WO2022096990A1 - Novel hetrocyclic compounds - Google Patents

Novel hetrocyclic compounds Download PDF

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Publication number
WO2022096990A1
WO2022096990A1 PCT/IB2021/059952 IB2021059952W WO2022096990A1 WO 2022096990 A1 WO2022096990 A1 WO 2022096990A1 IB 2021059952 W IB2021059952 W IB 2021059952W WO 2022096990 A1 WO2022096990 A1 WO 2022096990A1
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WIPO (PCT)
Prior art keywords
methyl
indolin
diamine
pyrimidine
diaminopyrimidin
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PCT/IB2021/059952
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French (fr)
Inventor
Rajiv Sharma
Sanjay Kumar
Brijesh Kumar Srivastava
Gautam Patel
Sanjay GITE
Sandip Patel
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Cadila Healthcare Limited
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Publication of WO2022096990A1 publication Critical patent/WO2022096990A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to novel compounds of general formula (I), their tautomeric forms & deuterated forms, their pharmaceutically acceptable salts, prodrugs and their pharmaceutically acceptable salts, their polymorphs, pre-mixtures with excipients and polymers, and pharmaceutical compositions containing them.
  • the present invention also relates to a process for preparing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts and pharmaceutical compositions containing them.
  • Antibiotic resistance is a serious concern worldwide as it would result in strains against which currently available antibacterial agents will be ineffective.
  • bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens.
  • Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity.
  • the compounds of the present invention though being primarily effective against Gram-positive pathogens are also effective against certain Gram-negative pathogens.
  • Gram-positive pathogens for example Staphylococci, Enterococci, Streptococci and Mycobacteria
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRCNS methicillin-resistant coagulase negative staphylococci
  • CAP community acquired pathogens
  • DHFR antibacterials as a class of antibacterial agents are well known and are being used extensively throughout the world. They are potent inhibitors of Gram positive as well as Gram negative pathogens and may be administered orally or intravenously.
  • Weakly basic, non-classical DHFR inhibitor trimethoprim is a potent antibacterial against both MRSA and E-coli and is a first line agent with sulfamethoxazole against Gram-negative and Gram-positive infections.
  • UK patent specification No. 875,562 discloses inter alia 2,4-diamino-5-benzyl-pyrimidines, wherein the benzyl moiety is substituted by three C1.4 alkoxy groups. Trimethoprim, 2, 4- diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine, is specifically disclosed in U.K. patent No. 875,562.
  • EP811096312 disclosed following general structure.
  • Wipo patent application no. WO96/16046 disclosed Novel Benzyl Pyrimidines with following formula:
  • Chloromenylmethyl-pyrimidinediamines as anti-bacterial agents are disclosed in patent application no. WO2001/83476 with following general structure:
  • Diaminopyrimidines as P2X3 and P2X2/3 antagonists for treatment of respiratory and gastrointestinal diseases are disclosed in patent application no. US20070049609.
  • Wipo patent application no. WO2010/025906 disclosed hybrid antimicrobials compounds and their use, wherein, benzyl pyrimidines and 4-quinolones or 4H-4-oxo-quinolizines are reported as antibacterials.
  • Wipo patent application no. WO2013070620 disclosed diaminopyrimidines, pharmaceutical compositions containing them and their use as antibacterial with the following formula:
  • Wipo patent application no. WO2013070620 disclosed Propargyl -linked 2,4-diaminopyrimidine derivatives as inhibitors of Dihydrofolate reductase (DHFR) with the following formula:
  • EP0051879 A2 disclosed substituted pyrimidines, their synthesis and compositions containing them, their use in medicine and intermediates for making them. The following structure has been claimed. following markush structure are disclosed in Wipo patent application no. WO2017/029202
  • the present invention describes a group of novel compounds useful as antibacterial agents.
  • the novel compounds are defined by the general formula (I) below:
  • the compounds of the present invention are useful in the treatment of mammals, as preventives and therapeutic agents for infectious diseases.
  • the compounds of this invention have excellent antimicrobial action against human and veterinary pathogens including but not limited to methicillin-resistant staphylococci and streptococci, as well as anaerobic organisms including those of bactericides and clostridia species, treatment of complicated skin and skin-structure infections, acid-fast Mycobacterium tuberculosis and Mycobacterium avium with better efficacy, potency and minimum toxic effects.
  • the compounds of the present invention have no CYP liability, no hERG liability and exhibited improved pharmacokinetics and more bioavailability than the marketed DHFR antibacterials such as Trimethoprim & Iclaprim.
  • novel compounds of general formula (I) include novel compounds of general formula (I), their tautomeric forms, their enantiomers, their diastereomers, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, novel intermediates involved in their synthesis and pharmaceutical compositions containing them or their mixtures suitable in the treatment of infectious diseases and processes for their preparation.
  • compositions containing novel compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • novel compounds of the present invention as DHFR inhibitors, by administering a therapeutically effective and non-toxic amount of novel compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals.
  • novel compounds of the present invention are defined by the general formula (I) as shown below:
  • R 1 at each occurrence independently represents hydrogen, halo, haloalkyl, NO 2 , NH 2 , linear or branched, substituted or unsubstituted groups selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, groups;
  • R 2 at each occurrence independently represents hydrogen, hydroxy, NO 2 , NH 2 , CN, halo, substituted or unsubstituted groups selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl (C 2 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl,-O(C 1 -C 6 )alkyl, -O(C 2 -C 6 )alkenyl, -O(C 2 -C 6 )alkynyl, acyl groups or NR’R” groups, wherein R’R” may be independently represent hydrogen, substituted or unsubstituted groups selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl;
  • ‘X’ & ‘Y’ may be selected from -C-or -N-;
  • R 3 represents CH 2 , substituted or unsubstituted groups selected from (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl or CH-R’ where R’ is selected from hydrogen, halo, haloalkyl, NH 2 , NO 2 , substituted or unsubstituted groups selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, aryl, heteroaryl or heterocyclyl group;
  • R 4 at each occurrence independently represents hydrogen, halo, haloalkyl, NO 2 , NH 2 , CN, aryl.
  • R 4 may be absent; each of R 5 & R 6 at each occurrence independently represents hydrogen, halo, substituted or unsubstituted groups selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 - C 7 )cycloalkyl, aryl, heteroaryl or heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkylsulfonyl, heterocyclylalkylsulfonyl, dialkylsulfamoyl, 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4- dihydroquinoline-3 -carboxylic acid; 1-alkyl-mono halo-4-oxo-
  • R7 at each occurrence independently represents hydrogen, halo, -CN, -COOH, -NH 2 , -OH, - SO 3 H, -CHO, -COR 8 , -NHCOR 8 , CSR 8 , -NHCSR 8 , -SH, -SO 2 R 8 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, halohexafluorocarbinol; where R 8 may be selected from hydrogen, halogen, haloalkyl, substituted or unsubstituted group selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy;
  • Z, T, P, and Q may be selected from -C- or-N- m represents an integer from 0-2; n represents an integer from 0-3;
  • the substituents may be selected from the following radicals, alone or in combination with other radicals, such as, hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, amidino, guanidino, hydrazino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl,
  • R 1 is selected from hydrogen, NH 2 , substituted or unsubstituted group selected from (C 1 - C 6 )alkyl;
  • R 2 is selected from hydrogen, NH 2 , substituted or unsubstituted group selected from (C 1 - C 6 )alkyl;
  • R 3 is selected from CH 2 , substituted or unsubstituted groups selected from (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl;
  • alkyl used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing one to twelve carbons, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, iso-hexyl, heptyl, octyl and the like.
  • alkenyl used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing two to twelve carbons; such as vinyl, allyl, 2-butenyl, 3- butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2- heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and the like.
  • alkenyl includes dienes and trienes of straight and branched chains.
  • alkynyl used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing two to twelve carbons, such as ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.
  • alkynyl includes di- and tri- ynes.
  • cycloalkyl used herein, either alone or in combination with other radicals, denotes a radical containing three to seven carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • cycloalkenyl used herein, either alone or in combination with other radicals, denotes a radical containing three to seven carbons, such as cyclopropenyl, 1-cyclobutenyl, 2- cylobutenyl, 1 -cyclopentenyl, 2-cyclopentenyl, 3 -cyclopentenyl, 1 -cyclohexenyl, 2- cyclohexenyl, 3 -cyclohexenyl, 1 -cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, and the like.
  • alkoxy used herein, either alone or in combination with other radicals, denotes a radical alkyl, as defined above, attached directly to an oxygen atom, such as methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, pentyloxy, hexyloxy, and the like.
  • alkenoxy used herein, either alone or in combination with other radicals, denotes an alkenyl radical, as defined above, attached to an oxygen atom, such as vinyloxy, allyloxy, butenoxy, pentenoxy, hexenoxy, and the like.
  • cycloalkoxy used herein, either alone or in combination with other radicals, denotes a radical containing three to seven carbon atoms, as defined above, attached directly to an oxygen atom, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like.
  • halo or “halogen” used herein, either alone or in combination with other radicals, such as “haloalkyl”, “perhaloalkyl” etc refers to a fluoro, chloro, bromo or iodo group.
  • haloalkyl denotes an alkyl radical, as defined above, substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups.
  • haloalkoxy denotes a haloalkyl, as defined above, directly attached to an oxygen atom, such as fluoromethoxy, chloromethoxy, fluoroethoxy chloroethoxy groups, and the like.
  • perhaloalkoxy denotes a perhaloalkyl radical, as defined above, directly attached to an oxygen atom, trifluoromethoxy, trifluoroethoxy, and the like.
  • aryl or “aromatic” used herein, either alone or in combination with other radicals, denotes an aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, such as phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like.
  • aralkyl denotes an alkyl group, as defined above, attached to an aryl, such as benzyl, phenethyl, naphthylmethyl, and the like.
  • aryloxy denotes an aryl radical, as defined above, attached to an alkoxy group, as defined above, such as phenoxy, naphthyloxy and the like, which may be substituted.
  • alkoxy group as defined above
  • aralkoxy denotes an arylalkyl moiety, as defined above, attached directly to an oxygen atom, such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy, and the like, which may be substituted.
  • heterocyclyl or “heterocyclic” used herein, either alone or in combination with other radicals, denotes saturated, partially saturated and unsaturated ring-shaped radicals, the heteroatoms selected from nitrogen, sulfur and oxygen.
  • saturated heterocyclic radicals include but not limited to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, and the like;
  • partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, di
  • heteroaryl or “heteroaromatic” used herein, either alone or in combination with other radicals, denotes unsaturated 5 to 6 membered heterocyclic radicals containing one or more hetero atoms selected from O, N or S, attached to an aryl group, such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl, benzothienyl, indolinyl, indolyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, benzoxazolyl, benzothizaolyl,
  • heterocyclylalkyl used herein, either alone or in combination with other radicals, represents a heterocyclyl group, as defined above, substituted with an alkyl group of one to twelve carbons, such as pyrrolidinealkyl, piperidinealkyl, morpholinealkyl, thiomorpholinealkyl, oxazolinealkyl, and the like, which may be substituted.
  • heteroaryl used herein, either alone or in combination with other radicals, denotes a heteroaryl group, as defined above, attached to a straight or branched saturated carbon chain containing 1 to 6 carbons, such as (2- furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl- 1(-2-pyrimidyl)ethyl and the like.
  • heteroaryloxy denotes heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl groups respectively, as defined above, attached to an oxygen atom.
  • acyl used herein, either alone or in combination with other radicals, denotes a radical containing one to eight carbons such as formyl, acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted.
  • acyloxy used herein, either alone or in combination with other radicals, denotes a radical acyl, as defined above, directly attached to an oxygen atom, such as acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy and the like.
  • acylamino used herein, either alone or in combination with other radicals, denotes an acyl group as defined earlier, attached to amino group which may be substituted, such as CH 3 CONH, C 2 H 5 CONH, C 3 H 7 CONH, C 4 H 9 CONH, C 6 H 5 CONH and the like, which may be substituted.
  • mono-substituted amino used herein, either alone or in combination with other radicals, denotes an amino group, substituted with one group selected from (C 1 -C 6 )alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups.
  • monoalkylamino group include methylamine, ethylamine, n-propyl amine, n-butylamine, n-pentylamine and the like.
  • disubstituted amino used herein, either alone or in combination with other radicals, denotes an amino group, substituted with two radicals that may be same or different selected from (C 1 -C 6 )alkyl, substituted alkyl, aryl, substituted aryl, or arylalkyl groups, such as dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like.
  • arylamino used herein, either alone or in combination with other radicals, denotes an aryl group, as defined above, linked through amino having a free valence bond from the nitrogen atom, such as phenylamino, naphthylamino, N-methyl anilino and the like.
  • aralkylamino used herein, either alone or in combination with other radicals, denotes an arylalkyl group as defined above linked through amino having a free valence bond from the nitrogen atom e.g. benzylamino, phene thylamino, 3-phenylpropylamino, 1 -napthylmethylamino, 2-(1-napthyl)ethylamino and the like.
  • carboxylic acid used herein, alone or in combination with other radicals, denotes a - COOH group, and includes derivatives of carboxylic acid such as esters and amides.
  • ester used herein, alone or in combination with other radicals, denotes -COO- group, and includes carboxylic acid derivatives, where the ester moieties are alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may be substituted;
  • aminocarbonyl used herein, either alone or in combination with other radicals, with other terms such as ‘aminocarbonylalkyl”, “n-alkylaminocarbonyl”, “N-arylaminocarbonyl”, “N,N- dialkylaminocarbonyl”, “N-alkyl-N-arylaminocarbonyl”, “N-alkyl-N-hydroxyaminocarbonyl”, and “N-alkyl-N-hydroxyaminocarbonylalkyl”, substituted or unsubstituted.
  • N- alkylaminocabonyl and “N,N-dialkylaminocarbonyl” denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical and with two alkyl radicals, respectively. Preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to aminocarbonyl radical.
  • N-arylaminocarbonyl and “N-alkyl-N- arylaminocarbonyl” denote amiocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl, and one aryl radical.
  • aminocarbonylalkyl includes alkyl radicals substituted with aminocarbonyl radicals.
  • hydroxyalkyl used herein, either alone or in combination with other radicals, denotes an alkyl group, as defined above, substituted with one or more hydroxy radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like.
  • aminoalkyl used herein, alone or in combination with other radicals, denotes an amino (-NH 2 ) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyl.
  • alkylamino used herein, alone or in combination with other radicals, denotes an alkyl radical, as defined above, attached to an amino group, which may be substituted, such as mono- and di-substituted alkylamino.
  • alkoxyalkyl used herein, alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like.
  • aryloxyalkyl used herein, alone or in combination with other radicals, includes phenoxymethyl, napthyloxymethyl, and the like.
  • aralkoxyalkyl used herein, alone or in combination with other radicals, includes C 6 H 5 CH 2 OCH 2 , C 6 H 5 CH 2 OCH 2 CH 2 , and the like.
  • alkylthio used herein, either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group of one to twelve carbon atoms, as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, such as methylthio, ethylthio, propylthio, butylthio, pentylthio and the like.
  • Examples of cyclic alkylthio are cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be substituted.
  • thioalkyl used herein, either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula -SR’, where R’ represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methyl thiomethyl, phenylthiomethyl and the like, which may be substituted.
  • arylthio used herein, either alone or in combination with other radicals, denotes an aryl group, as defined above, linked through a divalent sulfur atom, having a free valence bond from the sulfur atom such as phenylthio, napthylthio and the like.
  • alkoxycarbonylamino used herein, alone or in combination with other radicals, denotes an alkoxycarbonyl group, as defined above, attached to an amino group, such as methoxycarbonylamino, ethoxycarbonylamino, and the like.
  • aryloxycarbonylamino used herein, alone or in combination with other radicals, denotes an aryloxycarbonyl group, as defined above, attached to the an amino group, such as C 6 H 5 OCONH, C 6 H 5 OCONCH 3 , C 6 H 5 OCONC 2 H 5 , C 6 H 4 (CH 3 O)CONH, C 6 H 4 (OCH 3 )OCONH, and the like.
  • aralkoxycarbonylamino used herein, alone or in combination with other radicals, denotes an aralkoxycarbonyl group, as defined above, attached to an amino group C 6 H 5 CH 2 OCONH, C 6 H 5 CH 2 CH 2 CH 2 OCONH, C 6 H 5 CH 2 OCONHCH 3 , C 6 H 5 CH 2 OCONC 2 H 5 ,
  • aminocarbonylamino denotes a carbonylamino (-CONH 2 ) group, attached to amino(NH 2 ), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above.
  • alkylamidino denotes an alkyl radical, as discussed above, attached to an amidino group.
  • hydrazino used herein, either alone or in combination with other radicals, denotes - NHNH-, suitably substituted with other radicals, such as alkyl hydrazino, where an alkyl group, as defined above is attached to a hydrazino group.
  • alkoxyamino used herein, alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an amino group.
  • hydroxyamino used herein, alone or in combination with other radicals, denotes -NHOH moiety, and may be substituted.
  • sulfenyl or “sulfenyl and its derivatives” used herein, alone or in combination with other radicals, denotes a bivalent group, -SO- or RSO, where R is substituted or unsubstituted alkyl, aryl, heteroaryl, heterocyclyl, and the like.
  • alkylsulfonyl denotes divalent radical -SO 2 -, or RSO 2 -, where R is substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, heterocyclyl, and the like.
  • alkylsulfonyl denotes alkyl radicals, as defined above, attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.
  • arylsulfonyl used herein, either alone or in combination with other radicals, denotes aryl radicals, as defined above, attached to a sulfonyl radical, such as phenylsulfonyl and the like.
  • sulfonic acid or its derivatives denotes -SO 3 H group and its derivatives such as sulfonylamino(SO 2 NH 2 ); N- alkylaminosulfonyl and N,N-dialkylaminosulfonyl radicals where the sulfonylamino group is substituted with one and two alkyl groups respectively, such as N-methylaminosulfonyl, N- ethylaminosulfonyl, N,N-dimethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl and the like; N-arylaminosulfonyl and N-alkyl-N-arylaminosulfonyl groups where the sulfonylamino group is substituted with one aryl radical, or one alkyl and one aryl radical; -SO 3 R, wherein ‘R’ represents alky
  • Prodrugs of the compounds and their pharmaceutically acceptable salts may be formed by appropriately converting their functional groups such as -COOH, NH 2 etc. into corresponding esters, amides etc. but not limited to this.
  • Preferred salts may be selected from hydrochloride, hydrobromide, tosylate, besylate, sulphate, methanesulphonate, tartrate, citrate, lactate, acetate, oxalate, glutarate, ethanesulphonate, maleate, camphor sulfonate, glycolate, succinate, phosphate, nphthalene-1,5-disulfonate, naphthalene-2-sulphonate , benzoate, ascorbate, mandelate, malonate, 1-hydroxy-2-naphthoate, sodium, potassium, calcium, hexanoate etc but not limited to this.
  • EDAC.HC1 N-(3-Dimethyl aminopropyl)-N’ -ethyl carbodiimide hydrochloride
  • DIPEA Disopropyl ethyl amine
  • HPLC purity was determined by using Agilent 1100 instrument.
  • Wave length UV at 220 nm.
  • Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
  • Preferred compounds according to the present invention include but are not limited to:
  • the compounds of formula (I) can be synthesized using the following method, together with conventional techniques known to those skilled in the art, or variations thereon as appreciated by those skilled in the art. Referred methods include, but are not limited to those described below.
  • any reactive group in the substrate molecule may be protected, according to conventional chemical practice.
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the compounds of the present invention may optionally be converted to their pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (I) with suitable acids in suitable solvents by processes known in the art.
  • triphenylphosphine (0.085 g, 0.322 mmol), diacetoxy palladium (0.024 g, 0.107 mmol), ethanol (2.4 mL) and water (1.5 mL).
  • the reaction mixture was stirred for 18 h at 20-30° C under atmosphere of nitrogen. Progress of reaction was monitored by TLC.
  • the reaction mixture was poured in to water and extracted with EtOAc. The organic layer was separated, washed with saturated sodium bicarbonate followed by water, dried over sodium sulfate.
  • reaction mixture was evaporated on a rotatory evaporator under reduced pressure to afford 4-(indoline-5-yl)-1- naphthoic acid-2, 2, 2-trifluoroacetate as brown oil.(0.172 g, 0.426 mmol, 100 % yield) which was directly used for next step without further analysis and purification.
  • Example 16 4-(1-((
  • Example 60 4-(1-((2,4-di
  • Example 73 1-((2,4-diaminopyrimidin-5-yl)methyl)-4, 5, 6-trimethoxyindoline-2, 3-dione 1 H NMR (DMSO-d 6 , 400 MHz) ⁇ : 7.89 (s, 1H), 6.63 (s, 1H), 6.30 (s, 2H, NH 2 ), 5.98 (s, 2H, NH 2 ), 4.60 (s, 2H), 4.03 (s, 3H, OCH 3 ), 3.93 (s, 3H, OCH 3 ), 3.63 (s, 3H, OCH 3 ).
  • Example 152 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-8-methyl-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid dihydrochloride
  • Example 154 8-chloro-1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid dihydrochloride
  • Example 157 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-8-methoxy-4-oxo-1,4- dihydroquinoline-3-carboxylic acid dihydrochloride 1 H NMR (DMSO-d 6 , 400 MHz) ⁇ : 12.36 (s (br) , 1H, -COOH), 8.82 (s, 1H), 8.42 (s, 1H), 7.72-
  • Example 170 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-8-methoxy-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid bis 2,2,2-trifluoroacetic acid
  • Example 176 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-5,6,8-trifluoro-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid
  • 1 HNMR (DMSO-d 6 ) 14.69 (s, 1H), 8.73 (s, 1H), 7.72-7.64 (m, 1H), 7.26-7.2 (m, 2H), 6.83-6.36 (m, 5H), 4.15-4.06 (m, 1H), 4.0 (s, 2H), 3.07-2.97(m, 2H), 1.28-1.08(m, 4H).
  • Example 184 2,2',2''-nitrilotris(ethan 1--1-ol) cyclopropyl-7-(1-((2,4-diaminopyrimidin-5- yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and optionally one or more pharmaceutically acceptable excipients.
  • the novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • the compounds of Formula (I) are useful in the treatment of microbial infections in mammals, by oral, i.v, topical or parenteral administration.
  • the present invention includes a method for the treatment of at least one of cell proliferative diseases, autoimmune disease, inflammatory disease or bacterial, fungal or parasitic infection, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound or salt of the novel compound of formula (I).
  • the compounds of formula (I) may be administered, for example, orally, topically, parenterally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • the pharmaceutical composition is provided by employing conventional techniques.
  • the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.
  • the quantity of active component that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5 % - 90 % by weight of the composition.
  • the compound of formula (I) may be used alone or in any combination with one or more therapeutic agents such as Fluoroquinolones, Oxazolidinones, Aminoglycosides, b- Lactam Antibiotics and b-Lactamase inhibitors, Hybrid antibiotic, Vitamins or pharmaceutically acceptable salts thereof.
  • therapeutic agents such as Fluoroquinolones, Oxazolidinones, Aminoglycosides, b- Lactam Antibiotics and b-Lactamase inhibitors, Hybrid antibiotic, Vitamins or pharmaceutically acceptable salts thereof.
  • DHFR inhibition assay was performed by monitoring the rate of NADPH oxidation. Assay was carried out in a buffer containing 20 mM Tris HC1, 200 mM NaCl and 0.1 mM EDTA, pH 7.2. DHFR (0.8 mg/mL) was pre-incubated with NADPH (0.02 mM) and the test compounds for 10 min at 25 °C before the reaction was initiated by the addition of DHF (0.02 mM). The fluorescence intensity was measured in kinetic mode using Tecan M1000 pro at an excitation wavelength of 340 nm and emission wavelength of 440 nm. Enzyme inhibition was calculated from the amount of NADPH consumed in the reaction. The IC50 values were calculated using Graph pad prism.
  • MIC was determined by using reference broth microdilution method as described by the Clinical and Laboratory Standards Institute (CLSI). Briefly, bacterial cells ⁇ Staphylococcus aureus ATCC 29213 (Gram -i-ve), Escherichia coli ATCC 25922 (Gram -ve)) were cultured on Mueller Hinton agar plates. Stock solutions of NCEs and positive controls were prepared in DMSO or water as per their solubility. Further dilutions of NCEs were prepared in cation adjusted Mueller Hinton broth (CAMHB). NCEs were serially double diluted in 96 well plates. Inoculum densities were maintained at 5 X 10 4 cells per well. Plates were incubated at 37 o C for 20-24 h.
  • CLSI Clinical and Laboratory Standards Institute
  • Pharmacokinetics of the test compound 1 and trimethoprim was studied (Table 3) via per-oral and intravenous bolus routes of administration in BALB/c mice of 7 to 12 weeks of age. Animals were fasted for 12 h and food was supplied after 4.0 h of administration of the test compound. There was free access to water throughout the study. A homogenous suspension of the test substance was prepared in 1% Tween 80, 0.5 % w/v CMC in purified water and a per-oral dose of 3 mg/kg was administered. After the administration of the test compounds, blood samples were withdrawn at various time intervals through retro-orbital plexus and collected into heparinized micro centrifuge tubes. Plasma was separated by centrifugation at 4000 rpm for 15 min at ambient temperature and analyzed immediately. Remaining samples were stored at -70 °C until analyzed.
  • Samples were prepared by protein precipitation method: A 30 ⁇ L aliquot of plasma sample was spiked with 6 ⁇ L of internal standard (Alprazolam) and extracted by addition of 0.5 mL of acetonitrile in 2 mL micro centrifuge tubes. Samples were vortex-mixed for a minute and centrifuged at 10000 rpm for 5 min. The supernatant was transferred to HPLC vials for analysis.
  • internal standard Alpharazolam
  • the extracted samples were analyzed on LC-MS/MS system consisting of Shimadzu LC-20-AD, Prominence system equipped with a binary pump, a vacuum degasser and an auto sampler (Shimadzu Corporation, Kyoto, Japan) and an API 5500 ® mass spectrometer (Applied Biosystems Sciex, Toronto, Canada). Analyst 1.6.1 software was used for data acquisition and analysis (Applied Biosystems Sciex, Toronto, Canada).
  • Chromatographic separation was achieved using a mobile phase (A) 5 mM Ammonium formate +0.1%formic acid in water and (B) methanol: acetonitrile (20:80 % v/v); flowing at a flow rate of 1.0 mL/min (50% split to waste) through a ACE C18 50*4.6mm, 5p. Quantification was based on a series of calibrators ranging from 1 to 5000 ng/mL, prepared by adding test compound to drug free mice plasma. Quality control samples were analyzed in parallel to verify that the system performs in control.
  • Pharmacokinetic parameters namely; maximum plasma concentration (C max ), time point of maximum plasma concentration (t max ), area under the plasma concentration time curve from 0 h to infinity (AUCQ-L) and half-life of drug elimination during the terminal phase (t 1/2 ) were calculated from plasma concentration versus time data, by standard non-compartmental methods, using the Phoenix 64 (Certara) software.
  • mice Male ICR mice, 6-8 weeks of age were used. Animals were allowed access to feed and water ad libitum. Before start of experimental infection, mice were rendered neutropenic by injecting cyclophosphamide intraperitoneally on day -4 (150 mg/kg) and day -1 (100 mg/kg). On day 0, all neutropenic mice were infected with 0.5million per 0.05ml of MRSA (ATCC 33591), by intramuscular route in thigh tissue. After 2 hour of infection, animals were treated with vehicle and compound of example no. 200 (6.25, 12.5, 25, 50, 100 mg/kg, p. o) every six hours.
  • MRSA MRSA
  • mice were humanely sacrificed, thigh tissue was collected aseptically in tube containing 5 ml sterile PBS and homogenized. A 10-fold serial dilution series was prepared from tissue homogenates in PBS and two 20 pl aliquots per dilution were plated onto Mueller Hinton Agar plates. The plates were incubated at 35 ⁇ 2°C for approximately 16 to 18 hours and number of CFU was enumerated. The CFU count per thigh tissue was calculated. The ED50 is found to be 33 mg/kg, po, and qid, for compound of example 200 in this efficacy thigh infection model.
  • CYP inhibition and hERG inhibition The compounds of the present invention do not bear CYP and hERG liability, and are safe.

Abstract

The present invention relates to novel compounds of general formula (I), their tautomeric forms & deuterated forms, their pharmaceutically acceptable salts, prodrugs and their pharmaceutically acceptable salts, their polymorphs, pre-mixtures with excipients and polymers, and pharmaceutical compositions containing them. The present invention also relates to a process for preparing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts and pharmaceutical compositions containing them.

Description

NOVEL HETROCYCLIC COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to novel compounds of general formula (I), their tautomeric forms & deuterated forms, their pharmaceutically acceptable salts, prodrugs and their pharmaceutically acceptable salts, their polymorphs, pre-mixtures with excipients and polymers, and pharmaceutical compositions containing them. The present invention also relates to a process for preparing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts and pharmaceutical compositions containing them.
Figure imgf000002_0001
BACKGROUND OF THE INVENTION
Antibiotic resistance is a serious concern worldwide as it would result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention though being primarily effective against Gram-positive pathogens are also effective against certain Gram-negative pathogens.
Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and Mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium, community acquired pathogens (CAP), and so on.
Metabolic enzyme Dihydrofolate reductase (DHFR) has been a successfully and widely targeted protein for oncology and infectious disease indications, delivering efficacious drugs such as methotrexate and trimethoprim. DHFR antibacterials as a class of antibacterial agents are well known and are being used extensively throughout the world. They are potent inhibitors of Gram positive as well as Gram negative pathogens and may be administered orally or intravenously. Weakly basic, non-classical DHFR inhibitor trimethoprim is a potent antibacterial against both MRSA and E-coli and is a first line agent with sulfamethoxazole against Gram-negative and Gram-positive infections.
Propargyl-linked DHFR antibacterials are disclosed in Wipo patent application no. WO20 17/ 120575.
Structure aided design of chimeric antibiotics are disclosed in Bioorg. Med. Chem. Lett. 2012, 22, 2428-2433. Novel Dihydrofolate Reductase Inhibitors, Structure-Based versus Diversity- Based Library Design and High-Throughput Synthesis and Screening are disclosed In J. Med. Chem. 2003, 46, 2304-2312, wherein following general structures are disclosed as DHFR antibacterials.
Figure imgf000003_0001
2,4-diamino-5-(substituted) pyrimidines, useful as antimicrobials are disclosed in US patent no.
US4590271, with following general structure:
Figure imgf000004_0001
UK patent specification No. 875,562 discloses inter alia 2,4-diamino-5-benzyl-pyrimidines, wherein the benzyl moiety is substituted by three C1.4 alkoxy groups. Trimethoprim, 2, 4- diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine, is specifically disclosed in U.K. patent No. 875,562.
European patent application EP811096312 disclosed following general structure.
Figure imgf000004_0002
Wipo patent application no. WO96/16046 disclosed Novel Benzyl Pyrimidines with following formula:
Figure imgf000004_0003
Inhibitors of Dihydrofolate reductase are disclosed in US patent no. US4258045. Preparation of insecticidal 5-substituted-2,4-diaminopyrimidine derivatives are reported in US patent no. US5521192.
Chloromenylmethyl-pyrimidinediamines as anti-bacterial agents are disclosed in patent application no. WO2001/83476 with following general structure:
Figure imgf000005_0001
Substituted 5-benzyl-2,4-diaminopyrimidines are disclosed in WIPO patent application no.
WO2001032633 with following structures:
Figure imgf000005_0002
Preparation of Diaminopyrimidines as P2X3 and P2X2/3 antagonists for treatment of respiratory and gastrointestinal diseases are disclosed in patent application no. US20070049609.
Wipo patent application no. WO2010/025906 disclosed hybrid antimicrobials compounds and their use, wherein, benzyl pyrimidines and 4-quinolones or 4H-4-oxo-quinolizines are reported as antibacterials.
Wipo patent application no. WO2013070620 disclosed diaminopyrimidines, pharmaceutical compositions containing them and their use as antibacterial with the following formula:
Figure imgf000005_0003
Wipo patent application no. WO2013070620 disclosed Propargyl -linked 2,4-diaminopyrimidine derivatives as inhibitors of Dihydrofolate reductase (DHFR) with the following formula:
Figure imgf000006_0001
European patent application no. EP0051879 A2 disclosed substituted pyrimidines, their synthesis and compositions containing them, their use in medicine and intermediates for making them. The following structure has been claimed.
Figure imgf000006_0002
following markush structure are disclosed in Wipo patent application no. WO2017/029202
Figure imgf000006_0003
Zwitterionic Propargyl-linked antifolates useful for treating bacterial infections are disclosed in patent application no. WO2017/120575 with the following formula:
Figure imgf000006_0004
Synthesis and antibacterial activity evaluation of aminoguanidine or dihydrotriazine derivatives is reported by Jilin Medical University, China in Ind. J. Biochem. Biophy.2019, 56, 301-308.
Antibacterial, antibiofilm and molecular modeling study of some antitumor thiazole based chaicones as a new class of DHFR inhibitors are reported in Microbial Pathogenesis, 2019, 136, 103674 by College of Pharmacy, Taibah University, Saudi Arabia, wherein some synthesized antitumor derivatives of thiazole based chaicones including thiazolo [2,3-b]quinazoline and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine analogs were subjected to be tested against standard microbial strains. Some compounds showed higher activity against both Gram-positive and Gram- negative, bacteria with MIC of 1.0, 1.0, 2.0, 2.0 and 4.0 μg/mL against S. aureus, B. subtilis, M. luteus, E. coli and P. aeuroginosa respectively, which is better than ampicillin and very relative to ciprofloxacin. Compound shows a good anti-biofilm activity against the Gram positive bacteria. Molecular docking studies of synthesized compounds against DHFR enzyme were also carried out. These compounds could act as antitumor or antibacterial via DHFR inhibition. . The results highlight studied thiazole based chaicones as efficient leads for designing new future antibacterial drug candidates
Aminopyrimidine compound for antibacterial product and dihydrofolate reductase inhibitor medicinal preparation is reported by ZONK Drug R&D Limited, Peop. Rep. China in patent CN109988156.
Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection is reported by Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, USA in Bioorg. Med. Chem. Lett., 2019, 29, 1874-1880
Synthesis of novel dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties as potential antibacterial agent is reported in Bioorg. Med. Chem. Lett., 2019, 29, 1079-1084 by Department of Pharmacy, Jilin Medical University, China.
However, due to increase in antibacterial resistance and also otherwise there is a continuing need for discovering compounds which are more effective against resistant bacteria, have improved intestinal absorption, metabolic stability, and exhibit less toxicity. SUMMARY OF THE INVENTION
The present invention describes a group of novel compounds useful as antibacterial agents. The novel compounds are defined by the general formula (I) below:
Figure imgf000008_0001
The compounds of the present invention are useful in the treatment of mammals, as preventives and therapeutic agents for infectious diseases. The compounds of this invention have excellent antimicrobial action against human and veterinary pathogens including but not limited to methicillin-resistant staphylococci and streptococci, as well as anaerobic organisms including those of bactericides and clostridia species, treatment of complicated skin and skin-structure infections, acid-fast Mycobacterium tuberculosis and Mycobacterium avium with better efficacy, potency and minimum toxic effects. The compounds of the present invention have no CYP liability, no hERG liability and exhibited improved pharmacokinetics and more bioavailability than the marketed DHFR antibacterials such as Trimethoprim & Iclaprim.
EMBODIMENT(S) OF THE INVENTION
Among many embodiments of the present invention are included novel compounds of general formula (I), their tautomeric forms, their enantiomers, their diastereomers, their stereoisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, novel intermediates involved in their synthesis and pharmaceutical compositions containing them or their mixtures suitable in the treatment of infectious diseases and processes for their preparation.
In a further embodiment of the present invention is provided pharmaceutical compositions containing novel compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
In a still further embodiment is provided the use of novel compounds of the present invention as DHFR inhibitors, by administering a therapeutically effective and non-toxic amount of novel compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals.
In a still further embodiment is provided a process for preparing the novel compounds of the present invention.
DETAIL DESCRIPTION OF THE INVENTION
The novel compounds of the present invention are defined by the general formula (I) as shown below:
Wherein
Figure imgf000009_0001
R1 at each occurrence independently represents hydrogen, halo, haloalkyl, NO2, NH2, linear or branched, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)cycloalkyl, groups;
R2 at each occurrence independently represents hydrogen, hydroxy, NO2, NH2, CN, halo, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl (C2-C6)alkynyl, (C3-C7)cycloalkyl,-O(C1-C6)alkyl, -O(C2-C6)alkenyl, -O(C2-C6)alkynyl, acyl groups or NR’R” groups, wherein R’R” may be independently represent hydrogen, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl;
‘X’ & ‘Y’ may be selected from -C-or -N-;
R3 represents CH2, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl or CH-R’ where R’ is selected from hydrogen, halo, haloalkyl, NH2, NO2, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)cycloalkyl, aryl, heteroaryl or heterocyclyl group;
R4 at each occurrence independently represents hydrogen, halo, haloalkyl, NO2, NH2, CN, aryl. In an embodiment R4 may be absent; each of R5 & R6 at each occurrence independently represents hydrogen, halo, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C7)cycloalkyl, aryl, heteroaryl or heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkylsulfonyl, heterocyclylalkylsulfonyl, dialkylsulfamoyl, 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4- dihydroquinoline-3 -carboxylic acid; 1-alkyl-mono halo-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylic acid; 1-aryl- mono halo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 1- alkyl-dihalo-4-oxo-1,4- dihydroquinoline-3 -carboxylic acid; ethyl 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3- carboxylate; alkyl 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate; aryl 1- cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate; cycloalkyl 1 -cyclopropyl-6- fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, substituted/unsubstituted 1- cycloprop yl-6- fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate, substituted/unsubstituted-4-oxo- 1 ,4- dihydroquinoline-3 -carboxylate;
R7 at each occurrence independently represents hydrogen, halo, -CN, -COOH, -NH2, -OH, - SO3H, -CHO, -COR8, -NHCOR8, CSR8, -NHCSR8, -SH, -SO2R8, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkynyl, halohexafluorocarbinol; where R8 may be selected from hydrogen, halogen, haloalkyl, substituted or unsubstituted group selected from (C1-C6)alkyl, (C1-C6)alkoxy;
Z, T, P, and Q may be selected from -C- or-N- m represents an integer from 0-2; n represents an integer from 0-3;
When any of the substituents are further substituted, the substituents may be selected from the following radicals, alone or in combination with other radicals, such as, hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, amidino, guanidino, hydrazino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, arylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives.
In a preferred embodiment,
R1 is selected from hydrogen, NH2, substituted or unsubstituted group selected from (C1- C6)alkyl;
R2 is selected from hydrogen, NH2, substituted or unsubstituted group selected from (C1- C6)alkyl;
R3 is selected from CH2, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl;
The term “alkyl” used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing one to twelve carbons, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, iso-hexyl, heptyl, octyl and the like.
The term “alkenyl” used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing two to twelve carbons; such as vinyl, allyl, 2-butenyl, 3- butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2- heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and the like. The term “alkenyl” includes dienes and trienes of straight and branched chains.
The term “alkynyl” used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing two to twelve carbons, such as ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like. The term “alkynyl” includes di- and tri- ynes.
The term “cycloalkyl” used herein, either alone or in combination with other radicals, denotes a radical containing three to seven carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term “cycloalkenyl” used herein, either alone or in combination with other radicals, denotes a radical containing three to seven carbons, such as cyclopropenyl, 1-cyclobutenyl, 2- cylobutenyl, 1 -cyclopentenyl, 2-cyclopentenyl, 3 -cyclopentenyl, 1 -cyclohexenyl, 2- cyclohexenyl, 3 -cyclohexenyl, 1 -cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, and the like.
The term “alkoxy” used herein, either alone or in combination with other radicals, denotes a radical alkyl, as defined above, attached directly to an oxygen atom, such as methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, pentyloxy, hexyloxy, and the like.
The term “alkenoxy” used herein, either alone or in combination with other radicals, denotes an alkenyl radical, as defined above, attached to an oxygen atom, such as vinyloxy, allyloxy, butenoxy, pentenoxy, hexenoxy, and the like.
The term “cycloalkoxy” used herein, either alone or in combination with other radicals, denotes a radical containing three to seven carbon atoms, as defined above, attached directly to an oxygen atom, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like.
The term “halo” or “halogen” used herein, either alone or in combination with other radicals, such as “haloalkyl”, “perhaloalkyl” etc refers to a fluoro, chloro, bromo or iodo group. The term “haloalkyl” denotes an alkyl radical, as defined above, substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups. The term “haloalkoxy” denotes a haloalkyl, as defined above, directly attached to an oxygen atom, such as fluoromethoxy, chloromethoxy, fluoroethoxy chloroethoxy groups, and the like. The term “perhaloalkoxy” denotes a perhaloalkyl radical, as defined above, directly attached to an oxygen atom, trifluoromethoxy, trifluoroethoxy, and the like.
The term “aryl” or “aromatic” used herein, either alone or in combination with other radicals, denotes an aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, such as phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like. The term ‘aralkyl” denotes an alkyl group, as defined above, attached to an aryl, such as benzyl, phenethyl, naphthylmethyl, and the like. The term “aryloxy” denotes an aryl radical, as defined above, attached to an alkoxy group, as defined above, such as phenoxy, naphthyloxy and the like, which may be substituted. The term “aralkoxy” denotes an arylalkyl moiety, as defined above, attached directly to an oxygen atom, such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy, and the like, which may be substituted.
The term “heterocyclyl” or “heterocyclic” used herein, either alone or in combination with other radicals, denotes saturated, partially saturated and unsaturated ring-shaped radicals, the heteroatoms selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include but not limited to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, and the like; examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, and the like.
The term “heteroaryl” or “heteroaromatic” used herein, either alone or in combination with other radicals, denotes unsaturated 5 to 6 membered heterocyclic radicals containing one or more hetero atoms selected from O, N or S, attached to an aryl group, such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl, benzothienyl, indolinyl, indolyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, benzoxazolyl, benzothizaolyl, benzimidazolyl, and the like.
The term “heterocyclylalkyl” used herein, either alone or in combination with other radicals, represents a heterocyclyl group, as defined above, substituted with an alkyl group of one to twelve carbons, such as pyrrolidinealkyl, piperidinealkyl, morpholinealkyl, thiomorpholinealkyl, oxazolinealkyl, and the like, which may be substituted. The term “heteroaralkyl” used herein, either alone or in combination with other radicals, denotes a heteroaryl group, as defined above, attached to a straight or branched saturated carbon chain containing 1 to 6 carbons, such as (2- furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl- 1(-2-pyrimidyl)ethyl and the like. The terms “heteroaryloxy”, “heteroaralkoxy”, “heterocycloxy”, “heterocylylalkoxy” denotes heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl groups respectively, as defined above, attached to an oxygen atom.
The term “acyl” used herein, either alone or in combination with other radicals, denotes a radical containing one to eight carbons such as formyl, acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted. The term “acyloxy” used herein, either alone or in combination with other radicals, denotes a radical acyl, as defined above, directly attached to an oxygen atom, such as acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy and the like.
The term “acylamino” used herein, either alone or in combination with other radicals, denotes an acyl group as defined earlier, attached to amino group which may be substituted, such as CH3CONH, C2H5CONH, C3H7CONH, C4H9CONH, C6H5CONH and the like, which may be substituted.
The term “mono-substituted amino” used herein, either alone or in combination with other radicals, denotes an amino group, substituted with one group selected from (C1-C6)alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups. Examples of monoalkylamino group include methylamine, ethylamine, n-propyl amine, n-butylamine, n-pentylamine and the like.
The term ‘disubstituted amino” used herein, either alone or in combination with other radicals, denotes an amino group, substituted with two radicals that may be same or different selected from (C1-C6)alkyl, substituted alkyl, aryl, substituted aryl, or arylalkyl groups, such as dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like.
The term “arylamino” used herein, either alone or in combination with other radicals, denotes an aryl group, as defined above, linked through amino having a free valence bond from the nitrogen atom, such as phenylamino, naphthylamino, N-methyl anilino and the like.
The term “aralkylamino” used herein, either alone or in combination with other radicals, denotes an arylalkyl group as defined above linked through amino having a free valence bond from the nitrogen atom e.g. benzylamino, phene thylamino, 3-phenylpropylamino, 1 -napthylmethylamino, 2-(1-napthyl)ethylamino and the like.
The term “oxo” or “carbonyl” used herein, either alone (-C=O-) or in combination with other radicals, such as “alkylcarbonyl”, denotes a carbonyl radical (-C=O-) substituted with an alkyl radical such as acyl or alkanoyl, as described above.
The term “carboxylic acid” used herein, alone or in combination with other radicals, denotes a - COOH group, and includes derivatives of carboxylic acid such as esters and amides. The term “ester” used herein, alone or in combination with other radicals, denotes -COO- group, and includes carboxylic acid derivatives, where the ester moieties are alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may be substituted; heterocyclyloxycarbonyl, where the heterocyclic group, as defined earlier, which may be substituted.
The term “amide” used herein, alone or in combination with other radicals, represents an aminocarbonyl radical (H2N-C=O-), wherein the amino group is mono- or di-substituted or unsubstituted, such as methylamide, dimethylamide, ethylamide, diethylamide, and the like. The term “aminocarbonyl” used herein, either alone or in combination with other radicals, with other terms such as ‘aminocarbonylalkyl”, “n-alkylaminocarbonyl”, “N-arylaminocarbonyl”, “N,N- dialkylaminocarbonyl”, “N-alkyl-N-arylaminocarbonyl”, “N-alkyl-N-hydroxyaminocarbonyl”, and “N-alkyl-N-hydroxyaminocarbonylalkyl”, substituted or unsubstituted. The terms “N- alkylaminocabonyl” and “N,N-dialkylaminocarbonyl” denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical and with two alkyl radicals, respectively. Preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to aminocarbonyl radical. The terms “N-arylaminocarbonyl” and “N-alkyl-N- arylaminocarbonyl” denote amiocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl, and one aryl radical. The term “aminocarbonylalkyl” includes alkyl radicals substituted with aminocarbonyl radicals.
The term “hydroxyalkyl” used herein, either alone or in combination with other radicals, denotes an alkyl group, as defined above, substituted with one or more hydroxy radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like.
The term “aminoalkyl” used herein, alone or in combination with other radicals, denotes an amino (-NH2) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyl. The term “alkylamino” used herein, alone or in combination with other radicals, denotes an alkyl radical, as defined above, attached to an amino group, which may be substituted, such as mono- and di-substituted alkylamino.
The term “alkoxyalkyl” used herein, alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like. The term “aryloxyalkyl” used herein, alone or in combination with other radicals, includes phenoxymethyl, napthyloxymethyl, and the like. The term “aralkoxyalkyl” used herein, alone or in combination with other radicals, includes C6H5CH2OCH2, C6H5CH2OCH2CH2, and the like.
The term “alkylthio” used herein, either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group of one to twelve carbon atoms, as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, such as methylthio, ethylthio, propylthio, butylthio, pentylthio and the like. Examples of cyclic alkylthio are cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be substituted.
The term “thioalkyl” used herein, either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula -SR’, where R’ represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methyl thiomethyl, phenylthiomethyl and the like, which may be substituted.
The term “arylthio’ used herein, either alone or in combination with other radicals, denotes an aryl group, as defined above, linked through a divalent sulfur atom, having a free valence bond from the sulfur atom such as phenylthio, napthylthio and the like.
The term “alkoxycarbonylamino” used herein, alone or in combination with other radicals, denotes an alkoxycarbonyl group, as defined above, attached to an amino group, such as methoxycarbonylamino, ethoxycarbonylamino, and the like. The term “aryloxycarbonylamino” used herein, alone or in combination with other radicals, denotes an aryloxycarbonyl group, as defined above, attached to the an amino group, such as C6H5OCONH, C6H5OCONCH3, C6H5OCONC2H5, C6H4(CH3O)CONH, C6H4(OCH3)OCONH, and the like. The term “aralkoxycarbonylamino” used herein, alone or in combination with other radicals, denotes an aralkoxycarbonyl group, as defined above, attached to an amino group C6H5CH2OCONH, C6H5CH2CH2CH2OCONH, C6H5CH2OCONHCH3, C6H5CH2OCONC2H5,
C6H4(CH3)CH2OCONH, C6H4(OCH3)CH2OCONH, and the like.
The term “aminocarbonylamino”, “alkylaminocarbonylamino”, “dialkylaminocarbonylamino” used herein, alone or in combination with other radicals, denotes a carbonylamino (-CONH2) group, attached to amino(NH2), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above. The term “amidino” used herein, either alone or in combination with other radicals, denotes a - C(=NH)-NH2 radical. The term “alkylamidino” denotes an alkyl radical, as discussed above, attached to an amidino group.
The term “guanidino” used herein, either alone or in combination with other radicals, denotes HN=C(NH2)NH-, suitably substituted with other radicals, such as alkylguanidino, dialkylguanidino, where the alkyl group, as defined above is attached to a guanidino group, such as methylguanidino, ethylguanidino, dimethylguanidino, and the like.
The tem “hydrazino” used herein, either alone or in combination with other radicals, denotes - NHNH-, suitably substituted with other radicals, such as alkyl hydrazino, where an alkyl group, as defined above is attached to a hydrazino group.
The term “alkoxyamino” used herein, alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an amino group. The term “hydroxyamino” used herein, alone or in combination with other radicals, denotes -NHOH moiety, and may be substituted.
The term “sulfenyl” or “sulfenyl and its derivatives” used herein, alone or in combination with other radicals, denotes a bivalent group, -SO- or RSO, where R is substituted or unsubstituted alkyl, aryl, heteroaryl, heterocyclyl, and the like.
The term “sulfonyl” or “sulfones and its derivatives” used herein, either alone or in combination with other radicals, with other terms such as alkylsulfonyl, denotes divalent radical -SO2-, or RSO2-, where R is substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, heterocyclyl, and the like. “Alkylsulfonyl” denotes alkyl radicals, as defined above, attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like. The term “arylsulfonyl” used herein, either alone or in combination with other radicals, denotes aryl radicals, as defined above, attached to a sulfonyl radical, such as phenylsulfonyl and the like.
The term “sulfonic acid or its derivatives”, used herein, either alone or in combination with other radicals, denotes -SO3H group and its derivatives such as sulfonylamino(SO2NH2); N- alkylaminosulfonyl and N,N-dialkylaminosulfonyl radicals where the sulfonylamino group is substituted with one and two alkyl groups respectively, such as N-methylaminosulfonyl, N- ethylaminosulfonyl, N,N-dimethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl and the like; N-arylaminosulfonyl and N-alkyl-N-arylaminosulfonyl groups where the sulfonylamino group is substituted with one aryl radical, or one alkyl and one aryl radical; -SO3R, wherein ‘R’ represents alkyl, aryl, aralkyl groups, as defined above, which may be substituted.
The term “ph osphonic acid or its derivatives”, used herein, either alone or in combination with other radicals, denotes P(O)(OH)2, P(O)(O(C1-C6) alkyl)2, P(O)(O aryl)2, P(O)(OH)(O(C1- C6)alkyl), and the like.
Prodrugs of the compounds and their pharmaceutically acceptable salts may be formed by appropriately converting their functional groups such as -COOH, NH2 etc. into corresponding esters, amides etc. but not limited to this.
Preferred salts may be selected from hydrochloride, hydrobromide, tosylate, besylate, sulphate, methanesulphonate, tartrate, citrate, lactate, acetate, oxalate, glutarate, ethanesulphonate, maleate, camphor sulfonate, glycolate, succinate, phosphate, nphthalene-1,5-disulfonate, naphthalene-2-sulphonate , benzoate, ascorbate, mandelate, malonate, 1-hydroxy-2-naphthoate, sodium, potassium, calcium, hexanoate etc but not limited to this.
List of Abbreviation
DMF: Dimethyl formamide
DCM: Dichloromethane
EDAC.HC1: N-(3-Dimethyl aminopropyl)-N’ -ethyl carbodiimide hydrochloride,
HOBT : 1 -Hydroxy benzotriazole
TFA: Trifluoro acetic acid
DCC: Dicyclohexylcarbodiimide
DIPEA: Disopropyl ethyl amine
EtOAc: Ethyl acetate h: Hour(s) rt : room temperature min: Minute(s) tRet Retention time
HCl: Hydrochloric acid
RT: Room temperature [25-30 °C]
Cs2CO3: Cesium carbonate
TEA: Triethyl amine HBTU : N, N, N', N,'-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate
INSTRUMENT DETAILS
Mass spectrum was recorded on LC-MS 2010- A Shimadzu.
HPLC purity was determined by using Agilent 1100 instrument.
HPLC Column: YMC J Sphere C18 (150X4.6 mm)4p
Mobile phase: 0.05 % TFA in water: ACN gradient.
Flow rate: 1.0 ml/min.
Wave length: UV at 220 nm.
UPLC was determined on Acquity Ultra performance instrument.
UPLC Column: BEHC18 (2. lx 100mm) 1.7 μ
Mobile phase: 0.05 % TFA in water: ACN gradient.
Flow rate: 0.04 ml/min
NMR spectrum: Bruker Advance 400 MHz
Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
Preferred compounds according to the present invention include but are not limited to:
4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)- 1 -naphthoic acid;
5-((6-phenylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-(3-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine; 1-((2,4-diaminopyrimidin-5-yl)methyl)indoline-5-carboxylic acid;
5- ((6-(3-chlorophenyl)indolin- 1 -yl)methyl)pyrimidine-2,4-diamine;
5-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-(3-(trifluoromethoxy)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-(2-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(phenylethynyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride;
5-((4,6-difluoroindolin- 1 -yl)methyl)pyrimidine-2,4-diamine;
5-((5-(pyridin-4-yl)indolin- 1 -yl)methyl)pyrimidine-2,4-diamine hydrochloride;
5-((5-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride;
5-((5-(naphthalen-2-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride; 5-((6-chloroindolin- 1 -yl)methyl)pyrimidine-2,4-diamine hydrochloride;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-6-yl)benzoic acid compound with acetic acid (1:3);
5-((5-(4-(methylsulfonyl)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(4-(diethylamino)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(2,4-dichlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-(2,4-dichlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-(4-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-(4-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(quinolin-3-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine; ethyl 4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoate;
5-((5-(4-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-fhroro-2-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3-chloro-4-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-(3-chloro-4-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-(4-chloro-3-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
2-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-4-yl)benzoic acid compound with acetic acid (1:3);
3-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-4-yl)benzoic acid compound with acetic acid (1:3);
5-((5-(4-chloro-3-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
4-( 1 -(3-(2,4-diaminopyrimidin-5-yl)prop-2-yn- 1 -yl)indolin-5-yl)benzoic acid;
3-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid;
5-((5-(3-chlorophenyl)indolin-1-yl)methyl)-6-ethylpyrimidine-2,4-diamine;
5-((5-(4-(3-methoxyoxetan-3-yl)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
2-chloro-4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid;
1 -cyclopropyl-7 -(4-(4-( 1 -((2,4-diaminopyrimidin-5 -yl)methyl)indolin-5 -yl)benzoyl)piperazin- 1 - yl)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid;
5-((5-iodoindolin- 1 -yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3-morpholinopropoxy)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-nitrobenzoic acid; tert-butyl(4-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5yl)benzamido)butyl)carbamate;
2-acetamido-5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid trihydrochloride ; 5-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)thiophene-2-carboxylic acid;
4-ethyl 1 -methyl 2-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phenyl)succinate;
2-(4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phenyl)- 1,1,1 ,3,3,3-hexafluoropropan-2- ol diformate;
2-acetamido-4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid;
4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-hydroxybenzoic acid;
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)nicotinic acid;
5-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-hydroxybenzoic acid trihydrochloride; 5-((5-(4-(ethylsulfonyl)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phthalic acid;
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)furan-2-carboxylic acid;
4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-5-methylthiophene-2-carboxylic acid trihydrochloride ;
2-(4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phenyl)acetic acid trihydrochloride;
5-((5-(quinolin-8-yl)indolin- 1 -yl)methyl)pyrimidine-2,4-diamine trihydrochloride;
5-((5-(8-methoxyquinolin-5-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride;
5-((5-(6,7-dimethoxy-2,3-dihydro-1H-inden-4-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride ;
5-((5-(quinolin-5-yl)indolin- 1 -yl)methyl)pyrimidine-2,4-diamine trihydrochloride;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-hydroxy-2-naphthoic acid trihydrochloride ;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2,3,5,6-tetramethylbenzoic acid;
5-((5-(4-fluoronaphthalen-1-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride;
5-((5-(dibenzo[b,d]furan-3-yl)indolin- 1 -yl)methyl)pyrimidine-2,4-diamine trihydrochloride;
6-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-naphthoic acid;
6-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-methyl-1H-benzo[de]isoquinoline-1,3 (2H)-dione; 8-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-methyl-2H-benzo[b] [ 1 ,4]oxazin-3
(4H)-one trihydrochloride;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)naphthalene-1-sulfonic acid;
5-((5-(4-chloronaphthalen-1-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride; ethyl 4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-naphthoate trihydrochloride;
N-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)naphthalen-1-yl)acetamide;
5-((5-methoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-(indolin- 1 -ylmethyl)pyrimidine-2,4-diamine ;
Ethyl 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-
1.4-dihydroquinoline-3-carboxylate
Ethyl 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-
1.4-dihydroquinoline-3-carboxylate dihydrochloride
5-((4,5,6-trimethoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine;
1-((2, 4-diaminopyrimidin-5-yl)methyl)-4, 5, 6-trimethoxyindoline-2, 3-dione;
5-((5-chloroindolin- 1 -yl)methyl)pyrimidine-2,4-diamine;
5-((5-fluoroindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-bromoindolin- 1 -yl)methyl)pyrimidine-2,4-diamine;
2-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol;
5-((7-methoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-methoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5,6-dimethoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-1(,1,1,3,3,3 -hexafluoro-2-methoxypropan-2-yl)indolin- 1 -yl)methyl)pyrimidine-2,4-diamine;
5-((5-phenylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(2-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-methoxy-2-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-methoxy-2-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(trifluoromethoxy)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(6-methoxypyridin-3-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-chloroindolin- 1 -yl)methyl)pyrimidine-2,4-diamine;
5-((5-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine; 5-((5-(pyridin-4-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(phenylethynyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3,4,5-trimethoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3-(trifluoromethoxy)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(4-(trifluoromethoxy)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(2,4-dimethoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((2,3,3-trimethylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(naphthalen-2-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-fluoroindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(m-tolyl)indolin- 1 -yl)methyl)pyrimidine-2,4-diamine;
5-((4-(3-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-phenylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(pyridin-3-yl)indolin- 1 -yl)methyl)pyrimidine-2,4-diamine hydrochloride;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid;
5-((4-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(ethylsulfonyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-4-yl)benzoic acid;
4-(1-((2,4-diamino-6-ethylpyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid;
5-((4-(3-chlorophenyl)indolin-1-yl)methyl)-6-ethylpyrimidine-2,4-diamine;
5-((5-nitroindolin-1-yl)methyl)pyrimidine-2,4-diamine;
1-((2,4-diaminopyrimidin-5-yl)methyl)indoline-5-carbonitrile;
N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)isobutyramide;
N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)isobutyramide hydrochloride;
1-((2,4-diaminopyrimidin-5-yl)methyl)-N,N-dimethylindoline-5-carboxamide;
N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)acetamide;
1-((2,4-diaminopyrimidin-5-yl)methyl)-N-methylindoline-5-carboxamide; (1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)(morpholino) methanone;
1-((2,4-diaminopyrimidin-5-yl)methyl)indoline-5-carboxamide; ethyl ( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)carbamate;
2-chloro-N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-nitrobenzamide; 2-chloro-N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-3,4-dimethoxybenzamide; 5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)imidazo[1,2-a]pyridine-2-carboxylic acid; 7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5- carboxylic acid;
Cycloprop yl-7-(1-((2, 4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-oxo- 1,4- dihydroquinoline-3-carboxylic acid
Several synthetic routes may be employed to prepare the compounds of the present invention. The compounds of formula (I) can be synthesized using the following method, together with conventional techniques known to those skilled in the art, or variations thereon as appreciated by those skilled in the art. Referred methods include, but are not limited to those described below.
Scheme 1:
Figure imgf000024_0001
To a solution of Indoline derivative (intermediate 1), which can be synthesized as per the procedure known in the literature (WO95/01976) (0.1 g, 7.3 mole) in solvents such as dichloromethane, acetonitrile, DMF, DMSO, THF and like (10 mL) was reacted with pyrimidine pyridinium hydrobromide salt [intermediate II, synthesized as per procedure described in J. Med. Chem. 2003, 46, 2304-2312] in presence of base such as K2CO3, Na2CO3, CS2CO3 etc. under reflux condition to afford compound of general formula (I).
It will be appreciated that in any of the above mentioned reactions any reactive group in the substrate molecule may be protected, according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. T. W. Greene and P. G. M. Wuts “Protective groups in Organic Synthesis”, John Wiley & Sons, Inc, 1999, 3rd Ed., 201-245 along with references therein gives such conventional methods and are incorporated herein as references.
The compounds of the present invention may optionally be converted to their pharmaceutically acceptable salts.
The present invention is described in detail by the following examples which are provided for the sake of illustrations only and should not be in any way construed to limit the scope of the invention.
1H NMR spectral data given in the tables (vide infra) are recorded using a 300 MHz spectrometer (Bruker A VANCE-300) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCI3 using Tetramethyl silane as the internal standard.
The pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (I) with suitable acids in suitable solvents by processes known in the art.
The invention is further exemplified by the following examples below, which provides some of the several preferred embodiments of the present invention. These examples are provided merely as representative embodiments and should not be construed to limit the scope of the invention in any way.
Scheme 2
Figure imgf000025_0001
1 Example 1
Preparation of 4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-naphthoic acid
Figure imgf000026_0001
To a solution of 4-(indolin-5-yl)-1-naphthoic acid 2,2,2-trifluoroacetic acetate (0.172 g, 0.426 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (1.575 ml, 8.53 mmol) at 20-30° C. To the reaction mixture 1- ((2,4-diaminopyrimidin-5-yl)methyl)pyridin-1-ium bromide hydrobromide [Prepared according to literature procedure J. Med. Chem. 2003, 46, 2304-2312] (0.155 g, 0.426 mmol) was added at 20-30° C. The resulting suspension was stirred at 80-90° C for 2 h. Progress of the reaction was monitored by TLC. Product was purified by preparative HPLC using mobile phase ACN-Water to afford 35 mg of 4-(1-((2,4-diaminopyrimidin-5- yl)methyl)indolin-5-yl)-1-naphthoic acid as light yellow color solid. 1H NMR (DMSO-d6, 400 MHz) δ: 9.00 (d, J =8.8Hz, 1H), 8.33 (s, 1H),7.84 (d, J =8.0Hz, 1H), 7.70(d, J =6.8Hz, 2H), 7.40(d, J =6.8Hz,2H), 7.24 (d, J =7.2Hz, 1H), 7.15 (s, 1H), 6.82 (d, J =8.4Hz, 1H), 6.17 (s, 2H, NH2), 5.87 (s, 2H, NH2), 4.01 (s, 2H), 3.23 (t, J =0.4Hz, 2H), 2.96 (t, J =0.4Hz, 2H); ESI-MS (m/z): 412.170(100%) (M+H)+; UPLC Purity: 98.28% (2.93 min).
Synthesis of intermediate 1:
Figure imgf000026_0002
Preparation of 4-bromo-1-naphthoyl chloride (Intermediate 4)
Figure imgf000027_0001
To a 4-bromo-1-naphthoic acid (Intermediate 3) (1.000 g, 3.98 mmol) was added thionyl chloride (1.454 ml, 19.91 mmol) dropwise under stirring at 20-30° C and continued stirring for 3 h at 20-30° C. Progress of reaction was monitored by TLC. After completion of reaction, volatiles were evaporated off on a rotatory evaporator under reduced pressure to afford 4-bromo- 1-naphthoyl chloride as (Intermediate 4) brown oil. (1.07 g, 3.98 mmol, quantitative yield), which was directly used for next step without further purification.
Preparation of tert-butyl 4-bromo-1-naphthoate (Intermediate 5)
Figure imgf000027_0002
To a solution of 4-bromo- 1 -naphthoyl chloride (Intermediate 4) (1.070 g, 3.97 mmol) in THF (30 mL) was added potassium tert-butoxide (0.891 g, 7.94 mmol) at 0-10 °C in small portions. The reaction mixture was stirred for 18 h at 20-30° C. Progress of reaction was monitored by TLC. The reaction mixture was poured in to water (50 mL) and extracted with EtOAc. The organic layer was separated, washed with saturated sodium bicarbonate followed by water and dried over sodium sulfate. Evaporation of solvents afforded tert-butyl 4-bromo-1-naphthoate (0.33 g, 1.074 mmol, 27.1 % yield) as yellow oil. 1H NMR (DMSO- d6, 400 MHz) δ: 8.71-8.70 (dd, J =0.4 Hz, 1H), 8.27-8.26 (dd, J =0.4 Hz, 1H), 8.01(d, J =8.0 Hz, 1H), 7.91(d, 7=8.0 Hz,1H), 7.78 (t, 7 =1.2Hz, 1H), 7.77 (t, 7 =1.2 Hz, 1H), 1.63(s, 9H); ESI-MS (m/z): 390.17 (M- tBu).
Preparation of tert-butyl 5-(4-tert-butoxycarbonyl)naphthalen-1-yl)indoline-1-carboxylate (Intermediate 7)
Figure imgf000028_0001
To a solution of tert-butyl 4-bromo-1-naphthoate (Intermediate 5) (0.330 g, 1.074 mmol) in DMF (2.4 mL) was added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1- carboxylate [Intermediate 6 was prepared following procedure described in J. Med. Chem. 2012, 55(16), 7193-7207] (0.371 g, 1.074 mmol) under atmosphere of nitrogen at 25-30 °C. To the reaction mixture added triphenylphosphine (0.085 g, 0.322 mmol), diacetoxy palladium (0.024 g, 0.107 mmol), ethanol (2.4 mL) and water (1.5 mL). The reaction mixture was stirred for 18 h at 20-30° C under atmosphere of nitrogen. Progress of reaction was monitored by TLC. The reaction mixture was poured in to water and extracted with EtOAc. The organic layer was separated, washed with saturated sodium bicarbonate followed by water, dried over sodium sulfate. Evaporation of solvents on rotatory evaporator afforded crude tert-butyl 5-(4-(tert- butoxycarbonyl) naphthalen-1-yl) indoline- 1 -carboxylate as brown oil. The crude product was purified by column chromatography to afforded tert -butyl 5-(4-(tert-butoxycarbonyl) naphthalen- 1y-l) indoline- 1 -carboxylate (Intermediate 7) (0.19 g, 0.426 mmol, 39.7 % yield) as brown oil. 1H NMR (DMSO- d6, 400 MHz) δ: 8.74 (d, J=8.4Hz, 1H), 8.04 (d, J=7.6Hz, 1H), 7.93-7.87(q, J=0.4Hz, 1H), 7.67(d, J = 1.2Hz,1H), 7.65(s, 1H), 7.57 (d, J=7.2Hz, 1H), 7.47 (d, J=7.2Hz, 1H), 7.39 (d, J =8.8Hz, 1H), 7.32(s, 1H), 7.26 (d, J=8.0Hz, 1H), 4.0 (t, J =0.4Hz, 2H), 3.04 (t, J=0.4Hz, 2H), 1.68(s, 9H), 1.55(s, 9H); ESLMS (m/z): 390.17 (M- tBu).
Preparation of 4-(indoline-5-yl)-1-naphthoic acid-2, 2, 2-trifluoroacetate (Intermediate 1)
Figure imgf000028_0002
To a solution of tert-butyl 5-(4-(tert-butoxycarbonyl)naphthalen-1-yl)indoline-1-carboxylate (Intermediate 7) (0.190 g, 0.426 mmol) in DCM (2 mL) was added 2,2,2-trifluoroacetic acid (2 mL, 0.426 mmol) at 25-30 °C. The reaction mixture was stirred for 18 h at 20-30 °C under atmosphere of nitrogen. Progress of reaction was monitored by TLC. The reaction mixture was evaporated on a rotatory evaporator under reduced pressure to afford 4-(indoline-5-yl)-1- naphthoic acid-2, 2, 2-trifluoroacetate as brown oil.(0.172 g, 0.426 mmol, 100 % yield) which was directly used for next step without further analysis and purification.
Follwing examples prepared following procedure described for preparation of example 1.
Example 2
5-((6-phenylindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000029_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.69 (s, 1H), 7.63 (t, J=6.0Hz, 2H), 7.44 (d, J=7.2Hz, 2H), 7.41 (s, 1H), 7.32 (t, J =1.6Hz, 1H), 7.12 (d, J =7.6Hz, 1H), 6.91 (t, J=4.4Hz, 1H), 6.16 (s, 2H, NH2), 5.86 (s, 2H, NH2), 4.02 (s, 2H), 3.17 (t, J =0.4Hz, 2H), 2.87 (t, J =0.4Hz, 2H).
Example 3
5-((6-(3-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000029_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.69 (s, 1H), 7.36 (s, 1H), 7.34 (s, 1H), 7.13 (t, J = l.6Hz, 2H), 6.98 (d, J =1.2Hz, 1H), 6.92 (d, J =1.2Hz, 2H), 6.16 (s, 2H, NH2), 5.86 (s, 2H, NH2), 4.02 (s, 2H), 3.82 (s, 2H, OCH3), 3.17 (t, J =0.4Hz, 2H), 2.87 (t, J =0.4Hz, 2H).
Example 4
1-((2,4-diaminopyrimidin-5-yl)methyl)indoline-5-carboxylic acid
Figure imgf000030_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.66 (s, 1H), 7.60 (d, J =8.74Hz, 1H), 7.63 (s, 1H), 6.64 (d, J =8.4Hz, 1H), 6.16 (s, 2H, NH2), 5.88 (s, 2H, NH2), 3.98 (s, 2H), 3.23 (t, J = 16.0Hz, 2H), 2.87 (t, J = 16.0Hz, 2H).
Example 5
5-((6-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000030_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.69 (s, 2H), 7.68 (d, J =2AHz, 1H), 7.61 (t, J =2.8Hz, 1H), 7.60 (d, J =1.2Hz, 1H), 7.13 (d, J =7.6Hz, 1H), 7.05 (d, J =1.2Hz, 1H), 6.94 (d, J =1.6Hz, 1H), 6.15 (s, 2H, NH2), 5.87 (s, 2H, NH2), 4.04 (s, 2H), 3.17 (t, J =0.4Hz, 2H), 2.88 (t, J =1.6Hz, 2H).
Example 6
5-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000030_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.75 (dd, J = 1.2Hz, 1H), 7.66 (s, 1H), 7.25 (dd, J = 1.6Hz, 1H), 6.43 (t, 7=0.4 Hz, 1H), 6.41 (s, 2H, NH2), 5.88 (s, 2H, NH2), 4.15 (s, 2H), 3.39 (t, J =0.4Hz, 2H), 2.91 (t, J=0.4Hz, 2H).
Example 7
5-((6-(3-(trifluoromethoxy)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000031_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.69 (s, 2H), 7.68 (d, J =1.6Hz, 1H), 7.59 (d, J =6.0Hz, 1H),
7.31 (t, J=2.4Hz, 1H), 7.14 (d, J=7.6Hz, 1H), 7.06 (d, J=1.2Hz, 1H), 6.96, 6.94 (dd, J =1.6Hz, 1H), 6.15 (s, 2H, NH2), 5.86 (s, 2H, NH2), 4.04 (s, 2H), 3.18 (t, J =2.0Hz, 2H), 2.90(t, J =0.8Hz, 2H).
Example 8
5-((6-(2-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diainine
Figure imgf000031_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.69 (s, 1H), 7.32 (d, J =2.0Hz, 1H), 7.30 (d, J =0.8Hz, 1H),
7.28 (d, J =2.0Hz, 2H), 7.04 (s, 1H), 7.00 (t, J =5.2Hz, 1H), 6.70(s, J =4.4Hz, 1H), 6.22 (s, 2H, NH2), 5.93 (s, 2H, NH2), 3.95 (s, 2H), 3.76 (s, 3H, OCH3), 3.21 (t, J =0.4Hz, 2H), 2.87 (t, J = 16.0Hz, 2H).
Example 9
5-((5-(phenylethynyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride
Figure imgf000031_0003
1H NMR (DMSO-d6, 400 MHz) δ: 11.83 (s, 1H, HC1), 7.68 (s, 1H), 7.62 (s, 2H, NH2), 7.67 (s, 1H), 7.48 (d, J =2.0Hz, 1H), 7.6 (s, 2H, NH2), 7.38 (d, J =3.2Hz, 3H), 7.25 (t, J =0.8Hz, 2H), 6.64 (t, J=3.2Hz, 1H), 4.07 (s, 2H), 3.34 (t, J = 1.6Hz, 2H), 2.68 (t, J=0.8Hz, 2H).
Example 10 5-((4,6-difluoroindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000032_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.64 (s, 1H), 6.45 (d, J =2.0Hz, 1H), 6.42 (d, J = 2.0Hz, 1H),
6.17 (s, 2H, NH2), 5.89 (s, 2H, NH2), 3.99 (s, 2H), 3.29 (t, J =16.8Hz, 2H), 2.86 (t, J=0.4Hz, 2H).
Example 11
5-((5-(pyridin-4-yl)indolin-1-yl)methyl)pyrimidine-2,4-diainine hydrochloride
Figure imgf000032_0002
1 H NMR (DMSO-d6, 400 MHz) δ: 12.0( HC1 small hump but not integrated), 8.69 (d, J =6.8Hz,
2H) 8.50(s, 1H), 8.17 (d, J =6.8Hz, 3H), 7.83 (s, 2H, NH2), 7.68 (s, 2H, NH2), 6.79 (d, J=8.4Hz,
1H), 4.20(s, 2H), 3.51 (t, J =16.8Hz, 2H), 2.68 (t, J=0.4Hz, 2H).
Example 12
5-((5-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride
Figure imgf000032_0003
1H NMR (DMSO-d6, 400 MHz) δ: 11.99 (s, 1H, HC1), 8.41 (s, 1H), 7.75 (s, 4H, NH2), 7.73 (s, 1H), 7.08 (d, J = 1.2Hz, 1H), 7.61 (t, J =0.4Hz, 1H), 7.44 (d, J =8.0Hz, 2H), 7.29 (s, 1H), 6.71 (d, J=8.4Hz, 1H), 4.06 (s, 2H), 3.33 (t, J =0.4Hz, 2H), 2.99 (t, J =16.0Hz, 2H).
Example 13 5-((5-(naphthalen-2-yl)indolin-1-yl)methyl)pyrimidine-2,4-diainine hydrochloride
Figure imgf000033_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.99 (s, 1H, HC1), 8.43 (s, 1H), 8.10 (s, 1H), 7.94 (d, J =8.4Hz, 2H), 7.90 (d, J = 8.0Hz, 1H), 7.80 (s, 3H, NH2), 7.79 (d, J= 2Hz, 2H), 7.76 (s, 1H), 7.53 (t, J=0.4Hz, 2H), 7.44 (s, 1H, NH2), 6.77 (d, J=8.4Hz, 1H), 4.08 (s, 2H), 3.35 (t, J =16.8Hz, 2H), 3.05 (t, J=0.4Hz, 2H).
Example 14
5-((6-chloroindolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride
Figure imgf000033_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.99 (s, 1H, HC1), 8.39 (s, 1H), 7.71 (s, 4H, NH2), 7.06 (d, J =7.6Hz, 1H), 6.72 (s, 1H), 6.64 (d, J =2Hz, 1H), 4.01 (s, 2H), 3.29 (t, J =16.8Hz, 2H), 2.90 (t, J =0.4Hz, 2H).
Example 15 4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-6-yl)benzoic acid compound with acetic acid (1:3)
Figure imgf000033_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.89 (d, J=8.4Hz, 2H), 7.68 (s, 1H), 7.51 (d, J =8.4Hz, 2H), 7.48 (s, 1H), 7.11 (d, J =7.6Hz, 1H), 7.28 (s, 1H), 6.93, 6.91 (dd, J=0.4Hz, 1H), 6.28 (s, 1H, NH2), 6.17 (s, 1H, NH2), 5.81 (s, 2H, NH2), 4.01 (s, 2H), 3.15 (t, J =0.4Hz, 2H), 2.86 (t, J =0.4Hz, 2H), 2.06 (d, J =10.4Hz, 9H, Triacetate salt). Example 16
5-((5-(4-(methylsulfonyl)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000034_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.90 (d, J =8.8Hz, 2H), 7.83 (d, J =8.8Hz, 2H), 7.67 (s, 1H),
7.36 (d, J =8.8Hz, 2H), 6.79 (d, J =8.0Hz, 1H), 6.15 (s, 2H, NH2), 5.87 (s, 2H, NH2), 4.02 (s,
2H), 3.37 (s, 3H), 3.26 (t, J =16.8Hz, 2H), 2.96 (t, J =8.0Hz, 2H).
Example 17
5-((5-(4-(diethylamino)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000034_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.68 (s, 1H), 7.36 (d, J =8.8Hz, 2H), 7.28 (s, 1H), 7.23 (d, J
=1.6Hz, 1H), 6.70 (d, J =5.2Hz, 3H), 6.20 (s, 2H, NH2), 5.77 (s, 2H, NH2), 3.95 (s, 2H), 3.35- 3.30 (m, 4H), 3.17 (t, J =0.4Hz, 2H), 2.90(t, J=3.6Hz, 2H), 1.08 (t, J=0.4Hz, 6H).
Example 18
5-((5-(2,4-dichlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000034_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.68 (s, 2H), 7.65 (d, J =2.0Hz, 1H), 7.45 (d, J =2.0Hz, 1H),
7.43 (s, 2H), 7.37 (d, J =8.4Hz, 1H), 6.73 (s, 2H, NH2), 6.00 (s, 2H, NH2), 3.99 (s, 2H), 3.23 (t, J =0.4Hz, 2H), 2.91 (t, J=0.4Hz, 2H). Example 19
5-((4-(2,4-dichlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000035_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.71 (d, J =2AHz, 1H), 7.67 (s, 1H), 7.48 (d, J =2.0Hz, 1H),
7.36 (d, J =8.4Hz, 1H), 7.11 (s, 1H), 6.74 (d, J =2.6Hz, 1H), 6.53 (t, J =6.0Hz, 1H), 6.15 (s, 2H, NH2), 5.86 (s, 2H, NH2), 3.97 (s, 2H), 3.12 (t, J =0.4Hz, 2H), 2.65 (t, J =0.4Hz, 2H).
Example 20
5-((4-(4-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000035_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.50 (d, J =12.4Hz, 4H), 7.14 (t, J=0.4Hz, 1H), 6.72 (d, J=8.4Hz, 2H), 6.27 (s, 2H, NH2), 5.98 (s, 2H, NH2), 3.96 (s, 2H), 3.13 (t, J =16.0Hz, 2H), 2.92 (t, J=16.0Hz,2H).
Example 21
5-((6-(4-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000035_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.68 (s, 1H), 7.66 (d, J =1.6Hz, 2H), 7.48 (d, J =2.0Hz, 2H),
7.47 (s, 1H), 7.13 (d, J =7.2Hz, 1H), 6.99 (d, J =0.8Hz, 1H), 6.17 (s, 2H, NH2), 5.87 (s, 2H, NH2), 4.02 (s, 2H), 3.17 (t, J=0.4Hz, 2H), 2.87 (t, J=0.4Hz, 2H). Example 22
5-((5-(quinolin-3-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000036_0001
1H NMR (DMSO-d6, 400 MHz) δ: 9.19 (d, J=2.4Hz, 1H), 8.49 (d, J =2.0Hz, 1H), 8.00 (t, J =1.2Hz, 2H), 7.99-7.68 (m, 2H), 7.62-7.57 (m, 3H), 6.84 (d, J =8.4Hz, 1H), 6.17 (s, 2H, NH2), 5.88 (s, 2H, NH2), 4.03 (s, 2H), 3.27 (t, J=0.4Hz, 2H), 2.98 (t, J=0.4Hz, 2H).
Example 23 ethyl 4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoate
Figure imgf000036_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.96 (d, J=8.8Hz, 2H), 7.73 (d, J =8.8Hz, 2H), 7.67 (s, 1H),7.46 (d, J =8.0Hz, 2H), 6.78 (d, J =8.4Hz, 1H), 6.15 (s, 2H, NH2), 5.88 (s, 2H, NH2), 4.32 (q, J =21.6Hz, 2H), 4.01 (s, 2H), 3.25 (t, J =0.4Hz, 2H), 2.95 (t, J =0.4Hz, 2H), 1.34 (t, J =14.4Hz, 3H).
Example 24
5-((5-(4-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000036_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.59 (d, J =2.0Hz, 2H), 7.57 (d, J =1.6Hz, 2H), 7.56 (s, 1H), 7.49 (d, J =2.0Hz, 1H), 6.74 (d, J =8.4Hz, 1H), 6.40 (s, 2H, NH2), 6.10 (s, 2H, NH2), 4.13 (s, 2H), 3.23 (t, J=0.4Hz, 2H), 2.93 (t, J=0.4Hz, 2H). Example 25
5-((5-fluoro-2-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000037_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.63 (s, 1H), 6.91 (t, J=3.2Hz, 1H), 6.89 (s, 1H), 6.77 (d, J =1.6Hz, 1H), 6.13 (s, 2H, NH2), 5.84 (s, 2H, NH2), 3.91 (s, 1H), 3.89 (s, 1H), 3.60 (d, J=6.0Hz,
1H), 2.90 (m, 1H), 2.55-2.50 (m, 1H), 1.18 (d, J =6.0Hz, 3H).
Example 26
5-((5-(3-chloro-4-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000037_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.58 (d, J =l.6Hz, 1H), 7.45 (d, J =l.6Hz, 1H), 7.43 (d, J = 1.6Hz, 1H), 7.36 (s, 2H), 6.74 (d, J =8.0Hz, 1H), 6.14 (s, 2H, NH2), 5.87 (s, 2H, NH2), 4.11 (s, 2H), 3.21 (t, J =0.4Hz, 2H), 2.92 (t, J =0.4Hz, 2H), 2.33 (s, 3H).
Example 27
5-((4-(3-chloro-4-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000037_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.46 (s, 1H), 7.41 (d, J =8.0Hz, 1H), 7.34 (d, J
= 1.6Hz, 1H), 7.13 (t, J =0.4Hz, 1H), 6.72, 6.70 (dd, J =5.2Hz, 2H), 6.33 (s, 2H, NH2), 6.04 (s, 2H, NH2), 4.11 (s, 2H), 3.14 (t, J =0.8Hz, 2H), 2.94 (t, J =0.4Hz, 2H), 2.51 (s, 3H). Example 28
5-((4-(4-chloro-3-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diainine
Figure imgf000038_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.45 (d, J =8.4Hz, 2H), 7.30 (d, J =2.0Hz, 1H), 7.13 (t, J =0.4Hz, 1H), 6.73-6.69 (q, J =0.4Hz, 2H), 6.16 (s, 2H, NH2), 5.88 (s, 2H, NH2), 3.96
(s, 2H), 3.12 (t, J =0.4Hz, 2H), 2.91 (t, J =0.4Hz, 2H), 2.38 (s, 3H).
Example 29 2-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-4-yl)benzoic acid compound with acetic acid (1:3)
Figure imgf000038_0002
1 H NMR (DMSO-d6, 400 MHz) δ: 7.65 (s, 2H), 7.23 (s, 1H), 7.03 (s, 1H), 6.90 (t, J =0.8Hz, 1H), 6.80 (t, J =0.8Hz, 1H),6.63 (d, J =7.6Hz, 1H), 6.50 (d, J =6.8Hz, 1H), 6.17 (s, 2H, NH2), 5.81 (s, 2H, NH2), 3.93 (s, 2H), 3.04 (t, J =8.0Hz, 2H), 2.78 (t, J =0.4Hz, 2H), 2.33 (s, 9H, Triacetate salt).
Example 30
3-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-4-yl)benzoic acid compound with acetic acid (1:3)
Figure imgf000038_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.95 (s, 2H), 7.86 (s, 1H), 7.68 (s, 1H), 7.15 (t, J =0.8Hz, 2H), 6.72 (d, J =1.6Hz, 2H), 6.15 (s, 2H, NH2), 5.87 (s, 2H, NH2), 3.96 (s, 2H), 3.13 (t, J =0.8Hz, 2H), 2.92 (t, J = 16.8Hz, 2H), 2.29 (s, 9H, Triacetate salt).
Example 31
5-((5-(4-chloro-3-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000039_0001
1 H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.53 (s, 1H), 7.39 (d, J =4.4Hz, 3H), 7.34 (d, J =9.2Hz, 1H), 6.67 (d, J =8.4Hz, 1H), 6.16 (s, 2H, NH2), 5.88 (s, 2H, NH2), 4.01 (s, 2H), 3.29 (t, J =0.4Hz, 2H), 2.94 (t, J =0.4Hz, 2H), 2.31 (s, 3H).
Example 32
4-(1-(3-(2,4-diaminopyrimidin-5-yl)prop-2-yn-1-yl)indolin-5-yl)benzoic acid
Figure imgf000039_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.84 (d, J =8.0Hz, 3H), 7.74 (s, 1H), 7.46 (d, J =8.0Hz, 1H), 7.40(s, 1H), 7.36 (d, J =8.4Hz, 1H), 6.77 (d, J =8.4Hz, 1H), 6.27 (s, 2H, NH2), 5.86 (s, 2H, NH2), 4.23 (s, 2H), 3.41 (d, J =8.4Hz, 2H), 2.96 (d, J =8.4Hz, 2H).
Example 33 3-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid
Figure imgf000039_0003
1 H NMR (DMSO-d6, 400 MHz) δ: 8.06 (s, 1H), 7.72 (d, J =7.2Hz, 1H), 7.68 (s, 1H), 7.45 (d, J =2.2Hz, 1H), 7.36 (s, 1H), 7.32 (d, J =8.4Hz, 1H), 7.26 (t, J = 16.8Hz, 1H), 6.77 (d, J =8.4Hz, 1H), 6.14 (s, 2H, NH2), 5.86 (s, 2H, NH2), 3.97 (s, 2H), 3.19 (t, J =0.4Hz, 2H), 2.93 (t, J =0.4Hz, 2H).
Example 34
5-((5-(3-chlorophenyl)indolin-1-yl)methyl)-6-ethylpyrimidine-2,4-diamine
Figure imgf000040_0001
1 H NMR (DMSO-d6, 400 MHz) δ: 7.60 (s, 1H), 7.53 (d, J =8.0Hz, 1H), 7.39 (d, J =8.0Hz, 2H), 7.38 (s, 1H), 7.28 (d, J =1.6Hz, 1H), 6.77 (d, J =8.0Hz, 1H), 6.05 (s, 2H, NH2), 5.78 (s, 2H, NH2), 4.06 (s, 2H), 3.19 (t, J =0.4Hz, 2H), 2.89 (t, J = 16.8Hz, 2H), 2.51-2.46 (q, J =6.4Hz, 2H), 1.10 (t, J = 15.2Hz, 3H).
Example 35
5-((5-(4-(3-methoxyoxetan-3-yl)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000040_0002
1 H NMR (DMSO-d6, 400 MHz) δ: 7.68 (s, 1H), 7.62 (d, J =8.4Hz, 2H), 7.44 (d, J =8.4Hz, 2H), 7.40(d, J =9.6Hz, 1H), 7.37 (s, 1H), 6.76 (d, J =8.4Hz, 1H), 6.14 (s, 2H, NH2), 5.85 (s, 2H, NH2), 4.78 (s, 4H), 3.99 (s, 2H), 3.22 (t, J =0.4Hz, 2H), 3.04 (s, 3H, OCH3), 2.94 (t, J =8.4Hz, 2H).
Example 36
2-chloro-4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid
Figure imgf000041_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.39 (s, 1H), 7.32 (d, J = l.6Hz, 3H), 7.32 (s, 1H), 6.73 (d, J =8.4Hz, 1H), 6.13 (s, 2H, NH2), 5.85 (s, 2H, NH2), 3.98 (s, 2H), 3.20 (t, J =0.4Hz, 2H), 2.92 (t, J =7.6Hz, 2H).
Example 37 1-cyclopropyl-7-(4-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5- yl)benzoyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Figure imgf000041_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.63 (s, 1H), 7.66 (d, J =10Hz, 1H), 7.49 (d, J =8.0Hz, 3H), 7.48 (s, 3H), 7.42 (t, J =0.4Hz, 2H), 6.76 (d, J =8.4Hz, 1H), 6.15 (s, 2H, NH2), 5.86 (s, 2H, NH2), 4.00(S, 2H), 3.23 (t, J =0.4Hz, 2H), 2.94 (t, J =0.4Hz, 2H), 1.30, 1.24 (dd, J =7.2Hz, 2H), 1.09, 1.04 (dd, J =6.0Hz, 2H) Note: 1H of Cycloproyl CH was merge in piprazine ring protons).
Example 38
5-((5-iodoindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000041_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.63 (s, 1H), 7.30 (d, J =12AHz, 2H), 6.68 (s, 1H), 6.12 (s, 2H, NH2), 5.86 (s, 2H, NH2), 4.01 (s, 2H), 3.15 (t, J = 13.6Hz, 2H), 2.90 (t, J =0.8Hz, 2H).
Example 39
5-((5-(3-morpholinopropoxy)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000042_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.33 (s, 1H), 7.65 (s, 1H), 6.60 (d, J =1.2Hz, 2H), 6.12 (s, 2H,
NH2), 5.85 (s, 2H, NH2), 3.91 (s, 2H), 3.88 (t, J = 12.8Hz, 2H), 3.57 (t, J =0.4Hz, 4H), 3.03 (t, J
=0.4Hz, 2H), 2.80 (t, J =0.4Hz, 2H), 2.52 (t, J =3.2Hz, 6H), 1.85-1.80 (m, 2H).
Example 40
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-nitrobenzoic acid
Figure imgf000042_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.68 (d, J = 1.2Hz, 1H), 7.66, 7.65 (dd, J =0.4Hz, 2H), 7.66
(s, 2H), 7.42 (s, 1H), 7.31 (d, J =2.0Hz, 1H), 6.56 (s, 2H, NH2), 5.79 (s, 2H, NH2), 3.47 (t, J =0.4Hz, 2H), 3.36 (s, 2H), 2.97 (t, J =16.8Hz, 2H).
Example 41 tert-butyl (4-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5- yl)benzamido)butyl)carbamate
Figure imgf000042_0003
1H NMR (DMSO-d6, 400 MHz) δ: 8.44 (s, 1H), 7.85 (d, J =8.8Hz, 2H), 7.66 (d, J =4.HHz, 2H), 7.60(s, 1H), 7.44 (d, J =0.8Hz, 2H), 6.76 (d, J =8.0Hz, 1H), 6.15 (s, 2H, NH2), 5.87 (s, 2H, NH2), 4.00(S, 2H), 3.22 (t, J =2AHz, 4H), 3.20 (s, 1H, -NH), 2.94 (t, J =Q.6Hz, 4H), 1.49 (d, J =2.6Hz, 2H), 1.37 (s, 9H).
Example 42 2-acetamido-5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid trihydrochloride
Figure imgf000043_0001
1H NMR (DMSO-d6, 400 MHz) δ: 12.04 (s, 1H, -COOH), 10.99 (s, 1H, HC1), 8.47 (d, J =8.8Hz, 1H), 8.42 (s, 1H), 8.11 (d, J =2AHz, 1H), 7.81 (d, J =2AHz, 1H), 7.94 (s, 2H, NH2), 7.43 (s, 2H, NH2), 7.42 (s, 1H, -NH), 7.35 (d, J =8.0Hz, 1H), 6.72 (d, J =8.0Hz, 1H), 4.05 (s, 2H), 3.32 (t, J = 16.8Hz, 2H), 2.99 (t, J =1.2Hz, 2H), 2.15 (s, 3H).
Example 43
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)thiophene-2-carboxylic acid
Figure imgf000043_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.66 (s, 1H), 7.28 (s, 1H), 7.10 (d, J =3.6Hz, 2H), 7.06 (d, J =3.6Hz, 1H), 6.68 (d, J =8.0Hz, 1H), 6.13 (s, 2H, NH2), 5.86 (s, 2H, NH2), 3.96 (s, 2H), 3.19 (t,
J =0.4Hz, 2H), 2.90 (t, J =16.8Hz, 2H).
Example 44
4-ethyl 1-methyl 2-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phenyl)succinate
Figure imgf000043_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.51 (d, J =8.0Hz, 2H), 7.36 (s, 1H), 7.29 (d, J =8.4Hz, 3H), 6.74 (d, J =8.4Hz, 1H), 6.14 (s, 2H, NH2), 5.86 (s, 2H, NH2), 4.06 (t, J =0.8Hz, 3H), 3.97 (s, 2H), 3.32 (d, J =2AHz, 3H), 3.20 (t, J =0.4Hz, 2H), 3.06 (d, J = 10 AHz, 1H), 2.92 (t, J =8.0Hz, 2H), 2.74 (t, J =4.8Hz, 1H), 1.16 (t, J = 16.8Hz, 3H). Example 45
2-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phenyl)-1, 1,1333- hexafluoropropan-2-ol diformate
Figure imgf000044_0001
1 H NMR (DMSO-d6, 400 MHz) δ: 8.47 (s, 8H, extra proton), 8.47 (s, 1H), 7.68 (d, J =4.QHz, 4H), 7.43 (s, 1H), 7.40(d, J =8.0Hz, 1H), 6.76 (d, J =8.4Hz, 1H), 6.15 (s, 2H, NH2), 5.86 (s, 2H, NH2), 3.99 (s, 2H), 3.23 (t, J =0.8Hz, 2H), 2.93 (t, J =0.8Hz, 2H).
Example 46
2-acetamido-4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid
Figure imgf000044_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.73 (s, 1H), 8.15 (s, 1H), 7.95 (d, J =8.0Hz, 1H), 7.68 (s, 1H), 7.37 (d, J =8.4Hz, 2H), 7.11 (d, J =8.4Hz, 1H), 6.78 (s, 4H, NH2), 4.01 (s, 2H), 3.24 (t, J =6.0Hz, 2H), 2.68 (t, J =0.4Hz, 2H), 2.04 (s, 3H).
Example 47
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-hydroxybenzoic acid
Figure imgf000044_0003
1H NMR (DMSO-d6, 400 MHz) δ: 8.14 (s, 1H), 7.67 (d, J =3.6Hz, 2H), 7.38 (s, 1H), 7.33 (s, 1H), 6.50 (d, J =8.8Hz, 1H), 6.81 (d, J =8.4Hz, 1H), 5.77 (s, 4H, NH2), 4.00 (s, 2H), 3.26 (t, J =0.4Hz, 2H), 2.95 (t, J =8.8Hz, 2H).
Example 48
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)nicotinic acid
Figure imgf000045_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.97 (s, 1H), 8.91 (d, J = l.6Hz, 1H), 8.33 (d, J =2.0Hz, 1H),
7.68 (s, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 6.79 (d, J =8.0Hz, 1H), 6.26 (s, 2H, NH2), 6.00 (s, 2H, NH2), 4.02 (s, 2H), 3.24 (t, J = 16.8Hz, 2H), 2.68 (t, J =0.4Hz, 2H).
Example 49
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-hydroxybenzoic acid trihydrochloride
Figure imgf000045_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.04 (s, 1H, -HCI), 11.20 (s, 1H, -OH), 8.41 (s, 1H), 7.93 (s, 1H), 7.74 (d, J =2AHz, 3H), 7.67 (s, 1H), 7.30(d, J = 1.6Hz, 1H), 7.02 (s, 1H, NH2), 6.99 (s, 1H, NH2), 6.72 (s, 1H, NH2), 6.70(S, 1H, NH2), 4.12 (s, 2H), 3.30 (t, J =0.4Hz, 2H), 2.98 (t, J =0.4Hz, 2H).
Example 50
5-((5-(4-(ethylsulfonyl)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000045_0003
1H NMR (DMSO-d6, 400 MHz) δ: 8.16 (s, 1H), 7.85 (d, J =8.0Hz, 3H), 7.67 (s, 1H), 7.48 (d, J =8.4Hz, 2H), 6.78 (d, J =8.0Hz, 1H), 6.31 (s, 2H, NH2), 6.03 (s, 2H, NH2), 4.03 (s, 2H), 3.28 (t, J =8.8Hz, 4H), 2.96 (t, J =0.4Hz, 2H), 1.12 (t, J =14.4Hz, 3H).
Example 51
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phthalic acid
Figure imgf000046_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.73 (s, 1H),7.71 (d, J =6.4Hz, 1H), 7.69 (d, J =6.0Hz, 2H), 7.49 (s, 2H), 7.43 (d, J=8.0Hz,1H), 7.28 (s, 2H, NH2), 7.04 (s, 2H, NH2), 4.06 (s, 2H), 3.00(t, J =0.4Hz, 2H), 2.51 (t, J =0.4Hz, 2H).
Example 52
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)furan-2-carboxylic acid
Figure imgf000046_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.66 (s, 1H), 7.39 (d, J =8.0Hz, 2H), 6.72 (d, J =8.0Hz, 1H), 6.53 (d, J=8.4Hz, 1H), 6.52 (s, 1H), 6.13 (s, 2H, NH2), 5.86 (s, 2H, NH2), 3.97 (s, 2H), 3.18 (t, J =0.4Hz, 2H), 2.68 (t, J =0.4Hz, 2H).
Example 53
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-5-methylthiophene-2-carboxylic acid trihydrochloride
Figure imgf000046_0003
1H NMR (DMSO-d6, 400 MHz) δ: 12.02 (s, 1H, HCI), 8.41 (s, 1H), 7.73 (s, 2H, NH2), 7.70 (s, 2H, NH2 ), 7.60 (s, 1H), 7.19 (s, 1H), 7.12 (d, J =8.0Hz, 1H), 6.69 (d, J =8.4Hz, 1H), 4.03 (s, 2H), 3.31 (t, J =0.4Hz, 2H), 2.97 (t, J =0.4Hz, 2H), 2.29 (s, 3H).
Example 54
2-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phenyl)acetic acid trihydrochloride
Figure imgf000047_0001
1H NMR (DMSO-d6, 400 MHz) δ: 12.50 (s, 1H, -COOH, broad), 8.47 (d, J =9.6Hz, 2H), 8.15 (s, 2H), 7.51 (d, J =8.0Hz, 2H), 7.39 (s, 2H , NH2), 7.35 (d, J =8.0Hz, 1H), 7.28 (s, 2H, NH2), 6.72 (d, J =8.0Hz, 1H), 4.78 (s, 2H, HCI), 4.04 (s, 2H), 3.58 (s, 2H), 3.29 (t, J =0.4Hz, 2H), 2.96 (t, J =0.4Hz, 2H).
Example 55
5-((5-(quinolin-8-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride
Figure imgf000047_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.5 (s, 1H, HCI), 9.03 (d, J =3.6Hz, 1H), 8.92 (s, 1H), 8.46 (s, 1H), 8.16 (d, J =1.2Hz, 1H), 7.84 (s, 4H, NH2), 7.40 (d, J = 10.4Hz, 3H), 7.33 (d, J =1.6Hz, 1H), 7.31 (d, J =1.6Hz, 1H), 6.81 (d, J =8.4Hz, 1H), 4.13 (s, 2H), 3.41 (t, J =0.4Hz, 2H), 3.03 (t, J =0.4Hz, 2H).
Example 56
5-((5-(8-methoxyquinolin-5-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride
Figure imgf000047_0003
1H NMR (DMSO-d6, 400 MHz) δ: 12.37 (s, 1H, HCI), 9.13 (d, J =4.8Hz, 1H), 8.89 (d, J =1.2Hz, 1H), 8.45 (s, 1H), 8.00 (s, 1H), 7.72 (d, J =8.4Hz, 1H), 7.64 (s, 2H, NH2), 7.23 (s, 2H, NH2), 7.17 (d, J =8.0Hz, 1H), 7.16 (d, J =8.0Hz, 1H), 7.15 (d, J =1.6Hz, 1H), 6.82 (d, J =8.0Hz, 1H), 4.01 (s, 2H), 3.99 (s, 3H, -OCH3), 3.24 (t, J =0.4Hz, 2H), 2.95 (t, J =0.8Hz, 2H).
Example 57 5-((5-(6,7-dimethoxy-2,3-dihydro-1H-inden-4-yl)indolin-1-yl)methyl)pyrimidine-2,4- diamine trihydrochloride
Figure imgf000048_0001
1H NMR (DMSO-d6, 400 MHz) δ: 12.37 (s, 1H, HC1), 8.42 (s, 1H), 7.12 (d, J =6.4Hz, 1H), 7.69 (s, 4H, NH2), 7.38 (s, 1H), 7.25 (s, 1H), 6.67 (d, J =8.4Hz, 1H), 4.24 (s, 2H), 3.81 (s, 3H, - OCH3), 3.80 (s, 3H, -OCH3), 3.29 (t, J =16.8Hz, 2H), 2.96 (t, J =0.8Hz, 2H), 2.52-2.50 (m, 4H), 1.97-1.91 (t, J = 14.4Hz, 2H).
Example 58
5-((5-(quinolin-5-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride
Figure imgf000048_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.11 (s, 1H, HC1), 9.22 (d, J =4.4Hz, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.23 (d, J =12.8Hz, 1H), 8.05 (d, J =7.6Hz, 1H), 7.75 (d, J =0.4Hz, 1H), 7.29 (s, 1H), 7.28 (s, 4H, NH2), 7.22 (d, J =1.2Hz, 1H), 7.20 (d, J =1.6Hz, 1H), 6.83 (d, J =8.0Hz, 1H), 4.34 (s, 2H), 3.40 (t, J =0.4Hz, 2H), 3.04 (t, J =0.4Hz, 2H).
Example 59 4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-hydroxy-2-naphthoic acid trihydrochloride
Figure imgf000048_0003
1H NMR (DMSO-d6, 400 MHz) δ: 12.30 (s, 1H, -HC1), 11.90 (s, 1H, -OH), 8.44 (s, 1H), 8.39 (d, J =1.2Hz, 1H), 8.37 (d, J =1.2Hz, 1H), 7.85 (d, J =8.0Hz, 2H), 7.77 (s, 4H, NH2), 7.58 (s, 1H), 7.19 (s, 1H), 7.12, 7.10 (dd, J = 1.6Hz, 1H), 6.77 (d, J =8.0Hz, 1H), 4.26 (s, 2H), 3.35 (t, J = 16.0Hz, 2H), 3.01 (t, J =1.2Hz, 2H). Example 60
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2,3,5,6-tetramethylbenzoic acid
Figure imgf000049_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.71 (s, 1H), 6.76 (d, J =8.0Hz, 2H), 6.75 (s, 1H), 6.17 (s,
2H, NH2), 5.88 (s, 2H, NH2), 3.97 (s, 2H), 3.18 (t, J = l.2Hz, 2H), 2.90 (t, J = 16.0Hz, 2H), 2.14
(s, 6H), 1.91 (s, 6H).
Example 61
5-((5-(4-fluoronaphthalen-1-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride
Figure imgf000049_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.93 (s, 1H, HC1), 8.44 (s, 1H), 8.11 (d, J =7.6Hz, 1H), 7.92 (d, J =8.4Hz, 1H), 7.76 (s, 2H, NH2), 7.68 (s, 2H, NH2), 7.40 (d, J =1.2Hz, 2H), 7.62 (t, J = 1.2Hz, 2H), 7.20(s, 1H), 7.14 (t, J =4.0Hz, 1H), 6.78 (d, J =8.0Hz, 1H), 4.08 (s, 2H), 3.36 (t, J =0.4Hz, 2H), 3.02 (t, J =0.4Hz, 2H).
Example 62
5-((5-(dibenzo[b,d]furan-3-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride
Figure imgf000049_0003
1H NMR (DMSO-d6, 400 MHz) δ: 12.20 (s, 1H, HC1), 8.43 (s, 1H), 8.36 (s, 1H), 8.22 (d, J
=1.2Hz, 1H), 7.75 (d, J =8.8Hz, 2H), 7.70 (d, J =8.0Hz, 1H), 7.56 (s, 4H, NH2), 7.55 (d, J = 1.6Hz, 2H), 7.54 (t, J =2.8Hz, 1H), 7.47 (t, J =1.2Hz, 1H), 6.77 (d, J =8.4Hz, 1H), 4.08 (s, 2H), 3.34 (t, J =0.4Hz, 2H), 3.02 (t, J =16.0Hz, 2H). Example 63
6-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-naphthoic acid
Figure imgf000050_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.35 (s, 1H), 8.03 (d, J =2.8Hz, 2H), 8.02 (s, 1H), 8.00 (d, J = 1.6Hz, 1H), 7.92 (d, J =13.2Hz, 1H), 7.80 (d, J=8.8Hz,1H), 7.69 (s, 1H), 7.55 (s, 1H), 6.80 (d, J =8.0Hz, 1H), 6.16 (s, 2H, NH2), 5.87 (s, 2H, NH2), 4.00(s, 2H), 3.23 (t, J =16.0Hz, 2H), 2.96 (t, J =0.8Hz, 2H).
Example 64 6-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-methyl-1H-benzo[de]isoquinoline- 1,3 (2H)-dione
Figure imgf000050_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.55 (d, J =1.2Hz, 2H), 8.53 (d, J =1.2Hz, 1H), 8.51 (d, J =2.6Hz, 1H), 7.86 (d, J=7.2Hz,2H), 7.84 (s, 1H), 7.29 (s, 1H), 6.88 (d, J =8.0Hz, 1H), 6.19 (s, 2H, NH2), 5.89 (s, 2H, NH2), 4.07 (s, 2H), 3.44 (t, J = 10 AHz, 2H), 3.17 (s, 3H), 2.68 (t, J =4.0Hz, 2H).
Example 65
8-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-methyl-2H-benzo[b][1,4]oxazin-3 (4H)-one trihydrochloride
Figure imgf000050_0003
1H NMR (DMSO-d6, 400 MHz) δ: 12.09 (s, 1H, HC1), 8.41 (s, 1H), 7.73 (s, 2H, NH2), 7.67 (s, 1H), 7.65 (s, 2H, NH2), 7.19 (d, J = 1.6Hz, 1H), 7.11 (d, J =0.8Hz, 2H), 7.02 (t, J =0.8Hz, 1H), 6.67 (d, J =8.4Hz, 1H), 4.62 (s, 2H), 4.03 (s, 2H), 3.85 (s, 3H), 3.31 (t, J =5.2Hz, 2H), 2.96 (t, J =0.8Hz, 2H).
Example 66
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)naphthalene-1-sulfonic acid
Figure imgf000051_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.92 (d, J =8.4Hz, 1H), 8.80 (s, 1H, SO3H), 7.96 (d, J
=7.6Hz, 1H), 7.87 (d, J =8.4Hz, 1H), 7.44 (s, 1H), 7.51 (t, J =0.4Hz, 1H), 7.44 (t, J =14.4Hz, 1H), 7.35 (s, 2H, NH2), 7.33 (d, J =6.4Hz, 1H), 7.28 (d, J =1.6Hz, 1H), 7.17 (s, 2H, NH2), 6.95 (s, 1H), 6.79 (d, J =8.0Hz, 1H), 4.06 (s, 2H), 3.13 (t, J =0.4Hz, 2H), 3.00 (t, J =0.8Hz, 2H).
Example 67
5-((5-(4-chloronaphthalen-1-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride
Figure imgf000051_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.20 (s, 1H, HC1), 8.43 (s, 1H), 8.26 (d, J =8.0Hz, 1H), 7.96 (d, J =8.0Hz, 1H), 7.79 (s, 1H), 7.75 (d, J =8.0Hz, 1H), 7.72 (t, J =0.4Hz, 1H), 7.70 (s, 4H, NH2), 7.61 (t, J =3.2Hz, 1H), 7.36 (d, J =7.6Hz, 1H), 7.15-7.13 (q, J =3.2Hz, 1H), 6.79 (d, J =8.0Hz, 1H), 4.09 (s, 2H), 3.37 (t, J =0.4Hz, 2H), 3.02 (t, J =16.0Hz, 2H).
Example 68 ethyl 4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-naphthoate trihydrochloride
Figure imgf000051_0003
1H NMR (DMSO-d6, 400 MHz) δ: 12.0 (s, 1H, HC1), 8.84 (d, J =8.8Hz, 1H), 8.43 (s, 1H), 8.15 (d, J =7.6Hz, 1H), 8.0 (d, J =8.4Hz, 1H), 7.76 (s, 2H, NH2), 7.68 (s, 2H, NH2), 7.68 (t, J =3.2Hz, 1H), 7.66 (d, J =6.8Hz, 1H), 7.46 (d, J =7.6Hz, 1H), 7.24 (s, 1H), 7.17 (d, J =8.0Hz, 1H), 6.80 (d, J =8.0Hz, 1H), 4.46-4.41 (q, J =0.4Hz, 2H), 4.10 (s, 2H), 3.39 (t, J =0.4Hz, 2H), 3.04 (d, J =8.0Hz, 2H), 1.40 (t, J =0.4Hz, 3H.
Example 69
N-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)naphthalen-1-yl)acetamide
Figure imgf000052_0001
1H NMR (DMSO-d6, 400 MHz) δ: 9.93 (s, 1H, -NH), 8.11 (d, J =0.4Hz, 1H), 7.92 (d, J =8.0Hz, 1H), 7.72 (s, 1H), 7.66 (d, J =0.4Hz, 1H), 7.50 (t, J =0.4Hz, 1H), 7.49 (t, J =0.4Hz, 1H), 7.34 (d, J =7.6Hz, 1H), 7.17 (s, 1H), 7.13 (d, J =8.4Hz, 1H), 6.82 (d, J =8.0Hz, 1H), 6.40 (s, 2H, NH2), 6.00 (s, 2H, NH2), 4.03 (s, 2H), 3.26 (t, J =0.4Hz, 2H), 2.96 (d, J =8.0Hz, 2H), 2.33 (s, 3H).
Example 70
5-((5-methoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000052_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.65 (s, 1H), 6.74 (s, 1H), 6.62 (d, J =2Hz, 2H), 6.12 (s, 2H, NH2), 5.84 (s, 2H, NH2), 3.83 (s, 2H), 3.66 (s, 3H), 3.4 (t, J =0.4Hz, 2H), 2.80(t, J =0.4Hz, 2H).
Example 71
5-(indolin-1-ylmethyl)pyrimidine-2,4-diamine
Figure imgf000052_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.69 (s, 1H), 7.10 (d, J =6.4Hz 2H), 7.02 (d, J =7.6Hz, 2H), 7.01-7.03 (m, 2H, NH2), 6.62-6.69 (m, 2H, NH2), 3.98 (s, 2H), 2.91 (t, J =16.0Hz, 2H), 2.91 (t, J =0.4Hz, 2H).
Example 72
5-((4,5,6-trimethoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000053_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.69 (s, 2H, NH2), 7.53 (s, 2H, NH2), 6.25 (s, 1H), 3.96 (s, 2H), 3.79 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.29-3.16 (m, 2H), 3.14-2.84 (m, 2H).
Example 73 1-((2,4-diaminopyrimidin-5-yl)methyl)-4, 5, 6-trimethoxyindoline-2, 3-dione
Figure imgf000053_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.89 (s, 1H), 6.63 (s, 1H), 6.30 (s, 2H, NH2), 5.98 (s, 2H, NH2), 4.60 (s, 2H), 4.03 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.63 (s, 3H, OCH3).
Example 74
5-((5-chloroindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000053_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.64 (s, 1H), 7.07 (s, 1H), 7.06 (d, J =12.4Hz, 1H), 7.03 (d, J =6.4Hz, 1H), 6.17 (s, 2H, NH2), 5.91 (s, 2H, NH2), 3.92 (s, 2H), 3.16 (t, J =4.0Hz, 2H), 2.85 (t, J =0.4Hz, 2H).
Example 75
5-((5-fluoroindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000054_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.65 (s, 1H), 6.95 (d, J =2.4Hz, 1H), 6.93-6.80(m, 1H), 6.66- 6.63 (m, 1H), 6.13 (s, 2H, NH2), 5.86 (s, 2H, NH2), 3.87 (s, 2H), 3.11 (t, J =0.4Hz, 2H), 2.84 (t , J=0.4Hz, 2H).
Example 76
5-((5-bromoindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000054_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.64 (s, 1H), 7.19 (s, 1H), 7.18-7.14 (m, 1H), 6.62 (d, J =8.4Hz, 1H), 6.13 (s, 2H, NH2), 5.87 (s, 2H, NH2), 3.91 (s, 2H), 3.16 (t, J =0.4Hz, 2H), 2.88 (t, J =2.8Hz, 2H).
Example 77
2-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol
Figure imgf000054_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.65 (s, 1H), 7.30(d, J =9.2Hz, 2H), 6.73 (d, J =8.4Hz, 1H),
6.14 (s, 2H, NH2), 5.87 (s, 2H, NH2), 3.98 (s, 2H), 3.23 (t, J =0.8Hz, 2H), 2.90(t, J =0.4Hz, 2H), 1.64 (s, 1H).
Example 78
5-((7-methoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000054_0004
1H NMR (DMSO-d6, 400 MHz) δ: 11.5 (s, 1H, NH2), 7.71 (s, 1H), 7.56 (s, 1H), 7.4 (s, 2H), 6.83-6.74 (m, 1H, 2H, NH2), 4.20(s, 2H), 3.78 (s, 3H), 3.35 (t, J =7.6Hz, 2H), 2.94 (t, J =0.4Hz, 2H).
Example 79
5-((6-methoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000055_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.8 (s, 1H, NH2), 7.68 (s, 1H), 7.54 (s, 2H, NH2), 6.96 (d, J =8.0Hz, 1H), 6.27 (s, 1H, NH2),6.22-6.20(q, 2H), 3.98 (s, 2H), 3.69 (s, 3H), 3.25 (t, J = 28Hz, 2H), 2.92 (t, J=16Hz, 2H).
Example 80
5-((5,6-dimethoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000055_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.66 (s, 1H), 6.78 (s, 1H), 6.55 (s, 1H), 6.14 (s, 2H, NH2), 5.86s, 2H, NH2), 3.87 (s, 2H), 3.72 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 2.89 (t, J =14.4Hz, 2H), 2.73 (t, J=2Hz, 2H).
Example 81
5-((5-(1,1,1,3,3,3-hexafluoro-2-methoxypropan-2-yl)indolin-1-yl)methyl)pyrimidine-2,4- diamine
Figure imgf000055_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.66 (s, 1H), 7.15 (s, 2H), 6.78 (d, J =8.4Hz, 1H), 6.15 (s, 2H, NH2), 5.88 (s, 2H, NH2), 4.00(S, 2H), 3.40(S, 3H, OCH3), 3.27 (t, J =1Hz, 2H), 2.95 (t, J =8.4Hz, 2H). Example 82
5-((5-phenylindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000056_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.68 (s, 1H), 7.57 (d, J =14.4Hz, 2H), 7.56-7.33 (m, 4.0H), 7.26-7.22 (m, 2H), 6.76 (d, J =8.4Hz, 1H), 6.15 (s, 2H, NH2), 5.87 (s, 2H, NH2), 3.98 (s, 2H),
3.20(t, J=0.4Hz, 2H), 2.92 (t, J=0.4Hz, 2H).
Example 83
5-((5-(3-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diainine
Figure imgf000056_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.38 (s, 1H), 7.34 (d, J =6.0Hz, 1H), 7.32 (d, J =6.0Hz, 1H), 7.29 (s, 1H), 7.27 (s, 1H), 7.13 (s, 1H), 7.11 (s, 1H), 7.07 (d, J =2Hz, 1H), 6.83 (t, J= 1.6Hz, 1H), 6.76 (t, J =9.2Hz, 1H), 6.14 (s, 2H, NH2), 5.87 (s, 2H, NH2), 3.98 (s, 2H), 3.80(s, 2H, OCH3), 3.18 (t, J =6.4Hz, 2H), 2.94 (t, J =2Hz, 2H).
Example 84
5-((5-(2-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000056_0003
1H NMR (DMSO-d6, 400 MHz) δ: 11.8 (s, 1H, NH2), 7.71 (s, 1H), 7.26 (t, J =1.6Hz, 2H), 7.25 (d, J =1.6Hz, 1H), 7.22 (d, J =2Hz, 2H), 7.07 (s, 1H), 7.05 (s, 1H), 6.66 (s, 2H, NH2), 5.76 (s, 1H, NH2), 4.01 (s, 2H), 3.74 (s, 2H, OCH3), 3.29 (t, J =0.4Hz, 2H), 2.95 (t, J=1.6Hz, 2H).
Example 85
5-((5-methoxy-2-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000057_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.50(s, 1H, NH2), 8.20(s, 1H, NH2), 7.80(s, 1H), 7.54 (s, broad, 2H, NH2), 6.76 (s, 1H), 6.55 (d, J =2.8Hz, 1H), 6.26 (d, J =8.4Hz, 1H), 3.85 (t, J =2.8Hz, 2H), 3.81 (s, 3H, OCH3), 3.35 (s, 1H), 3.18-3.10(m, 1H), 2.56-2.50(m, 1H), 1.21 (d, J =6.0Hz, 3H, CH3).
Example 86
5-((5-methoxy-2-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000057_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.45 (s, 1H), 7.39 (d, J =1.6Hz, 2H), 7.37 (s, 3H), 7.09 (s,
1H), 7.08 (s, 1H), 7.05 (s, 2H, NH2), 6.80(s, 2H, NH2), 6.71 (t, J = 1.2Hz, 1H), 6.45 (d, J =8.0Hz,
1H), 4.61 (t, 7=0.4Hz, 1H), 3.86 (s, 2H), 3.40(9, 1H), 2.88 (s, 1H).
Example 87
5-((5-(trifluoromethoxy)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000057_0003
1H NMR (DMSO-d6, 400 MHz) δ: 11.50(s, 1H, NH2 ),7.68 (s, 1H), 7.49 (s, 2H, NH2), 7.43 (s, 1H, NH2), 7.08 (s, 1H), 6.64 (d, 7 =8.8 Hz, 2H), 3.99 (s, 2H), 3.30(t, 7 =16.8Hz, 2H), 2.94 (t, J =0.4Hz, 2H); ESI-MS(m/z): 326.05 (50%)(M+H)+; UPLC Purity: 93.22%(3.11 min)
Example 88
5-((5-(6-methoxypyridin-3-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000058_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.08 (d, J =2Hz, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.65 (d, 7 =2 Hz, 1H), 7.26 (s, 1H), 7.21 (t, J =6.0Hz, 1H), 6.73 (d, J =8.4Hz, 1H), 6.17 (s, 2H, NH2), 5.90(s, 2H, NH2), 3.98 (s, 2H), 3.86 (s, 3H, OCH3), 3.20(t, J =0.4Hz, 2H), 2.90(t, J =5.6Hz, 2H). Example 89
5-((6-chloroindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000058_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.64 (s, 1H), 7.01 (d, J =7.6Hz, 1H), 6.72 (s, 1H), 6.60(d, J =2Hz, 1H), 6.15 (s, 2H, NH2), 5.88 (s, 2H, NH2), 3.94 (s, 2H), 3.19 (t, J =8.4Hz, 2H), 2.82 (t, J =8.4Hz, 2H).
Example 90
5-((5-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000058_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.64 (s, 1H), 6.88 (s, 1H), 6.82 (d, J =8.0Hz, 1H), 6.58 (d, J =7.6Hz, 1H), 6.18 (s, 2H, NH2), 5.91 (s, 2H, NH2), 3.86 (s, 2H), 2.80(t, J =16.0Hz, 2H), 2.68 (t,
J=0.4Hz, 2H), 2.18 (s, 3H).
Example 91
5-((5-(pyridin-4-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000058_0004
1H NMR (DMSO-d6, 400 MHz) δ: 8.50(d, J =4.4Hz, 2H) 7.67 (s, 1H), 7.60(d, J =5.6Hz, 2H)
6.78 (d, J =9.2Hz, 1H), 6.15 (s, 2H, NH2), 5.87 (s, 2H, NH2), 4.03 (s, 2H), 3.25 (t, J =0.4Hz,
2H), 2.95 (t, J=1.6Hz, 2H).
Example 92
5-((5-(phenylethynyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000059_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.48 (s, 1H), 7.48 (d, J =2Hz, 2H), 7.47 (d, J =3.2Hz, 3H),
7.41 (s, 1H), 7.22 (d, J =1.6Hz, 1H), 6.68 (d, J =8.4Hz, 1H), 6.15 (s, 2H, NH2), 5.87 (s, 2H, NH2), 4.00(S, 2H), 3.29 (t, J =1.6Hz, 2H), 2.89 (t, J=0.8Hz, 2H).
Example 93
5-((5-(3,4,5-trimethoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000059_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.39 (s, 1H), 7.35 (d, J = 7.4Hz, 1H), 6.79 (s, 2H), 6.73 (d, J =8.4Hz, 1H),6.21 (s, 2H, NH2), 5.92 (s, 2H, NH2), 3.98 (s, 2H), 3.84 (s, 6.0H, - OCH3), 3.66 (s, 3H, OCH3), 3.20(t, J= 0.4Hz, 2H), 2.92 (t, J= 0.4Hz, 2H).
Example 94
5-((5-(3-(trifluoromethoxy)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000059_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.63 (s, 1H), 7.61 (d, J =1.6Hz, 2H), 7.53 (s, 2H), 7.39 (t, J =4.8Hz, 1H), 6.76 (d, J =8.4Hz, 1H), 6.24 (s, 2H, NH2), 5.96 (s, 2H, NH2), 4.00(s, 2H), 3.24 (t, J=16.8Hz, 2H), 2.92 (t, J =16.8Hz, 2H).
Example 95 5-((5-(4-(trifluoromethoxy)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000060_0001
1H NMR (DMSO-d6, 400 MHz) δ: 7.68 (s, 1H), 7.67 (d, J = 2.8Hz, 2H), 7.39-7.35 (q, J =7.2Hz,
4.0H), 6.76 (d, J =8.4Hz, 1H), 6.14 (s, 2H, NH2), 5.87 (s, 2H, NH2), 3.99 (s, 2H), 3.22 (t, J
=0.4Hz, 2H), 2.94 (t, J=8.0Hz, 2H).
Example 96
5-((5-(2,4-dimethoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000060_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.68 (s, 1H), 7.12 (d, J =4.0Hz, 2H), 7.11 (s, 1H), 6.70(s,
1H), 6.69 (s, 1H), 6.61 (d, J =2.4Hz, 1H), 6.14 (s, 2H, NH2), 5.87 (s, 2H, NH2), 3.94 (s, 2H),
3.78 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.17 (t, J =0.4Hz, 2H), 2.68 (t, J = 8.0Hz, 2H).
Example 97
5-((5-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000060_0003
1H NMR (DMSO-d6, 400 MHz) δ: 7.67 (s, 1H), 7.61 (s, 1H), 7.60 (s, 1H), 7.53 (t, J =2Hz, 1H),
7.42 (d, J =2Hz, 2H), 7.28 (d, J =0.8Hz, 1H), 7.28 (d, J =0.8Hz, 1H), 6.13 (s, 2H, NH2), 5.76 (s, 2H, NH2), 4.0 (s, 2H), 3.25 (t, J=0.4Hz, 2H), 2.94 (t, J =0.4Hz, 2H).
Example 98
5-((2,3,3-trimethylindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000060_0004
1H NMR (DMSO-d6, 400 MHz) δ: 7.80 (s, 2H, NH2), 7.59 (s, 1H), 7.10 (d, J =7.5Hz, 1H), 6.90
(t, J =7.5Hz, 1H), 6.66 (t, J =7.5Hz, 1H), 6.40 (d, J =7.2Hz, 1H), 6.10 (s, 2H, NH2), 4.05 (s, 2H), 3.18 (m, 1H), 2.10 (s, 3H), 1.8 (s, 3H), 1.2 (s, 3H), Note : Extra protons are found because of Isomer possibility
Example 99
5-((5-(naphthalen-2-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000061_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.08 (s, 1H), 7.93 (d, J =8.8Hz, 2H), 7.89 (d, J = 8.0Hz, 1H), 7.80 (d, J = 2Hz, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.52 (d, J =1.2Hz, 1H), 6.81 (d, J =8.0Hz, 1H), 6.16 (s, 2H, NH2), 5.87 (s, 2H, NH2), 4.01 (s, 2H), 3.24 (t, J =0.4Hz, 2H), 2.97 (t, J =0.4Hz, 2H).
Example 100
5-((6-fluoroindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000061_0002
1H NMR (DMSO-d6, 400 MHz) δ: 7.65 (s, 1H), 6.99 (d, J =0.4Hz, 1H), 6.55 (s, 1H), 6.52 (d, J = 6.8Hz, 1H), 6.14 (s, 2H, NH2), 5.88 (s, 2H, NH2), 3.94 (s, 2H), 3.19 (t, J =0.4Hz, 2H), 2.81 (t, J =0.4Hz, 2H).
Example 101
5-((5-(m-tolyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000061_0003
1H NMR (DMSO-d6, 400 MHz) δ 7.67(m, J = 2.0Hz, 1H), 7.37-7.26(m, 5H), 7.10(m, 1H), 6.76- 6.74(m, 1H), 6.18-6.15(m, 2H), 5.86-5.85(m, 2H), 3.97(s, 2H), 3.19(m, 2H), 2.91(m, 2H), 2.32(s, 3H).
Example 102
5-((4-(3-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000062_0001
1HNMR (DMSO-d6, 400 MHz) δ 7.67(s, 1H), 7.36-7.32(m, 1H), 7.14-7.10(m, 1H), 7.02-7.0(m, 1H), 6.97-6.96(m, 1H), 6.92-6.90(m, 1H), 6.72-6.70(m, 2H), 6.23(s, 2H), 5.95(s, 2H), 3.95(s, H), 3.79(s, 3H), 3.1 l(t, J=8.0Hz, 2H), 2.95-2.9 l(t, J=8.2Hz, 2H).
Example 103
5-((4-phenylindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000062_0002
1H NMR (DMSO-d6, 400 MHz) δ 7.67(s, 1H), 7.46-7.41(m, 4H), 7.36-7.32(m, 1H), 7.15- .1 l(m, 1H), 6.71(d, J=8.0Hz, 2H), 6.22(s, 2H), 5.94(s, 2H), 3.95(s, 2H), 3.14-3.10(m, 2H), .95-2.90(m, 2H).
Example 104
5-((5-(pyridin-3-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride
Figure imgf000062_0003
1H NMR (DMSO-d6, 400 MHz) δ 12.01(bs, 1H), 9.1 l(s, 1H), 8.71-8.68(m, 2H), 8.43(s, 1H), .98-7.95(m, 1H), 7.70-7.59(m, 5H), 6.79(d, J=8.4Hz, 1H), 4.11(s, 2H), 3.54-3.43(m, 2H), .17-3.06(m, 2H).
Example 105
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid
Figure imgf000062_0004
1H NMR (DMSO-d6, 400 MHz) δ 7.82(d, J=8.4Hz, 2H), 7.67(s, 1H), 7.43-7.33(m, 4H), 6.75(d, J=8.0Hz, 1H), 6.13(s, 2H), 5.86(s, 2H), 3.97(s, 2H), 3.20-3.16(m, 2H), 2.93-2.91(m, 2H).
Example 106
5-((4-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000063_0001
1H NMR (DMSO-d6, 400 MHz) 7.67(s, 1H), 7.48-7.40(m, 4H), 7.16-7.12(m, 1H), 6.75-6.71(m, 2H), 6.23(s, 2H), 5.94(s, 2H), 3.96(s, 2H), 3.15-3.11(m, 2H), 2.95-2.93(m, 2H).
Example 107
5-((5-(ethylsulfonyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000063_0002
1H NMR (DMSO-d6, 400 MHz) 7.63(s, 1H), 7.48-7.46(m, 1H), 7.40(s, 1H), 6.74(d, J=8.4Hz, 1H), 6.17(s, 2H), 5.88(s, 2H), 4.09(s, 2H), 3.41-3.36(m, 2H), 3.13-3.08(m, 2H), 2.99-2.94(m, 2H), 1.07(t, J=7.40, 3H).
Example 108
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-4-yl)benzoic acid
Figure imgf000063_0003
1H NMR (DMSO-d6, 400 MHz) 7.93-7.91(m, 2H), 7.67(s, 1H), 7.46-7.44(m, 2H), 7.16-7.12(m, 1H), 6.74-6.7 l(m, 2H), 6.14(s, 2H), 5.87(s, 2H), 3.95(s, 2H), 3.14-3.10(m, 2H), 2.96-2.92(m,
2H).
Example 109
4-(1-((2,4-diamino-6-ethylpyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid
Figure imgf000064_0001
1H NMR (DMSO-d6, 400 MHz) 7.83-7.81(m, 2H), 7.43-7.34(m, 4H), 6.78-6.76(m, 1H), 6.04(s, 2H), 5.78(s, 2H), 4.04(s, 2H), 3.3-3.28(m, 2H), 3.16-3.14(m, 2H), 2.88(m, 2H), 1.10(t, J=7.6Hz, 3H).
Example 110
5-((4-(3-chlorophenyl)indolin-1-yl)methyl)-6-ethylpyrimidine-2,4-diamine
Figure imgf000064_0002
1H NMR (DMSO-d6, 400 MHz) 7.48-7.41(m, 4H), 7.16-7.14(m, 1H), 6.77-6.7 l(m, 1H), 6.03(s, 2H), 5.76(s, 2H), 3.18-3.09(m, 4H), 2.91-2.87(m, 2H), 1.11(t, J=7.6Hz, 3H).
Example 111
5-((5-nitroindolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000064_0003
1H NMR (DMSO-d6, 400 MHz) 8.0-7.95(m, 1H), 7.83(m, 1H), 7.63(s, 1H), 6.68(d, J=8.8Hz, 1H), 6.25(s, 2H), 5.94(s, 2H), 4.20(s, 2H),3.55- 3.51(m, 2H), 3.04-2.99(m, 2H).
Example 112
1-((2,4-diaminopyrimidin-5-yl)methyl)indoline-5-carbonitrile
Figure imgf000064_0004
1H NMR (DMSO-d6, 400 MHz) 7.95(s, 1H), 7.49-7.47(m, 1H), 7.40(d, J=1.2Hz, 1H), 6.73(d, J=8.4Hz, 1H), 4.20(s, 2H), 3.45- 3.41(m, 2H), 3.07-3.03(m, 2H).
Example 113
N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)isobutyramide
Figure imgf000065_0001
1HNMR (DMSO-d6): 9.49 (s, 1H), 7.64 (s, 1H), 7.18 (dd, J1= 2 Hz, J2 = 8.4Hz, 2H), 6.61 (d, J =
8.4 Hz, 2H), 6.11 (s, 2H), 5.84 (s, 2H), 3.86 (s, 2H), 3.08 (t, J= 8.4 Hz, ,2H), 2. (t, J = 8 Hz, 2H),
1.24 (t, J = 6.8 Hz, 6H).
Example 114
N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)isobutyramide hydrochloride
Figure imgf000065_0002
1HNMR (DMSO-d6): 9.58 (s, 1H), 8.38 (s, 1H), 7.72-7.66 (m, 3H), 7.39 (m, 1H), 7.24-7.22 (dd, J1= 2 Hz, J2 = 8.4Hz, 1H), 6.6 (d, J = 8.8 Hz, 1H), 3.2 (t, J = 8 Hz, 2H),2.88 (t, J = 7.6 Hz,
2H),1.07 (t, J = 6.8 Hz, 6H).
Example 115 1-((2,4-diaminopyrimidin-5-yl)methyl)-N,N-dimethylindoline-5-carboxamide
Figure imgf000065_0003
1HNMR (DMSO-d6): 7.65 (s, 1H), 7.12 (t, J = 1.6 Hz, 2H), 6.65 (d, J = 8.84 Hz, 1H), 6.13 (bs,
2H), 5.68 (bs, 2H), 3.98 (s, 2H), 3.22 (t, J = 8.4 Hz, 2H), 2.95 (s, 6H), 2.88 (t, J = 7.6 Hz, 2H).
Example 116
N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)acetamide
Figure imgf000065_0004
1HNMR (DMSO-d6): 9.61 (s, 1H), 7.65 (s, 1H),7.34 (d, J = 2 Hz, 2H), 7.15 (dd, = 8.84, J2 = 8.4 Hz, 1H), 6.61 (bs, 2H), 5.68 (d, J = 8.4 Hz, 2H), 6.10 (s, 1H), 5.84 (s, 1H), 3.86 (s, 2H), 2.80 (t, J = 8 Hz, 2H), 2.67 (t, J = 1.6 Hz, 2H),1.97 (s,3H ).
Example 117 1-((2,4-diaminopyrimidin-5-yl)methyl)-N-methylindoline-5-carboxamide
Figure imgf000066_0001
1HNMR (DMSO-d6): 8.04-8.03 (m, 1H), 7.64 (s, 1H), 7-57-7.53 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.2-6.19 (m, 2H), 5.86 (s, 2H), 4.01 (s, 2H), 2.73-2.68 (m, 2H), 2.55 (s, 3H), 2.34-2.33 (m,2H ).
Example 118 (1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)(morpholino) methanone
Figure imgf000066_0002
1HNMR (DMSO-d6): 7.65 (s, 1H), 7.12 (d, J = 4.8 Hz, 2H), 6.65 (d, J = 4.8 Hz, 1H), 6.13 (m, 2H), 5.86 (s, 2H), 3.99 (s, 2H), 3.58 (m, 4H), 3.49 (m, 4H), 3.24 (d, J = 8.4 Hz, 2H), 2.89 (d, J = 8.4 Hz, 2H).
Example 119
1-((2,4-diaminopyrimidin-5-yl)methyl)indoline-5-carboxamide
Figure imgf000066_0003
1HNMR (DMSO-d6): 7.80 (dd, = 2 Hz, J2 = 8.4 Hz, 1H), 7.71 (s, 1H), 7.61 (s, 1H), 6.73 (d, J = 8.8 Hz, 2H), 4.28(s, 2H), 3.63 (t, J= 8.8 Hz, 2H), 3.14 (t, J = 3.2 Hz, 2H).
Example 120 ethyl (1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)carbamate
Figure imgf000067_0001
1HNMR (DMSO-d6): 9.1 (bs, 1H), 7.64 (s, 1H), 7.17 (m, 2H), 6.61 (d, J = 8.8 Hz, 1H), 6.10 (m, 2H), 5.85 (s, 2H), 4.06 (t, J = 7.2 Hz, 2H), 3.85(s, 2H), 3.05 (t, J = 8.8 Hz, 2H), 2.8 (t, J = 8.0 Hz, 2H).
Example 121
2-chloro-N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-nitrobenzamide
Figure imgf000067_0002
1HNMR (DMSO-d6): 10.41 (s, 1H), 8.41 (s, 1H), 8.29 (dd, = 2 Hz, J2 = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 7.46 (s, 1H), 6.68 (d, J = 8 Hz, 1H), 6.13 (s, 2H), 5.86 (s, 2H),3.91 (s, 2H), 3.12 (t, J = 8.0 Hz, 2H), 2.87 (t, J= 7.6 Hz, 2H).
Example 122
2-chloro-N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-3,4-dimethoxybenzamide
Figure imgf000067_0003
1HNMR (DMSO-d6): 7.97 (s, 1H), 7.94 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H) 4.6 (s, 2H), 4.03 (d, J = 7.6 Hz, 2H), 3.95 (s, 3H), 3.87 (s, 3H), 3.41 (t, J = 7.6 Hz, 2H).
Example 123
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)imidazo[1,2-a]pyridine-2-carboxylic acid
Figure imgf000068_0001
1HNMR (CD3OD + DC1): 8.50 (s, 1H), 8.12 (m, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.475 (s, 1H), 7.54 (m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.22 (s, 2H), 3.59-3.50 (m, 2H), 2.11-1.95 (s, 2H).
Example 124
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5- carboxylic acid
Figure imgf000068_0002
1HNMR (CD3OD): 7.73 (s, 1H), 7.32 (s, 1H), 7.30 (m, 1H), 7.24 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 2 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 4.28 (s, 2H), 3.59-3.50 (m, 4H), 4.02 (s, 2H), 3.36-3.35 (m, 1H), 3.18 (t, J = 8.4 Hz, 1H), 2.97 (t, J = 8.4 Hz, 2H).
Example 125 Cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acid
Figure imgf000068_0003
1H NMR (CD3OD + HC1) : 9.17 (s, 1H), 8.61-8.56 (m, 2H), 8.13 (d, J = 7.2 Hz, 1H), 7.84-7.78 (m, 3H), 4.37 (s, 2H), 4.14-4.13 (m, 1H), 3.66 (t, J = 8.0 Hz, 1H), 3.29 (t, J = 8.0 Hz, 1H), 1.56 (m, 2H), 1.37 (t, J = 7.2 Hz, 2H).
Example 126
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-naphthoic acid
Figure imgf000069_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.55 (s, 1H), 8.06 (d, J =8.0Hz, 2H), 7.99 (d, J =8.8Hz, 2H), 7.96(s, 1H), 7.93 (d, J =1.6Hz, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 7.14 (d, J=8.0Hz, 1H), 6.83 (d, J =8.0Hz, 1H), 6.20 (s, 2H, NH2 ), 5.92 (s, 2H, NH2 ), 4.03 (s, 2H), 3.25 (t, J =0.4Hz, 2H), 2.96 (t, J = 16.0Hz, 2H).
Example 127
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-4-yl)-1-naphthoic acid
Figure imgf000069_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.95 (d, J =7.2Hz, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 7.66 (d, J =7.2Hz, 1H), 7.51 (d, J =8.0Hz, 1H), 7.40 (d, J=1.6Hz, 2H), 7.38 (d, J=1.6Hz, 1H), 7.15 (d, J=7.6Hz, 1H), 6.77 (d, J =7.6Hz, 1H), 6.14 (s, 2H, NH2 ), 5.85 (s, 2H, NH2 ), 4.00 (s, 2H), 3.09 (t, J =2.4Hz, 2H), 2.68 (t, J =0.4Hz, 2H).
Example 128
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)-6-methoxyindolin-5-yl)-1-naphthoic acid
Figure imgf000070_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.90 (d, J = 10.0Hz, 1H), 8.11 (d, J =7.2Hz, 1H), 8.74 (s, 1H), 7.63 (d, J =8.8Hz, 1H), 7.59 (t, 7=1.2Hz, 2H), 7.47 (t, J=0.4Hz, 1H), 7.36 (d, 7=7.6Hz, 1H), 6.89 (s, 1H), 6.66 (s, 1H), 6.23 (s, 2H, NH2), 5.94 (s, 2H, NH2), 4.09 (s, 2H), 3.54 (s, 3H, - OCH3), 3.23 (t, 7 =2AHz, 2H), 2.85 (t, J = 16.0Hz, 2H).
Example 129
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-6-yl)-1-naphthoic acid
Figure imgf000070_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.95 (d, 7 =8.8Hz, 1H), 8.18 (t, 7 =0.4Hz, 1H), 7.95 (d, 7 =8.0Hz, 1H), 7.72 (s, 1H), 7.68 (t, J=0.4Hz, 1H), 7.63 (d, 7 =1.2Hz, 1H), 7.47 (d, 7 =7.2Hz, 1H), 7.24 (s, 2H, NH2), 7.17 (s, 2H, NH2), 6.83 (s, 1H), 6.73 (d, 7 =7.6Hz, 1H), 6.56 (s, 1H), 4.02 (s, 2H), 3.29 (t, 7 =0.4Hz, 2H), 2.98 (t, 7 =0.4Hz, 2H).
Example 130
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)naphthalen-2-ol
Figure imgf000070_0003
1H NMR (DMSO-d6, 400 MHz) δ: 9.76 (s, 1H, -OH), 8.14 (s, 2H, NH2), 7.73 (t, 7 =2.8Hz, 2H),
7.38 (s, 1H), 7.21 (s, 1H), 8.14 (s, 2H, NH2), 7.16 (s, 1H), 7.10 (s, 1H), 7.09 (d, 7 =2.0Hz, 2H), 6.91 (d, J =2AHz, 1H), 6.75 (d, J =8.0Hz, 1H), 4.04 (s, 2H), 3.60 (t, J =0.4Hz, 2H), 3.10 (t, J =0.4Hz, 2H).
Example 131
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)naphthalen-1-ol
Figure imgf000071_0001
1H NMR (DMSO-d6, 400 MHz) δ: 10.12 (s, 1H, -OH), 8.20 (d, J =2.8Hz, 1H), 7.83 (d, J = 1.6Hz, 1H), 7.82 (d, J =3.6Hz, 1H), 7.28 (s, 1H), 7.43 (t, J =0.8Hz, 2H), 7.16 (d, J =7.6Hz, 1H), 7.12 (s, 1H), 7.06 (d, J =8.0Hz, 1H), 6.90 (d, J =7.6Hz, 1H), 6.77 (s, 2H, NH2), 6.44 (s, 2H, NH2), 4.02 (s, 2H), 3.25 (t, J =0.4Hz, 2H), 2.95 (t, J =0.4Hz, 2H).
Example 132 1-chloro-6-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)naphthalen-2-ol
Figure imgf000071_0002
1H NMR (DMSO-d6, 400 MHz) δ: 10.20 (s, 1H, -OH), 8.50 (s, 2H, NH2), 8.04 (s, 1H), 8.03 (d, J = 1.6Hz, 2H), 7.86 (d, J =2.0Hz, 1H), 7.82 (d, J =7.2Hz, 1H), 7.68 (s, 1H), 7.26 (d, J =9.2Hz, 1H), 6.75 (d, J =8.0Hz, 1H), 6.44 (s, 2H, NH2), 4.00 (s, 2H), 3.24 (t, J = 16.8Hz, 2H), 2.96 (t, J =0.4Hz, 2H).
Example 133
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid
Figure imgf000072_0001
1H NMR (DMSO-d6, 400 MHz) δ: 15.48 (s, 1H, -COOH), 9.07 (d, J = 13.2Hz, 1H), 8.37 (d, J =8.8Hz, 1H), 8.01 (s, 1H), 7.91 (d, J =8.0Hz, 1H), 7.69 (s, 2H), 7.64 (d, J=8.4Hz, 1H), 7.11 (s, 2H, NH2), 6.80 (d, J =8.0Hz, 1H), 6.75 (s, 2H, NH2), 4.12 (s, 2H), 3.05 (t, J =0.4Hz, 2H), 2.66
(t, J = 1.6Hz, 2H), 1.46 (t, J = 14.4Hz, 3H).
Example 134
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-naphthoic acid
Figure imgf000072_0002
1H NMR (DMSO-d6, 400 MHz) δ: 9.45 (s, 1H), 8.84 (d, J =8.8Hz, 1H), 8.10 (d, J =8.8Hz, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.64 (d, J =6.0Hz, 1H), 7.54 (t, J=1.2Hz, 2H), 6.81 (d, J =8.0Hz, 1H), 6.62 (s, 2H, NH2), 6.29 (s, 2H, NH2), 4.05 (s, 2H), 3.92 (t, J =4.8Hz, 2H), 3.59 (t, J =0.4Hz, 2H).
Example 135
1-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phenoxy)-3-(pyrrolidin-1- yl)propan-2-ol triformate
Figure imgf000072_0003
1H NMR (DMSO-d6, 400 MHz) δ: 8.33 (s(br), 3H, -COOH), 7.66 (s, 1H), 7.46 (d, H = 8.4 Hz, 2H), 7.31-7.25 (m, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8 Hz, 1H), 6.23 (s(br), 2H), 5.99 (S(br), 2H), 3.99-3.87 (m, 7H), 3.19-3.15 (m, 2H), 2.92-2.89 (m, 2H), 2.80-2.50 (m, 4H), 1.74- 1.72 (m, 4H).
Example 136
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-isopropyl-4-oxo-1,4- dihydroquinoline-3-carboxylic acid
Figure imgf000073_0001
1H NMR (DMSO-d6, 400 MHz) δ: 15.43 (s, 1H, -COOH), 8.87 (s, 1H), 8.40 (d, J =8.8Hz, 1H), 8.17 (s, 1H), 7.93 (d, J =8.4Hz, 1H), 7.70 (s, 2H), 7.65 (d, J=8.0Hz,1H), 7.10(s, 2H, NH2), 6.80 (d, J =8.0Hz, 1H), 6.62 (s, 2H, NH2), 5.51 (t, J = 12.8Hz, 1H), 4.09 (s, 2H), 3.02 (t, J =0.4Hz, 2H), 2.68 (t, J =3.2Hz, 2H), 1.60 (d, J =6.4Hz, 6H).
Example 137
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-methyl-4-oxo-1,4- dihydroquinoline-3-carboxylic acid
Figure imgf000073_0002
1H NMR (DMSO-d6, 400 MHz) δ: 15.43 (s, 1H, -COOH), 9.05 (s, 1H), 8.36 (d, J =8.4Hz, 1H), 7.96 (d, J =8.0Hz, 1H), 7.93 (s, 1H), 7.70 (d, J =8.8Hz, 1H), 7.65(s, 1H), 7.64 (s, 1H), 7.11 (s, 2H, NH2), 6.97 (s, 2H, NH2), 6.80 (d, J =8.4Hz, 1H), 4.19 (s, 2H), 4.10 (s, 2H), 3.36 (t, J =0.4Hz, 2H), 2.68 (t, J =0.4Hz, 2H). Example 138
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-(2-(dimethylamino)ethyl)-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid
Figure imgf000074_0001
1H NMR (CD3COOD, 400 MHz) δ: 9.21 (s, 1H), 8.54 (d, J =8.4Hz, 1H), 7.98 (s, 2H), 7.88 (d, J
=8.4Hz, 1H), 7.64 (d, J =8.0Hz, 2H), 6.86 (d, J =1.6Hz, 1H), 6.16 (s, 2H, -NH2), 5.88m (S, 2H, NH2), 5.16 (s, 2H), 4.21 (s, 2H), 3.84 (s, 2H), 3.41 (t, J = 16.0Hz, 2H), 3.14 (d, J =1.2Hz, 2H),
3.09 (s, 6H).
Example 139
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-naphthamide
Figure imgf000074_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.45 (s, 1H), 8.04 (s, 1H), 7.99 (d, J =2.0Hz, 2H), 7.98 (s, 1H), 7.82 (d, J =2.0Hz, 1H), 7.80 (d, J =1.6Hz, 1H), 7.44-7.42 (d, J =2.4Hz, 1H), 7.47 (t, J =7.2Hz, 1H), 7.42 (t, J =4.0Hz, 1H), 6.81 (d, J =8.4Hz, 1H), 6.16 (s, 2H, -NH2), 5.88m (S, 2H, NH2), 4.02 (s, 2H), 3.26 (t, J =0.4Hz, 2H), 2.99 (t, J =0.8Hz, 2H).
Example 140
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-naphthonitrile
Figure imgf000075_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.19-8.17 (dd, J =0.4Hz, 2H), 8.14 (d, J =2AHz, 1H), 7.84 (t, J =4.8Hz, 1H), 7.82 (s, 2H), 7.80 (d, J =1.2Hz, 1H), 7.69 (t, J =1.6Hz, 1H), 7.53 (d, J =7.6Hz, 1H), 6.85 (d, J =8.0Hz, 1H), 6.16 (s, 2H, -NH2), 5.88 (S, 2H, NH2), 4.06 (s, 2H), 3.30 (t, J
=2.0Hz, 2H), 2.99 (t, J =0.4Hz, 2H).
Example 141
Ethyl 7-(3-(2-acetamidoethyl)-1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1- cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate bis(2,2,2-trifluoroacetate)
Figure imgf000075_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.20 (s, 1H, -NH), 8.52 (s, 2H), 8.22 (d, J =8.4Hz, 2H), 8.15 (d, J =1.2Hz, 1H), 7.68 (s, 2H), 7.59 (s, 1H), 6.75 (d, J =8.0Hz, 1H), 6.16 (s, 2H, -NH2), 5.88 (S, 2H, NH2), 4.23 (s, 2H), 4.22 (m, 1H), 4.20 (q, 2H), 3.30 (t, J =0.8Hz, 2H), 3.17 (t, J =0.4Hz, 2H), 3.06 (m, 1H), 2.53 (s, 3H), 2.51-2.449 (q, 2H), 1.69 (s, 3H), 1.31-1.13 (q, 4H).
Example 142
7-(3-(2-acetamidoethyl)-1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-cyclopropyl- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Figure imgf000076_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.78 (s, 1H), 8.34 (s, 1H), 8.22 (d, J =7.6Hz, 1H), 8.15 (d, J = 11.6Hz, 2H), 7.93 (s, 1H, -NH), 7.76 (s, 1H), 7.69 (d, J = 13.2Hz, 2H), 6.83 (s, 1H), ), 6.16 (s, 2H, -NH2), 5.88 (S, 2H, NH2), 4.13 (m, 1H), 4.09 (s, 2H), 3.99 (d, J =8.8Hz, 2H), 3.96-3.64 (m, 4H), 3.45 (t, J =0.8Hz, 2H), 1.79 (s, 3H) 1.63-1.05 (m, 2H).
Example 143
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-ethyl-6-fluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid
Figure imgf000076_0002
1H NMR (DMSO-d6, 400 MHz) δ: 15.13 (s, 1H, -COOH), 9.08 (d, J = 10.0Hz, 1H), 8.10(s, 1H), 7.98 (s, 1H), 7.69(s, 3H), 7.48 (s, 2H, -NH2), 6.82 (d, J =8.0Hz, 1H), 6.74 (S, 2H, NH2), 4.72,4.68 (dd, J =14.4Hz, 2H), 4.09 (s, 2H), 3.37 (t, J =2.0Hz, 2H), 3.02 (t, J =0.4Hz, 2H), 1.44 (t, J = 14.4Hz, 3H).
Example 144 7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-ethyl-6-fluoro-8-methoxy-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid
Figure imgf000076_0003
1H NMR (DMSO-d6, 400 MHz) δ: 14.95 (s, 1H, -COOH), 8.91 (s, 1H), 7.94 (d, J =9.2Hz, 1H), 7.72 (s, 1H), 7.25 (s, 2H, -NH2), 7.22 (s, 1H), 6.85 (S, 2H, NH2), 6.82 (s, 1H), 6.81 (d, J =8.0Hz, 1H), 4.76,4.71 (q, J = 13.6Hz, 2H), 4.08 (s, 2H), 3.38 (s, 3H, OCH3), 3.32 (t, J =0.4Hz, 2H), 2.68 (t, J =0.4Hz, 2H), 1.40 (t, J =0.4Hz, 3H).
Example 145 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)-6-fluoroindolin-5-yl)-6-fluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid
Figure imgf000077_0001
1H NMR (DMSO-d6, 400 MHz) δ: 14.90 (s, 1H, -COOH), 8.80 (s, 1H), 8.78 (s, 1H), 8.25 (d, J =6.0Hz, 1H), 8.16 (s, 2H, -NH2), 8.10 (d, J =9.6Hz, 1H), 7.60 (s, 2H, -NH2), 7.28 (d, J =7.6Hz, 1H), 6.73 (d, J =10.2Hz, 1H), 4.13 (s, 2H), 3.94-3.89 (m, 1H), 3.45 (t, J =16.8Hz, 2H), 3.01 (t, J =0.4Hz, 2H), 1.3- 1.2 (d, J =3.2Hz, 4H).
Example 146
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-ethyl-6-fluoro-8-methoxy-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid dihydrochloride
Figure imgf000077_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.49 (s, 1H, -COOH), 8.99 (s, 1H), 8.41 (s, 1H), 7.96 (d, J =9.6Hz, 1H), 7.61 (s, 2H, -NH2), 7.35 (S, 2H, NH2), 7.26 (s, 1H), 7.22 (s, 1H), 6.80 (d, J =8.4Hz, 1H), 4.71,4.66 (q, J =0.4Hz, 2H), 4.08 (s, 2H), 3.66 (s, 3H, OCH3), 3.36 (t, J =16.0Hz, 2H), 3.01 (t, J =0.4Hz, 2H), 1.39 (t, J =0.4Hz, 3H). Example 147
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-1-isopropyl-4-oxo-1,4- dihydroquinoline-3-carboxylic acid
Figure imgf000078_0001
1H NMR (DMSO-d6, 400 MHz) δ: 15.12 (s, 1H, -COOH), 8.89 (s, 1H), 8.18 (s, 2H), 8.14 (d, J =8.0Hz, 1H), 7.98 (s, 2H, -NH2), 7.70 (s, 2H), 7.17 (S, 2H, NH2), 6.79 (d, J =8.4Hz, 1H), 5.48- 5.42 (m, 1H), 4.11 (s, 2H), 3.40 (t, J = 16.8Hz, 2H), 3.04 (t, J = 16.8Hz, 2H), 1.58 (d, J =6.4Hz, 6H).
Example 148 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)-6-methoxyindolin-5-yl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acid
Figure imgf000078_0002
1H NMR (DMSO-d6, 400 MHz) δ: 15.31 (s, 1H, -COOH), 8.76 (s, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 7.85 (d, J =6.4Hz, 1H), 7.98 (s, 2H, -NH2), 7.78 (S, 2H, NH2), 7.26 (s, 2H), 6.60 (s, 1H), 4.16 (s, 2H), 3.90-3.86 (m, 1H), 3.83 (s, 3H, -OCH3), 3.36 (t, J =2.8Hz, 2H), 2.95 (t, J =0.4Hz, 2H), 1.34 (d, J =1.6Hz, 2H), 1.30 (d, J =7.6Hz, 2H).
Example 149 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)-6-fluoroindolin-5-yl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acid
Figure imgf000079_0001
1H NMR (DMSO-d6, 400 MHz) δ: 15.20 (s, 1H, -COOH), 8.90 (s, 1H), 8.78 (d, J = 11.6Hz, 1H), 8.42 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.73 (s, 2H, -NH2), 7.70 (s, 1H), 7.48 (S, 2H, NH2), 6.73 (d, J = 13.2Hz, 1H), 4.12 (s, 2H), 3.93-3.88 (m, 1H), 3.42 (t, J =0.4Hz, 2H), 3.00 (t, J = 16.8Hz, 2H), 1.31 (d, J =6.0Hz, 2H), 1.28 (d, J =6.0Hz, 2H).
Example 150
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-(4-fluorobenzyl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acid dihydrochloride
Figure imgf000079_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.04 (s, 1H, -COOH), 9.21 (s, 1H), 8.35 (d, J =8.4Hz, 2H), 7.88 (d, J = 1.6Hz, 2H), 7.86 (s, 2H), 7.75 (s, 2H, -NH2), 7.65 (s, 1H), 7.55 (d, J =8.0Hz, 1H), 7.50 (S, 2H, NH2), 7.20 (d, J =8.8Hz, 2H), 6.70 (d, J =8.4Hz, 1H), 5.91 (s, 2H), 4.06 (s, 2H), 3.36 (t, J = 16.8Hz, 2H), 3.00 (t, J =0.8Hz, 2H).
Example 151 1-cyclopropyl-7-(1-((2,4-diamino-6-ethylpyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-8- methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Figure imgf000080_0001
1H NMR (DMSO-d6, 400 MHz) δ: 14.78 (s, 1H, NH2), 12.26 (S, 1H, -COOH), 8.79 (s, 1H), 7.86 (d, J =9.2Hz, 1H),7.66 (s, 2H, -NH2), 7.63 (S, 1H, NH2), 7.24 (s, 2H), 6.90 (d, J =8.8Hz, 1H), 4.26 (s, 2H), 4.24-4.18 (m, 1H), 3.42 (s, 3H, OCH3), 3.27 (t, J =0.4Hz, 2H), 2.95 (t, J =0.4Hz, 2H), 2.33 (q, J =0.4Hz, 2H), 1.88 (t, J = 15.2Hz, 3H), 1.03-0.89 (d, J =2.0Hz, 4H).
Example 152 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-8-methyl-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid dihydrochloride
Figure imgf000080_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.20 (s, 1H, -COOH), 8.91 (s, 1H), 8.43 (s, 1H), 7.96 (d, J =2.2Hz, 1H), 7.92 (s, 2H, NH2), 7.78 (s, 2H, -NH2), 7.37 (s, 1H), 7.13 (s, 1H), 6.79 (d, J =8.4Hz, 1H), 4.36-4.34 (m, 1H), 4.07 (s, 2H), 3.71 (s, 3H,-CH3), 3.35 (t, J =0.4Hz, 2H), 3.00 (t, J =0.8Hz, 2H), 1.24 (d, J =6.4Hz, 2H), 1.03 (d, J =8.4Hz, 2H).
Example 153 (S)-10-(1-((2,4-diamino-6-ethylpyrimidin-5-yl)methyl)indolin-5-yl)-9-fluoro-3-methyl-7- oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid
Figure imgf000080_0003
1H NMR (DMSO-d6, 400 MHz) δ: 15.01 (s, 1H, -COOH), 9.06 (s, 1H), 7.70 (d, J =9.6Hz, 1H), 7.21 (s, 1H), 7.18 (s, 2H, NH2), 7.17 (s, 1H), 7.10 (s, 2H, -NH2), 6.84 (d, J =8.8Hz, 1H), 4.97 (d, J =6.4Hz, 1H), 4.52 (d, J = 10.4Hz, 2H), 4.30 (d, J =6.4Hz, 2H), 4.11 (s, 2H), 3.23 (t, J =0.4Hz, 2H), 2.91 (t, J =16.0Hz, 2H), 1.46 (d, J =6.8Hz, 3H), 1.26 (t, J =0.4Hz, 3H).
Example 154 8-chloro-1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid dihydrochloride
Figure imgf000081_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.98 (s, 1H, -COOH), 8.92 (s, 1H), 8.08 (d, J =8.4Hz, 1H), 7.77 (s, 1H), 7.28 (s, 1H), 7.30 (s, 2H, NH2), 7.16 (s, 2H, -NH2), 7.04 (s, 1H), 6.78 (d, J =8.0Hz, 1H), 4.40-4.20 (m, 1H), 4.09 (s, 2H), 3.38 (t, J =0.4Hz, 2H), 3.02 (t, J =1.2Hz, 2H), 1.24 (d, J =4.0Hz, 2H), 1.16 (d, J =14.4Hz, 2H).
Example 155 5-acetamido-1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro- 8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid trihydrochloride
Figure imgf000081_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.20 (s, 1H, -COOH), 10.09 (s, 1H, -NH), 8.78 (d, J =7.6Hz, 1H), 8.42 (s, 1H), 7.78 (s, 2H), 7.39 (s, 2H, -NH2 ), 7.13 (S, 2H, NH2 ), 6.80 (d, J =8.0Hz, 1H), 4.22 (s, 3H, -OCH3), 4.02 (s, 2H), 3.51-3.38 (m, 1H), 3.03 (t, J =0.4Hz, 2H), 2.67 (t, J =0.4Hz, 2H), 2.11 (s, 3H), 1.04, 1.01 (q, J =4.4Hz, 4H).
Example 156
5-amino-1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-8- methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Figure imgf000082_0001
1H NMR (DMSO-d6, 400 MHz) δ: 14.68 (s, 1H, -COOH), 8.64 (s, 1H), 7.73 (s, 1H), 7.6 (s (br), 2H, -NH2 ), 7.29-7.19 (m, 5H), 6.78 (d, J =8.4Hz, 1H), 4.12-4.09 (m, 1H), 4.07 ( s, 2H), 3.38-3.33 (m, 5H), 3.00 (t, 2H, J = 8 Hz), 1.04, 1.01 (m,4H).
Example 157 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-8-methoxy-4-oxo-1,4- dihydroquinoline-3-carboxylic acid dihydrochloride
Figure imgf000082_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.36 (s(br) , 1H, -COOH), 8.82 (s, 1H), 8.42 (s, 1H), 7.72-
7.71 (m, 1H), 7.65-7.21 (m, 6H), 6.79 (d, J = 8.0 Hz, 1H), 4.28-4.23 (m, 1H), 4.10 (s, 2H), 3.40-
3.35 (m, 5H), 3.05-3.01 (t, 2H, J = 3.2 Hz), 1.23-1.18 (m,4H).
Example 158
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate
Figure imgf000083_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.83 (s, 1H), 7.80 (d, J =9.6Hz, 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.19 (s, 4H, -NH2 ), 6.79 (d, J =8.0Hz, 2H), 4.25-4.20 (q, J = 0.4Hz, 2H), 4.22-4.04 (m, 1H), 4.04 (s, 2H), 3.31 (t, J = 0.4Hz, 2H), 2.97 (t, J = 0.4Hz, 2H), 1.27 (t, J = 0.4Hz, 3H), 1.16 (s, 2H), 1.18 (d, J =6.0 Hz, 2H).
Example 159
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate dihydrochloride
Figure imgf000083_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.21 (s, 2H, HC1), 8.71 (s, 1H), 8.53 (d, J =8.8Hz, 1H), 7.82 (s, 2H), 7.56 (s, 4H, -NH2 ), 7.19 (s, 2H), 6.77 (d, J =8.0Hz, 1H), 4.27-4.21 (q, J =7.2 Hz, 2H), 4.01 (s, 2H), 3.77-3.72 (m, 1H), 3.46-3.37 (m, 2H), 3.06-2.99 (m, 2H), 1.29 (t, J =7.2 Hz, 3H), 1.16-1.12 (m, 2H), 1.10-1.08 (m, 2H).
Example 160 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid dihydrochloride
Figure imgf000083_0003
1H NMR (DMSO-d6, 400 MHz) δ: 12.23 (s(br) , 1H, -COOH), 8.77 (s, 1H), 8.42 (s, 1H), 7.98- 7.96 (m, 1H), 7.77-7.70 (m, 4H), 7.27-7.22 (m, 2H), 6.79 (d, J = 8.0 Hz, 1H), 4.18-4.16 (m, 1H), 4.11 (s, 2H), 3.42 (t, J = 8 Hz, 2H), 3.03 (t, 2H, J = 8 Hz), 1.26-1.15 (m,4H).
Example 161 (S)-10-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-3-ethyl-9-fluoro-7-oxo-2,3- dihydro-7H- [ 1 ,4 ]oxazi no [2,3,4-ij ] quinoline-6-carboxy lie acid dihydrochloride
Figure imgf000084_0001
1H NMR (DMSO-d6, 400 MHz) δ: 12.15 (s(br) , 1H, -COOH), 9.04 (s, 1H), 8.42 (s, 1H), 7.75-7.67 (m, 5H), 7.21-7.16 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 4.80-4.76 (m, 1H), 4.67 (d, J = 10 Hz, 1H), 4.40 (d, J = 10 Hz, 1H), 4.06 (s, 2H), 3.35 (t, 2H, J = 8 Hz), 2.98 (t, 2H, J = 8 Hz), 1.88-1.72 (m,2H), 0.93 (t, J = 8 Hz, 3H).
Example 162
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-1-(4-fluorophenyl)-8- methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid dihydrochloride
Figure imgf000084_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.15 (s(br) , 1H, -COOH), 8.48 (s, 1H), 8.38 (s, 1H), 7.97 (d, J = 9 Hz, 1H), 7.77-7.58 (m, 6H), 7.41-7.37(m, 2H), 7.13-7.09 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 3.36-3.31 (m, 2H), 2.97 (t, 2H, J = 8 Hz), 2.69 (s, 3H).
Example 163 (R)-10-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-9-fluoro-3-methyl-7-oxo-2,3- dihydro-7H- [ 1 ,4 ]oxazi no [2,3,4-ij ] quinoline-6-carboxy lie acid
Figure imgf000085_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.59 (s(br) , 1H, -COOH), 9.08(s, 1H), 7.99 (s, 1H), 7.88-7.85 (m, 1H), 7.34-7.32 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 4.84-4.81(m, 1H), 4.53-4.50 (m, 2H), 4.20- 4.18 (m, 2H), 3.36-3.34 (m, 2H), 3.09-3.03 (m, 2H),1.66 (d, J = 6 Hz, 3H).
Example 164
(S)-10-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-9-fluoro-3-methyl-7-oxo-2,3- dihydro-7H- [ 1 ,4 ]oxazi no [2,3,4-ij ] quinoline-6-carboxy lie acid
Figure imgf000085_0002
1H NMR (DMSO-d6, 400 MHz) δ: 15.08 (s(br) , 1H, -COOH), 9.05(s, 1H), 7.70-7.67 (m, 2H), 7.20-7.16 (m, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.15 (s(br) , 2H), 5.87 (s(br), 2H), 4.98-4.95 (m, 1H), 4.53-4.50 (m, 1H), 4.40-4.37 (m, 1H), 4.02 (s, 2H), 3.28-3.24 (m, 2H), 2.95-2.89 (m, 2H),1.48 (d, J = 6.4 Hz, 3H).
Example 165
8-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylic acid
Figure imgf000085_0003
1H NMR (DMSO-d6, 400 MHz) δ: 15.31 (s(br) , 1H, -COOH), 12.07 (s(br), 2H), 8.31-8.28 (m, 1H), 8.10-7.61 (m, 5H), 7.26-7.19 (m, 3H), 6.85 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 3.42-3.38 (m, 2H), 3.06-3.02 (m, 2H).
Example 166 6-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid
Figure imgf000086_0001
1H NMR (DMSO-d6, 400 MHz) δ: 15.36 (s(br) , 1H, -COOH), 12.07 (s(br), 2H), 9.09 (s, 1H), 8.49 (s, 1H), 8.42-8.40 (m, 1H), 8.23-8.22 (m, 1H), 8.08-7.31 (m, 5H), 6.79 (d, J = 8 Hz, 1H), 4.64 (q, J = 6.8 Hz, 2H), 4.07 (s, 2H), 3.36-3.32 (m, 2H), 3.04-2.99 (m, 2H), 1.45 (t, J = 6.8 Hz, 3H).
Example 167 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid
Figure imgf000086_0002
1H NMR (DMSO-d6): 14.98 (s, 1H), 8.75 (s, 1H), 8.26 (d, J = 6.8 Hz, 1H), 8.05 (d, J = 10.8 Hz, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.45 (s, 1H), 6.83 (d, J = 8.4 Hz, 2H), 6.19 (s, 2H), 5.89 (s, 2H), 4.06 (s, 2H), 3.96 (m, 1H), 2.98 (m, 2H), 1.32 (m, 2H), 1.25 (m, 2H).
Example 168 1-(cyclopropylmethyl)-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acid
Figure imgf000087_0001
1HNMR (CD3OD + HC1) : 9.42 (s, 1H), 8.63 (d, J = 8.05 Hz, 1H), 8.37 (s, 1H), 8.17 (d, J = 9.2
Hz, 1H), 7.87-7.8 (m, 3H), 7.08 (d, J = 8.4 Hz, 1H), 4.74 (d, J = 7.2 Hz, 2H), 4.37 (s, 2H), 3.66
(m, 2H), 3.29 (m, 2H), 1.57 (m, 1H), 0.85-0.8(m, 2H), 0.69-0.60(m, 2H).
Example 169 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-4-oxo-1,4- dihydro-1,8-naphthyridine-3-carboxylic acid bis 2,2,2-trifluoroacetic acid
Figure imgf000087_0002
1HNMR (DMSO-d6): 14.7 (s, 1H), 12.35 (s, 1H), 8.8 (s, 1H), 8.57 (d, J = 3.5 Hz,1H), 8.2-8.0 (m, 2H), 7.9-7.7 (m, 3H), 6.78 (d, J = 2.8 Hz, 1H), 4.1 (s, 2H), 3.96 (m, 1H), 3.54-3.49 (m, 2H), 3.1-3.0 (m, 2H), 1.24-1.1 (m, 4H).
Example 170 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-8-methoxy-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid bis 2,2,2-trifluoroacetic acid
Figure imgf000088_0001
1HNMR (DMSO-d6): 14.8 (s, 1H), 11.95 (s, 1H), 8.79 (s, 1H), 8.55 (s, 1H), 7.92 (d, J = 9.6 Hz, 1H), 7.73-7.22 (m, 4H), 6.8 (d, J= 8.0 Hz, 1H), 4.28 (s, 2H), 4.16 (s, 2H), 3.4 (s, 3H), 3.04-3.0 (m, 2H), 1.26- 1.11 (m, 4H).
Example 171
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-(2,4-difluorophenyl)-6-fluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid
Figure imgf000088_0002
1HNMR (DMSO-d6): 14.6 (s, 1H), 8.96 (s, 1H), 8.16 (d, J = 10.4 Hz, 1H), 8.0-7.96 (m, 1H), 7.76-7.71 (m, 1H), 7.64 (s, 1H), 7.46-7.04 (m, 3H), 6.97-6.7(m, 3H), 4.04 (s, 2H), 2.95 (t, J = 8 Hz, 2H).
Example 172
10-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-9-fluoro-7-oxo-2,3-dihydro-7H-
[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid bis 2,2,2-trifluoroacetic acid
Figure imgf000089_0001
1H NMR (DMSO-d6): 15.11 (s, 1H), 11.86 (s, 1H), 8.97 (s, 1H), 8.4 (s, 1H), 7.72-7.52 (m, 5H), 7.2-7.12 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H), 4.58-4.55 (m, 4H), 4.07 (s, 2H), 3.01-.2.94 (m, 2H). Example 173 1-cyclopropyl-7-(1-((2,4-diamino-6-ethylpyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid
Figure imgf000089_0002
1H NMR (DMSO-d6): 14.99 (s, 1H), 8.76 (s, 1H), 8.26 (d, J = 6.8 Hz, 1H), 8.07 (d, J = 10.8 Hz, 1H), 7.47-7.45 (m, 2H), 6.88 (d, J = 8.0 Hz, 1H), 4.13 (s, 2H), 3.96(m, 1H), 3.29-3.25 (m, 2H), 2.97-2.93 (m, 2H), 1.33-1.24(m, 4H),1.12(t, J = 7.2 Hz, 3H).
Example 174
1-(6-amino-3,5-difluoropyridin-2-yl)-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Figure imgf000089_0003
1H NMR (DMSO-d6): 14.94 (s, 1H), 9.04 (s, 1H), 8.4 (d, J = 8 Hz,1H), 8.07 (t, J = 9.2 Hz,1H), 7.92 (d, J = 9.6 Hz, 1H), 7.80 (s,1H), 7.71-7.38 (m, 2H), 7.28-7.05 (m, 1H), 6.98-6.68 (m, 5H), 4.03(s,2H), 2.97 (t, J = 8.2 Hz,1H).
Example 175
1-(6-amino-3,5-difluoropyridin-2-yl)-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)- 6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Figure imgf000090_0001
1H NMR (DMSO-d6): 14.58 (s, 1H), 9.03 (s, 1H), 8.14-8.03 (m, 2H), 7.66 (s, 1H), 7.36-7.24 (m,
3H), 6.87(s, 2H), 6.72 (d, J = 8.4 Hz, 1H), 4.05 (s, 2H), 2.97 (t, J = 7.6 Hz, 2H).
Example 176 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-5,6,8-trifluoro-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid
Figure imgf000090_0002
1HNMR (DMSO-d6): 14.69 (s, 1H), 8.73 (s, 1H), 7.72-7.64 (m, 1H), 7.26-7.2 (m, 2H), 6.83-6.36 (m, 5H), 4.15-4.06 (m, 1H), 4.0 (s, 2H), 3.07-2.97(m, 2H), 1.28-1.08(m, 4H).
Example 177
5-((5-(6,7-difluoro-2-methylquinolin-8-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine
Figure imgf000091_0001
1H NMR (DMSO-d6): 8.43 (d, J = 8.4 Hz, 1H), 7.75-7.7 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H),7.43
(m,2H), 6.78 (d, J = 8.4 Hz, 1H),6.15 (m,2H), 5.86 (s,2H), 4.02(s,2H), 3.24 (t, J = 8.4 Hz, 1H),
2.94 (d, J= 8.0Hz, 1H), 2.67 (s, 3H).
Example 178 1-cyclopropyl-7-((1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)amino)-6-fluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid
Figure imgf000091_0002
1H NMR (DMSO-d6): 15.56 (s, 1H), 8.81 (s, 1H), 8.56 (s, 1H), 7.87 (d, J = 11.6 Hz, 1H), 7.68 (s,
1H), 7.57 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.08 (d, J= 8.4 Hz, 1H), 6.77(d, J = 8.4 Hz, 1H),
6.15 (s, 2H), 5.85(m, 2H), 3.95(s, 2H),3.6(m, 1H), 2.91 (t, J= 8.Hz, 1H), 1.15-1.07 (m,4H).
Example 179 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid compound with sulfuric acid
Figure imgf000091_0003
1H NMR (DMSO-d6, 400 MHz) δ: 11.67 (s, 1H, -COOH), 8.77 (s, 1H), 7.98 (d, J =8.0Hz, 1H),
7.70 (s, 2H), 7.55 (s, 2H, NH2), 7.27 (s, 1H), 7.25 (s, 2H, -NH2), 6.78 (d, J =8.4Hz, 1H), 4.16 (m, 1H), 4.10 (s, 2H), 3.40 (t, J =8.0Hz, 2H), 3.03 (t, J =8.0Hz, 2H), 1.25 (d, J =12.0Hz, 2H), 1.18 (t, J = 12.0Hz, 2H).
Example 180 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid compound with 2,3-dihydroxysuccinic acid
Figure imgf000092_0001
1H NMR (DMSO-d6, 400 MHz) δ: 14.62 (s, 1H, -COOH), 8.77 (s, 1H), 7.98 (d, J =9.2Hz, 1H), 7.70 (s, 1H), 7.18 (s, 2H, NH2), 7.14 (s, 2H, -NH2), 6.87 (s, 2H), 6.80 (d, J =8.0Hz, 1H), 4.24 (s, 2H), 4.16 (m, 1H), 4.08 (s, 2H), 3.35 (t, J =8.0Hz, 2H), 3.20 (s, 2H, -OH), 3.00 (t, J =8.8Hz, 2H), 1.24 (d, J =9.2Hz, 2H), 1.17 (d, J =6.4Hz, 2H).
Example 181 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid compound with acetic acid
Figure imgf000092_0002
1H NMR (DMSO-d6, 400 MHz) δ: 14.60 (s, 1H, -COOH), 11.86 (s, 1H, -COOH), 8.77 (s, 1H), 7.97 (d, J =8.0Hz, 1H), 7.96 (s, 1H), 7.70 (s, 2H, NH2), 7.35 (s, 2H), 7.25 (s, 2H, -NH2), 6.80 (d, J =2.2Hz, 1H), 4.17-4.16 (m, 1H), 4.08 (s, 2H), 3.38 (t, J =8.4Hz, 2H), 3.00 (t, J =8.0Hz, 2H), 2.32 (s, 1H), 1.91 (s, 2H), 1.19 (d, J =6.8Hz, 2H ), 1.15 (d, J =7.6Hz, 2H).
Example 182 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid compound with 2-hydroxypropane-1,2,3-tricarboxylic acid
Figure imgf000093_0001
1H NMR (DMSO-d6, 400 MHz) δ: 14.60 (s, 1H, -COOH), 8.77 (s, 1H), 7.98 (d, J =8.0Hz, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 7.36 (s, 1H), 7.26 (s, 2H, NH2), 7.22 (s, 2H, NH2), 6.80 (d, J =8.4Hz, 1H), 4.17-4.16 (m, 1H), 4.08 (s, 2H), 3.64 (s, 4H), 3.09 (t, J =7.2Hz, 2H), 3.02 (s, 1H, -OH), 3.00 (t, J =8.0Hz, 2H), 1.23 (s, 2H), 1.18 (d, J =5.2Hz, 2H). Example 183 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid compound with succinic acid
Figure imgf000093_0002
1H NMR (DMSO-d6, 400 MHz) δ: 14.61 (s, 1H, -COOH), 8.77 (s, 1H), 7.98 (d, J =8.0Hz, 1H), 7.70 (s, 1H), 7.22 (s, 2H), 7.09 (s, 2H, NH2), 6.81 (d, J =8.0Hz, 1H), 6.62 (s, 2H, -NH2), 4.18- 4.16 (m, 1H), 4.07 (s, 2H), 3.32 (t, J =8.0Hz, 2H), 2.98 (t, J =8.0Hz, 2H), 2.67 (t, J =2.0Hz, 4H), 1.39 (d, J =5.6Hz, 2H ), 1.37 (s, 2H).
Example 184 2,2',2''-nitrilotris(ethan 1--1-ol) cyclopropyl-7-(1-((2,4-diaminopyrimidin-5- yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
Figure imgf000094_0001
1H NMR (DMSO-d6, 400 MHz) δ: 14.60 (s, 1H, -COOH), 8.77 (s, 1H), 7.97 (d, J =9.6Hz, 1H), 7.76 (s, 1H), 7.22 (s, 2H), 6.83 (d, J =8.8Hz, 1H), 6.29 (s, 2H, -NH2), 5.17 (s, 2H, -NH2), 4.61 (s, 3H, -OH), 4.17-4.19 (m ,1H), 4.05 (s, 2H), 3.55 (d, J =5.6Hz, 6H), 3.28 (t, J =8.4Hz, 2H), 2.98 (t, J =8.4Hz, 2H), 2.52 (d, J =5.2Hz, 6H), 1.21 (d, J =7.6Hz, 2H), 1.18 (d, J =6.8Hz, 2H).
Example 185
Sodium 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro- 4-oxo-1,4-dihydroquinoline-3-carboxylate
Figure imgf000094_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.59 (s, 1H), 7.69 (s, 2H), 7.96 (s, 1H), 7.17 (d, J =1.2Hz, 1H), 6.81 (d, J =8.8Hz, 1H), 6.16 (s, 2H, -NH2), 5.88 (s, 2H, NH2), 4.03 (s, 2H), 3.99-3.95 (m, 1H), 3.27 (t, J =8.0Hz, 2H), 2.93 (t, J =8.0Hz, 2H), 1.11 (d, J =5.2Hz, 2H), 1.05 (s, 2H).
Example 186
Potassium 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8- difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
Figure imgf000095_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.78 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 7.69 (s, 1H), 7.18 (d, J = 10.4Hz, 1H), 6.81 (d, J =8.4Hz, 1H), 6.15 (s, 2H, -NH2), 5.86 (s, 2H, NH2), 4.02 (s, 2H), 3.99 (m, 1H), 3.25 (d, J =8.0Hz, 2H), 3.11 (d, J =9.2Hz, 2H), 1.06 (d, J =7.6Hz, 2H), 1.03 (s, 2H).
Example 187
Calcium 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro- 4-oxo-1,4-dihydroquinoline-3-carboxylate
Figure imgf000095_0002
1H NMR (DMSO-d6, 400 MHz) δ: δ: 8.81 (s, 1H), 7.93 (d, J =4.8Hz, 1H), 7.90 (s, 1H), 7.21 (s, 2H), 6.82 (d, J =8.8Hz, 1H), 6.17 (s, 2H, -NH2), 5.88 (s, 2H, NH2), 4.15-4.10 (m, 1H), 4.04 (s, 2H), 3.05 (d, J =6.HHz, 2H), 2.95 (d, J =5.2Hz, 2H), 1.18 (s, 4H).
Example 188
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate
Figure imgf000095_0003
1H NMR (DMSO-d6, 400 MHz) δ: 8.83 (s, 1H), 7.80 (d, J =9.6Hz, 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.19 (s, 4H, -NH2), 6.79 (d, J =8.0Hz, 2H), 4.25-4.20 (q, J =7.2Hz, 2H), 4.22-4.04 (m, 1H), 4.04 (s, 2H), 3.31 (t, J =8.0Hz, 2H), 2.97 (t, J =8.0Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.16 (s, 2H), 1.18 (d, J = 6.0Hz, 2H).
Example 189
Methyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate
Figure imgf000096_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.52 (s, 1H), 7.78 (d, J =8.8Hz, 1H), 7.69 (s, 1H), 7.19 (s, 2H), 6.81 (d, J =8.4Hz, 1H), 6.16 (s, 2H, -NH2), 5.93 (s, 2H, -NH2), 4.03 (s, 2H), 4.00-3.86 (m, 1H), 3.76 (s, 3H), 3.28 (t, J =8.4Hz, 2H), 2.96 (t, J =8.0Hz, 2H), 1.17 (s, 2H), 1.10 (d, J =6.8Hz, 2H).
Example 190
Isobutyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-
4-oxo-1,4-dihydroquinoline-3-carboxylate
Figure imgf000096_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.52 (s, 1H), 7.81 (d, J =9.6Hz, 1H), 7.70 (s, 1H), 7.20 (s, 2H), 6.81 (d, J =8.4Hz, 1H), 6.62 (s, 2H, -NH2), 6.30 (s, 2H, -NH2), 4.14 (s, 2H), 4.05 (s, 1H), 3.99 (d, J =6.4Hz, 2H), 3.32 (t, J =8.0Hz, 2H), 2.98 (t, J =8.0Hz, 2H), 2.02-1.94 (m, 1H), 1.12 (d, J =6.8Hz, 4H), 0.98 (d, J =6.8Hz, 6H).
Example 191 Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate succinate
Figure imgf000097_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.52 (s, 1H), 7.80 (d, J =9.2Hz, 1H), 7.79 (s, 1H), 7.25 (s, 2H), 6.81 (d, J =8.0Hz, 1H), 6.53 (s, 2H, -NH2), 6.24 (s, 2H, -NH2), 4.28-4.23 (q, J =1.6Hz, 2H), 4.05 (s, 2H), 4.01-3.91 (m, 1H), 3.30 (t, J =8.0Hz, 2H), 3.19 (t, J =8.0Hz, 2H), 2.33 (s, 4H), 1.29 (t, J =7.2 Hz, 3H), 1.16 (s, 2H), 1.11 (d, J =6.4Hz, 2H).
Example 192
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate 2-hydroxypropane-1,2,3-tricarboxylate
Figure imgf000097_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.44-11.19 (s, 2H, -COOH, broad), 8.52 (s, 1H), 7.81 (d, J =9.2Hz, 1H), 7.70 (s, 1H), 7.66 (s, 2H), 7.19 (s, 2H, -NH2), 7.04 (s, 2H, -NH2), 6.78 (d, J =8.0Hz, 1H), 4.28-4.23 (q, J =7.2Hz, 2H), 4.07 (s, 2H), 4.00 (m, 1H), 3.35 (t, J =8.0Hz, 2H), 3.12 (s, 1H, -OH), 3.00 (t, J =8.0Hz, 2H), 2.33 (s, 4H), 1.29 (t, J =7.2Hz, 3H), 1.24 (s, 4H).
Example 193 Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate sulfate
Figure imgf000098_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.66 (s, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 7.82 (d, J =9.6Hz, 1H), 7.75 (s, 2H, -NH2), 7.71 (s, 2H, -NH2), 7.25 (s, 1H), 7.19 (s, 1H), 6.77 (d, J =8.0Hz, 1H), 4.27-4.22 (q, J =7.2Hz, 2H), 4.09 (s, 2H), 3.99 (s, 1H), 3.39 (t, J =8.0Hz, 2H), 3.02 (t, J =8.8Hz, 2H), 1.29 (t, J =22Hz, 3H), 1.17 (s, 2H), 1.12 (d, J =5.6Hz, 2H).
Example 194
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate ethanesulfonate
Figure imgf000098_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.80 (s, 1H, -SO3H), 8.52 (s, 1H), 8.42 (s, 1H), 7.81 (d, J =9.6Hz, 1H), 7.75 (s, 2H, -NH2), 7.65 (s, 2H, -NH2), 7.24 (s, 1H), 7.19 (s, 1H), 6.77 (d, J =8.4Hz, 1H), 4.24-4.20 (q, J =7.2Hz, 2H), 4.09 (s, 2H), 4.00-3.99 (m, 1H), 3.39 (t, J =8.4Hz, 2H), 3.02 (t, J =8.4Hz, 2H), 2.42-2.37 (q, J =7.2Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.24 (t, J =2.0Hz, 2H), 1.22 (s, 2H), 1.17 (s, 3H).
Example 195
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate methanesulfonate
Figure imgf000099_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.69 (s, 1H, -SO3H), 8.53 (s, 1H), 8.42 (s, 1H), 7.82 (d, J =9.6Hz, 1H), 7.75 (s, 1H), 7.71 (s, 1H, -NH2), 7.63 (s, 2H, -NH2), 7.24 (s, 1H, -NH2), 7.21 (d, J =8.4Hz, 1H), 6.77 (d, J =8.0Hz, 1H), 4.27-4.22 (q, J =6.8Hz, 2H), 4.09 (s, 2H), 4.00-4.00 (m, 1H), 3.37 (t, J =8.4Hz, 2H), 3.02 (t, J =8.0Hz, 2H), 2.31 (s, 3H), 1.29 (t, J =7.2Hz, 3H), 1.12 (d, J =5.6Hz, 2H), 1.09 (d, J =6.8Hz, 2H).
Example 196
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate benzenesulfonate
Figure imgf000099_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.69 (s, 1H, -SO3H), 8.53 (s, 1H), 8.42 (s, 1H), 7.82 (d, J =8.8Hz, 1H), 7.75 (s, 1H), 7.70 (s, 1H), 7.40 (s, 4H, -NH2), 7.30 (t, J =2.4Hz, 3H), 7.24 (s, 1H), 7.20 (d, J =7.2Hz, 1H), 6.77 (d, J =8.0Hz, 1H), 4.27-4.21 (q, J =6.8Hz, 2H), 4.09 (s, 2H), 4.00- 3.99 (m, 1H), 3.45 (t, J =7.2Hz, 2H), 3.02 (t, J =8.4Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.12 (d, J =52Hz, 2H), 1.07 (d, J =7.2Hz, 2H).
Example 197
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate 4-methylbenzenesulfonate
Figure imgf000100_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.67 (s, 1H, -SO3H), 8.53 (s, 1H), 8.42 (s, 1H), 7.82 (d, J =8.4Hz, 1H), 7.75 (s, 2H, -NH2), 7.71 (s, 1H), 7.60 (s, 2H, -NH2), 7.47 (t, J =8.4Hz, 2H), 7.24 (s, 1H), 7.20 (d, J =8.0Hz, 1H), 7.11 (d, J =8.0Hz, 1H), 6.77 (d, J =8.0Hz, 1H), 4.27-4.21 (q, J =6.8Hz, 2H), 4.09 (s, 2H), 4.00-3.99 (m, 1H), 3.39 (t, J =8.4Hz, 2H), 3.02 (t, J =8.4Hz, 2H), 2.29 (s, 3H), 1.29 (t, J =7.2Hz, 3H), 1.17 (s, 2H), 1.12 (d, J =5.6Hz, 2H).
Example 198
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate naphthalene-1,5-disulfonate
Figure imgf000100_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.67 (s, 1H, -SO3H), 8.86 (d, J =8.4Hz, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 7.93 (d, J =0.8Hz, 2H), 7.92 (s, 1H), 7.81 (d, J =8.4Hz, 1H), 7.75 (s, 2H, -NH2), 7.71 (s, 2H, -NH2), 7.40 (t, J =7.2Hz, 2H), 7.21 (s, 1H), 7.18 (d, J =8.0Hz, 1H), 6.77 (d, J =8.4Hz, 1H), 4.27-4.21 (q, J =7.2Hz, 2H), 4.08 (s, 2H), 4.01-3.99 (m, 1H), 3.38 (t, J =8.4Hz, 2H), 3.02 (t, J =8.4Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.17 (s, 2H), 1.12 (t, J =5.2Hz, 2H).
Example 199 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid hydrochloride
Figure imgf000101_0001
1H NMR (DMSO-d6, 400 MHz) δ: 14.60 (s(br) , 1H), 12.03 (s(br), 1H, -COOH), 8.77 (s, 1H), 8.42 (s, 1H), 7.98-7.96 (m, 1H), 7.77-7.70 (m, 4H), 7.27-7.22 (m, 2H), 6.79 (d, J = 8.0 Hz, 1H), 4.18- 4.16 (m, 1H), 4.11 (s, 2H), 3.42 (t, J= 8 Hz, 2H), 3.03 (t, 2H, J = 8 Hz), 1.26-1.15 (m, 4H).
Example 200
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate 2-hydroxyethane-1-sulfonate
Figure imgf000101_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.68 (s, 1H, -SO3H), 8.53 (s, 1H), 8.42 (s, 1H), 7.83, 7.80 (dd, J = 1.2Hz, 1H), 7.71 (s, 2H, -NH2), 7.25 (s, 2H, -NH2), 7.21 (s, 1H), 7.19 (s, 1H), 6.77 (d, J =8.4Hz, 1H), 4.27-4.21 (q, J =7.2Hz, 2H), 4.08 (s, 2H), 4.01-3.99 (m, 1H), 3.62 (t, J =6.8Hz, 2H), 3.39 (t, J =8.0Hz, 2H), 3.02 (t, J =8.0Hz, 2H), 2.61 (t, J =6.8Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.17 (s, 2H), 1.12 (t, J =5.2Hz, 2H).
Example 201
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1- yl)methanesulfonate
Figure imgf000102_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.76 (s, 1H, -SO3H), 8.52 (s, 1H), 8.41 (s, 1H), 7.81 (d, J =8.8Hz, 1H), 7.75 (s, 2H, -NH2), 7.71 (s, 2H, -NH2), 7.24 (s, 1H), 7.19 (s, 1H), 6.77 (d, J =8.0Hz, 1H), 4.27-4.23 (q, J =6.8Hz, 2H), 4.09 (s, 2H), 4.09-3.99 (m, 1H), 3.39 (t, J =8.0Hz, 2H), 3.02 (t, J =8.0Hz, 2H), 2.89 (s, 1H), 2.40 (s, 1H), 2.33 (s, 1H), 2.26 (t, J =3.6Hz, 1H), 2.21 (t, J =3.6Hz, 1H), 1.93 (t, J =4.8Hz, 1H), 1.92 (s, 1H), 1.88 (s, 1H), 1.31 (s, 4H), 1.11 (s, 2H), 1.04 (d, J =6.8Hz, 2H), 0.99 (s, 3H), 0.75 (s, 3H).
Example 202
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate (S)-2-hydroxy-2-phenylacetate
Figure imgf000102_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.52 (s, 1H), 7.81 (d, J =8.8Hz, 1H), 7.69 (s, 1H), 7.40 (d, J =2.2Hz, 2H), 7.31 (d, J =7.2Hz, 2H), 7.26 (t, J =7.2Hz, 1H), 7.21 (s, 2H), 6.81 (d, J =8.0Hz, 1H), 6.41 (s, 2H, -NH2), 6.23 (s, 2H, -NH2), 4.93 (s, 1H), 4.27-4.21 (q, J =7.2Hz, 2H), 4.09 (s, 2H), 4.04-4.00 (m, 1H), 3.70 (s, 1H, -OH), 3.29 (t, J =8.0Hz, 2H), 3.05 (t, J =8.0Hz, 2H), 1.29 (t, J =2.2Hz, 3H), 1.12 (t, J =6.4Hz, 2H), 1.08 (d, J =6.0Hz, 2H). Example 203
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate malonate
Figure imgf000103_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.52 (s, 1H), 7.81 (d, J =9.6Hz, 1H), 7.70 (s, 1H), 7.35 (s, 2H, -NH2), 7.19 (s, 2H), 6.98 (s, 2H, -NH2), 6.79 (d, J =8.4Hz, 1H), 4.27-4.21 (q, J =7.2Hz, 2H), 4.07 (s, 2H), 4.07-3.99 (m, 1H), 3.34 (t, J =8.0Hz, 2H), 2.99 (t, J =8.0Hz, 2H), 2.91 (s, 2H), 1.29 (t, J =7.2Hz, 3H), 1.17 (s, 2H), 1.12 (d, J =4.8Hz, 2H).
Example 204
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate 2-hydroxysuccinate
Figure imgf000103_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.52 (s, 1H), 7.81 (d, J =9.6Hz, 1H), 7.70 (s, 1H), 7.18 (s, 2H, -NH2), 7.08 (s, 2H, -NH2), 6.84 (s, 1H), 6.80 (d, J =8.4Hz, 2H), 4.37 (s, 1H, broad), 4.27- 4.21 (q, J =7.2Hz, 2H), 4.11 (d, J =6.4Hz, 1H), 4.08 (s, 2H), 4.05-4.00 (m, 1H), 3.31 (t, J =8.4Hz, 2H), 2.98 (t, J =8.0Hz, 2H), 2.36 (d, J =5.6Hz, 2H), 1.29 (t, J =6.8Hz, 3H), 1.24 (s, 2H), 1.12(d, J =6.0Hz, 2H). Example 205
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate ethane-1,2-disulfonate
Figure imgf000104_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.74 (s, 1H, -SO3H), 8.52 (s, 1H), 8.43 (s, 1H), 7.81 (d, J =8.4Hz, 1H), 7.72 (s, 2H, -NH2), 7.64 (s, 2H, -NH2), 7.24 (s, 1H), 7.20 (d, J =1.6 Hz, 1H), 6.77 (d, J =8.4Hz, 1H), 4.27-4.21 (q, J =7.2Hz, 2H), 4.09 (s, 2H), 4.01-3.99 (m, 1H), 3.45 (t, J =1.2Hz, 4H), 3.02 (t, J =8.0Hz, 2H), 2.66 (d, J =7.2Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.25 (s, 2H), 1.12 (d, J =5.6Hz, 2H).
Example 206
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate naphthalene-2-sulfonate
Figure imgf000104_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.80 (s, 1H, -SO3H), 8.52 (s, 1H), 8.43 (s, 1H), 8.15 (s, 1H), 7.97 (t, J =3.6Hz, 1H), 7.90 (t, J =3.2Hz, 1H), 7.86 (d, J =8.4Hz, 2H), 7.81 (d, J =9.2Hz, 1H), 7.76 (s, 1H), 7.72 (s, 2H, -NH2), 7.70 (s, 1H), 7.61 (s, 2H, -NH2), 7.52-7.50 (q, J =2.8Hz, 1H), 7.24 (s, 1H), 6.77 (d, J =8.4Hz, 1H), 4.27-4.21 (q, J =7.2Hz, 2H), 4.09 (s, 2H), 4.00-3.99 (m, 1H), 3.38 (t, J =8.4Hz, 2H), 3.01 (t, J =8.4Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.24 (s, 2H), 1.12 (d, J =5.6Hz, 2H). Example 207
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate 2-hydroxybenzoate
Figure imgf000105_0001
1H NMR (DMSO-d6, 400 MHz) δ: 13.50 (s, 1H, -COOH),8.52 (s, 1H), 7.81 (d, J =9.2Hz, 3H), 7.76 (s, 2H, -NH2), 7.71 (s, 2H, -NH2), 7.21 (t, J =8.0Hz, 3H), 6.79 (d, J =8.4Hz, 1H), 6.68 (d, J =1.2Hz, 2H), 4.27-4.21 (q, J =7.2Hz, 2H), 4.09 (s, 2H), 4.01-3.99 (m, 1H), 3.36 (t, J =8.4Hz, 2H), 3.00 (t, J =8.0Hz, 2H), 1.29 (t, J =7.2Hz, 2H), 1.24 (s, 2H), 1.16 (s, 2H).
Example 208
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate 2,5-dihydroxybenzoate
Figure imgf000105_0002
1H NMR (DMSO-d6, 400 MHz) δ: 13.23 (s, 1H, -COOH), 8.69 (s, 1H), 8.52 (s, 1H), 7.81 (d, J =9.6Hz, 1H), 7.74 (s, 1H), 7.52 (s, 2H, -NH2), 7.38 (s, 2H, -NH2), 7.22 (t, J =6.8Hz, 2H), 7.13 (s, 1H), 6.80 (d, J =8.0Hz, 1H), 6.74, 6.72 (dd, J =3.2Hz, 1H), 6.58 (d, J =8.4Hz, 1H), 4.36 (s, 1H, -OH), 4.27-4.21 (q, J =7.2Hz, 2H), 4.07 (s, 2H), 4.01-4.00 (m, 1H), 3.45 (t, J =7.2Hz, 2H), 3.35 (t, J =8.0Hz, 2H), 1.29 (t, J =7.2Hz, 2H), 1.27 (s, 2H), 1.16 (s, 2H).
Example 209 Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate 2-hydroxy-5-sulfobenzoate
Figure imgf000106_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.66 (s, 1H, -OH), 11.35 (s, 1H, -COOH), 8.53 (s, 1H), 8.42 (s, 1H), 8.04 (s, 1H, -SO3H), 8.03 (t, J =4.4Hz, 2H), 7.80 (s, 1H), 7.75 (s, 2H, -NH2), 7.71 (s, 2H, -NH2), 7.20 (d, J =8.0Hz, 2H), 6.89 (d, J =8.4Hz, 1H), 6.77 (d, J =8.4Hz, 1H), 4.27-4.22 (q, J =1.2Hz, 2H), 4.09 (s, 2H), 4.01-3.99 (m, 1H), 3.39 (t, J =8.4Hz, 2H), 3.02 (t, J =8.0Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.17 (s, 2H), 1.12 (d, J =4.8Hz, 2H).
Example 210
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate 2,3-dihydroxysuccinate
Figure imgf000106_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.52 (s, 1H), 7.81 (t, J =9.2Hz, 1H), 7.69 (s, 1H), 7.21 (s,
2H), 6.80 (d, J =8.0Hz, 1H), 6.61 (s, 2H, -NH2), 6.32 (s, 2H, -NH2), 4.27-4.21 (q, J =7.2Hz, 2H), 4.13 (s, 2H), 4.05 (s, 2H), 4.01-4.00 (m, 1H), 3.30 (t, J =8.4Hz, 2H), 2.97 (t, J =8.4Hz, 2H), 2.50 (d, J =1.6Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.16 (s, 2H), 1.11 (d, J =6.8Hz, 2H).
Example 211
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate 1-hydroxy-2-naphthoate
Figure imgf000107_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.52 (s, 1H), 8.21 (t, J =8.4Hz, 1H), 7.81 (d, J =10.0Hz, 2H), 7.75 (s, 2H, -NH2), 7.73 (s, 2H), 7.52 (s, 2H, -NH2), 7.49 (d, J =6.8Hz, 1H), 7.21 (s, 1H), 7.20
(d, J =8.QHz, 2H), 7.08 (d, J =8.0Hz, 1H), 6.79 (d, J =8.0Hz, 1H), 4.27-4.21 (q, J =7.2Hz, 2H), 4.09 (s, 2H), 4.01-3.99 (m, 1H), 3.38 (t, J =8.4Hz, 2H), 3.01 (t, J =8.0Hz, 2H), 1.29 (t, J =2.2Hz, 3H), 1.16 (s, 2H), 1.12 (t, J =6.8Hz, 2H).
Example 212 Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate nicotinate
Figure imgf000107_0002
1H NMR (DMSO-d6, 400 MHz) δ: 9.06 (d, J = 1.6Hz, 1H), 8.75, 8.74 (dd, J =l.6Hz, 1H), 8.52 (s, 1H), 8.26 (t, J =2.0Hz, 1H), 7.81 (d, J =8.4Hz, 1H), 7.71 (s, 1H), 7.51 (t, J =4.8Hz, 1H), 7.19
(t, J =9.6Hz, 2H), 6.81 (d, J =8.0Hz, 1H), 6.51 (s, 2H, -NH2), 6.40 (s, 2H, -NH2), 4.27-4.21 (q, J =1.2Hz, 2H), 4.05 (s, 2H), 4.01-3.99 (m, 1H), 3.30 (t, J =8.4Hz, 2H), 2.97 (t, J =8.4Hz, 2H), 1.29 (t, J =2.2Hz, 3H), 1.16 (s, 2H), 1.11 (t, J =6.8Hz, 2H).
Example 213 Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate pentane-1-sulfonate
Figure imgf000108_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.82 (s, 1H, -SO3H), 8.52 (s, 1H), 8.41 (s, 1H), 7.81 (d, J =9.6Hz, 1H), 7.72 (s, 2H, -NH2), 7.63 (s, 2H, -NH2), 7.24 (s, 1H), 7.20 (d, J =7.2Hz, 1H), 6.77 (d, J =8.QHz, 1H), 4.27-4.21 (q, J =7.2Hz, 2H), 4.09 (s, 2H), 4.01-3.99 (m, 2H), 3.39 (t, J =8.4Hz, 2H), 3.02 (t, J =8.4Hz, 2H), 2.50 (t, J =2.0Hz, 2H), 1.57-1.53 (m, 1H), 1.31-1.27 (m, 7H), 1.25 (t, J =3.6Hz, 3H), 1.17 (s, 2H), 1.12 (t, J =5.2Hz, 2H).
Example 214
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4- oxo-1, 4-dihydroquinoline-3-carboxylate (R)-5-oxopyrrolidine-2-carboxylate
Figure imgf000108_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.52 (s, 1H), 7.89 (s, 1H), 7.81 (t, J =9.6Hz, 1H), 7.69 (s, 1H), 7.21 (s, 2H), 6.81 (d, J =8.0Hz, 1H), 6.23 (s, 2H, -NH2), 5.96 (s, 2H, -NH2), 4.24 (d, J =6.8Hz, 2H), 4.05 (s, 3H), 3.27 (d, J =8.0Hz, 2H), 2.97 (d, J =8.0Hz, 2H), 2.15 (s, 2H), 2.12 (t, J =6.0Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.16 (s, 2H), 1.11 (d, J =6.0Hz, 2H).
Example 215
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-4-oxo- 1,4-dihydroquinoline-3-carboxylate
Figure imgf000109_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.49 (s, 1H), 8.06 (d, J =6.8Hz, 1H), 7.87 (d, J = 10.4Hz, 1H), 7.69 (s, 1H), 7.38 (d, J =9.6Hz, 2H), 6.81 (d, J =8.0Hz, 1H), 6.45 (s, 2H, -NH2), 6.14 (s, 2H, - NH2), 4.26-4.20 (q, J =7.2Hz, 2H), 4.05 (s, 2H), 3.72 (s, 1H), 3.30 (t, J =8.4Hz, 2H), 2.99 (t, J =8.0Hz, 2H), 1.30 (t, J =7.2Hz, 3H), 1.25 (s, 2H), 1.13 (s, 2H).
Example 216
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-4-oxo- 1,4-dihydroquinoline-3-carboxylate hydrochloride
Figure imgf000109_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.99 (s, 1H, -HC1), 8.51 (s, 1H), 8.42 (s, 1H), 8.06 (d, J =6.8Hz, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.76 (s, 2H, -NH2), 7.72 (s, 2H, -NH2), 7.44 (s, 1H), 6.77 (d, J =8.4Hz, 1H), 4.26-4.21 (q, J =6.8Hz, 2H), 4.10 (s, 2H), 3.78-3.76 (m, 1H), 3.04 (t, J =8.0Hz, 2H), 2.53 (t, J =7.2Hz, 2H), 1.29 (t, J =6.8Hz, 3H), 1.26 (t, J =6.4Hz, 2H), 1.14 (t, J =2.4Hz, 2H).
Example 217
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-4-oxo- 1,4-dihydroquinoline-3-carboxylate ethanesulfonate
Figure imgf000109_0003
1H NMR (DMSO-d6, 400 MHz) δ: 11.79 (s, 1H, -SO3H), 8.51 (s, 1H), 8.42 (s, 1H), 8.06 (d, J =6.4Hz, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.71 (s, 2H, -NH2), 7.71 (s, 2H, -NH2), 7.44 (s, 1H), 6.77 (d, J =8.4Hz, 1H), 4.26-4.21 (q, J =6.8Hz, 2H), 4.10 (s, 2H), 3.79-3.74 (m, 1H), 3.41 (t, J =7.6Hz, 2H), 3.04 (t, J =8.0Hz, 2H), 2.42-2.38 (q, J =7.2Hz, 2H), 1.27 (t, J =7.2Hz, 3H), 1.21 (t, J =8.0Hz, 3H), 1.14 (t, J =2.4Hz, 2H), 1.08 (s, 2H).
Example 218
Ethyl (S)-10-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-9-fluoro-3-methyl-7-oxo-
2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate
Figure imgf000110_0001
1H NMR (DMSO-d6, 400 MHz) δ: 8.67 (s, 1H), 7.69 (s, 1H), 7.52 (d, J = 10.0Hz, 1H), 7.16 (s, 2H), 6.77 (d, J =8.4Hz, 1H), 6.15 (s, 2H, -NH2), 5.87 (s, 2H, -NH2), 4.76 (d, J =6.8Hz, 1H), 4.45 (d, J =12Hz, 1H), 4.35-4.25 (m, 1H), 4.22 (d, J =4AHz, 2H), 4.01 (s, 2H), 3.24 (t, J =8.4Hz, 2H), 2.92 (t, J =8.4Hz, 2H), 1.42 (d, J =6.8Hz, 3H), 1.29 (t, J =7.2Hz, 3H).
Example 219
Ethyl (S)-10-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-9-fluoro-3-methyl-7-oxo- 2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate hydrochloride
Figure imgf000110_0002
1H NMR (DMSO-d6, 400 MHz) δ: 12.10 (s, 1H, -HC1), 8.68 (s, 1H), 8.41 (s, 1H), 7.75 (s, 2H, - NH2), 7.68 (s, 2H, -NH2), 7.51 (s, 1H), 7.41 (s, 1H), 7.15 (d, J =8.4Hz, 1H), 6.72 (d, J =8.4Hz, 1H), 4.76 (d, J =6.8Hz, 1H), 4.43 (d, J =10.0Hz, 1H), 4.33-4.25 (m, 1H), 4.23 (d, J =4.0Hz, 2H), 4.07 (s, 2H), 3.45 (t, J =7.2Hz, 2H), 3.35 (t, J =7.2Hz, 2H), 1.42 (d, J =6.8Hz, 3H), 1.30 (t, J =12Hz, 3H).
Example 220
Ethyl (S)-10-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-9-fluoro-3-methyl-7-oxo- 2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate ethanesulfonate
Figure imgf000111_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.76 (s, 1H, -SO3H), 8.68 (s, 1H), 8.41 (s, 1H), 7.72 (s, 2H, - NH2), 7.62 (s, 2H, -NH2), 7.52 (d, J = 10.0Hz, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 6.72 (d, J =8.QHz, 1H), 4.76 (d, J =6.8Hz, 1H), 4.43 (d, J =10.0Hz, 1H), 4.43 (q, J =4.0Hz, 2H), 4.27-4.21 (m, 1H), 4.06 (s, 2H), 3.44 (d, J =6.8Hz, 2H), 2.99 (t, J =8.4Hz, 2H), 2.42-2.36 (q, J =7.2Hz, 2H), 1.42 (d, J =6.8Hz, 3H), 1.30 (t, J =7.2Hz, 3H), 1.29 (t, J =7.2Hz, 3H).
Example 221
Ethyl (S)-10-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-9-fluoro-3-methyl-7-oxo-
2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate 2-hydroxyethane-1-sulfonate
Figure imgf000111_0002
1H NMR (DMSO-d6, 400 MHz) δ: 11.69 (s, 1H, -SO3H), 8.68 (s, 1H), 8.41 (s, 1H, -NH2), 7.72 (d, J =6.4Hz, 2H), 7.61 (s, 2H, -NH2), 7.51 (s, 1H, -NH2), 7.20 (s, 1H), 7.16 (d, J =8.QHz, 1H), 6.72 (d, J =8.4Hz, 1H), 4.77 (d, J =6.8Hz, 1H), 4.28 (d, J =3.6Hz, 1H), 4.27-4.25 (m, 1H), 4.23 (t, J =3.2Hz, 2H), 4.06 (s, 2H), 3.68 (t, J =6.8Hz, 2H), 3.36 (t, J =8.4Hz, 2H), 2.99 (t, J =8.4Hz, 2H), 2.62 (t, J =6.8Hz, 2H), 1.42 (d, J =6.8Hz, 3H), 1.30 (t, J =7.2Hz, 3H).
Example 222
Ethyl (S)-10-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-9-fluoro-3-methyl-7-oxo- 2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate methanesulfonate
Figure imgf000112_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.75 (s, 1H, -SO3H), 8.68 (s, 1H), 8.41 (s, 1H, -NH2), 7.72 (s, 2H), 7.62 (s, 2H, -NH2), 7.51 (s, 1H), 7.20 (s, 1H, -NH2), 7.15 (d, J =8.0Hz, 1H), 6.72 (d, J =8.4Hz, 1H), 4.77 (d, J =6.8Hz, 1H), 4.43 (d, J =10.0Hz, 1H), 4.42-4.31 (m, 1H), 4.22 (t, J =3.2Hz, 2H), 4.06 (s, 2H), 3.35 (t, J =8.4Hz, 2H), 2.99 (t, J =8.4Hz, 2H), 2.32 (s, 3H), 1.42 (d, J =6.8Hz, 3H), 1.30 (t, J =7.2Hz, 3H).
Example 223
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-8- methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate
Figure imgf000112_0002
1H NMR (DMSO-d6, 400 MHz) δ: 8.55 (s, 1H), 7.72 (t, J = 10.0Hz, 2H), 7.18 (d, J =9.2Hz, 2H), 6.82 (d, J =8.0Hz, 1H), 6.16 (s, 2H, -NH2), 5.87 (s, 2H, -NH2), 4.26-4.12 (q, J =6.8Hz, 2H), 4.05 (m, 1H), 4.03 (s, 2H), 3.33 (s, 3H, -OCH3), 3.27 (d, J =8.4Hz, 2H), 2.95 (d, J =8.4Hz, 2H), 1.29 (t, J =2.2Hz, 3H), 1.11 (t, J =7.2Hz, 2H), 1.07 (s, 2H).
Example 224
Ethyl 1- cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6-fluoro-8- methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate hydrochloride
Figure imgf000113_0001
1H NMR (DMSO-d6, 400 MHz) δ: 11.97 (s, 1H, -HC1), 8.56 (s, 1H), 8.42 (s, 1H), 7.75 (s, 1H, -
NH2), 7.73 (d, J =9.6Hz, 2H), 7.65 (s, 2H, -NH2), 7.23 (s, 1H, -NH2), 7.20 (d, J =8.0Hz, 1H), 6.78 (d, J =8.0Hz, 1H), 4.26-4.21 (q, J =6.8Hz, 2H), 4.08 (m, 1H), 4.06 (s, 2H), 3.68 (s, 3H, -
OCH3), 3.47 (d, J =1.2Hz, 2H), 3.01 (d, J =8.0Hz, 2H), 1.29 (t, J =7.2Hz, 3H), 1.11 (d, J
=1.6Hz, 2H), 1.09 (d, J =5.2Hz, 2H).
In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and optionally one or more pharmaceutically acceptable excipients. The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of Formula (I) are useful in the treatment of microbial infections in mammals, by oral, i.v, topical or parenteral administration.
In some embodiments, the present invention includes a method for the treatment of at least one of cell proliferative diseases, autoimmune disease, inflammatory disease or bacterial, fungal or parasitic infection, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound or salt of the novel compound of formula (I).
For the treatment of any of the above-mentioned diseases the compounds of formula (I) may be administered, for example, orally, topically, parenterally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.
The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5 % - 90 % by weight of the composition.
In an embodiment, the compound of formula (I), may be used alone or in any combination with one or more therapeutic agents such as Fluoroquinolones, Oxazolidinones, Aminoglycosides, b- Lactam Antibiotics and b-Lactamase inhibitors, Hybrid antibiotic, Vitamins or pharmaceutically acceptable salts thereof.
DHFR assay protocol
DHFR inhibition assay was performed by monitoring the rate of NADPH oxidation. Assay was carried out in a buffer containing 20 mM Tris HC1, 200 mM NaCl and 0.1 mM EDTA, pH 7.2. DHFR (0.8 mg/mL) was pre-incubated with NADPH (0.02 mM) and the test compounds for 10 min at 25 °C before the reaction was initiated by the addition of DHF (0.02 mM). The fluorescence intensity was measured in kinetic mode using Tecan M1000 pro at an excitation wavelength of 340 nm and emission wavelength of 440 nm. Enzyme inhibition was calculated from the amount of NADPH consumed in the reaction. The IC50 values were calculated using Graph pad prism.
Determination of in vitro MIC
MIC was determined by using reference broth microdilution method as described by the Clinical and Laboratory Standards Institute (CLSI). Briefly, bacterial cells {Staphylococcus aureus ATCC 29213 (Gram -i-ve), Escherichia coli ATCC 25922 (Gram -ve)) were cultured on Mueller Hinton agar plates. Stock solutions of NCEs and positive controls were prepared in DMSO or water as per their solubility. Further dilutions of NCEs were prepared in cation adjusted Mueller Hinton broth (CAMHB). NCEs were serially double diluted in 96 well plates. Inoculum densities were maintained at 5 X 104 cells per well. Plates were incubated at 37 º C for 20-24 h. All QC results were within specified ranges as published in CLSI document M100-S25. Table 1 In-vitro enzymatic DHFR inhibition & MIC values (pg/mL) of novel DHFR inhibitors against Gram-positive bacteria & Gram negative bacteria
Figure imgf000115_0001
#ND = Not detected Table 1 In Vitro enzymatic DHFR inhibition & MIC values (pg/mL) of novel DHFR inhibitors against Gram-positive bacteria & Gram negative bacteria (continued)
Figure imgf000116_0001
Figure imgf000117_0001
Table 2 In -vitro MIC values (pg/mL) of novel DHFR inhibitor 1- cyclopropyl-7-(1-((2,4- diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3- carboxylic acid hydrochloride[Example 199] against various Gram-positive bacteria
Figure imgf000117_0002
Pharmacokinetics: Pharmacokinetics of the test compound 1 and trimethoprim was studied (Table 3) via per-oral and intravenous bolus routes of administration in BALB/c mice of 7 to 12 weeks of age. Animals were fasted for 12 h and food was supplied after 4.0 h of administration of the test compound. There was free access to water throughout the study. A homogenous suspension of the test substance was prepared in 1% Tween 80, 0.5 % w/v CMC in purified water and a per-oral dose of 3 mg/kg was administered. After the administration of the test compounds, blood samples were withdrawn at various time intervals through retro-orbital plexus and collected into heparinized micro centrifuge tubes. Plasma was separated by centrifugation at 4000 rpm for 15 min at ambient temperature and analyzed immediately. Remaining samples were stored at -70 °C until analyzed.
Samples were prepared by protein precipitation method: A 30 μL aliquot of plasma sample was spiked with 6 μL of internal standard (Alprazolam) and extracted by addition of 0.5 mL of acetonitrile in 2 mL micro centrifuge tubes. Samples were vortex-mixed for a minute and centrifuged at 10000 rpm for 5 min. The supernatant was transferred to HPLC vials for analysis. The extracted samples were analyzed on LC-MS/MS system consisting of Shimadzu LC-20-AD, Prominence system equipped with a binary pump, a vacuum degasser and an auto sampler (Shimadzu Corporation, Kyoto, Japan) and an API 5500 ® mass spectrometer (Applied Biosystems Sciex, Toronto, Canada). Analyst 1.6.1 software was used for data acquisition and analysis (Applied Biosystems Sciex, Toronto, Canada). Chromatographic separation was achieved using a mobile phase (A) 5 mM Ammonium formate +0.1%formic acid in water and (B) methanol: acetonitrile (20:80 % v/v); flowing at a flow rate of 1.0 mL/min (50% split to waste) through a ACE C18 50*4.6mm, 5p. Quantification was based on a series of calibrators ranging from 1 to 5000 ng/mL, prepared by adding test compound to drug free mice plasma. Quality control samples were analyzed in parallel to verify that the system performs in control. Pharmacokinetic parameters namely; maximum plasma concentration (Cmax), time point of maximum plasma concentration (tmax), area under the plasma concentration
Figure imgf000118_0001
time curve from 0 h to infinity (AUCQ-L) and half-life of drug elimination during the terminal phase (t1/2) were calculated from plasma concentration versus time data, by standard non-compartmental methods, using the Phoenix 64 (Certara) software.
Figure imgf000118_0002
“Values indicate mean ± SD for n=3 mice
In-vivo Experiment: Male ICR mice, 6-8 weeks of age were used. Animals were allowed access to feed and water ad libitum. Before start of experimental infection, mice were rendered neutropenic by injecting cyclophosphamide intraperitoneally on day -4 (150 mg/kg) and day -1 (100 mg/kg). On day 0, all neutropenic mice were infected with 0.5million per 0.05ml of MRSA (ATCC 33591), by intramuscular route in thigh tissue. After 2 hour of infection, animals were treated with vehicle and compound of example no. 200 (6.25, 12.5, 25, 50, 100 mg/kg, p. o) every six hours. After 24h post treatment, mice were humanely sacrificed, thigh tissue was collected aseptically in tube containing 5 ml sterile PBS and homogenized. A 10-fold serial dilution series was prepared from tissue homogenates in PBS and two 20 pl aliquots per dilution were plated onto Mueller Hinton Agar plates. The plates were incubated at 35±2°C for approximately 16 to 18 hours and number of CFU was enumerated. The CFU count per thigh tissue was calculated. The ED50 is found to be 33 mg/kg, po, and qid, for compound of example 200 in this efficacy thigh infection model. CYP inhibition and hERG inhibition: The compounds of the present invention do not bear CYP and hERG liability, and are safe.

Claims

We Claim:
1. Compound having the structure of general formula (I),
Wherein
Figure imgf000120_0001
R1 at each occurrence is selected from hydrogen, halo, haloalkyl, NO2, NH2, linear or branched, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, groups;
R2 at each occurrence is independently selected from hydrogen, hydroxy, NO2, NH2, CN, halo, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl (C2- C6)alkynyl, (C3-C7)cycloalkyl,-O(C1-C6)alkyl, -O(C2-C6)alkenyl, -O(C2-C6)alkynyl, acyl groups or NR’R” groups, wherein R’R” may be independently represent hydrogen, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl;
‘X’ & ‘Y’ is selected from -C-or -N-;
R3 is selected from CH2, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl or CH-R’ where R’ is selected from hydrogen, halo, haloalkyl, NH2, NO2, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, aryl, heteroaryl or heterocyclyl group;
R4 at each occurrence is selected from hydrogen, halo, haloalkyl, NO2, NH2, CN, aryl. In an embodiment R4 may be absent; each of R5 & R6 at each occurrence is independently selected from hydrogen, halo, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)cycloalkyl, aryl, heteroaryl or heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, alkylsulfonyl, heterocyclylalkylsulfonyl, dialkylsulfamoyl, 1- cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylic acid; 1-alkyl-mono halo- 4-oxo- 1,4-dihydroquinoline-3-carboxylic acid; 1-aryl- mono halo-4-oxo-1,4- dihydroquinoline-3-carboxylic acid; 1 -alkyl-dihalo-4-oxo- 1 ,4-dihydroquinoline-3- carboxylic acid; ethyl 1 -cycloprop yl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate; alkyl 1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate; aryl 1- cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylate; cycloalkyl 1 - cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylate, substituted/unsubstituted 1 - cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3- carboxylate, substituted/unsubstituted-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate;
R7 at each occurrence is independently selected from hydrogen, halo, -CN, -COOH, - NH2, -OH, -SO3H, -CHO, -COR8, -NHCOR8, CSR8, -NHCSR8, -SH, -SO2R8, (C1- C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkynyl, halohexafluorocarbinol; wherein R8 is selected from hydrogen, halogen, haloalkyl, substituted or unsubstituted group selected from (C1- C6)alkyl, (C1-C6)alkoxy;
Z, T, P, and Q is selected from -C- or-N-; m represents an integer from 0-2., n represents an integer from 0-3.
2. The compound of formula (I) as claimed in claim 1, wherein R1 is selected from hydrogen, NH2, substituted or unsubstituted group selected from (C1-C6)alkyl.
3. The compound of formula (I) as claimed in claim 1, wherein R2 is selected from hydrogen, NH2, substituted or unsubstituted group selected from (C1-C6)alkyl.
4. The compound of formula (I) as claimed in claim 1, wherein R3 is selected from CH2, substituted or unsubstituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl.
5. Compound of formula (I) as claimed in claim 1 , wherein compound is selected from:
4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)- 1 -naphthoic acid;
5-((6-phenylindolin-1-yl)methyl)pyrimidine-2,4-diamine; 5-((6-(3-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine; 1- ((2,4-diaminopyrimidin-5-yl)methyl)indoline-5 -carboxylic acid;
5- ((6-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)pyrimidine-2,4-diamine; 5-((6-(3-(trifluoromethoxy)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine; 5-((6-(2-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(phenylethynyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride; 5-((4,6-difluoroindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(pyridin-4-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride; 5-((5-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride;
5-((5-(naphthalen-2-yl)indolin- 1 -yl)methyl)pyrimidine-2,4-diamine hydrochloride;
5-((6-chloroindolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-6-yl)benzoic acid compound with acetic acid (1:3);
5-((5-(4-(methylsulfonyl)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(4-(diethylamino)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(2,4-dichlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-(2,4-dichlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-(4-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-(4-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(quinolin-3-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine; ethyl 4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoate;
5-((5-(4-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-fluoro-2-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3-chloro-4-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-(3-chloro-4-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-(4-chloro-3-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
2-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-4-yl)benzoic acid compound with acetic acid (1:3);
3-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-4-yl)benzoic acid compound with acetic acid (1:3);
5-((5-(4-chloro-3-methylphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
4-(1-(3-(2,4-diaminopyrimidin-5-yl)prop-2-yn-1-yl)indolin-5-yl)benzoic acid;
3-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid;
5-((5-(3-chlorophenyl)indolin-1-yl)methyl)-6-ethylpyrimidine-2,4-diamine;
5-((5-(4-(3-methoxyoxetan-3-yl)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
2-chloro-4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid; 1-cyclopropyl-7-(4-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5- yl)benzoyl)piperazin- 1 -yl)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylic acid; 5-((5-iodoindolin-1-yl)methyl)pyrimidine-2,4-diamine; 5-((5-(3-morpholinopropoxy)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-nitrobenzoic acid; tert-butyl(4-(4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin- 5yl)benzamido)butyl)carbamate;
2-acetamido-5-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid trihydrochloride ;
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)thiophene-2-carboxylic acid;
4-ethyl 1 -methyl 2-(4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5- yl)phenyl)succinate;
2-(4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phenyl)- 1 , 1 , 1 ,3,3,3- hexafluoropropan-2-ol diformate;
2-acetamido-4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-hydroxybenzoic acid;
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)nicotinic acid;
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-hydroxybenzoic acid trihydrochloride ;
5-((5-(4-(ethylsulfonyl)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phthalic acid;
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)furan-2-carboxylic acid;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-5-methylthiophene-2-carboxylic acid trihydrochloride;
2-(4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)phenyl)acetic acid trihydrochloride ;
5-((5-(quinolin-8-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride;
5-((5-(8-methoxyquinolin-5-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride ;
5-((5-(6,7-dimethoxy-2,3-dihydro-1H-inden-4-yl)indolin-1-yl)methyl)pyrimidine-2,4- diamine trihydrochloride;
5-((5-(quinolin-5-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-hydroxy-2-naphthoic acid trihydrochloride ; 4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2,3,5,6-tetramethylbenzoic acid;
5-((5-(4-fluoronaphthalen-1-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride ;
5-((5-(dibenzo[b,d]furan-3-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride ;
6-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-naphthoic acid;
6-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2-methyl-1H- benzo[de]isoquinoline- 1 ,3 (2H)-dione;
8-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-methyl-2H- benzo[b][ 1,4] oxazin-3 (4H)-one trihydrochloride;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)naphthalene-1-sulfonic acid;
5-((5-(4-chloronaphthalen-1-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine trihydrochloride ; ethyl 4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1-naphthoate trihydrochloride ;
N-(4-( 1 -((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)naphthalen- 1 -yl)acetamide;
5-((5-methoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-(indolin-1-ylmethyl)pyrimidine-2,4-diamine;
Ethyl 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-
4-oxo- 1 ,4-dihydroquinoline-3-carboxylate
Ethyl 1-cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-6,8-difluoro-
4-oxo- 1 ,4-dihydroquinoline-3-carboxylate dihydrochloride
5-((4,5,6-trimethoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine;
1-((2, 4-diaminopyrimidin-5-yl)methyl)-4, 5, 6-trimethoxyindoline-2, 3-dione;
5-((5-chloroindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-fluoroindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-bromoindolin-1-yl)methyl)pyrimidine-2,4-diamine;
2-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2- ol;
5-((7-methoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-methoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine; 5-((5,6-dimethoxyindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-( 1,1,1 ,3 ,3,3-hexafluoro-2-methoxypropan-2-yl)indolin- 1 -yl)methyl)pyrimidine-2,4- diamine;
5-((5-phenylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(2-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-methoxy-2-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-methoxy-2-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(trifluoromethoxy)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(6-methoxypyridin-3-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-chloroindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-methylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(pyridin-4-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(phenylethynyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3,4,5-trimethoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3-(trifluoromethoxy)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(4-(trifluoromethoxy)phenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(2,4-dimethoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((2,3,3-trimethylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(naphthalen-2-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((6-fluoroindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(m-tolyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-(3-methoxyphenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((4-phenylindolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(pyridin-3-yl)indolin-1-yl)methyl)pyrimidine-2,4-diamine hydrochloride;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid;
5-((4-(3-chlorophenyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
5-((5-(ethylsulfonyl)indolin-1-yl)methyl)pyrimidine-2,4-diamine;
4-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-4-yl)benzoic acid;
4-(1-((2,4-diamino-6-ethylpyrimidin-5-yl)methyl)indolin-5-yl)benzoic acid; 5-((4-(3-chlorophenyl)indolin-1-yl)methyl)-6-ethylpyrimidine-2,4-diamine;
5-((5-nitroindolin- 1 -yl)methyl)pyrimidine-2,4-diamine; 1- ((2,4-diaminopyrimidin-5-yl)methyl)indoline-5 -carbonitrile;
N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)isobutyr amide;
N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)isobutyramide hydrochloride; 1- ((2,4-diaminopyrimidin-5-yl)methyl)-N,N-dimethylindoline-5-carboxamide;
N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)acetamide; 1- ((2,4-diaminopyrimidin-5-yl)methyl)-N-methylindoline-5-carboxamide; (1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)(morpholino) methanone;
1-((2,4-diaminopyrimidin-5-yl)methyl)indoline-5-carboxamide; ethyl (1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)carbamate;
2-chloro-N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-nitrobenzamide; 2-chloro-N-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-3,4- dimethoxybenzamide;
5-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)imidazo[1,2-a]pyridine-2- carboxylic acid;
7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-2,3-dihydrobenzo[b][1,4]dioxine- 5-carboxylic acid;
Cyclopropyl-7-(1-((2,4-diaminopyrimidin-5-yl)methyl)indolin-5-yl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acid.
6. A pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) as claimed in any of preceding claims and suitable pharmaceutically acceptable excipients.
7. A pharmaceutical composition comprising compounds of formula (I) in combination with one or more pharmaceutically active agents selected from group comprising Fluoroquinolones, Oxazolidinones, Aminoglycosides, b-Lactam Antibiotics and b- Lactamase inhibitors, Hybrid antibiotic, Vitamins or pharmaceutically acceptable salts thereof. The compound as claimed in claim 1 or its pharmaceutical composition is useful in the prevention or treatment of mammals as preventives and therapeutic agents for infectious diseases. A method of treating cell proliferative diseases, autoimmune disease, inflammatory disease or bacterial, fungal or parasitic infection, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as claimed in claim 1.
PCT/IB2021/059952 2020-11-05 2021-10-28 Novel hetrocyclic compounds WO2022096990A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000059884A1 (en) * 1999-01-26 2000-10-12 Dana-Farber Cancer Institute, Inc. Pharmaceutically active compounds and methods of use thereof
WO2013169889A1 (en) * 2012-05-08 2013-11-14 Anvyl Llc Alpha 7 nicotinic acetylcholine receptor allosteric modulators, their derivatives and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000059884A1 (en) * 1999-01-26 2000-10-12 Dana-Farber Cancer Institute, Inc. Pharmaceutically active compounds and methods of use thereof
WO2013169889A1 (en) * 2012-05-08 2013-11-14 Anvyl Llc Alpha 7 nicotinic acetylcholine receptor allosteric modulators, their derivatives and uses thereof

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