, heteroaryl, halogen and carboxyl, etc. The number of substituents may be 1-5, R′ and R″ are preferably each independently H, an optionally substituted C1-4 alkyl or an optionally substituted C3-6 cycloalkyl. For example, the substituted alkyl per se or as a substituent of other groups may be hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl and haloalkyl, etc. It should be understood, when the substituent is aryl, heteroaryl, heterocyclic group, cyano, nitro and carboxyl, the number thereof is usually 1. When the substituent is halogen, the number of substituents can be up to 5 depending on the carbon chain length of the alkyl, alkenyl, alkynyl and alkoxy groups; exemplary substituents are trifluoromethyl and pentafluoroethyl, etc.
In Formula I and each formula of the disclosure, unless otherwise described, the number of ring carbon atoms of each carbocyclic group is preferably 3-8. Preferred carbocyclic groups are C3-8 cycloalkyl groups or C3-8 cycloalkenyl. The substituents on the carbocyclic group are preferably C1-4 alkyl, halogenated C1-4 alkyl, C1-4 alkoxy, halogen, hydroxyl, carboxyl, amino (—NR′R″), aryl, heterocyclic group, heteroaryl and carboxyl, etc. The number of substituents may be 1-5, R′ and R″ are preferably each independently H, an optionally substituted C1-4 alkyl or an optionally substituted C3-6 cycloalkyl. It should be understood, when the substituent is aryl, heteroaryl, heterocyclic group, cyano, nitro and carboxyl, the number thereof is usually 1. When the substituent is halogen, the number of substituents can be up to 5.
In Formula I and each formula of the disclosure, unless otherwise described, the aryl refers to C6-14 aryl, the heteroaryl refers to 5-10 membered heteroaryl, and the heterocyclic group refers to 4-10 membered heterocyclic group. The substituents on each of the aryl, heteroaryl and heterocyclic group can each be independently selected from 1-5 groups consisting of C1-4 alkyl, halogenated C1-4 alkyl, C1-4 alkoxy, halogen, hydroxyl, carboxyl, amino (—NR′R″), an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic group, halogen, amido, aminoacyl (—C(O)—NR′R″) and carboxyl, etc.; wherein R′ and R″ each are independently hydrogen, an optionally substituted C1-10 alkyl, an optionally substituted C3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Preferably, R′ and R″ each are independently hydrogen, an optionally substituted C1-4 alkyl, an optionally substituted C3-6cycloalkyl. The number of substituents may be 1-5. The said optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic group may be optionally substituted by 1-5 groups selected from C1-4 alkyl, halogenated C1-4 alkyl, C1-4 alkoxy, halogen, hydroxyl, carboxyl, amino (—NR′R″), aminoacyl (—C(O)—NR′R″) and carboxyl, wherein, the said R′ and R″ are preferably each independently H, optionally substituted C1-4 alkyl or optionally substituted C3-6 cycloalkyl. It should be understood, when the substituent is aryl, heteroaryl, heterocyclic group, cyano, nitro and carboxyl, the number thereof is usually 1. When the substituent is halogen, the number of substituents can be up to 5.
In one or more embodiments of the compound of Formula I, the Z ring is selected from the following groups:
preferably the Z ring is selected from the following groups:
more preferably the Z ring is selected from the following groups:
wherein * indicates the position at which the Z ring is attached to the rest of the compound; each R4 is independently selected from a group consisting of hydrogen, halogen and an optionally substituted alkyl, preferably hydrogen, halogen and an optionally substituted C1-3 alkyl; each R4 is independently selected from a group consisting of hydrogen, halogen and an optionally substituted alkyl, preferably hydrogen, halogen and an optionally substituted C1-3 alkyl. In some embodiments, each R4 is independently selected from a group consisting of hydrogen and an optionally substituted alkyl, preferably hydrogen and an optionally substituted C1-3 alkyl.
In one or more embodiments of the compound of Formula I, the Z ring is selected from the following groups:
In one or more embodiments of the compound of Formula I, the Z ring is selected from the following groups:
In one or more embodiments of the compound of Formula I, the Z ring is selected from the following groups:
preferably the Z ring is selected from the following groups:
In one or more embodiments of the compound of Formula I, A1, A2 and A3 are each independently selected from N and CR1, wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. In some embodiments, only one of A1, A2 and A3 is N, and the other two are independently CR1, preferably, R1 is independently H, C1-3 alkyl or halogen. In more preferred embodiment, A3 is CH, one of A1 and A2 is N and the other is CR1, wherein, R1 is H, C1-3 alkyl or halogen. In some embodiments, A1 is N, both of A2 and A3 are CH. In some embodiments, A2 is N, both A1 and A3 are CH. In some embodiments, all of A1, A2 and A3 are CR1, each R1 is independently H, C1-3 alkyl or halogen. Preferably, A3 is CH, one of A1 and A2 is CR1, wherein R1 is halogen; more preferably, both of A2 and A3 are CH, A1 is CR1, wherein R1 is halogen.
In one or more embodiments of the compound of Formula I, when the Z ring is not
A1, A2 and A3 are each independently selected from N and CR1, wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. In some embodiments, only one of A1, A2 and A3 is N, and the other two are independently CR1, preferably, R1 is independently H. C1-3 alkyl or halogen. In more preferred embodiment, A3 is CH, one of A1 and A2 is N and the other is CR1, wherein, R1 is H. C1-3 alkyl or halogen. In some embodiments, A1 is N, both of A2 and A3 are CH. In some embodiments, A2 is N, both A1 and A3 are CH. In some embodiments, all of A1, A2 and A3 are CR1, each R1 is independently H, C1-3 alkyl or halogen. Preferably, A3 is CH, one of A1 and A2 is CR1, wherein R1 is C1-3 alkyl or halogen; more preferably, both of A2 and A3 are CH, A1 is CR1, wherein R1 is C1-3 alkyl or halogen. Preferably, A2 is CH, one of A1 and A3 is CR1, wherein R1 is C1-3 alkyl or halogen; more preferably, both of A1 and A2 are CH, A3 is CR1, wherein R1 is C1-3 alkyl or halogen.
In one or more embodiments of the compound of Formula I, when the Z ring is
A1 is CR1, A2 and A3 each are independently N or CR1, wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. Preferably, A1, A2 and A3 each are independently CR1, wherein R1 is independently H, halogen or C1-3 alkyl. In some embodiments. A1 is CR1, both of A2 and A3 are CH, wherein R1 is C1-3 alkyl or halogen. In some embodiments. A2 is CR1, both of A1 and A3 are CH, wherein R1 is C1-3 alkyl or halogen. In some embodiments, A3 is CR1, both of A1 and A2 are CH, wherein R1 is C1-3 alkyl or halogen. In some embodiments, all of A1, A2 and A3 are CH. Preferably, A1 is CR1, both of A2 and A3 are CH; or both of A1 and A2 are CH, A3 is CR1, wherein R1 is C1-3 alkyl or halogen.
The substituents on the Z ring can be 1-3 groups selected from a group consisting of hydroxy, halogen, C1-4 alkyl, C1-4 alkoxy, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, C1-4 alkyl substituted with hydroxy. C1-4 alkoxy substituted with hydroxy and amino (—NR′R″), wherein R and R″ each are preferably independently H or C1-4 alkyl. In some embodiments, when the Z ring is substituted, the substituents can be 1-3 groups selected from halogen or C1-4 alkyl.
In one or more embodiments of the compound of Formula I, each R1 is preferably independently hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy. In some embodiments. R1 is an optionally substituted C1-3 alkyl. Preferably, when R1 is substituted, the substituents can be 1-5 groups selected from halogen, hydroxy, amino (—NR′R″), etc., wherein R′ and R″ each are preferably independently H, an optionally substituted C1-4 alkyl or an optionally substituted C3-6 cycloalkyl. Preferably, R1 is halogen, C1-3 alkyl or halogenated C1-3 alkyl. In some embodiments, R1 is hydrogen, C1-3 alkyl or halogen. In some embodiments. R1 is hydrogen or halogen.
In one or more embodiments of the compound of Formula I, preferably, R2 and R3 are each independently halogen or C1-3 alkyl. In some embodiments. R2 and R3 together with the attached C form a 3-6 membered cycloalkyl.
In one or more embodiments of the compound of Formula I, L is an unsubstituted alkylene, preferably an unsubstituted C1-3 alkylene, more preferably methylene.
In one or more embodiments of the compound of Formula I, the said aryl is preferably a phenyl. The said heteroaryl is a 5-10-membered heteroaryl containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms. In some embodiments, the said heteroaryl is a 5-10-membered heteroaryl containing 1 or 2 nitrogen atoms. The said heteroaryl includes but is not limited to pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, indolizinyl, thienyl, furyl, and thiazolyl, etc. The said carbocyclic group is preferably a C3-8 cycloalkyl or a C3-8 cycloalkenyl. The said heterocyclic group is preferably a 4-10 membered heterocyclic group containing O, S and/or N, including but not limited to azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydroisoquinolyl and morpholinyl, etc.
In one or more embodiments of the compound of Formula I, Cy is an optionally substituted 5-7 membered nitrogen-containing heterocyclic group. Preferably, the 5-7 membered nitrogen-containing heterocyclic group is covalently attached to L through its ring nitrogen atom. Further preferably, Cy is an optionally substituted piperazinyl. Preferably, when Cy is substituted, the substituents on Cy can be 1-3 groups selected from a group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, an optionally substituted 6-14 membered aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 4-10 membered heterocyclic group and an optionally substituted C3-8 cycloalkyl. The optionally substituted 6-14 membered aryl, the optionally substituted 5-10 membered heteroaryl, the optionally substituted 4-10 membered heterocyclic group and the optionally substituted C3-8 cycloalkyl each can be independently substituted by 1-5 substituents selected from a group consisting of halogen, an optionally substituted alkyl (such as an optionally substituted C1-4 alkyl), an optionally substituted alkoxy (such as an optionally substituted C1-4 alkoxy), an optionally substituted carbocyclic group (such as an optionally substituted C3-8 cycloalkyl), an optionally substituted alkenyl (such as an optionally substituted C2-4 alkenyl), an optionally substituted alkynyl (such as an optionally substituted C2-4 alkynyl), an amino (—NR′R″), an aminoacyl (—C(O)—NR′R″) and carboxyl, wherein the said R′ and R″ each are preferably independently H, an optionally substituted C1-10 alkyl, an optionally substituted C3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl; preferably H, an optionally substituted C1-4 alkyl or an optionally substituted C3-8 cycloalkyl. In some preferred embodiments, the substituent(s) include at least —C(O)—NR′R″, and optionally include one or two of substituents selected from a group consisting of halogen, C1-4 alkyl and halogenated C1-4 alkyl. Preferably, the said an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl and an optionally substituted alkynyl each can be independently substituted by 1-5 substituents selected from a group consisting of halogen, hydroxy and amino, such as halogenated C1-4 alkyl and halogenated C1-4 alkoxy, etc.
In some preferred embodiments, Cy is substituted by an optionally substituted 5-10 membered heteroaryl, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl. Preferably, the 5-10 membered heteroaryl or 5-10 membered nitrogen-containing heteroaryl is at least substituted by —C(O)—NR′R″ or —COOH and optionally further substituted by one or two substituents selected from a group consisting of halogen, C1-4 alkyl and halogenated C1-4 alkyl. In some particularly preferred embodiments, Cy is piperazinyl substituted with an optionally substituted pyridyl, and the said pyridyl is at least substituted with —C(O)—NR′R″. Preferably, in the embodiments as described herein, when the said R′ and R″ are substituted, the substituents can be 1-5 groups selected from a group consisting of halogen, hydroxy and amino.
In one or more embodiments of the compound of Formula I, A1, A2 and A3 are each independently CR1; each R1 is independently H, C1-3 alkyl or halogen; L is —CH2— or —CH2CH2—; Cy is piperazinyl substituted with pyridyl, and the said pyridyl is substituted with —C(O)—NR′R″ and optionally further substituted by one or two substituents selected from a group consisting of halogen, C1-4 alkyl and halogenated C1-4 alkyl; R′ and R″ each are independently H, C1-4 alkyl optionally substituted by hydroxy, or C3-8 cycloalkyl.
In one or more embodiments of the compound of Formula I. A1, A2 and A3 are each independently CR1; each R1 is independently H, C1-3 alkyl or halogen; L is —CH2—; Cy is piperazinyl substituted with pyridyl, and the said pyridyl is substituted with —C(O)—NR′R″ and optionally further substituted by one or two substituents selected from a group consisting of halogen and C1-4 alkyl; R′ and R″ each are independently H, C1-4 alkyl optionally substituted by hydroxy, or C1-8 cycloalkyl.
One group of preferred compounds of Formula I in this disclosure is represented by compounds of Formula II (including Formulae IIa and IIb):
or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, wherein:
In one or more embodiments of the compound of Formula IIa, W is CH2, O or N—C1-3 alkyl, preferably O, CH2 or N—CH3.
In one or more embodiments of the compound of Formula I1b, Z3, Z4 and Z5 are independently selected from a group consisting of CR4, O, S and N; and when Z1 is N, at least one of Z3, Z4 and Z5 is N; or when Z1 is N and all of Z3, Z4 and Z5 are CR4, A1 is CR1.
In one or more embodiments of the compound of Formula IIb, the Z ring is selected from the following groups:
preferably the Z ring is selected from following groups:
more preferably the Z ring is selected from following groups:
wherein * indicates the position at which the Z ring is attached to the rest of the compound; each R4 is independently selected from hydrogen, halogen and an optionally substituted alkyl, preferably hydrogen, halogen and an optionally substituted C1-3 alkyl; each R4′ is independently selected from a group consisting of hydrogen, halogen and an optionally substituted alkyl, preferably hydrogen, halogen and an optionally substituted C1-3 alkyl. In some embodiments, each R4 is independently selected from a group consisting of hydrogen and an optionally substituted alkyl, preferably hydrogen and an optionally substituted C1-3 alkyl.
In one or more embodiments of the compound of Formula II (including Formulae IIa and IIb), the Z ring is selected from the following groups:
more preferably, the Z ring is selected from the following groups:
In one or more embodiments of the compound of Formula II (including Formulae IIa and IIb), A1, A2 and A3 are each independently selected from N and CR1, wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. In some embodiments, only one of A1, A2 and A3 is N, and the other two are independently CR1, preferably, R1 is independently H. C1-3 alkyl or halogen. In more preferred embodiment, A3 is CH, one of A1 and A2 is N and the other is CR1, wherein, R1 is H. C1-3 alkyl or halogen. In some embodiments, A1 is N, both of A2 and A3 are CH. In some embodiments, A2 is N, both A1 and A3 are CH. In some embodiments, all of A1, A2 and A3 are CR1, each R1 is independently H, C1-3 alkyl or halogen. Preferably, A3 is CH, one of A1 and A2 is CR1, wherein R1 is halogen; more preferably, both of A2 and A3 are CH, A1 is CR1, wherein R1 is halogen.
In one or more embodiments of the compound of Formula II (including Formulae IIa and IIb), each R1 is preferably independently hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy. In some embodiments, R1 is an optionally substituted C1-3 alkyl. Preferably, when R1 is substituted, the substituents can be 1-5 groups selected from halogen, hydroxy, and amino (—NR′R″), etc. wherein, R′ and R″ each are preferably independently H, an optionally substituted C1-4 alkyl or an optionally substituted C3-6 cycloalkyl. Preferably, R1 is C1-3 alkyl or halogenated C1-3 alkyl. In some embodiments, R1 is hydrogen, C1-3 alkyl or halogen. In some embodiments. R1 is hydrogen or halogen.
In one or more embodiments of the compound of Formula II (including Formulae IIa and IIb), when the Z ring is not
A1, A2 and A3 are each independently selected from N and CR1, wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. In preferred embodiments, only one of A1, A2 and A3 is N, and the other two are independently CR1, preferably, R1 is independently H, C1-3 alkyl or halogen. In more preferred embodiment, one of A1 and A2 is N and the other is CR1, A3 is CH, wherein, R1 is H. C1-3 alkyl or halogen. In some embodiments. A1 is N, both of A2 and A3 are CH. In some embodiments, A2 is N, both A1 and A3 are CH. In some embodiments, all of A1, A2 and A3 are CR1, each R1 is independently H, C1-3 alkyl or halogen. Preferably, A3 is CH, one of A1 and A2 is CR1, wherein, R1 is C1-3 alkyl or halogen; more preferably, both of A2 and A3 are CH, A1 is CR1, wherein, R1 is C1-3 alkyl or halogen. Preferably, A2 is CH, one of A1 and A3 is CR1, wherein, R1 is C1-3 alkyl or halogen; more preferably, both of A1 and A2 are CH, A3 is CR1, wherein, R1 is C1-3 alkyl or halogen.
In one or more embodiments of the compound of Formula IIb, when the Z ring is
A1 is CR1, A2 and A3 each are independently N or CR1, wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. Preferably, A1, A2 and A3 each are independently CR1, wherein R1 is independently H, halogen or C1-3 alkyl. In some embodiments, A1 is CR1, both of A2 and A3 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments, A2 is CR1, both A1 and A3 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments, A3 is CR1, both A1 and A2 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments, all of A1, A2 and A3 are CH. Preferably, A1 is CR1, both of A2 and A3 are CH; or both of A1 and A2 are CH, A3 is CR1, wherein, R1 is C1-3 alkyl or halogen.
In one or more embodiments of the compound of Formula II (including Formulae IIa and IIb), R6 is an optionally substituted 6-14 membered aryl or an optionally substituted 5-10 membered heteroaryl. An exemplary 6-14 membered aryl group is phenyl. The said 5-10 membered heteroaryl is preferably a 5-10 membered nitrogen-containing heteroaryl, including but is not limited to pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridazinyl and indolizinyl, preferably pyridyl, pyrimidinyl and pyridazinyl. Preferably, when R6 is substituted, the substituents can be 1-5 groups selected from a group consisting of halogen, an optionally substituted alkyl (such as C1-4 alkyl and halogenated C1-4 alkyl), an optionally substituted alkoxy (such as C1-4 alkoxy and halogenated C1-4 alkoxy), aminoacyl (—C(O)—NR′R″) and carboxyl. More preferably, R, is substituted with at least one aminoacyl group, preferably, R6 is substituted in the para position with an optionally substituted aminoacyl group. Preferably, the said optionally substituted aminoacyl is —C(O)—NR′R″, wherein the R′ and R″ each are preferably independently H, an optionally substituted C1-10 alkyl, an optionally substituted C3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl, preferably H, an optionally substituted C1-4 alkyl or an optionally substituted C3-6 cycloalkyl. Preferably, when the said R and R″ are substituted, the substituents can be 1-5 groups selected from a group consisting of halogen, hydroxy, oxygen and amino. Preferably, the number of carbon atoms of the optionally substituted alkyl and optionally substituted alkoxy is 1-4, preferably, the substituents can be 1-5 groups selected from a group consisting of halogen, hydroxyl, oxygen and amino. In some preferred embodiments, the substituents on RF include at least aminoacyl (—C(O)—NR′R″), and optionally include any one or two groups of halogen, C1-4 alkyl and halogenated C1-4 alkyl.
In one or more embodiments of the compound of Formula II, R6 is:
wherein, B1, B2, B3 and B4 are independently selected from a group consisting of N and CR7; R7 is selected from a group consisting of hydrogen, halogen, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl and an optionally substituted alkynyl; wherein R′ and R″ each are independently hydrogen, an optionally substituted C1-10 alkyl, an optionally substituted C3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Preferably, R′ and R″ each are independently hydrogen, an optionally substituted C1-4 alkyl (including deuterated C1-4 alkyl), an optionally substituted C3-6 cycloalkyl. * indicates the position at which the said group is attached to the rest of the compound. Preferably, the group containing B1, B2, B3 and B4 is phenyl, pyridyl, pyrimidinyl or pyridazinyl. Preferably, R7 is H, halogen, C1-3 alkyl, C1-3 alkoxy or halogenated C1-3 alkyl. Preferably, B3 is N, B4 is CR7, both of B1 and B2 are CH, wherein R7 is H, halogen, C1-3 alkyl, C1-3 alkoxy or halogenated C1-3 alkyl. Preferably, when the said R′ and R″ are substituted, the substituents can be 1-5 groups selected from a group consisting of halogen, hydroxy and amino. Preferably, R′ is hydrogen, R″ is hydrogen, C1-3 alkyl, C3-6 cycloalkyl, halogenated C1-3 alkyl, deuterated C1-3 alkyl or hydroxy C1-3 alkyl. In some embodiments, R′ is hydrogen, R″ is hydrogen, C1-3 alkyl, deuterated C1-3 alkyl, C3-6 cycloalkyl, or halogenated C1-3 alky.
Preferably, in the embodiments as described herein, the said R7 is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl or an optionally substituted alkynyl, which can be independently substituted by 1-5 substituents selected from a group consisting of halogen, hydroxy and amino.
In one or more embodiments of the compound of Formula IIa, n is 1 or 2.
In one or more embodiments of the compound of Formula IIa, m is 1 or 2.
In one or more embodiments of the compound of Formula IIa, when m is 0, W is O or CH2.
In one or more embodiments of the compound of Formula IIa, W is selected from O, CH2 and N—CH3; A1, A2 and A3 each are independently selected from N and CR1; R6 is:
wherein, B1, B2, B3 and B4 are independently selected from a group consisting of N and CR7; R′ and R″ each are independently hydrogen, an optionally substituted C1-10 alkyl, an optionally substituted C3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Preferably, R′ and R″ each are independently hydrogen, an optionally substituted C1-4 alkyl, an optionally substituted C3-6 cycloalkyl. R1 is selected from hydrogen, halogen, an optionally substituted alkyl, an optionally substituted alkoxy and an optionally substituted carbocyclic group, preferably H, halogen and C1-3 alkyl. R7 is selected from a group consisting of hydrogen, halogen, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl and an optionally substituted alkynyl; preferably hydrogen, C1-3 alkyl, halogenated C1-3 alkyl or halogen, n is 1 or 2. Preferably, A1, A2 and A3 each are independently selected from N and CR1; wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. In some embodiments, only one of A1, A2 and A3 is N, and the other two are independently CR1, preferably, R1 is independently H, C1-3 alkyl or halogen. In some embodiments, one of A1 and A2 is N and the other is CR1, A3 is CH, wherein, R1 is H, C1-3 alkyl or halogen. In some embodiments, A1 is N, both of A2 and A3 are CH. In some embodiments. A2 is N, both of A1 and A3 are CH. In some embodiments, all of A1, A2 and A3 are CR1, each R1 is independently H, C1-3 alkyl or halogen. Preferably, A3 is CH, one of A1 and A2 is CR1, wherein, R1 is C1-3 alkyl or halogen; more preferably, both of A2 and A3 are CH, A1 is CR1, wherein, R1 is C1-3 alkyl or halogen. Preferably, A2 is CH, one of A1 and A3 is CR1, wherein, R1 is C1-3 alkyl or halogen; more preferably, both of A1 and A2 are CH, A3 is CR1, wherein, R1 is C1-3 alkyl or halogen. In some embodiments. A2 is CR1, both A1 and A3 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments, A3 is CR1, both A1 and A2 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments, all of A1, A2 and A3 are CH. Preferably, A1 is CR1, both of A2 and A3 are CH; or both of A1 and A2 are CH, A3 is CR1, wherein, R1 is C1-3 alkyl or halogen. Preferably, B1, B2, B3 and B4 are independently selected from a group consisting of N and CR7; wherein R7 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R7 is hydrogen, C1-3 alkyl, halogenated C1-3 alkyl or halogen. Preferably, both of B1 and B2 are CH, B3 is N, Ba is CR7, wherein R7 is H, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R7 is hydrogen, C1-3 alkyl, halogenated C1-3 alkyl or halogen. Preferably, R′ and R″ each are independently hydrogen, an optionally substituted C1-4 alkyl, an optionally substituted C3-6 cycloalkyl. Preferably, when the said R′ and R″ are substituted, the substituents can be 1-5 groups selected from a group consisting of halogen, hydroxy and amino. Preferably, R′ is hydrogen. R″ is hydrogen, C1-3 alkyl, C3-6 cycloalkyl, halogenated C1-3 alkyl, deuterated C1-3 alkyl or hydroxy C1-3 alkyl. Preferably, R7 is hydrogen, halogen or an optionally substituted C1-3 alkyl. Preferably, R7 is hydrogen, halogen, C1-3 alkyl or halogenated C1-3 alkyl. Preferably, n is 1 or 2; m is 1 or 2. More preferably, n is 1; m is 1 or 2.
In one or more embodiments of the compound of Formula Jib, the Z ring is selected from:
A1, A2 and A3 each are independently N or CR1; wherein each R4 is independently selected from a group consisting of hydrogen, halogen and an optionally substituted alkyl, preferably hydrogen, halogen and an optionally substituted C1-3 alkyl; each R4′ is independently selected from a group consisting of hydrogen, halogen and an optionally substituted alkyl, preferably hydrogen, halogen and an optionally substituted C1-3 alkyl. In some embodiments, each R4 is independently selected from a group consisting of hydrogen and an optionally substituted alkyl, preferably hydrogen and an optionally substituted C1-3 alkyl; preferably, the Z ring is selected from:
wherein, B1, B2, B3 and B4 are independently selected from a group consisting of N and CR7; R′ and R″ each are independently hydrogen, an optionally substituted C1-10 alkyl, an optionally substituted C3-8 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Preferably, R and R″ each are independently hydrogen, an optionally substituted C1-4 alkyl, an optionally substituted C3-6 cycloalkyl. R1 is selected from a group consisting of hydrogen, halogen, an optionally substituted alkyl, an optionally substituted alkoxy and an optionally substituted carbocyclic group. R7 is selected from a group consisting of hydrogen, halogen, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl and an optionally substituted alkynyl. Preferably, A1, A2 and A3 each are independently selected from N and CR1; wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. Preferably, only one of A1, A2 and A3 is N, and the other two are independently CR1, preferably, R1 is independently H, C1-3 alkyl or halogen. Preferably, one of A1 and A2 is N and the other is CR1, A3 is CH, wherein, R1 is H, C1-3 alkyl or halogen. Preferably. A1 is N, and both of A2 and A3 are CH. In some embodiments, A2 is N, and both of A1 and A3 are CH. In some embodiments, all of A1, A2 and A3 are CR1, each R1 is independently H, C1-3 alkyl or halogen. Preferably, A3 is CH, one of A1 and A2 is CR1, wherein, R1 is C1-3 alkyl or halogen; more preferably, both of A2 and A3 are CH, A1 is CR1, wherein, R1 is C1-3 alkyl or halogen. Preferably, A2 is CH, one of A1 and A3 is CR1, wherein, R1 is C1-3 alkyl or halogen; more preferably, both of A1 and A2 are CH, A3 is CR1, wherein, R1 is C1-3 alkyl or halogen. Preferably, B1, B2, B3 and B4 are independently selected from a group consisting of N and CR7; wherein R7 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R7 is hydrogen, C1-3 alkyl, halogenated C1-3 alkyl or halogen. Preferably, both of B1 and B2 are CH, B3 is N. B4 is CR7, wherein R7 is H, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R7 is hydrogen, C1-3 alkyl, halogenated C1-3 alkyl or halogen. Preferably, R′ and R″ each are independently hydrogen, an optionally substituted C1-3 alkyl, an optionally substituted C3-6 cycloalkyl. Preferably, when the said R′ and R″ are substituted, the substituents can be 1-5 groups selected from a group consisting of halogen, hydroxy and amino. Preferably, R′ is hydrogen. R″ is hydrogen, C1-3 alkyl. C3-6 cycloalkyl, halogenated C1-3 alkyl, deuterated C1-3 alkyl, or hydroxy C1-3 alkyl. Preferably, R7 is hydrogen, halogen, C1-3 alkyl, or halogenated C1-3 alkyl.
In one or more embodiments of the compound of Formula II. A1, A2 and A3 are each independently CR1; each R1 is independently H, C1-3 alkyl or halogen; R6 is pyridyl substituted with —C(O)—NR′R″ and optionally further substituted by one or two substituents selected from a group consisting of halogen, C1-4 alkyl and halogenated C1-4 alkyl; R′ and R″ each are independently H, C1-4 alkyl optionally substituted by hydroxy, or C3-8 cycloalkyl.
In one or more embodiments of the compound of Formula II, A1, A2 and A3 are each independently CR1; each R1 is independently H, C1-3 alkyl or halogen; R6 is pyridyl substituted with —C(O)—NR′R″ and optionally further substituted by one or two substituents selected from a group consisting of halogen and C1-4 alkyl; R′ and R″ each are independently H, C1-4 alkyl optionally substituted by hydroxy, or C3-8 cycloalkyl.
One group of preferred compounds of Formula I in this disclosure is represented by compounds of Formula III (including Formulae IIIa and IIIb):
or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, wherein:
In one or more embodiments of the compound of Formula IIIa, W is O, CH2 or N—C1-3 alkyl, preferably O, CH2 or N—CH3.
In one or more embodiments of the compound of Formula IIIb, the Z ring is selected from the following groups:
preferably the Z ring is selected from following groups:
more preferably the Z ring is selected from following groups:
wherein each R4 is independently selected from a group consisting of hydrogen, halogen and an optionally substituted alkyl, preferably hydrogen, halogen and an optionally substituted C1-3 alkyl; each R4′ is independently selected from a group consisting of hydrogen, halogen and an optionally substituted alkyl, preferably hydrogen, halogen and an optionally substituted C1-3 alkyl. In some embodiments, each R4 is independently selected from a group consisting of hydrogen and an optionally substituted alkyl, preferably hydrogen and an optionally substituted C1-3 alkyl.
In one or more embodiments of the compound of Formula III (including Formulae IIIa and IIIb), the Z ring is selected from the following groups:
preferably from the following groups:
In one or more embodiments of the compound of Formula III (including Formulae IIIa and IIIb), A1, A2 and A3 are each independently selected from N and CR1, wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. In some embodiments, only one of A1, A2 and A3 is N, and the other two are independently CR1, preferably, R1 is independently H. C1-3 alkyl or halogen. In more preferred embodiment, A3 is CH, one of A1 and A2 is N and the other is CR1, wherein, R1 is H, C1-3 alkyl or halogen. In some embodiments, A1 is N, both of A2 and A3 are CH. In some embodiments. A2 is N, both A1 and A3 are CH. In some embodiments, all of A1, A2 and A3 are CR1, each R1 is independently H, C1-3 alkyl or halogen. Preferably, A3 is CH, one of A1 and A2 is CR1, wherein R1 is halogen; more preferably, both of A2 and A3 are CH, A1 is CR, wherein R1 is halogen.
In one or more embodiments of the compound of Formula III (including Formulae IIIa and IIIb), when the Z ring is not
A1, A2 and A3 each are independently selected from N and CR1, wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. In preferred embodiments, only one of A1, A2 and A3 is N, and the other two are independently CR1, preferably, R1 is independently H, C1-3 alkyl or halogen. In more preferred embodiment, one of A1 and A2 is N and the other is CR1, A3 is CH, wherein, R1 is H. C1-3 alkyl or halogen. In some embodiments. A1 is N, and both of A2 and A3 are CH. In some embodiments, A2 is N and both of A1 and A3 are CH. In some embodiments, all of A1, A2 and A3 are CR1, each R1 is independently H, C1-3 alkyl or halogen. Preferably, A3 is CH, one of A1 and A2 is CR, wherein, R1 is C1-3 alkyl or halogen; more preferably, both of A2 and A3 are CH, A1 is CR1, wherein, R1 is C1-3 alkyl or halogen. Preferably, A2 is CH, one of A1 and A3 is CR, wherein, R1 is C1-3 alkyl or halogen; more preferably, both of A1 and A2 are CH, A3 is CR1, wherein, R1 is C1-3 alkyl or halogen. In some embodiments. A1 is CR1, both of A2 and A3 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments, A2 is CR1, both A1 and A3 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments. A3 is CR1, both A1 and A2 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments, all of A1, A2 and A3 are CH. Preferably, A1 is CR1, both of A2 and A3 are CH; or both of A1 and A2 are CH, A3 is CR1, wherein, R1 is C1-3 alkyl or halogen.
In one or more embodiments of the compound of Formula IIIb, when the Z ring is
A1 is CR1, A2 and A3 each are independently N or CR, wherein R1 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R1 is hydrogen, C1-3 alkyl or halogen. Preferably, A1, A2 and A3 each are independently CR1, R1 is independently H, halogen or C1-3 alkyl. In some embodiments. A1 is CR1, both of A2 and A3 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments, A2 is CR1, both A1 and A3 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments. A3 is CR1, both A1 and A2 are CH, wherein, R1 is C1-3 alkyl or halogen. In some embodiments, all of A1, A2 and A3 are CH. Preferably, A1 is CR1, both of A2 and A3 are CH; or both of A1 and A2 are CH, A3 is CR1, wherein, R1 is C1-3 alkyl or halogen.
In one or more embodiments of the compound of Formula III (including Formulae IIIa and IIIb), B1, B2, B3 and B4 are independently selected from a group consisting of N and CR7; wherein R7 is preferably selected from a group consisting of hydrogen, halogen, an optionally substituted C1-3 alkyl, an optionally substituted C1-3 alkoxy, more preferably, R7 is H, C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl or halogen. In some preferred embodiments, both of B1 and B2 are CH, B3 is N, B4 is CR7, wherein R7 is preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R7 is hydrogen, C1-3 alkyl, halogenated C1-3 alkyl or halogen.
In one or more embodiments of the compound of Formula III. R′ and R″ each are independently hydrogen, an optionally substituted C1-4 alkyl or an optionally substituted C3-6 cycloalkyl; Preferably, R′ is hydrogen, R″ is hydrogen, C1-3 alkyl, halogenated C1-3 alkyl, deuterated C1-3 alkyl or hydroxy C1-3 alkyl.
In one or more embodiments of the compound of Formula IIIa, n is 1 or 2.
In one or more embodiments of the compound of Formula IIIa, m is 1 or 2.
In one or more embodiments of the compound of Formula IIIa, when m is 0, W is O or CH2.
In some preferred embodiments, in the said —C(O)—NR′R″ described herein, R′ and R″ each are independently H, C1-4 alkyl or C3-6 cycloalkyl. In further preferred embodiments, R′ is hydrogen and R″ is hydrogen or C1-3 alkyl.
One group of preferred compounds of Formula I in this disclosure is represented by compounds of Formula IV (including Formulae IVa, IVb and IVc):
or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, wherein:
In one or more embodiments of the compound of Formula IV, the 5-membered ring containing Z3, Z4 and Z5 is selected from the following groups:
preferably the Z ring is selected from following groups:
wherein each R4 is independently selected from a group consisting of hydrogen, halogen and an optionally substituted alkyl, preferably hydrogen, halogen and an optionally substituted C1-3 alkyl; each R4′ is independently selected from a group consisting of hydrogen, halogen and an optionally substituted alkyl, preferably hydrogen, halogen and an optionally substituted C1-3 alkyl. In some embodiments, each R4 is independently selected from a group consisting of hydrogen and an optionally substituted alkyl, preferably hydrogen and an optionally substituted C1-3 alkyl.
In one or more embodiments of the compound of Formula IV (including Formulae IVa, IVb and IVc), R8, R9 and R10 each are preferably hydrogen, halogen, an optionally substituted C1-3 alkyl or an optionally substituted C1-3 alkoxy, more preferably, R8, R9 and R10 each are hydrogen, C1-3 alkyl or halogen. In some embodiments, R8 is C1-3 alkyl or halogen, and both of R9 and R10 are H. In some embodiments, R9 is C1-3 alkyl or halogen, and both of R9 and R10 are H. In some embodiments, both of R8 and R9 are H, and R10 is C1-3 alkyl or halogen. In some embodiments, all of R8, R9 and R10 are H. Preferably, R8 is C1-3 alkyl or halogen, both of R9 and R10 are H; or both of R8 and R9 are H, R10 is C1-3 alkyl or halogen.
In one or more embodiments of the compound of Formula IV (including Formulae IVa, IVb and IVc), R7 is selected from a group consisting of hydrogen, halogen, an optionally substituted C1-3 alkyl, and an optionally substituted C1-3 alkoxy, preferably, R7 is H, C1-3 alkyl. C1-3 alkoxy, halogenated C1-3 alkyl or halogen. More preferably, R7 is H, C1-3 alkyl or halogen.
In one or more embodiments of the compound of Formula IV. R′ and R″ each are independently hydrogen, an optionally substituted C1-4 alkyl or an optionally substituted C3-6 cycloalkyl; Preferably, R′ is hydrogen, R″ is hydrogen, C1-3 alkyl, halogenated C1-3 alkyl, hydroxy C1-3 alkyl or C3-6 cycloalkyl. More preferably, R′ is hydrogen. R″ is hydrogen, C1-3 alkyl, halogenated C1-3 alkyl, or hydroxy C1-3 alkyl.
In one or more embodiments of the compound of Formula IV, the 5-membered ring containing Z3, Z4 and Z5 is selected from the following groups:
wherein each R4 is independently selected from a group consisting of hydrogen and C1-3 alkyl; each R4′ is independently selected from a group consisting of hydrogen and C1-3 alkyl; preferably, the 5-membered ring containing Z3, Z4 and Z5 is selected from the following groups:
It should be understood that although W. Z1, Z2, Z3, Z4, Z5, A1, A2, A3, L, Cy, R6, B1, B2, B3, B4, R7, R8, R9, R10, R′, R″, n and m are described separately above, the described features, especially the preferred features, can be arbitrarily combined to form the scope of different compounds of Formula I (including Formulae II, III and IV) in this disclosure. For example, in some embodiments of compounds of Formula I (including Formulae II, III and IV) of this disclosure.
The preferred compounds of Formula I include, without limitation:
Some of the compounds of the present disclosure may exist as stereoisomers including optical isomers. The disclosure includes all stereoisomers and the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
Examples of pharmaceutically acceptable salts include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base salts formed with bases, such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl-glucamine.
Examples of prodrugs of the compounds of the disclosure include the simple esters of carboxylic acid-containing compounds (e.g., those obtained by condensation with a C1-4 alcohol according to methods known in the art); esters of hydroxy containing compounds (e.g., those obtained by condensation with a C1-4 carboxylic acid, C3-6 diacid or anhydride thereof, such as succinic anhydride and fumaric anhydride according to methods known in the art); imines of amino containing compounds (e.g., those obtained by condensation with a C1-4 aldehyde or ketone according to methods known in the art); carbamate of amino containing compounds, such as those described by Leu, et al., (J. Med. Chem. 42: 3623-3628 (1999)) and Greenwald, et al., (J. Med. Chem. 42: 3657-3667 (1999)); and acetals and ketals of alcohol-containing compounds (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).
The compounds of this disclosure may be prepared using methods known to those skilled in the art, or the novel methods of this disclosure. Specifically, the compounds of this disclosure with Formula I (including Formulae II, III and IV) can be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of methyl 4-oxotetrahydrofuran-3-carboxylate and trifluoromethanesulfonic anhydride (Tf2O) under the catalysis of N,N-diisopropylethylamine (DIEA) produced methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate. Suzuki reaction of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate and (4-(methoxycarbonyl)-2-nitrophenyl)boronic acid under the catalysis of Pd2(dba)3 produced methyl 4-(4-(methoxycarbonyl)-2-nitrophenyl)-2,5-dihydrofuran-3-carboxylate. Reaction of methyl 4-(4-(methoxycarbonyl)-2-nitrophenyl)-2,5-dihydrofuran-3-carboxylate and Fe/AcOH under the catalysis of AcOH produced methyl 4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]quinoline-7-carboxylate. Reduction reaction of methyl 4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]quinoline-7-carboxylate and lithium aluminum hydride (LiAlH4) produced 7-(hydroxymethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Chlorination of 7-(hydroxymethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one with SOCl2 produced 7-(chloromethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Substitution reaction of 7-(chloromethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one and N-methyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI produced the target compound 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one.
Other related compounds can be prepared using similar methods. For example, replacement of N-methyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Replacement of N-methyl-5-(piperazin-1-yl)picolinamide with 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Replacement of N-methyl-5-(piperazin-1-yl)picolinamide with N,6-dimethyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Replacement of N-methyl-5-(piperazin-1-yl)picolinamide with 6-chloro-N-ethyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-chloro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Replacement of N-methyl-5-(piperazin-1-yl)picolinamide with N-ethyl-6-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one.
The compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 2. Substitution reaction of methyl 4-fluoro-3-nitrobenzoate and methyl 1H-pyrrole-2-carboxylate under the catalysis of Cs2CO3 produced methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate. Reaction of methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate and Fe/AcOH under the catalysis of AcOH produced methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-7-carboxylate. Reduction reaction of methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-7-carboxylate and LiAlH4 produced 7-(hydroxymethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one. Chlorination of 7-(hydroxymethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one with SOCl2 under the catalysis of DMF produced 7-(chloromethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one. Substitution reaction of 7-(chloromethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one and N,6-dimethyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one.
Other related compounds can be prepared using similar methods. For example, replacement of methyl 1H-pyrrole-2-carboxylate with methyl 1H-imidazole-2-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-a]quinoxalin-4(5H)-one. Replacement of methyl 1H-pyrrole-2-carboxylate with methyl 1H-imidazole-5-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,5-a]quinoxalin-4(5H)-one. Replacement of methyl 1H-pyrrole-2-carboxylate with methyl 1H-pyrazole-5-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. Replacement of methyl 1H-pyrrole-2-carboxylate with methyl 5-methyl-1H-pyrrole-2-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one.
The compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 3. Reduction reaction of methyl 4-fluoro-3-nitrobenzoate and H2 under the catalysis of Pd/C produced methyl 3-amino-4-fluorobenzoate. Reaction of methyl 3-amino-4-fluorobenzoate and 1H-pyrazole-5-carboxylic acid under the catalysis of DIEA and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) produced methyl 4-fluoro-3-(1H-pyrazole-5-carboxamido)benzoate. The intramolecular ring closure reaction of methyl 4-fluoro-3-(1H-pyrazole-5-carboxamido)benzoate under the catalysis of K2CO3 produced methyl 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate. Reduction reaction of methyl 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate and LiAlH4 produced 7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. Chlorination of 7-(hydroxymethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one with SOCl2 produced 7-(chloromethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution reaction of 7-(chloromethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one and N,6-dimethyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one.
Other related compounds can be prepared using similar methods. For example, replacement of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. Replacement of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. Replacement of methyl 3-amino-4-fluorobenzoate with methyl 3-amino-4,5-difluorobenzoate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. Replacement of methyl 3-amino-4-fluorobenzoate with methyl 3-amino-5-chloro-4-fluorobenzoate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one. Replacement of 1H-pyrazole-5-carboxylic acid with 3-methyl-1H-pyrazole-5-carboxylic acid produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one.
The compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 4. Reaction of methyl 4-formyl-3-nitrobenzoate, glyoxal and NH3-MeOH produced methyl 4-(1H-imidazol-2-yl)-3-nitrobenzoate. Reduction of methyl 4-(1H-imidazol-2-yl)-3-nitrobenzoate with SnCl2·2H2O produced methyl 3-amino-4-(1H-imidazol-2-yl)benzoate. Reaction of methyl 3-amino-4-(1H-imidazol-2-yl)benzoate and triphosgene (BTC) produced methyl 5-oxo-5,6-dihydroimidazo[1,2-c]quinazoline-8-carboxylate. Reduction of methyl 5-oxo-5,6-dihydroimidazo[1,2-c]quinazoline-8-carboxylate with LiAlH4 produced 8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one. Reaction of 8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one and SOCl2 produced 8-(chloromethyl)imidazo[1,2-c]quinazolin-5(6H)-one. Reaction of 8-(chloromethyl)imidazo[1,2-c]quinazolin-5(6H)-one and N,6-dimethyl-5-(piperazin-1-yl)picolinamide produced the target compound 8-((4-(2-methyl-6-methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one.
Other related compounds can be prepared using similar methods. For example, replacement of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridine-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one. Replacement of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 8-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one.
The compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 5. Reaction of methyl 3-amino-4-bromobenzoate and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid under the catalysis of Pd(PPh3)2Cl2 and Na2CO3 produced methyl 5-oxo-5,6-dihydropyrrolo[1,2-c]quinazoline-8-carboxylate. Reduction of methyl 5-oxo-5,6-dihydropyrrolo[1,2-c]quinazoline-8-carboxylate with LiAlH4 produced 8-(hydroxymethyl)pyrrolo[1,2-c]quinazolin-5(6H)-one. Reaction of 8-(hydroxymethyl)pyrrolo[1,2-c]quinazolin-5(6H)-one and methanesulfonyl chloride under the catalysis of triethylamine produced (5-oxo-5,6-dihydropyrrolo[1,2-c]quinazolin-8-yl)methyl methanesulfonate. Reaction of (5-oxo-5,6-dihydropyrrolo[1,2-c]quinazolin-8-yl)methyl methanesulfonate and N,6-dimethyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI produced the target compound 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-c]quinazolin-5(6H)-one.
Other related compounds can be prepared using similar methods. For example, replacement of (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid with (1-(tert-butoxycarbonyl)-1H-pyrazol-5-yl)boronic acid produced the target compound 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-c]quinazolin-5(6H)-one.
The compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 6. Esterification of methyl 2-oxocyclopentane-1-carboxylate and trifluoromethanesulfonic anhydride under the catalysis of DIEA produced methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate. Borylation of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate and bis(pinacolato)diboron under the catalysis of Pd(dppf)Cl2·CH2Cl2 produced methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate. Suzuki reaction of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate and methyl 4-bromo-3-fluoro-5-nitrobenzoate under the catalysis of Pd(PPh3)2Cl2 produced methyl 3-fluoro-4-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-5-nitrobenzoate. Reaction of methyl 3-fluoro-4-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-5-nitrobenzoate and Fe/AcOH produced methyl 9-fluoro-4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinoline-7-carboxylate. Reduction of methyl 9-fluoro-4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinoline-7-carboxylate with LiAlH4 produced 9-fluoro-7-(hydroxymethyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one. Chlorination of 9-fluoro-7-(hydroxymethyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one with SOCl2 under the catalysis of DMF produced 9-fluoro-7-(chloromethyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one. Reaction of 9-fluoro-7-(chloromethyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one and N,6-dimethyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one.
Other related compounds can be prepared using similar methods. For example, replacement of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one. Replacement of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with N-cyclopropyl-6-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one. Replacement of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with N-cyclopropyl-6-fluoro-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one.
The compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 7. Reaction of 3-methyl-1H-pyrazole-5-carbonyl chloride and 5-bromo-2,3-difluoroaniline under the catalysis of NaH produced N-(5-bromo-2,3-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxamide. Reaction of N-(5-bromo-2,3-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxamide and K2CO3 produced 7-bromo-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Reaction of 7-bromo-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one and (tributylstannyl)methanol under the catalysis of XphosPdG2 produced 9-fluoro-7-(hydroxymethyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Reaction of 9-fluoro-7-(hydroxymethyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one and SOCl2 under the catalysis of DMF produced 7-(chloromethyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Reaction of 7-(chloromethyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide under the catalysis of KI and DIEA produced the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxaline-4(5H)-one.
Other related compounds can be prepared using similar methods. For example, replacement of 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide with N,6-dimethyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxaline-4(5H)-one. Replacement of 3-methyl-1H-pyrazole-5-carbonyl chloride with 4-methyl-1H-pyrazole-5-carbonyl chloride produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-9-fluoro-3-methylpyrazolo[1,5-a]quinoxaline-4(5H)-one. Replacement of 3-methyl-1H-pyrazole-5-carbonyl chloride with 3-chloro-1H-pyrazole-5-carbonyl chloride produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-2-chloro-9-fluoropyrazolo[1,5-a]quinoxaline-4(5H)-one. Replacement of 3-methyl-1H-pyrazole-5-carbonyl chloride with 1H-pyrazole-5-carbonyl chloride, replacement of 5-bromo-2,3-difluoroaniline with 3-bromo-2,6-difluoroaniline, and replacement of 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide with N,6-dimethyl-5-(piperazin-1-yl)picolinamide, produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. Replacement of 5-bromo-2,3-difluoroaniline with 3-bromo-2,6-difluoroaniline, and replacement of 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide with N,6-dimethyl-5-(piperazin-1-yl)picolinamide, produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methylpyrazolo[1,5-a]quinoxaline-4(5H)-one. Replacement of 3-chloro-1H-pyrazole-5-carbonyl chloride with 1H-pyrazole-5-carbonyl chloride, replacement of 5-bromo-2,3-difluoroaniline with 3-bromo-2,6-difluoroaniline, and replacement of 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide with N,6-dimethyl-5-(piperazin-1-yl)picolinamide, produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one.
The compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 8. Reaction of methyl 4-bromothiophene-3-carboxylate and (2-amino-4-(methoxycarbonyl)phenyl)boronic acid under the catalysis of NaOAc and Pd(dppf)Cl2 produced methyl 4-oxo-4,5-dihydrothieno[3,4-c]quinoline-7-carboxylate. Reaction of methyl 4-oxo-4,5-dihydrothieno[3,4-c]quinoline-7-carboxylate and LiAlH4 produced 7-(hydroxymethyl)thieno[3,4-c]quinolin-4(5H)-one. Reaction of 7-(hydroxymethyl)thieno[3,4-c]quinolin-4(5H)-one and SOCl2 under the catalysis of DMF produced 7-(chloromethyl)thieno[3,4-c]quinolin-4(5H)-one. Reaction of 7-(chloromethyl)thieno[3,4-c]quinolin-4(5H)-one and N,6-dimethyl-5-(piperazin-1-yl)picolinamide under the catalysis of KI and DIEA produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinolin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinoline-4(5H)-one.
Other related compounds can be prepared using similar methods. For example, replacement of methyl 4-bromothiophene-3-carboxylate with methyl 2-bromothiophene-3-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinolin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinoline-4(5H)-one. Replacement of methyl 4-bromothiophene-3-carboxylate with methyl 3-bromothiophene-2-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[2,3-c]quinolin-4(5H)-one. Replacement of methyl 4-bromothiophene-3-carboxylate with methyl 5-bromothiazole-4-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thiazolo[4,5-c]quinolin-4(5H)-one.
An important aspect of the present disclosure is the discovery that compounds of Formula I (including Formulae II, III and IV) are PARP inhibitors, especially selective PARP1 inhibitors. Therefore, the compounds of Formula I (including Formulae II, III and IV) or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof can be used to treat a variety of diseases or conditions responsive to the inhibition of PARP activity (especially PARP1 activity), or used to prepare a medicament for treating or preventing diseases or conditions responsive to the inhibition of PARP activity (especially PARP1 activity).
In the disclosure, the diseases or conditions responsive to the inhibition of PARP activity (especially PARP1 activity), include cancer. Cancer can be a solid tumor or hematological tumor, including but is not limited to liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (such as small cell lung cancer), Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer. Preferably, the cancer is responsive to the inhibition of PARP activity, especially PARP1 activity.
Therefore, the present disclosure includes methods for the treatment or prevention of diseases or conditions responsive to the inhibition of PARP activity (especially PARP1 activity), comprising administering to a subject (especially mammal, more specifically human) in need thereof an effective amount of the compound of Formula I (including Formulae II, III and IV) or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, or a pharmaceutical composition comprising an effective amount of the compound of Formula I (including Formulae II, III and IV) or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof.
In practicing the therapeutic methods, effective amounts of pharmaceutical preparations are administered to an individual exhibiting the symptoms of one or more of these disorders. The pharmaceutic preparations comprise a therapeutically effective amount of the compound of Formula I (including Formulae II, III and IV), formulated for oral, intravenous, local or topical application, for the treatment of cancer and other diseases. The amount is effective to ameliorate or eliminate one or more symptoms of the disorders. An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate or in some manner reduce the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to an effective regimen. The amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptom.
In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I (including Formulae II, III and IV) as a PARP inhibitor, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof and a pharmaceutically acceptable carrier.
Another embodiment of the present disclosure is directed to a pharmaceutical composition effective to treat or prevent cancer comprising a compound of Formula I (including Formulae II, III and IV) as a PARP inhibitor, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof and prodrugs thereof, in combination with at least one known anticancer agent or a pharmaceutically acceptable salt thereof. In particular, the compound herein can be combined with other anticancer drugs related to the mechanism of DNA damage and repair, such as ATM inhibitors, ATR inhibitors, Wee1 inhibitors. DNA-PK inhibitors; HDAC inhibitors such as Volinota, Romididesin, Papiseta and Bailesta; other anticancer drugs related to cell division, including Chk1/2 inhibitors, CDK4/6 inhibitors such as Paposinib; other targeted anticancer agents, including USP1 inhibitors, PRMT5 inhibitors, Polθ inhibitors, RAD51 inhibitors, and so on. Other known anticancer agents which may be used for anticancer combination therapy include, but are not limited to alkylating agents, such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin and carboplatin; topoisomerase I inhibitors, such as camptothecin, irinotecan and topotecan; topoisomerase II inhibitors, such as doxorubicin, epirubicin, aclacinomycin, mitoxantrone, elliptinium and etoposide: RNA/DNA antimetabolites, such as 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine and methotrexate; DNA antimetabolites, such as 5-fluoro-2′-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea and thioguanine; antimitotic agent such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; antibodies such as mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, Ofatumumab, Dinutuximab. Blinatumomab, ipilimumab, avastin, herceptin and mabthera; Antibody-Drug Conjugates (ADC) such as T-DM1, Trastuzumab Deruxtecan, Trastuzumab Emtansine, Datopotamab Deruxtecan. Gemtuzumab Ozogamicin, Brentuximab Vedotin, Inotuzumab Ozogamicin, Sacituzumab govitecan, Enfortumab Vedotin, Belantamab Mafodotin; kinase inhibitors such as imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, Idelalisib, pazopanib, Torisel and everolimus. Other known anticancer agents which may be used for anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib. Ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide. Venetoclax, Aldesleukin (recombinant human interleukin-2) and Sipueucel-T (prostate cancer treatment vaccine).
In practicing the methods of the present disclosure, the compound of the disclosure may be administered together with at least one known anticancer agent in a unitary pharmaceutical composition. Alternatively, the compound of the disclosure may be administered separately from at least one known anticancer agent. In one embodiment, the compound of the disclosure and at least one known anticancer agent are administered substantially simultaneously, i.e. all agents are administered at the same time or one after another, provided that compounds reach therapeutic levels in the blood at the same time. In another embodiment, the compound of the disclosure and at least one known anticancer agent are administered according to individual dose schedule, provided that the compounds reach therapeutic levels in the blood.
Another embodiment of the present disclosure is directed to a bioconjugate to inhibit tumor. The bioconjugate is consisted of the compound described herein and at least one known therapeutically useful antibody, such as trastuzumab or rituximab, or growth factor, such as EGF or FGF, or cytokine, such as IL-2 or IL-4, or any molecule that can bind to cell surface. The antibodies and other molecules could deliver the compound described herein to its targets, making it an effective anticancer agent. The bioconjugates could also enhance the anticancer effect of the therapeutically useful antibodies, such as trastuzumab or rituximab.
Another embodiment of the present disclosure is directed to a pharmaceutical composition effective to inhibit tumor comprising the PARP inhibitor of Formula I (including Formulae II, III and IV), or pharmaceutically acceptable salts thereof, or prodrugs thereof, in combination with radiation therapy. In this embodiment, the compound of the disclosure may be administered at the same time as the radiation therapy or at a different time.
Yet another embodiment of the present disclosure is directed to a pharmaceutical composition effective for post-surgical treatment of cancer, comprising the PARP inhibitor of Formula I (including Formulae II, III and IV), or pharmaceutically acceptable salts thereof, or prodrug thereof. The disclosure also relates to a method of treating cancer by surgically removing tumor and then treating the mammal with the pharmaceutical composition described herein.
Pharmaceutical compositions of this disclosure include all pharmaceutical preparations which contain the compounds of the present disclosure in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal amounts of each component in the pharmaceutical preparations is within the skill of the art. Typically, the compounds or the pharmaceutically acceptable salt thereof may be administered to mammals, orally at a dose of about 0.0025 to 50 mg per kg body weight per day. Preferably, from approximately 0.01 mg/kg to approximately 10 mg/kg body weight is orally administered. If a known anticancer agent is also administered, it is administered in an amount that is effective to achieve its intended purpose. The optimal amounts of such known anticancer agents are well known to those skilled in the art.
The unit oral dose may comprise from approximately 0.01 to approximately 50 mg, preferably approximately 0.1 to approximately 10 mg of the compound of the disclosure. The unit dose may be administered one or more times, with one or more tablets daily, each containing from approximately 0.1 to approximately 50 mg, conveniently approximately 0.25 to 10 mg of the compound of the disclosure or its solvates.
In a topical formulation, the compound of the disclosure may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.
The compound of the disclosure may be administered as a raw chemical. The compounds of the disclosure may also be administered as part of a suitable pharmaceutical preparation containing pharmaceutically acceptable carriers (comprising excipients and auxiliaries), which facilitate the processing of the compounds into pharmaceutically acceptable preparations. Preferably, the pharmaceutical preparations, particularly oral preparations and those used for the preferred administration, such as tablets, draggers, and capsules, as well as solutions suitable for injection or oral administration, contain from approximately 0.01% to 99%, preferably from approximately 0.25% to 75% of active compound(s), together with excipient(s).
Also included within the scope of the present disclosure are the non-toxic pharmaceutically acceptable salts of the compounds of the present disclosure. Acid addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like. Base addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methyl-glucamine and the like.
The pharmaceutical preparations of the disclosure may be administered to any mammal, so long as they may experience the therapeutic effects of the compounds of the disclosure. Foremost among such mammals are humans and veterinary animals, although the disclosure is not intended to be so limited.
The pharmaceutical preparations of the present disclosure may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively or concurrently, administration may be by oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, type of concurrent treatment, frequency of treatment, and the nature of the effect desired.
The pharmaceutical preparations of the present disclosure are manufactured in a known manner, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, processing the mixture of granules after adding suitable auxiliaries if desired or necessary, thereby obtaining tablets or dragee cores.
Suitable excipients are, in particular, fillers, such as saccharides, e.g, lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g, tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, including, e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, in particular, flow-regulating agents and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropyl methylcellulose phthalate, are used. Dyes or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations, which may be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active compounds in the form of granules, which may be mixed with fillers, such as lactose; binders, such as starches; and/or lubricants, such as talc or magnesium stearate and stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds, e.g., aqueous solutions and alkaline solutions of water-soluble salts. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate or triglycerides or polyethylene glycol-400, or cremophor, or cyclodextrins. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, e.g., sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, suspension stabilizers may also be contained.
In accordance with one aspect of the present disclosure, compounds of the disclosure are employed in topical and parenteral formulations and are used for the treatment of skin cancer.
The topical formulations of this disclosure are formulated preferably as oils, creams, lotions, ointments and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C12). The preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers are found in U.S. Pat. Nos. 3,989,816 and 4,444,762.
Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed. A typical example of such a cream is one which includes approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil and approximately 1 part almond oil.
Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which includes approximately 30% almond oil and approximately 70% white soft paraffin by weight.
The present disclosure also involves use of the compounds of the disclosure for the manufacture of a medicament for the treatment of clinical symptoms in response to inhibition of the activity of PARP. The medicament may include the above-mentioned pharmaceutical compositions.
The following examples are illustrative, but not limiting, of the method and compositions of the present disclosure. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the disclosure.
All reagents were of commercial quality. Solvents were dried and purified by standard methods. Mass spectrum analyses were recorded on a Platform II (Agilent 6110) quadrupole mass spectrometer fitted with an electrospray interface. 1H NMR spectra was recorded at 400 MHz, on a Brücker Ascend 400 apparatus. Chemical shifts were recorded in parts per million (ppm) downfield from TMS (0.00 ppm), and J coupling constants were reported in hertz (Hz).
The following compounds of Examples 2-23 were prepared using a synthesis method similar to that described in Example 1.
1H NMR (400 MHz)
The following compounds of Examples 25-27 were prepared using a synthesis method similar to that described in Example 1 or Example 24.
1H NMR (400 MHz)
The compound of Example 29 was prepared using a synthesis method similar to that described in Example 7R
1H NMR (400 MHz)
The compound of Example 30 was prepared using a synthesis method similar to that described in Example 31.
The following compounds of Examples 32-33 were prepared using a synthesis method similar to that described in Example 31.
The following compounds of Examples 34-35 were prepared using a synthesis method similar to that described in Example 24.
The following compounds of Examples 36-47 were prepared using a synthesis method similar to that described in Example 28.
1H NMR (400 MHz)
The following compounds of Examples 49-50 and 63-64 were prepared using a synthesis method similar to that described in Example 1.
The following compounds of Examples 51-53 were prepared using a synthesis method similar to that described in Example 31.
The following compounds of Examples 54-58, 62, and 66-72 were prepared using a synthesis method similar to that described in Example 28.
The following compounds of Examples 59-61 and 65 were prepared using a synthesis method similar to that described in Example 24.
1H NMR (400 MHz)
The following compounds of Examples 74-78 were prepared using a synthesis method similar to that described in Example 73.
1H NMR (400 MHz)
The following compounds of Examples 80-82 were prepared using a synthesis method similar to that described in Example 79.
1H NMR (400 MHz)
The following compounds of Examples 84-85 and 104 were prepared using a synthesis method similar to that described in Example 83.
The following compounds of Examples 86-103 were prepared using a synthesis method similar to that described in Example 73.
1H NMR (400 MHz)
The following compounds of Examples 107-108, 121-122, 138-139, 143 and 149 were prepared using a synthesis method similar to that described in Example 83.
The following compounds of Examples 109-117, 123-130, 133-137, 140-142, 144, and 146-148 were prepared using a synthesis method similar to that described in Example 73.
The compound of Example 118 was prepared using a synthesis method similar to that described in Example 48.
The following compounds of Examples 119-120 were prepared using a synthesis method similar to that described in Example 31.
The following compounds of Examples 131-132, and 150 were prepared using a synthesis method similar to that described in Example 48.
The compound of Example 145 was prepared using a synthesis method similar to that described in Example 24.
1H NMR (400 MHz)
The solution of recombinant poly(ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) (40 ng enzyme/well) and the compounds to be tested were mixed, respectively. The solutions were added to a 96-well plate coated with histone mixture, incubated at room temperature for 1 h, then 50 μL 0.3 ng/mL Streptavidin-HRP was added to each well. The plates were incubated for 30 minutes at room temperature. Finally, the plates were treated with streptavidin-HRP followed by addition of the ELISA ECL substrate to produce chemiluminescence that can be measured using a chemiluminescence reader. Inhibition of the tested compound to PARP1/2 enzyme activity was calculated according to the following formula.
IC50 value is obtained by fitting the s-shaped dose response curve equation by using XL Fit software. The curve equation is Y=100/(1+10{circumflex over ( )}(log C−log IC50)), C is the compound concentration.
Table 1 summarize the inhibitory effects of compounds on PARP1 and PARP2 enzyme activity (IC50).
Relative to PARP2 enzyme, most of the compounds tested have potent and selective inhibitory effect on PARP1 enzyme.
The cells were cultured in complete medium (DMEM medium+10% FBS+Insulin+glutathione). When the confluence reached about 80%, cells were digested and gently dispensed from the bottom of the dish with a 1 mL pipette. Cell suspension was collected and centrifuged at 500 rpm for 3 min. The supernatant was discarded, and the cell pellet were re-suspended in complete medium. The cells were seeded into a culture dish at an appropriate proportion, and then cultured in a 5% CO2 incubator at 37° C. The assay was carried out when the cells were in optimum condition and the confluence was reached 80%. Cells in the logarithmic growth phase were taken to centrifugate, and the culture supernatant was removed. The cells were resuspended in refresh complete medium and counted. The resuspended cells were seeded at 3000/well in a 96-well plate and incubated at 37° C., 5% CO2 incubator overnight. The compound was prepared as below: 1000× dilution tested compound solution to 40× test compound solution by adding 5 μL 1000× compound solution to 120 μL Medium (25 fold dilution). The solution was mixed by oscillation. 0.1% DMSO was used as the control.
The next day, the 96-well plate inoculated with cells was taken out from the incubator, and the culture supernatant was removed. Then fresh medium of 195 uL/well and 5 μL/well of 40× test compound solution as mentioned above were added into the 96 well plate, respectively. Finally, the plate was incubated for 7 days in a 37° C. 5% CO2 incubator. The medium containing compound was changed on the fourth day. After 7 days, 20 μL of CCK-8 was added to each well and shaken gently, then was cultured for 4 hours. The plate was shaken for 5 min after incubation, the absorbance values of 450 nm or 650 nm wavelengths were recorded respectively (OD=absorbance value of 450 nm−absorbance value of 650 nm) by using the multifunction readout instrument.
Data were analyzed by software GraphPad Prism 6.0. The inhibitory activity of compounds on cell proliferation was plotted using cell survival rate against the compound concentration as coordinates. Cell survival rate %=(ODcompound−ODbackground)/(ODDMSO−ODbackground)×100. The IC50 value was fitted by the s-shaped dose response curve equation: Y=100/(1+10{circumflex over ( )}(log C−log IC50)), and C was the compound concentration.
Table 2 summarizes the inhibitory effect data (IC50)) of the compounds on the proliferation of human breast cancer cells MDA-MB-436.
The compounds tested have good inhibitory effect on the proliferation of BRCA mutated human breast cancer cells MDA-MB-436.
Having now fully described this disclosure, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the disclosure or any embodiment thereof. All patents, patent applications and publications cited herein are fully incorporated by reference herein in their entirety.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202111000443.7 | Aug 2021 | CN | national |
| 202111447991.4 | Nov 2021 | CN | national |
| 202210274490.9 | Mar 2022 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/115259 | 8/26/2022 | WO |
