WO2013054351A1 - Heterocyclic compounds - Google Patents
Heterocyclic compounds Download PDFInfo
- Publication number
- WO2013054351A1 WO2013054351A1 PCT/IN2012/000538 IN2012000538W WO2013054351A1 WO 2013054351 A1 WO2013054351 A1 WO 2013054351A1 IN 2012000538 W IN2012000538 W IN 2012000538W WO 2013054351 A1 WO2013054351 A1 WO 2013054351A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- carbamoyl
- pyrimidin
- methanesulfonate
- phenyl
- Prior art date
Links
- 0 CCC(CC)C(C)(CC1)CC(C)(*)CCCC1Nc1nc(N(*)c2ccc(CC(*C3C4C3)C3NC4=*)c3c2)ncc1* Chemical compound CCC(CC)C(C)(CC1)CC(C)(*)CCCC1Nc1nc(N(*)c2ccc(CC(*C3C4C3)C3NC4=*)c3c2)ncc1* 0.000 description 3
- VGOJAAUTLZDMSV-UHFFFAOYSA-N CS(Oc(cc(cc1)N)c1C(NC1CC1)=O)(=O)=O Chemical compound CS(Oc(cc(cc1)N)c1C(NC1CC1)=O)(=O)=O VGOJAAUTLZDMSV-UHFFFAOYSA-N 0.000 description 1
- BQYHGOKHNIMUDF-UHFFFAOYSA-N [O-][N+](c(cc1)cc(O)c1C(NC1CC1)=O)=O Chemical compound [O-][N+](c(cc1)cc(O)c1C(NC1CC1)=O)=O BQYHGOKHNIMUDF-UHFFFAOYSA-N 0.000 description 1
- UKWUOTZGXIZAJC-UHFFFAOYSA-N [O-][N+](c(cc1)cc(O)c1C(O)=O)=O Chemical compound [O-][N+](c(cc1)cc(O)c1C(O)=O)=O UKWUOTZGXIZAJC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to novel pyrimidine class of compounds, their pharmaceutically acceptable salts, and pharmaceutically acceptable compositions containing them and their use in treating and preventing disease conditions associated with Janus Activated Kinases (JAKs).
- JAKs Janus Activated Kinases
- a class of compounds of formula (I) which are useful for inhibiting JAKs. More particularly, the present invention relates to novel compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, use of these compounds in medicine and the intermediates involved in their preparation.
- the present invention also relates to a process for the preparation of the compounds of formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them.
- the compounds of the general formula (I) suppress a variety of immune and inflammatory functions by inhibition of JAKs such as JAK-2 and JAK-3 where such inhibition of JAK kinases is beneficial.
- JAKs such as JAK-2 and JAK-3 where such inhibition of JAK kinases is beneficial.
- it could be used in the treatment of inflammatory, immune, and allergic disorders including rheumatic diseases such as rheumatoid arthritis, juvenile arthritis, and ankylosing spondylitis, dermatological diseases including psoriasis and pemphigus, allergic disorders including allergic rhinitis, atopic dermatitis,, and contact dermatitis, pulmonary conditions- including asthma and chronic obstructive pulmonary disease (COPD), and other immune and inflammatory diseases including Crohn disease, ulcerative colitis, systemic lupus erythematosus, autoimmune chronic active hepatitis, acute myeloid leukemia (AML) and/or inflammation that can benefit from such inhibition and many other
- the compounds of the invention are JAK kinases inhibitor, they have very useful anti-inflammatory and anti-allergic, immune-suppressive, and anti-proliferative activity and they can be used in patients as drugs, particularly in the form of pharmaceutical compositions as set forth below, for the treatment of disease-states and conditions.
- J AK Janus Kinases
- JAKs are members of intracellular nonreceptor tyrosine kinases comprising four family members (JAK-1, JAK-2, JAK-3 and TYK-2).
- JAKs play a critical role in the cytokine mediated JAK-STAT signaling pathway. Association of individual JAK to activated cytokine receptors leads to autophosphorylation and subsequent phosphorylation of STAT proteins that ultimately lead to gene expression (Kisseleva et al, Gene, 2002, 285,1; Yamamoto et al, Genome Biology, 2004, 5, 253).
- the association with relevant signaling pathways makes JAK an important target for therapeutic intervention in the treatment of autoimmune disorders, various inflammatory diseases and cancers (Yu H. et al, Nat. Rev. Cancer, 2009, 9, 798).
- JAK-3 is predominantly located in the endoplasmic membranes of hematopoietic cell (Ghoreschi K. et al, Immunol Rev. 2009, 228, 273) and specifically associates with the common cytokine receptor ⁇ chain (yC) family (IL-2, IL-4, IL-7, IL- 9, IL-13 and IL-15) (O'Shea J., J. Ann. Rheumatic Dis., 2004, 64, U67).
- yC family IL-2, IL-4, IL-7, IL- 9, IL-13 and IL-15
- JAK-2 JAK-2
- MPDs myeloproliferative disorders
- Tofacitinib (CP-690550) from the Pfizer has completed phase III clinical trials for rheumatoid arthritis (RA) and it is jnirmntlyjunder_re_view_forJhe-treatmentof-m
- Ruxolitinib (INCBO 18424) is an orally bioavailable JAK1/JAK2 inhibitor and is approved for the treatment of intermediate and high risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis by US FDA on November 16, 2011. Vertex Pharmaceuticals is developing VX-509 as specific JAK3 inhibitor, which is involved in signaling pathways that control the survival and proliferation of a lymphocyte. During 2010, Vertex initiated a Phase-IIa clinical trial of VX-509 in patients with moderate-to-severe rheumatoid arthritis (RA). Galapagos NV has initiated a Phase II clinical study for GLPG0634, a novel selective JAK1 and JAK2 inhibitor being developed for inflammatory conditions, such as RA (Ken Garber, Nature Biotechnology, 2011, 29, 467-468).
- Patent applications from the Pfizer (WO 2011/075334, WO 2011/045702 and
- WO2008/029237 described the use of pyrrolo [2,3-D]-pyrimidine compounds as JAK inhibitors for the prevention or treatment of arthritis.
- the present invention therefore provides compounds, methods for their manufacture and pharmaceutical compositions comprising the compounds of the invention together with suitable pharmaceutical carriers. Specifically the present invention provides novel JAK inhibitors that exhibit desired anti-inflammatory effect with fewer side effects.
- Yet another object of the present invention is to provide a process for the preparation of novel compounds represented by the general formula (I), their stereoisomers, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates.
- Yet another object of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their pharmaceutically _ac.ceptahle_salts,_or— their— mixtures-in-eombffl
- the present invention discloses novel pyrimidine class of compounds which inhibit JAK kinase.
- JAK inhibitors are useful for the treatment or prevention of pathological conditions or diseases such as myeloproliferative disorders, leukemia, lymphomas and solid tumors; bone marrow, organ transplant rejection; or immune-mediated diseases such as autoimmune and inflammation diseases, including rheumatoid arthritis, inflammatory bowel diseases.
- the invention further provides a method of treating a disease characterized by inflammatory, allergic, or proliferative processes, in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound of formula (I), according to the invention or a solvate, or salt thereof.
- Ri represents optionally substituted groups selected from (C 3 -C 8 ) cycloalkyl, aralkyl, heteroaralkyl, (Ci-C 6 )alkyl, (C 2 -C4)alkenyl, and (C 2 -C4)alkynyl;
- substituted whenever used alone or in combination with other radicals, denotes suitable substituents on that radical such as substituted alkyl, substituted alkenyl, substituted alkynyl etc.
- the suitable substituent on the groups representing Ri include , hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, hydrazino, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkenoxy, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkylthio, thioalkyl groups.
- R 3 at each occurrence independently represents hydrogen, halogen, nitrq, cyano, - (CH 2 )r-C(0)R 4 ,-(CH 2 )r-C(0)OR4, - ⁇ (3 ⁇ 4) 2 > -NH(CH 2 )r-C(0)R 4> -NH(CH 2 )r-C(0)OR 4 , -NH(CH 2 )r-S(0) 2 0R 4 wherein r represents an integer from 0-2; R4 at each occurrence independently represents hydrogen, optionally substituted groups selected from (Q- C 6 )alkyl, (C2-C 4 )alkenyl, and (C 2 -C 4 )alkynyl; or the group NR5R6 wherein R 5 and R independently represents hydrogen, optionally substituted groups selected from (Ci- C 6 )alkyl, (C 2 -Gt)alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 8 ) cyclo
- 'm' represents an integer from 0-4;
- the present invention provides a compound wherein the moiety:
- the present invention provides a compound wherein Ri is selected from the group consisting of:
- substituted used in combination with other radicals, otherwise than those disclosed specifically, denotes suitable substituents on that radical such as substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted aryl, etc, mentioned anywhere in the specification.
- The' suitable 'substituent include, but are not limited to the following radicals, alone or in combination with other radicals, such as, hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, hydrazino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carb
- 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, w-propyl, wo-propyl, w-butyl, ec-butyl, /-butyl, amyl, t-amyl, n-pentyl , «-hexyl, wo-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-butyrtyl, 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, w-propoxy, wo-propoxy, rc-butoxy, /-butoxy, wo-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” 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 fiuoromethyl, 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, chlorofnethoxy, fluoroethoxy chloroethoxy groups, 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 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 l to 6 carbons, such as (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3- thienyl)methyl, (2-pyridyl)methyl, 1 -methyl- l-(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, /.so-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, wo-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 CH3CONH, C 2 H 5 CONH, C 3 H 7 CONH, C4H 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 -C6)alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups.
- monoalk lamino group include methylamine, ethylamine, ⁇ -propylamine, 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 r C6)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, phenethylamino, 3- phenylpropylamino, 1-napthylmethylamino, 2-(l-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”, “ ⁇ , ⁇ -dialkylaminocarbonyl”, “N-alkyl- N-arylaminocarbonyl”, “N-alkyl-N-hydroxyaminocarbonyl”, and “N-alkyl-N- hydroxyaminocarbonylalkyl", substituted or unsubstituted.
- N- alkylaminocabonyl and ⁇ , ⁇ -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 aminocarbonyl 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 HsCH 2 OCH 2 , C 6 H 5 CH2OCH 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, methylthiomethyl, 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 H4(CH 3 0)CONH, C 6 H4(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 H5, C 6 H4(CH 3 )CH 2 OCONH, C 6 H4(OCH 3 )CH 2 OCONH, and the like.
- 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.
- 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.
- alkylsulfonyl or “sulfones and its derivatives” used herein, either alone or in combination with other radicals, with other terms such as alkylsulfonyl, denotes divalent radical -S0 2 -, or RS0 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, propylsulfonyt 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 derivatives used herein, either alone or in combination with other radicals, denotes -SO 3 H group and its derivatives such as sulfonylamino(S0 2 NH 2 ); N-alkylaminosulfonyl and ⁇ , ⁇ -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 alkyl radical
- DIPEA Diisopropylethylamine
- EDAC.HC1 N-(3-Dimethyl aminopropyl)-N'-ethyl carbodiimide hydrochloride
- LiOH Lithium hydroxide
- the sulfoxide (6) can be prepared from controlled oxidation of sulfide (5) with an appropriate oxidizing agent such as m- CPBA, per acetic acid in a solvent such as DCM at -10 - 0 °C.
- Compound (6) is treated with aromatic amino compounds of general formula (7) wherein all the symbols are as described earlier under acidic condition using acids such as PTSA in solvent(s) like dimethyl formammide (DMF) or NMP at temperature 100-110 °C to get the compounds of general formula (1) wherein all the symbols are described as earlier.
- acids such as PTSA in solvent(s) like dimethyl formammide (DMF) or NMP at temperature 100-110 °C to get the compounds of general formula (1) wherein all the symbols are described as earlier.
- compounds of formula (I) can also be synthesized as shown in Scheme-II.
- compound (9) can be prepared by treating commercially available ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate (8) with aromatic amino compounds of general formula (7) in a suitable solvent such as n-butanol. Chlorination of (9) using suitable chlorinating agent such as POCI 3 , SOCl 2 in a suitable solvent such as toluene under refluxing condition afford chloro compound (10).
- Chloro compound (10) and primary amine of formula (3) are reacted together in the presence of suitable base such as DIPEA in suitable solvent such as dioxane at RT and subsequent hydrolysis under basic condition using base such as LiOH to afford the acid derivative of formula (12).
- suitable base such as DIPEA
- suitable solvent such as dioxane at RT
- base such as LiOH
- Amidation of acid compound (12) is carried out using similar procedure described in the scheme-I to get the compounds of general formula (1) wherein all the symbols are described as earlier.
- the invention is further exemplified by the following non-limiting examples. These examples are provided for better illustration of the preferred mode of carrying out the invention and should not be construed as limiting the scope of the invention in any way. It will be appreciated that while working these examples and preparing other compounds of the present invention, the skilled person will be using the skills and diligence expected from a person skilled in the art.
- Step-I Preparation of methyl 5-amino-2-hydroxybenzoate.
- Step-II Preparation of methyl 5-((/ert-butoxycarbonyl)amino)-2-hydroxybenzoate.
- Triethylamine 27 mL, 0.194 mol was added drop wise to a solution of 5-amino-2- hydroxybenzoate (25 g, 0.149 mol) and di-iert-butyl dicarbonate (48.9 mL, 0.224 mol) in DCM (60 mL) at RT.
- Mixture was stirred at same temperature for 4-5 h. After completion of reaction, the mixture was quenched in water and extracted in DCM. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford the desired title product (28 g, 70 %).
- Step-III Preparation of methyl 5-((tert-butoxycarbonyl)amino)-2- ((methylsulfonyl)oxy)benzoate.
- the title compound was prepared using a procedure similar to that described in the preparation of 4-aminophenyl methanesulfonate (step-I) using methyl 5-((tert- butoxycarbonyl)amino)-2-hydroxybenzoate (10.0 g, 0.037 mol) and methanesulfonyl chloride (3.23 mL, 0.0411 mol) to afford desired product (10.5 g, 81 %).
- Step-V Preparation of 4-((tert-butoxycarbonyl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate.
- Step- VI Preparation of 4-amino-2-(cyclopropylcarbamoyl)phenyl methanesulfonate.
- Step-I Preparation of 4-((/ert-butoxycarbonyl)amino)-2-(hydroxymethyl)phenyl methanesulfonate.
- Step-II Preparation of 4-amino-2-(hydroxymethyl)phenyl methanesulfonate.
- the deprotection of Boc group is carried out by similar procedure to that described in step- VI of preparation of 4-amino-2-(cyclopropylcarbamoyl)phenyl methanesulfonate using 4-((tert-butoxycarbonyl)amino)-2-(hydroxymethyl)phenyl methanesulfonate (6.0 g, 18.9 mmol) to get desired title product (3.5 g, 73 %).
- Step-II Preparation of 2-(cyclopropylcarbamoyl)-5-nitrophenyl methanesulfonate
- the title compound was prepared using a procedure similar to that described in the preparation of 4-aminophenyl methanesulfonate (step-I) using N-cyclopropyl-2- hydroxy-4-nitrobenzamide (1.0 g, 4.5 mmol) and methanesulfonyl chloride (0.8 mL, 5.4 mmol) to afford desired product (0.70 g, 76 %).
- Step-Ill Preparation of 5-amino-2-(cyclopropylcarbamoyl)phenyl methanesulfonate.
- step-II The title compound was prepared using a procedure similar to that described in the preparation of 4-aminophenyl methanesulfonate (step-II) using 2- (cyclopropylcarbamoyl)-5-nitrophenyl methanesulfonate (l.l g, 3.7 mmol) to get desired title product (0.7 g, 76 %).
- Step-I Preparation of 2-cyano-N-(2-hydroxy-5-nitrophenyl)acetamide.
- Step-II Preparation of 2-(2-cyanoacetamido)-4-nitrophenyl methanesulfonate.
- step-I The title compound was prepared using a procedure similar to that described in the preparation of 4-aminophenyl methanesulfonate (step-I) using 2-cyano-N-(2-hydroxy- 5-nitrophenyl)acetamide (4.0 g, 18 mmol) and methanesulfonyl chloride (1.7 mL, 27.1 mmol) to afford desired product (4.0 g, 74%).
- Step-Ill Preparation of 4-amino-2-(2-cyanoacetamido)phenyl methanesulfonate.
- Step-I Preparation of (R)-4-((3-methylbutan-2-yl)amino)-2-(methylthio)pyrimidine-5- carboxylic acid.
- reaction mixture was concentrated by rotary evaporation to remove a majority of the dioxane, and then acidified with 10 M HC1 to pH ⁇ 5 resulting in the formation of a white precipitate.
- the solid compound filtered, washed with water and dried under vacuum to afford the (R)-4-((3-methylbutan-2-yl)amino)-2- (methylthio)pyrimidine-5-carboxylic acid, as white solid. (12 g, 84 %).
- Step-II Preparation of (R)-4-((3-methylbutan-2-yl)amino)-2-(methylthio)pyrimidine-5- carboxamide.
- Step-III Preparation of 4-(((R)-3-methylbutan-2-yl)amino)-2- (methylsulfinyl)pyrimidine-5-carboxamide.
- Step-IV (R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate:
- Step-III Preparation of (S)-4-((l-hydroxy-3-methylbutan-2-yl)amino)-2-((4- ((methylsulfonyl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid.
- Step IV Preparation of (S)-4-((5-carbamoyl-4-((l-hydroxy-3-methylbutan-2- yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate.
- the title compound was synthesized by a process similar to that of step-II of example 1 (step-I) using (S)-4-((l-hydroxy-3-methylbutan-2-yl)amino)-2-((4- ((methylsulfonyl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid (0.30 g, 0.97 mmol) to get the desired product ((0.063 g, 16 %).
- 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 quantity of active component, that is, the compounds of formula (1) 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.
- the present invention pertains to methods of treating a JAK- associated disease or disorder in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof.
- a JAK- associated disease can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the JAK, including over expression and/or abnormal activity levels.
- a JAK-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating JAK activity.
- JAK-associated diseases include diseases involving the immune system including, for example, organ transplant rejection (e.g., allograft rejection and graft versus host disease). Further examples of JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or autoimmune thyroid disorders. Further examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, atopic dermatitis and rhinitis.
- JAK-associated diseases include viral diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV).
- EBV Epstein Barr Virus
- HBV Human Papilloma Virus
- JAK-associated diseases or conditions include skin disorders such as atopic dermatitis, psoriasis (for example, psoriasis vulgaris), skin sensitization, and the like.
- JAK- associated diseases are those involving IL-6 pathways including Castleman's disease, Kaposi's sarcoma, and others.
- JAK-associated diseases or conditions include immune reactions (such as diarrhea, skin irritation, skin rash, contact dermatitis or allergic contact sensitization) caused by certain therapeutics in some patients.
- Further examples of JAK-associated diseases include hyperpropliferative disorders including polycythemia vera, essential thrombocytopenia, myeloid metaplasia with myelofibrosis, and the like.
- the JAK-associated disease is cancer such as, for example, prostate, renal, hepatocellular, pancreatic, gastric, breast, lung, cancers of the head and neck, glioblastoma, leukemia, lymphoma or multiple myeloma.
- the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
- the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response associated with such treatment with a JAK inhibitors as are well known, in a tissue, system, animal, individual or human.
- One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-inflammatory agents, and/or immunosuppressants can be used in combination with the compounds of the present invention for treatment of JAK- associated diseases, disorders or conditions.
- a JAK inhibitor used in combination with a chemotherapeutic in the treatment of multiple myeloma may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects.
- additional pharmaceutical agents used in the treatment of multiple myeloma for example, can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and velcade.
- Additive or synergistic effects are desirable outcomes of combining a JAK inhibitor of the present invention with an additional agent.
- resistance of multiple myeloma cells to agents such as dexamethasome may be reversible Upon treatment with a JAK inhibitor of the present invention.
- the agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
- compositions When employed as pharmaceuticals, the compounds described herein can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophuialmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
- topical including transdermal, epidermal, ophuialmic and to mucous membranes including intranasal, vaginal and rectal delivery
- pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal
- Parenteral administration includes intravenous, intraarterial ⁇ subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
- Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
- Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
- JA 2 and JAK3 inhibition assay may be performed as described in
- JAK2 and JAK3 kinases are used as GST-JAK-3(811- 1124), and GST-JAK- 2(808-1 132) respectively.
- JAK-2 or JAK-3 enzymatic activity is determined using a time-resolved fluorescence energy transfer technology.
- the phosphorylation of a synthetic biotinylated peptide substrate (Acetate-GGEEEEYFELVKKK (Biotin)-CONH 2 ) by either JAK-2 or JAK-3 in the presence of ATP is quantified using Europium labeled anti phosphotyrosine antibody and Streptavidin- Allophycocyanin
- Both JAK-2 and JAK-3 enzymes used in these assays contain the kinase domain (JH-1 domain) of the full length proteins and are used as glutathione S-transferase (GST) fusion proteins.
- Inhibitors are dissolved in dimethylsulfoxide (DMSO). Dilutions are prepared in 90% DMSO followed by additional dilutions steps as required to perform an 8-point concentration- response.
- DMSO dimethylsulfoxide
- the reaction mix consists of 5 ⁇ iL of diluted compound, 10 ⁇ 1_ of assay buffer and 5 ⁇ 1_ of enzyme dilution. After incubation . for 60 minutes at room temperature the reaction is stopped by the addition of EDTA. For detection of the product anti- phosphotyrosine antibody and Streptavidin-APC are added and after 60 minutes the samples are measured in an EnVision 2102 Multilabel Reader (Perkin Elmer, Inc., Wellesley, MA, USA, in the following mentioned as "PerkinElmer”) with excitation wavelength of 320nm and emission at 665nm.
- EnVision 2102 Multilabel Reader Perkin Elmer, Inc., Wellesley, MA, USA, in the following mentioned as "PerkinElmer”
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to novel pyrimidine class of compounds, their pharmaceutically acceptable salts, and pharmaceutically acceptable compositions containing them and their use in medicine.
Description
HETEROCYCLIC COMPOUNDS
FIELD OF INVENTION
The present invention relates to novel pyrimidine class of compounds, their pharmaceutically acceptable salts, and pharmaceutically acceptable compositions containing them and their use in treating and preventing disease conditions associated with Janus Activated Kinases (JAKs).
Specifically are disclosed herein, a class of compounds of formula (I) which are useful for inhibiting JAKs. More particularly, the present invention relates to novel compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, use of these compounds in medicine and the intermediates involved in their preparation.
(I)
The present invention also relates to a process for the preparation of the compounds of formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them.
The compounds of the general formula (I) suppress a variety of immune and inflammatory functions by inhibition of JAKs such as JAK-2 and JAK-3 where such inhibition of JAK kinases is beneficial. Thus, it could be used in the treatment of inflammatory, immune, and allergic disorders including rheumatic diseases such as rheumatoid arthritis, juvenile arthritis, and ankylosing spondylitis, dermatological diseases including psoriasis and pemphigus, allergic disorders including allergic rhinitis, atopic dermatitis,, and contact dermatitis, pulmonary conditions- including asthma and chronic obstructive pulmonary disease (COPD), and other immune and inflammatory diseases including Crohn disease, ulcerative colitis, systemic lupus erythematosus, autoimmune chronic active hepatitis, acute myeloid leukemia (AML) and/or inflammation that can benefit from such inhibition and many other related conditions.
As the compounds of the invention are JAK kinases inhibitor, they have very useful anti-inflammatory and anti-allergic, immune-suppressive, and anti-proliferative activity and they can be used in patients as drugs, particularly in the form of
pharmaceutical compositions as set forth below, for the treatment of disease-states and conditions.
BACKGROUND OF THE INVENTION
Janus Kinases (J AK) are members of intracellular nonreceptor tyrosine kinases comprising four family members (JAK-1, JAK-2, JAK-3 and TYK-2). JAKs play a critical role in the cytokine mediated JAK-STAT signaling pathway. Association of individual JAK to activated cytokine receptors leads to autophosphorylation and subsequent phosphorylation of STAT proteins that ultimately lead to gene expression (Kisseleva et al, Gene, 2002, 285,1; Yamamoto et al, Genome Biology, 2004, 5, 253). The association with relevant signaling pathways makes JAK an important target for therapeutic intervention in the treatment of autoimmune disorders, various inflammatory diseases and cancers (Yu H. et al, Nat. Rev. Cancer, 2009, 9, 798).
JAK-3 is predominantly located in the endoplasmic membranes of hematopoietic cell (Ghoreschi K. et al, Immunol Rev. 2009, 228, 273) and specifically associates with the common cytokine receptor γ chain (yC) family (IL-2, IL-4, IL-7, IL- 9, IL-13 and IL-15) (O'Shea J., J. Ann. Rheumatic Dis., 2004, 64, U67). The pivotal roles in signaling through yC family of cytokine receptors and unique tissue distribution make JAK-3 an ideal biological target to manage the abnormal cytokine activities implicated in many cancer cells and inflammatory lymphocytes.
Discovery of the single point mutation in JAK-2 (V617F) common in patient diagnosed with myeloproliferative disorders (MPDs) has accelerated the search for JAK-2 inhibitors for the treatment of diseases resulting from JAK-2 pathways. (Pardanani A., Leukemia, 2008, 22, 23).
There has been significant progress in the JAK field. Tofacitinib (CP-690550) from the Pfizer has completed phase III clinical trials for rheumatoid arthritis (RA) and it is jnirmntlyjunder_re_view_forJhe-treatmentof-m
regulatory agencies around the world. Ruxolitinib (INCBO 18424) is an orally bioavailable JAK1/JAK2 inhibitor and is approved for the treatment of intermediate and high risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis by US FDA on November 16, 2011. Vertex Pharmaceuticals is developing VX-509 as specific JAK3 inhibitor, which is involved in signaling pathways that control the survival and proliferation of a lymphocyte. During 2010, Vertex initiated a Phase-IIa clinical trial of
VX-509 in patients with moderate-to-severe rheumatoid arthritis (RA). Galapagos NV has initiated a Phase II clinical study for GLPG0634, a novel selective JAK1 and JAK2 inhibitor being developed for inflammatory conditions, such as RA (Ken Garber, Nature Biotechnology, 2011, 29, 467-468).
Patent applications from the Pfizer (WO 2011/075334, WO 2011/045702 and
WO2008/029237) described the use of pyrrolo [2,3-D]-pyrimidine compounds as JAK inhibitors for the prevention or treatment of arthritis.
02
Patent applications from Portola (WO 2010/129802, WO 2009/145856, WO
2009/136995) discloses pyrimidine class of compounds as Spleen Tyrosine Kinases (SYK) or JAK inhibitors.
Rigel has filed number of patent applications (WO 2011/017178, WO
2010/085684, WO 2010/078369, WO 2010/075558,WO 2010/039518, US 8158621, 1^329_67α,_υ8_7329^
US7906644) claiming pyrimidine class of compounds as useful modulators of JAK pathways or as inhibitors of JAK kinases particularly JAK-2, JAK-3 or both.
WO 201 1/017178
WO 2010/078369 WO 2010/075558
WO 2010/039518 US 7906644
Avila Therapeutics reported pyrimidine class of compounds as protein kinase inhibitors WO 2010123870, WO 2009/158571, WO 20 51183).
WO:2008151183
WO2009158571
There is high unmet need to develop further JAK inhibitors in treating various medical conditions or diseases associated with JAK activation. Though several
compounds having such beneficial properties have been proposed in the literature, however, none of these compounds are yet to reach the market and so therefore there remains a need to develop newer medicines, which have the desired anti-inflammatory activities but have reduced or negligible side effects. We herein disclose such novel compounds. The present invention therefore provides compounds, methods for their manufacture and pharmaceutical compositions comprising the compounds of the invention together with suitable pharmaceutical carriers. Specifically the present invention provides novel JAK inhibitors that exhibit desired anti-inflammatory effect with fewer side effects.
OBJECTS OF THE INVENTION
It is an object of the present invention to develop novel compounds, which inhibit JAK kinase and shows anti-inflammatory activities.
It is another object of the present invention to provide novel compounds represented by the general formula (I), their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or mixtures thereof which JAK kinase.
In is yet another object of the present invention to provide novel compounds represented by the general formula (I), their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof having enhanced activities, without side effects or with reduced side effects.
Yet another object of the present invention is to provide a process for the preparation of novel compounds represented by the general formula (I), their stereoisomers, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates.
Yet another object of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their pharmaceutically _ac.ceptahle_salts,_or— their— mixtures-in-eombffl
diluents and other media normally employed in preparing such compositions. The above and other embodiments are described in details hereinafter.
SUMMARY OF INVENTION
Thus, the present invention discloses novel pyrimidine class of compounds which inhibit JAK kinase. These JAK inhibitors are useful for the treatment or prevention of pathological conditions or diseases such as myeloproliferative disorders, leukemia, lymphomas and solid tumors; bone marrow, organ transplant rejection; or
immune-mediated diseases such as autoimmune and inflammation diseases, including rheumatoid arthritis, inflammatory bowel diseases.
The invention further provides a method of treating a disease characterized by inflammatory, allergic, or proliferative processes, in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound of formula (I), according to the invention or a solvate, or salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one aspect of the invention there is provided compounds of the general formula (I),
(I)
wherein Ri represents optionally substituted groups selected from (C3-C8) cycloalkyl, aralkyl, heteroaralkyl, (Ci-C6)alkyl, (C2-C4)alkenyl, and (C2-C4)alkynyl; The term "substituted" whenever used alone or in combination with other radicals, denotes suitable substituents on that radical such as substituted alkyl, substituted alkenyl, substituted alkynyl etc. The suitable substituent on the groups representing Ri include , hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, hydrazino, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkenoxy, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkylthio, thioalkyl groups.
-R-2-represents-optionally-substto
(C2-C4)alkynyl, (C3-C8) cycloalkyl, aryl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from N, O or S;
R3 at each occurrence independently represents hydrogen, halogen, nitrq, cyano, - (CH2)r-C(0)R4,-(CH2)r-C(0)OR4, - Ν(¾)2 > -NH(CH2)r-C(0)R4>-NH(CH2)r-C(0)OR4, -NH(CH2)r-S(0)20R4 wherein r represents an integer from 0-2; R4 at each occurrence independently represents hydrogen, optionally substituted groups selected from (Q- C6)alkyl, (C2-C4)alkenyl, and (C2-C4)alkynyl; or the group NR5R6 wherein R5 and R independently represents hydrogen, optionally substituted groups selected from (Ci-
C6)alkyl, (C2-Gt)alkenyl, (C2-C4)alkynyl, (C3-C8) cycloalkyl, aryl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from N, O or S, or R5, R together with N can form a 4-7 membered ring, which may be optionally substituted and which may optionally further contain one or more heteroatoms selected from , O or S;
'X' represents O;
'm' represents an integer from 0-4;
In one preferred embodiment of this invention, there is provided a compound of formula
or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof.
In another preferred embodiment of the invention, there is provided a compound of formula
or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof.
In another preferred embodiment of the invention, there is provided a co of formula
or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof.
In another preferred embodiment of the invention, there is provided a compound of formula
or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof.
In a further preferred embodiment, the present invention provides a compound wherein the moiety:
is selected from the group comprising of:
In another preferred embodiment, the present invention provides a compound wherein Ri is selected from the group consisting of:
In a still preferred embodiment of this invention, there is provided a compound of formula (I), said compound being selected from:
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
(S)-4-((5-carbam0yl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methoxyphenyl methanesulfonate;
(R)-2-amino-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (dimethylamino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- fluorophenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl ethanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl propane-2-sulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl 2,2,2-trifluoroethanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methylphenyl ethanesulfonate;
(R)-2-acetamido-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
(R)-2-(al ly lam ino)-4-((5 -carbamoy l-4-((3 -methy lbutan-2-yl)am ino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methylphenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- hydroxyphenyl methanesulfonate;
(R)-methyl 5-((5-carbamOyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- ((methylsulfonyl)oxy)benzoate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methoxyphenyl ethanesulfonate;
(R)-2-carbamoyl-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (methylcarbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-((2- fluorobenzyl)carbamoyl)phenyl methanesulfonate;
(R)-2-(benzylcarbamoyl)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin- 2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-(((R)-3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-(((R)-l- phenylethyl)carbamoyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(((R)-3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-(((S)-l- phenylethyl)carbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- ((pyridin-3-ylmethyl)carbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-((4- fluorobenzyl)carbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (phenylcarbamoyl)phenyl methanesulfonate;
(R)-2-(allylcarbamoyl)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-2-(5-((5-carbamoyl-4-(((R)-3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- ((methylsulfonyl)oxy)benzamido)propanoic acid;
(R)-methyl 2-(5-((5-carbamoyl-4-(((R)-3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)-2-((methylsulfonyl)oxy)benzamido)propanoate;
4-((5-carbamoyl-4-(((R)-3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-(((S)-3- methylbutan-2-yl)carbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (dimethylcarbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (pyrrolidine-l-carbonyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (piperidine-l-carbonyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (mo holine-4-carbonyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
(R)-3-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-5- (hydroxymethyl)phenyl methanesulfonate;
(S)-4-((5-carbamoyl-4-(( 1 -hydroxy-3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(S)-4-((4-(( 1 -amino-3-methyl- 1 -oxobutan-2-yl)amino)-5-carbamoylpyrimidin-2- yl)amino)phenyl methanesulfonate;
(S)-4-((5-carbamoyl-4-((l-cyano-2-methylpropyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((2-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((4-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
2- amino-4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidtn-2-yl)amino)-2-methylphenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fiuorobenzyl)amino)pyrimidin-2-yl)amino)-2-methylphenyl ethanesulfonate;
4- ((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
5- ((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)-2-methoxyphenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)-2-(morpholine-4- carbonyl)phenyl methanesulfonate;
3- ((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)-5-(morpholine-4- carbonyl)phenyl methanesulfonate; (
(R)-4-((5-carbamoyl-4-(( 1 -phenylethyl)amino)pyrimidin-2-yl)amino)phenyl ethanesulfonate;
(R)-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2-yl)amino)-3-fluorophenyl methanesulfonate;
(R)-2-acetamido-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-2-(allylamino)-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4- ((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-carbamoylphenyl methanesulfonate;
4- ((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-(pyrrolidine-l- carbonyl)phenyl methanesulfonate;
4-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-(dimethylamino)phenyl methanesulfonate;
5- ((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
2- amino-5-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl
methanesulfonate;
3- ((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-5- (cyclopropylcarbamoyl)phenyl methanesulfonate;
3-((4-(benzylamίno)-5-carbamoylpyΓimidin-2-yl)amino)-5-(mo holine-4- carbonyl)phenyl methanesulfonate;
3- ((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-5-(pyrrolidine-l- carbony phenyl methanesulfonate;
4- ((5-carbamoyl-4-((4-methoxybenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyI-4-((2,6-difluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-(hydroxymethyl)phenyl methanesulfonate;
4-((5 -carbamoy l-4-((3 -fluorobenzy l)amino)pyrim idin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-((2,4-dimethylbenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl propane-2-sulfonate; 4-((5-carbamoyl-4-((2,4-difluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl propane-2- sulfonate;
(R)-3-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- fluorophenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methoxyphenyl ethanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methoxyphenyl methanesulfonate;
(R)-2-amino-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)am ino)phenyl methanesulfonate;
(R)-2-acetamido-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-2-carbamoyl-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
(R)-2-(allylcarbamoyl)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-2-(benzylcarbamoyl)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin- 2-yl)amino)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-((4- fluorobenzyl)carbamoyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-((2- fluorobenzyl)carbamoyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (phenylcarbamoyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (dimethylcarbamoyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (diethylcarbamoyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (pyrrolidine-l-carbonyl)phenyl methanesulfonate;
(R)- 5 -((5 -carbamoy l-4-((3 -methy lbutan-2-y l)amino)pyrimidin-2-y l)amino)-2- (morpholine-4-carbonyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (cyclopropy 1(2, 3 -dimethylbenzyl)carbamoy l)phenyl methanesul fonate ;
(R)-3-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-5- (cyclopropylcarbamoyt)phenyl methanesulfonate;
(R)-3-carbamoyl-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-3-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-5- (mo hόline-4-carbonyl)phenyl methanesulfonate;
(R)-3-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-5- (pyrrolidine-l-carbonyl)phenyl methanesulfonate;
4-((4-(allylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((4-(allylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-methylphenyl
methanesulfonate;
4- ((4-(allylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-methylphenyl
ethanesulfonate;
5- ((4-(allylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-methoxyphenyl
ethanesulfonate;
5-((4-(aIlylamino)-5-carbamoyIpyrimidin-2-yl)amino)-2-methoxyphenyl
methanesulfonate;
4-((5-carbamoyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)phenyl
methanesulfonate;
4-((5-carbamoyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
4-((5-carbamoyl-4-(isopentylamino)pyfimidin-2-yl)amino)phenyl methanesulfonate;
2- amino-4-((5-carbamoyl-4-(isopentylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
3- ((5-carbamoyl-4-(isopentylamino)pyrimidin-2-yl)amino)-5-(mo holine-4- carbonyl)phenyl methanesulfonate;
3-((5-carbamoyl-4-(isopentylamino)pyrimidin-2-yl)amino)-5-(pyrrolidine-l- carbonyl)phenyl methanesulfonate
2-(allylcarbamoyl)-4-((5-carbamoyl-4-(isopentylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-(isopentylamino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
3- ((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4- ((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
2- amino-4-((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4- ((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)-2-(dtmethylamino)phenyl methanesulfonate;
3 -((5 -carbamoyl-4-(isobutylam ino)pyrim idin-2-yl)amino)-2-methylphenyl methanesulfonate;
2,6-dibromo-4-((5-carbamoyW4-(isobutylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
5- ((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)-2-fluorophenyl methanesulfonate;
4-((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)-2-(hydroxymethyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)phenyl propane-2- sulfonate;
4-((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
4-((4-(sec-butylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl methanesulfonate;
3- ((4-(sec-butylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl methanesulfonate;
4- ((5-carbamoyl-4-((2,2,2-trifluoroethyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
2- amino-4-((5-carbamoyl-4-((2,2,2-trifluoroethyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
3- ((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2-yl)amino)-5- (morpholine-4-carbonyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
2-carbamoyl-4-((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
2- amino-4-((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(cyclopropylamino)pynmidin-2-yl)amino)phenyl methanesulfonate;
4- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-2- (dimethylamino)phenyl methanesulfonate;
3- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
2- amino-5-((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
5- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
4- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
3- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-5-(pyrrolidine-l- carbonyl)phenyl methanesulfonate;
3 -((5 -carbamoy l-4-(cyclopropylamino)pyrimidin-2-yl)amino)-5 -(morphol ine-4- carbonyl)phenyl methanesulfonate;
4- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)phenyl propane-2- sulfonate;
4-((5-carbamoyl-4-(cyclobutylamino)pyrimidin-2-yl)amino)phenyl
methanesulfonate;
4-((5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
5-((5-carbamoyl-4-(cyclopentylaminp)pyrimidin-2-yl)amino)-2-methoxyphenyl ethanesulfonate;
4-((5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-yl)amino)-2-(pyrrolidine-l- carbonyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-yl)amino)-2- (dimethylamino)phenyl methanesulfonate;
4-((5-carbamoyt-4-((l-(5-cyanopyridin-2-yl)piperidin-4-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((cyclopentylmethyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((dicyclopropylmethyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((dicyclopropylmethyl)amino)pyrimidin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-((dicyclopropylmethyl)amino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-((dicyclopropylmethyl)amino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
(R)-2-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl methanesMlfonate;
(R)-2-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-5- methylphenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-(( 1 -phenylethyl)amino)pyrimidin-2-yl)amino)phenyl 4- fluorobenzenesulfonate;
(R)-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2-yl)amino)phenyl benzenesulfonate;
(R)-4-((5-carbamoyl-4-(( 1 -phenylethyl)amino)pyrimidin-2-yl)amino)phenyl 4- isopropylbenzenesulfonate;
(R)-4-((5-carbamoyl-4-(( l-phenylethyl)amino)pyrimidin-2-yl)amino)phenyl 3- methylbenzenesulfonate;
(R)-4-((5-carbamoyl-4-(( 1 -phenylethyl)amino)pyrimidin-2-yl)amino)phenyl 4- (trifluoromethoxy)benzenesulfonate;
4-((5-carbamoyl-4-((2-chloro-6-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate ;
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The term "substituted" used in combination with other radicals, otherwise than those disclosed specifically, denotes suitable substituents on that radical such as substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted aryl, etc, mentioned anywhere in the specification. The' suitable 'substituent include, but are not limited to the following radicals, alone or in combination with other radicals, such as, hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, hydrazino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, 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, sulfonyl derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives.
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, w-propyl, wo-propyl, w-butyl, ec-butyl, /-butyl, amyl, t-amyl, n-pentyl , «-hexyl, wo-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-butyrtyl, 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, w-propoxy, wo-propoxy, rc-butoxy, /-butoxy, wo-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" 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 fiuoromethyl, 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, chlorofnethoxy, fluoroethoxy chloroethoxy groups, 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 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 'heterocyclic" includes, unless otherwise specified, the term "heteroaryl" as defined hereinafter.
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 l to 6 carbons, such as (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3- thienyl)methyl, (2-pyridyl)methyl, 1 -methyl- l-(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, /.so-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, wo-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 monoalk lamino group include methylamine, ethylamine, ^-propylamine, 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 (CrC6)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, phenethylamino, 3- phenylpropylamino, 1-napthylmethylamino, 2-(l-napthyl)ethylamino and the like.
The term "oxo" or "carbonyl" used herein, either alone (-C=0-) or in combination with other radicals, such as "alkylcarbonyl", denotes a carbonyl radical (- C=0-) 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=0-), 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", "Ν,Ν-dialkylaminocarbonyl", "N-alkyl- N-arylaminocarbonyl", "N-alkyl-N-hydroxyaminocarbonyl", and "N-alkyl-N- hydroxyaminocarbonylalkyl", substituted or unsubstituted. The terms "N- alkylaminocabonyl" and "Ν,Ν-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 aminocarbonyl 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 C6HsCH2OCH2, 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, methylthiomethyl, 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(CH30)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 "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 "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 -S02-, or RS02-, 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, propylsulfonyt 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 derivatives", used herein, either alone or in combination with other radicals, denotes -SO3H group and its derivatives such as sulfonylamino(S02NH2); N-alkylaminosulfonyl and Ν,Ν-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. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
List of Abbreviation
PTSA: para-Toluenesulfonic acid
NMP: N-Methylpyrrolidinone
m-CPBA: 3-Chloroperbezoic acid
EtOAc: Ethyl acetate
DCM: Dichloromethane
MeOH: Methanol
EtOH: Ethanol
CHCI3: Chloroform
DMF: Dimethyl formamide
DMSO: Dimethylsulfoxide
DIPEA: Diisopropylethylamine
EDAC.HC1: N-(3-Dimethyl aminopropyl)-N'-ethyl carbodiimide hydrochloride
HOBT: 1-Hydroxybenzotriazole
HC1: Hydrochloric acid
POCI3: Phosphorous oxychloride
LiOH: Lithium hydroxide
NEt3.- Triethylamine
THF: Tetrahydrofuran
SOCl2: Thionyl chloride
NaBfLt: Sodium borohydride
h: Hour(s) ,
RT : Room temperature [25-30 °C]
The compounds of present invention may be prepared according to the synthetic schemes provided below along with suitable modifications/variations thereof which are within the scope of a skilled person:
Scheme-I
The starting material of formula (6) wherein all the symbols are as described earlier are prepared as described in or in an analogous manner to the methods described in WO2010129802 or US patent No. 2010/0249092 Al .
Commercially available ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (2) and primary amine of formula (3) wherein all the symbols are described as earlier are reacted together in the presence of suitable base such as DIPEA in a solvent such as dioxane at RT and subsequent in-situ hydrolysis under basic condition using base such as LiOH to afford the acid derivative of formula (4). Compound (4) is converted to its amide derivative of formula (5) using suitable carboxyl group activating agents such as EDAC.HCI, dicyclohexyl carbodiimide and the like in the presence of. a suitable additive such as HOBT and a suitable base like NEt3or DIPEA in suitable solvent(s) like DMF or DCM at RT to afford mixed carbonate intermediate, which is then reacted with aq. ammonia to afford the product (5). The sulfoxide (6) can be prepared from controlled oxidation of sulfide (5) with an appropriate oxidizing agent such as m- CPBA, per acetic acid in a solvent such as DCM at -10 - 0 °C. Compound (6) is treated
with aromatic amino compounds of general formula (7) wherein all the symbols are as described earlier under acidic condition using acids such as PTSA in solvent(s) like dimethyl formammide (DMF) or NMP at temperature 100-110 °C to get the compounds of general formula (1) wherein all the symbols are described as earlier.
Alternatively, compounds of formula (I) can also be synthesized as shown in Scheme-II. For example, compound (9) can be prepared by treating commercially available ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate (8) with aromatic amino compounds of general formula (7) in a suitable solvent such as n-butanol. Chlorination of (9) using suitable chlorinating agent such as POCI3, SOCl2 in a suitable solvent such as toluene under refluxing condition afford chloro compound (10). Chloro compound (10) and primary amine of formula (3) are reacted together in the presence of suitable base such as DIPEA in suitable solvent such as dioxane at RT and subsequent hydrolysis under basic condition using base such as LiOH to afford the acid derivative of formula (12). Amidation of acid compound (12) is carried out using similar procedure described in the scheme-I to get the compounds of general formula (1) wherein all the symbols are described as earlier.
The invention is further exemplified by the following non-limiting examples. These examples are provided for better illustration of the preferred mode of carrying out the invention and should not be construed as limiting the scope of the invention in any way. It will be appreciated that while working these examples and preparing other compounds of the present invention, the skilled person will be using the skills and diligence expected from a person skilled in the art.
Instrument details
The Ή NMR spectra were recorded on a Brucker Avanc-400 spectrometer (400 MHz). The chemical shifts (δ) are reported in parts per million (ppm) relative to TMS, in DMSO-ak solution. Signal multiplicities are represented by s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), bs (broad singlet), and m (multiplet). Mass spectra (ESI-MS) were obtained on Shimadzu LC-MS 2010-A spectrometer. Preparation of Intermediates
Synthesis of 4-aminophenyI methanesulfonate [Intermediate (i)].
Step-I: Preparation of 4-nitrophenyl methanesulfonate
The solution of 4-nitrophenol (10 g, 0.0719 mol) and NEt3 (13.48 mL, 0.0934 mol) in DCM (100 mL) was added to methanesulfonyl chloride (6.88 mL, 0.0863 mol) at 0°-5°C. The mixture was stirred for 1 h. at RT. After completion of reaction, mixture was quenched in water and organic compound was extracted by DCM. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford 4-nitrophenyl methanesulfonate as solid. (14 g, 90 %).
Ή NMR (DMSO-de): δ 3.50 (3H, s), 7.62 (2H, m, J = 2.4 Hz), 8.35 (2H, d, J = 2.4 Hz);
ESI (m/z): 217.8 (M+H).
Step-II: Preparation of 4-aminophenyl methanesulfonate
The mixture of 4-nitrophenyl methanesulfonate (14 g, 0.0645 mol) and iron metal powder (28.90 g, 0.516 mol) in EtOH (150 mL) was stirred at RT. A solution of ammonium chloride (5.17 g, 0.0967 mol) dissolved in water was added and the resulting reaction mixture was heated to reflux for 2-3 h. Reaction mixture was diluted with DCM, filtered through celite, washed with DCM, and combined organic extract
was washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum to provide the desired product (9.0 g, 74 %) as black solid.
Ή NMR (DMSO-d6): δ 3.32 (3H, s), 5.26 (2H, s), 6.55 (2H, d, J= 6.58 Hz), 6.97 (2H, d, J = 6.95 Hz);
ESI (m/z): 187.5 (M+H).
Synthesis of 4-amino-2-(cyclopropylcarbamoyI)phenyI methanesulfonate [intermediate (xxiv)].
Step-I: Preparation of methyl 5-amino-2-hydroxybenzoate.
To a solution of 5-aminosalicylic acid (30 g, 0.196 mol), DMF (0.10 mL) in
MeOH (90 mL) was added oxalyl chloride (32.37 g, 0.255 mol) at 0-5 °C. The reaction mixture was heated at 60 -65 °C for 5-6 h. After completion of reaction, the mixture was quenched in water and extracted in EtOAc. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford the desired title product (27 g, 82 %).
Step-II: Preparation of methyl 5-((/ert-butoxycarbonyl)amino)-2-hydroxybenzoate. Triethylamine (27 mL, 0.194 mol) was added drop wise to a solution of 5-amino-2- hydroxybenzoate (25 g, 0.149 mol) and di-iert-butyl dicarbonate (48.9 mL, 0.224 mol) in DCM (60 mL) at RT. Mixture was stirred at same temperature for 4-5 h. After completion of reaction, the mixture was quenched in water and extracted in DCM. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford the desired title product (28 g, 70 %).
Step-III: Preparation of methyl 5-((tert-butoxycarbonyl)amino)-2- ((methylsulfonyl)oxy)benzoate.
The title compound was prepared using a procedure similar to that described in the preparation of 4-aminophenyl methanesulfonate (step-I) using methyl 5-((tert- butoxycarbonyl)amino)-2-hydroxybenzoate (10.0 g, 0.037 mol) and methanesulfonyl chloride (3.23 mL, 0.0411 mol) to afford desired product (10.5 g, 81 %).
Step-IV: Preparation of 5-((tert-butoxycarbonyl)amino)-2-
((methylsulfonyl)oxy)benzoic acid.
To a solution of methyl 5-((ter/-butoxycarbonyl)amino)-2- ((methylsulfonyl)oxy)benzoate in THF:H20 (2: 1, 15 mL) was added LiOH.H20 at RT. Mixture was stirred at same temperature for 4-5 h. After completion of hydrolysis the reaction mixture was quenched in water and made its pH to acidic (3-4) by adding acetic acid. The compound is extracted in EtOAc. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford the desired title product (2.0 g, 80 %).
Step-V: Preparation of 4-((tert-butoxycarbonyl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate.
The above acid (0.53 g, 1.6 mmol) was dissolved in DMF (5 mL) and treated with HOBT (0.24 g, 1.7 mmol) and EDAC.HCl (0.4 g, 2 mmol) and mixture was stirred for 1-1.5 h at RT. After completion of acid activation cyclopropylamine (0.1.2 mL, 1.8 mmol) was added and the reaction was stirred at same temperature for 1-2 h. After completion of reaction the mixture was quenched in water and extracted in EtOAc. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford the desired title product (0.45g, 81 %).
Step- VI: Preparation of 4-amino-2-(cyclopropylcarbamoyl)phenyl methanesulfonate.
The 4-((tert-butoxycarbonyl)amino)-2-(cyclopropylcarbamoyl)phenyl methanesulfonate (0.45 g, 1.22 mmol) was treated with methanolic HC1 at RT for 2-3 h. After completion of reaction the mixture was quenched in water and extracted in EtOAc. The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure to afford the desired title product (0.24 g, 75 %).
Synthesis of 4-amino-2-(hydroxymethyl)phenyI methanesulfonate [intermediate (xvii)].
Step-I: Preparation of 4-((/ert-butoxycarbonyl)amino)-2-(hydroxymethyl)phenyl methanesulfonate.
To a solution of methyl 5-((tert-butoxycarbonyl)amino)-2-
((methylsulfonyl)oxy)benzoate (1.0 g, 2.8 mmol) in THF (mL) was added NaBLLj (1.1 g, 2.8 mmol) at once and mixture stirred at 60-65 °C for 40-48 h. After completion of reaction the mixture was quenched in water and extracted in EtOAc. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford the desired title product (0.75 g, 82 %).
Step-II: Preparation of 4-amino-2-(hydroxymethyl)phenyl methanesulfonate. The deprotection of Boc group is carried out by similar procedure to that described in step- VI of preparation of 4-amino-2-(cyclopropylcarbamoyl)phenyl methanesulfonate using 4-((tert-butoxycarbonyl)amino)-2-(hydroxymethyl)phenyl methanesulfonate (6.0 g, 18.9 mmol) to get desired title product (3.5 g, 73 %).
Synthesis of 5-amino-2-(cyclopropylcarbamoyl)phenyl methanesulfonate [intermediate (lv)].
Step-I: Preparation of N-cyclopropyl-2-hydroxy-4-nitrobenzamide
Amidation of 2-hydroxy-4-nitrobenzoic acid was carried out using similar procedure to that described in step-V for preparation of 4-amino-2-(cyclopropylcarbamoyl)phenyl methanesulfonate using 4- nitosalicylic acid (1.0 g, 5.4 mmol) and cyclopropylamine (0.38 mL, 5.4 mmol) to get desired title product (1.0 g, 83 %).
Step-II: Preparation of 2-(cyclopropylcarbamoyl)-5-nitrophenyl methanesulfonate
The title compound was prepared using a procedure similar to that described in the preparation of 4-aminophenyl methanesulfonate (step-I) using N-cyclopropyl-2- hydroxy-4-nitrobenzamide (1.0 g, 4.5 mmol) and methanesulfonyl chloride (0.8 mL, 5.4 mmol) to afford desired product (0.70 g, 76 %).
Step-Ill: Preparation of 5-amino-2-(cyclopropylcarbamoyl)phenyl methanesulfonate.
The title compound was prepared using a procedure similar to that described in the preparation of 4-aminophenyl methanesulfonate (step-II) using 2- (cyclopropylcarbamoyl)-5-nitrophenyl methanesulfonate (l.l g, 3.7 mmol) to get desired title product (0.7 g, 76 %).
Synthesis of 4-amino-2-(2-cyanoacetamido)phenyl methanesulfonate [intermediate (xiii)].
Step-I: Preparation of 2-cyano-N-(2-hydroxy-5-nitrophenyl)acetamide.
Amidation of cyanoacetic acid (3.31 g, 38.9 mmol) was carried out using similar procedure to that described in step-V for preparation of 4-amino-2- (cyclopropylcarbamoyl)phenyl methanesulfonate using 2-amino-4-nitrophenol (5.0 g, 32 mmol) to get desired title product (5.5 g, 77 %).
Step-II: Preparation of 2-(2-cyanoacetamido)-4-nitrophenyl methanesulfonate.
The title compound was prepared using a procedure similar to that described in the preparation of 4-aminophenyl methanesulfonate (step-I) using 2-cyano-N-(2-hydroxy- 5-nitrophenyl)acetamide (4.0 g, 18 mmol) and methanesulfonyl chloride (1.7 mL, 27.1 mmol) to afford desired product (4.0 g, 74%).
Step-Ill: Preparation of 4-amino-2-(2-cyanoacetamido)phenyl methanesulfonate.
Reduction of nitro group of 2-(2-cyanoacetamido)-4-nitrophenyl methanesulfonate (4.0 g, 13.3 mmol) was carried out using a procedure similar to that
described in the preparation of 4-aminophenyl methanesulfonate (step-II) to get desired title product (2.8 g, 77%).
The following aromatic amino compounds which are used as intermediates for the preparation of final compound of formula (I) were . prepared following analogous procedure as provided in the above detailed examples and/or general reaction schemes
yl)carbamoyl)phenyl methanesulfonate
Ξ 0
odv. 1 4-amino-2-(cyclopropylcarbamoyl)phenyl o=s=o
methanesulfonate
0
XXV. 1 4-amino-2-(phenylcarbamoyl)phenyl o=s=o
methanesulfonate
cxvi. 1 4-amino-2-(benzylcarbamoyl)phenyl o=s=o
methanesulfonate
0
xvii. 1 (R)-4-amino-2-((l- o=s=o
phenylethyl)carbamoyl)phenyl methanesulfonate
= 0
cviii. 1 (S)-4-amino-2-((l- o=s=o
phenylethyl)carbamoyl)phenyl methanesulfonate
0
ixix. 1 4-amino-2-((2- o=s=o
fluorobenzyl)carbamoyl)phenyl methanesulfonate
F 0
XXX. 1 4-amino-2-((4- o=s=o
fluorobenzyl)carbamoyl)phenyl γ methanesulfonate
^ΝΗ2 .
0
o=s=o 4-amino-2-(2-hydroxyacetamido)phenyl methanesulfonate
HoJ N H
xxii. 1
o=s=o 4-amino-2-(2-methoxyacetamido)phenyl methanesulfonate
H 2 H
Preparation of compounds of formula (I)
Example 1
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyI methanesulfonate:
Step-I: Preparation of (R)-4-((3-methylbutan-2-yl)amino)-2-(methylthio)pyrimidine-5- carboxylic acid.
Ethyl 4-chloro-2-(methylthio)pyrimidine 5-carboxylate (13.3 g, 57.3 mmol) was dissolved in dioxane (100 mL) and DIPEA (57.3 mL, 57.3 mmol) was added to the reaction mixture at 0° C followed by (R)-(-)-2-amino-3-methylbutane and reaction mixture was stirred at 0° C for 30 min. and then 6 h. at RT. LiOH (5 g, 57.3 mmol) was dissolved in 50 mL water and added in to reaction and stirred overnight at 28°C. After completion of reaction, the reaction mixture was concentrated by rotary evaporation to remove a majority of the dioxane, and then acidified with 10 M HC1 to pH ~ 5 resulting in the formation of a white precipitate. The solid compound filtered, washed with water and dried under vacuum to afford the (R)-4-((3-methylbutan-2-yl)amino)-2- (methylthio)pyrimidine-5-carboxylic acid, as white solid. (12 g, 84 %).
lH NMR (DMSO-d6): δ 0.88 (6H, m), 1.11 (3H, d, J= 6.8 Hz), 1.82 (1H, m), 2.45 (3H, s), 4.14 (1H, m), 8.42 (1H, d, J= 8.4 Hz), 8.49 (1H, s);
Step-II: Preparation of (R)-4-((3-methylbutan-2-yl)amino)-2-(methylthio)pyrimidine-5- carboxamide.
(R)-4-((3-methylbutan-2-yl)amino)-2-(methylthio)pyrimidine-5-carboxylic acid (12 g, 47.1 mmol) was dissolved in DMF (100 mL) under nitrogen atmosphere and treated with HOBT (6.4 g, 47.1 mmol) and EDAC.HCI (13.5 g, 70.5 mmol) at RT.
After stirring 1 hr. aq. Ammonia (40 mL) was added at 0° C, and it was stirred for 1 h.
at RT. After completion of reaction, reaction mixture was quenched by 200 mL of water resulting in the formation of a white precipitate. The solid compound was isolated by filtration, washed with water and dried under reduced pressure to afford (R)-4-((3-methylbutan-2-yl)amino)-2-(methylthio)pyrimidine-5-carboxamide, as white solid. (11.5 g, 95 %).
Ή NMR (DMSO-d6): δ 0.86 (3H, m), 0.89 (3H, m), 1.09 (3H, d, J= 6.8 Hz), 1.80 (1H, m), 2.44 (3H, s), 4.10 (1H, m), 7.41 (1H, s), 8.03 (1H, s), 8.49 (1H, s), 9.19 (1H, d, J = 8.4 Hz); :
Step-III: Preparation of 4-(((R)-3-methylbutan-2-yl)amino)-2- (methylsulfinyl)pyrimidine-5-carboxamide.
(R)-4-((3-methylbutan-2-yl)amino)-2-(methylthio)pyrimidine-5-carboxamide (4 g, 15.7 mmol) was dissolved in dioxin and chloroform (1:1) (100 mL). Reaction mixture was cooled up to -2° C and treated with m-CPBA (60%) (4.1 g, 24.1 mmol) and it was stirred for 50 min at 0° C. After completion of reaction, reaction mixture was quenched by 10% aq. sodium metabisulfite (100 mL) and organic compound was extracted by chloroform and washed with aq. 10 % sodium bicarbonate. The organic layer was dried over sodium sulfate (15 g) and the solvent was removed under reduced pressure to 4-(((R)-3-methylbutan-2-yl)amino)-2-(methylsulfinyl)pyrimidine-5- carboxamide, as white solid. (3.5 g, 73 %).
'H NMR (DMSO-d6): δ 0.86 (6H, m), 1.12 (3H, d, J= 6.4 Hz), 1.82 (1H, m), 2.80 (3H, s), 4.10 (1H, m), 7.72 (1H, s), 8.29 (1H, s), 8.74 (1H, s), 9.36 (1H, m);
Step-IV: (R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate:
To a solution of 4-(((R)-3-methylbutan-2-yl)amino)-2- (methylsulfinyl)pyrimidine-5-carboxamide (5 g, 0.0185 mol) and PTSA (5 g, 0.0203 mol) in NMP (20 mL) was added 4-aminophenyl methanesulfonate (3.46 g, 0.0185 mol) at RT. The reaction mixture was heated at 100 -110 °C for 1-2 h. After completion of reaction, the mixture was diluted with water (100 mL) and the compound was extracted in EtOAc. Organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to afford the crude product. Crude product was purified by flash chromatography over silica gel (100-200 mesh) with 2 % MeOH/CHCl3 to provide the desired title product (3.7 g, 51%).
H NMR (DMSO-d6): δ 0.90 (3H, d, J= 6.8 Hz), 0.93 (3H, d, J= 6.8 Hz), 1.13 (3H, d, J = 6.4 Hz), 1.88 (1H, m), 3.33 (3H, s), 4.08 (1H, m), 7.26 (2H, d, J = 2.0 Hz), 7.85 (1H, d, J= 2.0 Hz), 8.52 (1H, s), 9.28(2H, d, J= 8.4 Hz), 9.64 (1H, s);
ESI (mlz) 394.1 (M+H).
Example 2
(S)-4-((5-carbamoyl-4-((l-hydroxy-3-methyIbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyI methanesulfonate.
Step-I: Preparation of ethyl 4-hydroxy-2-((4-
((methylsulfonyl)oxy)phenyl)amino)pyrimidine-5-carboxyIate.
A mixture of commercially available ethyl 4-hydroxy-2-
(methylthio)pyrimidine-5-carboxylate (35 g, 0.16 mol), 4-aminophenyl methanesulfonate (36.7 g, 0.196 mol) in Mrbutanol (175 mL) was refluxed for 4-5 h. After completion of reaction the mixture was cooled to 25-30 °C and EtOAc (200 mL) was added and stirred mixture for 1 h. The pptd compound was filtered and washed with cold EtOAc to get desired title product (18 g, 31%).
Step-II: Preparation of ethyl 4-chloro-2-((4-
((methylsulfonyl)oxy)phenyl)amino)pyrimidine-5-carboxylate.
To a solution of 4-hydroxy-2-((4-
((methylsulfonyl)oxy)phenyl)amino)pyrimidine-5-carboxylate (20 g, 0.056 mol) in toluene ( 200 mL) was added POCl3 (15 mL, 0.113 mol) drop wise at RT. Refluxed the reaction mixture for 2-3 h. After completion of reaction the reaction mixture was cooled to 5-10 °C and stirred at same temperature for 1 h. The pptd. compound was filtered and washed with cold toluene to get desired title product (15 g, 60%).
Step-III: Preparation of (S)-4-((l-hydroxy-3-methylbutan-2-yl)amino)-2-((4- ((methylsulfonyl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid.
The title compound was synthesized by a process similar to that of step-I of example 1 (step-I) using ethyl 4-chloro-2-((4-
((methylsulfonyl)oxy)phenyl)amino)pyrimidine-5-carboxylate (0.50 g, 1.08 mmol) and (S)-2-amino-3-methylbutan-l-ol (0.14 g, 1.29 mmol) and hydrolyzing the product using LiOH (0.40 g, 10.76 mmol) to get the desired product (0.30 g, 68%).
Step IV: Preparation of (S)-4-((5-carbamoyl-4-((l-hydroxy-3-methylbutan-2- yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate.
The title compound was synthesized by a process similar to that of step-II of example 1 (step-I) using (S)-4-((l-hydroxy-3-methylbutan-2-yl)amino)-2-((4- ((methylsulfonyl)oxy)phenyl)amino)pyrimidine-5-carboxylic acid (0.30 g, 0.97 mmol) to get the desired product ((0.063 g, 16 %).
Several compounds of the present invention can be prepared following the processes described above in schemes 1 & 2 as well as Examples 1 & 2 along with suitable modifications, alterations etc. as are within the scope of a skilled person. The following compounds are prepared:
(R)-4-((5-carbamoyl-4-((3- 0.76 (3H, d, J= 6.8 Hz), 1.07 (3H, t, J= 8.8 methylbutan-2- Hz), 1.35 (2H, s), 1.79 (IH, m), 3.19 (3H, yl)amino)pyrimidin-2-yl)amino)- s), 4.09 (IH, s), 4.44 (2H, t, J = 4.0 Hz),
2-(dimethylamino)phenyl 7.35 (2H, m), 7.80 (2H, m), 8.20 (IH, d, J = methanesulfonate 2.4 Hz), 8.47 (IH, t, J = 2.2 Hz), 8.57 (2H, m), 8.98 (IH, t, J= 6.0 Hz), 9.28 (IH, d, J = 8.4 Hz), 9.77 (IH, s).
(R)-4-((5-carbamoyl-4-((3- 1.38 (t, 3H, J = 7.2 Hz), 1.32 (2H, s), 1.78 methylbutan-2- (IH, m), 3.15 (3H, s), 4.05 (IH, s), 4.45 yl)am ino)pyrim idin-2-y 1 )am ino)- (2H, t, J = 4 Hz), 3.64 (m, 2H); 7.62 (m, 2-fluorophenyl methanesulfonate 2H), 8.34 (m, 2H).
(R)-4-((5-carbamoyl-4-((3- 0.9 (6H, d, J = 6.8 Hz), 1.1 (3H, d, J = 6.8 methylbutan-2- Hz), 1.3 (3H, t, J = 7.6 Hz), 1.8 (IH, m), 3.4 yl)amino)pyrimidin-2- (2H, q, J = 7.6 Hz), 3.3 (3H, s), 4 (IH, m), yI)amino)phenyl ethanesulfonate 7.3 (IH, t, J = 7.2 Hz), 4.4 (IH, m), 7.1
(2H, d, J= 8.8 Hz), 7.7 (2H, d J= 18.8 Hz), 8.5 (IH, s), 9.2 (IH, d, J= 8.0 Hz), 9.6 (IH, s).
(R)-4-((5-carbamoyl-4-((3- 0.91 (3H, m), 0.97 (3H, m), 1.18 (3H, m), methylbutan-2- 1.42 (6H, d, J= 6.8 Hz), 1.85 (IH, m ), 3.70 yl)amino)pyrimidin-2- (IH, m ), 4.05 ( IH, m), 7.25 (2H, d, J = yl)amino)phenyl propane-2- 8.8 Hz), 7.78 (2H, d, J= 8.8 Hz), 8.49 (IH, sulfonate s), 9.54 (IH, s), 9.87 (IH, s).
10. (R)-4-((5-carbamoyl-4-((3- 0.9 (6H, d, J = 6.8 Hz), 1.1 (3H, d, J = 6.8 methylbutan-2- Hz), 1.8 (IH, m), 4.1 (IH, m), 5.2 ( 2H, q), yl)amino)pyrimidin-2- 7.3 (2H , d, J= 7.2 Hz), 7.6 (IH, s) 7.7 (2H, yl)amino)phenyl 2,2,2- d, J = 7.5 Hz), 8.1 (IH, s) 8.4 (IH, s ), 9.9 trifluoroethanesulfonate (IH, s), 10.2 (IH, s).
ι ΐ · (R)-4-((5-carbamoyl-4-((3- 0.89 (6H, m), 1.14 (3H, d, J= 6.8 Hz), 1.39 methylbutan-2- ' (3H, t, J = 7.2 Hz), 2.26 (3H, s), 3.53 (2H, yl)amino)pyrimidin-2-yl)amino)- m), 4.05 (IH, m), 7.17 (IH, d, J = 8.8 Hz), 2-methylphenyl ethanesulfonate 7.58 (IH, dd, Jl = 2.8 Hz & J2 = 8.8 Hz),
7.85 (IH, d, J = 2.4 Hz), 8.52 (IH, s), 0.26 (IH, m), 9.55 (IH, s).
12. (R)-2-acetamido-4-((5- 0.90 (6H, m), 1.13 (3H, m), 1.75 (2H, m), carbamoy l-4-((3 -methy lbutan-2- 2.09 (3H, s), 3.27 (3H, s), 4.15 (IH, m), yl)amino)pyrimidin-2- 7.24 (IH, d, J= 8.8 Hz), 7.49 (IH, m), 8.38 yl)amino)phenyI (IH, s), 8.51 (IH, s), 9.25 (IH, d, J = 8.0 methanesulfonate Hz), 9.52 (IH, s), 9.62 (IH, s).
13. (R)-4-((5-carbamoyl-4-((3- 0.95 (6H, d, J = 6.8 Hz), 1.12 (3H; d, J = methylbutan-2- 6.8 Hz), 1.84 (IH, m), 3.95 (2H, s), 4.13 yl)amino)pynmidin-2-yl)amino)- (IH ,m), 7.25 (IH, d, J= 7.2 Hz), 7.57 (IH,
2-(2-cyanoacetamido)phenyl q, J = 8.8 Hz), 8.43 (IH, m), 8.56 (IH, s), methanesulfonate 9.27 (IH, d, J = 8.4 Hz), 9.62 (IH, s), 9.94
(IH, s).
14. (R)-2-(allylamino)-4-((5- 0.91 (6H, m), 1.25 (3H, m), 1.81 (IH, m), carbamoyl-4-((3-methyibutan-2- 3.59 (3H, s), 3.74 (2H, m), 4.12 (IH, m), yl)amino)pyrimidin-2- 5.11 (IH, dd, Jl = 1.6 & J2 = 10 Hz), 5.22 yl)amino)phenyl (IH, dd, Jl = 17.2 & J2 = 1.6 Hz), 5.65 methanesulfonate (IH, t, J = 6.0 Hz), 5.91 (IH, m), 7.03 (IH, d, J= 2.4 Hz), 7.2 (IH, d, J= 1.2 Hz), 8.50 (IH, s), 9.28 (IH, m), 9.33 (IH, s).
15. (R)-4-((5-carbamoyl-4-((3- 0.89 (6H, m), 1.13 (3H, d, J= 6.4 Hz), 1.84 methylbutan-2- (IH, m), 2.26 (3H, s), 3.4 (3H, s), 4.09-4.07 yl)amino)pyrimidin-2-yl)amino)- (IH, m), 7.22 (IH, d, J= 8.0 Hz), 7.59 (IH,
2-methylphenyl methanesulfonate m). 7.85 (IH, d, J = 2.4 Hz), 9.28 (IH, d, J = 8.0 Hz), 9.56 (lH,s).
(R)-4-((5-carbamoyl-4-((3- 0.83-0.96 (6H, m), 1.13 (3H, d, J = 6.4Hz), methylbutan-2- 1.80-1.90 (IH, m), 3.19 (3H, s), 4.15 (IH, yl)am ino)pyrim idin-2-y l)amino)- m), 4.41 (2H, d, J = 6.0 Hz), 7.13 (IH, m),
2-hydroxyphenyl 7.37 (2H, m), 7.53 (IH, d, J= 8.8 Hz), 7.60 methanesulfonate (IH, m), 8.20 (IH, s), 8.55 (IH, s), 8.8 (IH, t, J = 11.6 Hz), 9.33 (IH, d, J = 8.4 Hz), 9.92 (lH, s),
(R)-methyl 5-((5-carbamoyl-4- 0.91 (6H, m), 1.15 (3H, m), 1.83 (IH, m),
((3 -methy lbutan-2- 3.35 (3H, m), 3.83 (3H, s), 4.15 (IH, m), y l)am ino)pyrimidin-2-yl)am ino)- 7.38 (IH, d, J= 8.8 Hz), 7.88 (IH, m), 8.55
2-((methylsulfonyl)oxy)benzoate (IH, s), 8.60 (IH, d, J = 2.8 Hz), 9.32 (IH, d, J = 8.4 Hz), 9.83 (IH, s), 0.91 (6H, m), 1.15 (3H, m), 1.83 (lH, m),
(R)-4-((5-carbamoyl-4-((3- 0.95 (6H, m), 1.18 (3H, d, J= 6.8 Hz), 1.38 methylbutan-2- (3H, t, J = 7.2 Hz), 1.85-1.77 (IH, m), 3.32 yl)amino)pyrimidin-2-yl)amino)- (2H, m), 3.83 (3H, s), 4.09 (IH, m), 7.15 2-methoxypheny 1 ethanesulfonate (IH, d, J = 8.8 Hz), 7.30 (IH, dd, J = 2.4
Hz, J = 8.8 Hz), 7.80 (IH, d, J = 2.4 Hz), 8.53 (IH ,s), 9.33 (IH, m), 9.58 (IH, s).
(R)-2-carbamoyl-4-((5- 0.89 (6H, m), 1.12 (3H, d, J= 6.4 Hz), 1.79 carbamoyl-4-((3 -methylbutan-2- (IH, m), 3.31 (3H, s), 4.07 (IH, m), 7.15 yl)amino)pyrimidin-2- (IH, bs), 7.29 (IH, d, J= 8.8 Hz), 7.57 (IH, yl)amino)phenyl s), 7.74 (3H, m), 8.22 (IH, d, J = 2.8 Hz), methanesulfonate 8.54 (IH, s), 9.28 (IH, d, J = 8.8 Hz), 9.73
(IH, s).
(R)-4-((5-carbamoyl-4-((3- 0.90 (6H, m), 1.11 (3H, d, J= 6.4 Hz), 1.80 methylbutan-2- (IH, t, J= 6.2 Hz), 2.74 (3H, d, J= 4.8 Hz), yl)amino)pyrimidin-2-yl)amino)- 3.30 (3H, m), 4.09 (IH, t, J = 5.4 Hz), 7.29
2-(methylcarbamoyl)phenyl (IH, d, J= 8.8 Hz), 7.71 (IH, m), 8.24 (IH, methanesulfonate d, J = 2.4 Hz), 8.32 (IH, d, J = 3.2 Hz),
8.54 (IH, s), 9,29 (IH, d, J = 8.4 Hz), 9.77 (IH, s).
(R)-4-((5-carbamoyl-4-((3- 0.5 (2H, t, J = 4.0 Hz), 0.6 (5H, t, J = 4 0 methylbutan-2- Hz), 0.8 (6H, d), 1.2 (2H, m),1.8 (IH, m), yl)amino)pyrimidin-2-yl)amino)- 2.6 (IH, m), 3.3 (3H, s), 4.1(1H, s), 7.2 (IH, 2-(cyclopropylcarbamoyl)phenyl d), 7.6 (IH, d, J = 8.2 Hz), 8.1 (IH, d, J = methanesulfonate 8.5 Hz), 8.5 (IH, s), 9.4 (IH, s), 9.7 (IH. s).
(R)-4-((5-carbamoyI-4-((3- 0.87 (6H, m), 1.04 (3H, d, J= 6.4 Hz), 1.73 methylbutan-2- (IH, m), 3.32 (3H, s), 3.98 (IH, m), 7.21 yl)amino)pyrimidin-2-yl)amino)- (IH, m), 7.78 (IH, m), 8.13 (IH, m), 9.34 2-((2- (IH, m), 10.99 (IH, s).
fluorobenzyl)carbamoyl)phenyl
methanesulfonate
(R)-2-(benzy lcarbamoyl)-4-((5 - 0.83 (6H, m), 1.02 (3H, d, J= 5.6 Hz), 1.88 carbamoyl-4-((3-methylbutan-2- (IH, m), 3.36 (3H, s), 3.95 (lH,m), 4.48 yl)amino)pyrimidin-2- (2H, m), 6.84 (2H, d, J= 8.8 Hz), 7.25 (5H, yl)amino)phenyl m), 7.53 (IH, m), 8.17 (IH, s), 9.14 (2H, methanesulfonate m), 9.21 (IH, s).
4-((5-carbamoyl-4-(((R)-3- 0.85 (6H, m), 1.03 (d, 3H, 2H, J = 6.8 Hz), methylbutan-2- 1.42 (3H, d, J= 6.8 Hz), 1.82-1.76 (IH, m), yl)amino)pyrimidin-2-yl)amino)- 3.06 (3H, s), 4.01 (IH, m), 5.12-5.05 (IH, 2-(((R)-l- m), 7.16 (bs, IH), 7.25-7.22 (IH, m), 7.34- phenylethyl)carbamoyl)phenyl 7.28 (3H, m), 7.41 (2H, d, J = 7.2 Hz), methanesulfonate 7.83-7.80 (2H, m), 8.10 (2H, d, J= 2.4 Hz),
8.53 (s, IH), 8.84 (IH, d, J = 8.0 Hz), 9.26 (IH, d, J= 8.4 Hz), 9.75 (s, IH).
4-((5-carbamoyl-4-(((R)-3- 0.85 (6H, m), 1.03 (3H, d, J= 6.4 Hz,), 1.42 methylbutan-2- (3H, d, J= 7.2 Hz), 1.75 (IH, m), 3.06 (3H, yl)amino)pyrimidin-2-yl)amino)- s), 4.00 (IH, m), 5.05 (IH, m), 7.15 (IH, 2-(((S)-l- bs), 7.24 (IH, t, J = 7.2 Hz), 7.28 (3H, m), phenylethyl)carbamoyl)phenyl 7.41 (2H, d, J= 7.2 Hz), 7.80 (m, 2H), 8.09 methanesulfonate (IH, d, J = 2.4 Hz), 8.53 (s, IH), 8.84 (IH,
d, J = 8.0 Hz), 9.26 (IH, d, J 8.4 Hz), 9.75 (s, IH).
(R)-4-((5-carbamoyl-4-((3- 0.76 (3H, d, = 6.8 Hz), 0.81 (3H, d, J = methylbutan-2- 6.8 Hz), 1.02 (3H, d, J = 6.4 Hz), 1.65 (d, yl)amino)pyrimidin-2-yl)amino)- IH, J = 5.6 Hz), 3.33 (m, 3H,) 4.04 (IH, d, 2-((pyridin-3- J = 7.2 Hz), 7.09 (t, 2H, J = 7.4 Hz), 7.39 ylmethyl)carbamoyl)phenyl (2H, m), 7.37 (IH, m), 7.71 (3H, t, J = 9.4 methanesulfonate Hz), 8.48 (IH, s), 8.54 (IH, s), 9.28 (IH, d,
J = 8.4 Hz), 9.86 (IH, s), 10.47 (IH, s), 9.77 (IH, s).
(R)-4-((5-carbamoyl-4-((3- 0.85 (m, 6H), 1.08 (d, 3H, J = 6.8 Hz), methylbutan-2- 1.82-1.70 (IH, m), 3.17 (3H, s), 3.95 (IH, yl)amino)pyrimidin-2-yl)amino)- m), 4.40 (2H, d, J = 5.6 Hz), 7.12 (2H, m), 2-((4- 7.31 (IH, d, J= 9.2 Hz), 7.38 (2H, m), 7.79 fluorobenzyl)carbamoyl)phenyl (IH, m), 8.18 (IH, d, J= 2.4 Hz), 8.53 (IH, methanesulfonate s), 8.93 (IH, d, J= 6.0 Hz) 9.28 (IH, d, J =
8.4 Hz), 9.76 (lH, s).
(R)-4-((5-carbamoyl-4-((3- 0.76 (d, 3H, J= 6.8 Hz),1.07 (t, 3H, J = 8.8 methylbutan-2- Hz), 1.35 (s, 2H), 1.79 (m, IH), 3.19 (s, yl)amino)pyrimidin-2-yl)amino)- 3H), 4.09 (s, IH), 4.44 (t, 2H, J = 4.0 Hz),
2-(phenylcarbamoyl)phenyl 7.35 (m, 2H), 7.80 (m, 2H), 8.20 (d, IH, J = methanesulfonate 2.4 Hz), 8.47 (t, IH, J = 2.2 Hz), 8.57 (m,
2H), 8.98 (t, IH, J= 6.0 Hz), 9.2 (d, 1H J = 8.4 Hz), 9.77 (s, IH).
(R)-2-(allylcarbamoyl)-4-((5- 0.89 (6H, m), 1.11 (3H, d, J= 6.8 Hz), 1.80 carbamoyl-4-((3 -methylbutan-2- (IH, s), 3.30 (3H, m), 3.85 (IH, s), 4.07 yl)amino)pyrimidin-2- (IH, m), 5.09 (IH, m), 5.23 (IH, m), 5.85 yl)amino)phenyl (IH, m), 7.30 (IH, d, J= 8.8 Hz), 7.77 (IH, methanesulfonate m), 8.18 (IH, d, J= 2.4 Hz), 8.56 (IH, t, J =
6.8 Hz), 9.29 (IH, d, J= 8.4 Hz), 9.76 (IH, s).
(R)-2-(5-((5-carbamoyl-4-(((R)- 12.75 (IH, bs), 9.29 (IH, s), 9.17 (IH, d, J 3-methylbutan-2- = 8.4 Hz), 8.90 (IH, d, J = 6.4 Hz), 8.46
yl)amino)pyrimidin-2-yl)amino)- (1H, s), 8.22 (IH, s), 7.74 (IH, bs), 7.58 2- (IH, m), 7.17 (IH, bs), 6.85 (IH, d, J = 8.8
((methylsulfonyl)oxy)benzamido) Hz,), 4.39 (lH, m,), 4.06 (IH, m), 3.31 (3H, propanoic acid s), 1.75 (IH, m), 1.39 (3H, d, J = 7.2 Hz),
1.03 (3H, d, J= 6.4 Hz), 0.84 (6H, m).
(R)-methyl 2-(5-((5-carbamoyl-4- 0.91 (6H, m), 1.11 (3H, d, J = 6.8 Hz), 1.35 (((R)-3 -methylbutan-2- (3H, d, J = 7.6 :Hz), 1.79 (IH, m), 3.30 (3H, yl)amino)pyrimidin-2-yl)amino)- s), 3.66 (3H, s), 4.05-4.11 (IH, m), 4.41 2- (IH, m), 7.18 (IH, bs), 7.31 (IH, d, J= 8.8
((methylsulfonyl)oxy)benzamido) Hz), 7.79 (2H, m), 8.17 (IH, s), 8.54 (IH, propanoate s), 8.76 (IH, d, J= 6.4 Hz), 9.28 (IH, d, J=
8.4Hz), 9.76 (IH, s).
4-((5-carbamoyl-4-(((R)-3- 0.8 (12H, m), 1.1 (6H, d, J = 6.8 Hz), 1.8 methylbutan-2- (2H, m), 3.3 (3H, s), 3.7 (IH, d, J= 8.4 Hz), yl)amino)pyrimidin-2-yl)amino)- 4 (IH, d, J = 8.4 Hz ), 7.3 (IH, d, J = 8.8 2-(((S)-3 -methylbutan-2- Hz), 7.8 ( 2H, d, J= 8.52 Hz), 8.0 (IH, d, J yl)carbamoyl)phenyl = 2.4 Hz), 8.1 (IH, d, J= 8.4 Hz), 8.5 (IH, methanesulfonate s), 9.3 (IH, d, J = 8.4 Hz), 9.7 (IH, s).
(R)-4-((5-carbamoyl-4-((3- 0.8 (6H, d, J = 7.6 Hz), 1.2 (2H, m), 1.8 methylbutan-2- (IH, m), 2.6 (3H, s), 2.8 (3H, s), 3.3 (3H, yl)amino)pyrimidin-2-yl)amino)- s), 4.1 (IH, s), 7.2 (IH, d, J = 8.4 Hz), 7.6
2-(dimethylcarbamoyl)phenyl (IH, d, J= 8.4 Hz), 8.1 (IH, d, J= 8.6 Hz), methanesulfonate 8.5 (IH, s), 9.4 (IH, s).
(R)-4-((5-carbamoyl-4-((3- 0.8 (6H, m), 1.1 (3H, d, J= 6.4 Hz), 1.8 (m, methylbutan-2- 3H), 1.9 (2H, m), 3.1 (2H, m), 3.3 (3H, s), yl)amino)pyrimidin-2-yl)amino)- 3.6 (3H, d, J = 6.5 Hz ), 4.1 (IH, m), 7.4 2-(pyrrolidine- 1 -carbonyl)phenyl (IH, d, J= 8.0 Hz), 7.6 (IH, d, J= 2.4 Hz), methanesulfonate 8.1 (IH, s), 8.5 (IH, s), 9.6 (IH, s), 10 (IH, s).
(R)-4-((5-carbamoyl-4-((3- 0.87 (6H, m), 1.12 (3H, d, J= 6.8 Hz), 1.55 methylbutan-2- (5H, m), 1.77 (IH, m), 3.11 (2H, m), 3.50 yl)amino)pyrimidin-2-yl)amino)- (2H, m), 3.65 (IH, m), 4.01 (IH, m), 7.15
2-(piperidine- 1 -carbonyl)phenyI (1H, bs), 7.31 (3H, s), 7.34 (IH, d, J = 8.8 methanesulfonate Hz,), 7.70 (IH, m), 7.83 (IH, bs), 8.03 (IH, m), 8.54 (IH, IH), 9.31 (IH, d, J= 8.4 Hz), 9.78 (IH, s).
(R)-4-((5-carbamoyl-4-((3- 0.8 (6H, m) 1.1 (3H, m), 1.8 (IH, m) 3.1 methylbutan-2- (3H, s) ,3.5 (3H, m) 3.6 (4H, m), 4.1 (IH, yl)amino)pyrimidtn-2-yl)amino)- m), 7.4 (IH, d, J = 8.0 Hz), 7.6 (IH, d, J = 2-(morpholine-4-carbonyl)phenyl 2.4 Hz), 8.1 (IH, s), 8.5 (IH, s), 9.2 (IH, s), methanesulfonate 9.8 (IH, s).
(R)-4-((5-carbamoyl-4-((3- 0.92 (6H, m), 1.12 (3H, d, J= 6.4 Hz), 1.83 methylbutan-2- (IH, m), 3.40 (3H, s), 4.18 (IH, m), 4.56 yl)amino)pyrimidin-2-yl)amino)- (2H, d, J= 5.6 Hz), 5.22 (IH, t, J= 5.4 Hz),
2-(hydroxymethyl)phenyl 7.22 (IH, d, J= 8.8 Hz), 7.67 (IH, m), 8.12 methanesulfonate (IH, d, J= 2 Hz), 8.52 (IH, s), 9.26 (IH, d,
J= 8.4 Hz), 9.60 (lH, s).
(R)-3-((5-carbamoyl-4-((3- 0.90 (3H,d, J= 6.4 Hz), 0.94 (3H, d,.J= 6.8 methylbutan-2- Hz), 1.13 (3H, d, J= 6.8 Hz), 1.79 (IH, m), yl)amino)pyrimidin-2-yl)amino)- 3.35 (3H, s), 4.09 (IH, m), 7.14 (bs, IH), 5 -(hydroxymethy l)phenyl 6.91 (2H, dd, Jl = 8.0 Hz, J2 = 2 Hz), 7.35 methanesulfonate (IH, t, J= 8.2 Hz), 7.59 (IH, d, J= 8.0 Hz),
7.80 (IH, bs), 8.06 (IH, s), 8.54 (IH, s), 9.17 (IH, s), 9.28 (IH , d, J= 8.4 Hz).
(S)-4-((5-carbamoyl-4-((l- 0.9 (6H, d, J = 6.0 Hz), 2.01 (IH, m), 3.41 hydroxy-3 -methy lbutan-2- (IH, m ), 3.56 (IH, s), 4.01 (IH, s), 4.75 yl)amino)pyrimidin-2- (IH, m), 7.26 (2H, dd, J = 8.8 Hz), 7.86 yl)amino)phenyl (2H, d, J = 8.0 Hz), 9.31 (IH, s), 8.5 (IH, methanesulfonate s), 9.61 (IH, s).
(S)-4-((4-(( 1 -amino-3-methyl- 1 - 0.9 (6H, d, J = 6.8 Hz), 4.43 (IH, t, J = 7.2 oxobutan-2-yl)amino)-5 - Hz), 7.12 (IH, s), 7.2 (2H, d, J = 7.1 Hz), carbamoylpyrimidin-2- 7.51 (IH, s), 7.88 (2H, d, J = 8.8 Hz), 8.56 yl)amino)phenyl (IH, s), 9.54 (IH, d, J = 8.5 Hz), 9.74 (IH, methanesulfonate s)..
(S)-4-((5-carbamoyl-4-(( 1 -cyano- 1.03 (6H, m), 2.31 (IH, m), 3.35 (3H, s),
2-methylpropyl)amino)pyrimidin- 4.91 (IH, t, J= 6.8 Hz), 7.27 (2H, d, J= 8.8
2-yl)amino)phenyl Hz), 7.32 (IH, s), 7.85 (2H, d. J = 8.8 Hz), methanesulfonate 7.96 (IH, s), 8.67 (IH, s), 9.74 (IH, d, J =
7.2 Hz), 9.91 (lH. s).
4-((5-carbamoyl-4-((2- 2.90 (3H, s), 4.67 (2H, d, J = 6 Hz), 7.05 fluorobenzyl)amino)pyrimidin-2- (2H, d, J= 9.2 Hz), 7.33 (5H, t, J= 1.2 Hz), yl)amino)phenyl 7.58 (2H, d, J = 8.8 Hz), 8.54 (IH, s), 9.39 methanesulfonate (IH, s), 9.45 (IH, s), 9.47 (IH, s).
4-((5 -carbamoy l-4-((3 - 2.90 (3H, s), 4.67 (2H, d, J = 6.0 Hz), 7.05 fluorobenzyl)amino)pyrimidin-2- (2H, d, J= 9.2 Hz), 7.33 (5H, t, 7= 1.2 Hz), yl)amino)phenyl 7.58 (2H, d, J = 8.8 Hz), 8.54 (IH, s), 9.39 methanesulfonate (IH, s), 9.45 (IH, s), 9.47 (IH, s).
4-((5-carbamoyl-4-((4- 2.90 (3H, s), 4.67 (2H, d, J = 6.0 Hz), 7.05 fluorobenzyl)amino)pyrimidin-2- (2H, d, J= 9.2 Hz), 7.33 (5H, t, J= 1.2 Hz), yl)amino)phenyl 7.58 (2H, d, J = 8.8 Hz), 8.54 (IH, s), 9.39 methanesulfonate (IH, s), 9.45 (lH, s), 9.47 (lH, s).
2-am ino-4-((5-carbamoy l-4-((3 - 4.6 (2H, d, J = 6.8 Hz) 5.7 ( 2H, s) 6.8-7.3 fluorobenzyl)amino)pyrimidin-2- (7H, m) 8.5 (IH, s) 9.4 (IH, s) 9.5 (IH, t, J yl)amino)phenyl = 6.4 Hz), 7.21 (IH, d, J = 8.6 Hz), 7.67 methanesulfonate (IH, m), 8.12 (IH, d, J= 2Hz), 8.52 (IH, s),
9.22 (IH, d, J= 8.3 Hz), 9.65 (IH, s).
4-((5-carbamoyl-4-((3- 0.90 (3H, d, J = 6.0 Hz ), 0.94 (3H, d, J = fluorobenzyl)amino)pyrimidin-2- 6.0 Hz), 1.12 (6H, m), 1.88 (IH, m), 2.88 y l)am ino)-2-methylpheny 1 (2H, m), 4.07 (3H, m), 7.23 (2H, d, J = 8.8 methanesulfonate Hz), 7.51 (IH, t, J= 6.2 Hz), 7.74 (2H, d, J
= 8.4 Hz), 8.51(1H, s), 9.25 (2H, d, J = 8.0 Hz), 9.48 (IH, s).
4-((5 -carbamoyl-4-((3 - 1.38 (3H, t, J = 7.6 Hz), 2.14 (3H, s), 3.51 fluorobenzyl)amino)pyrimidin-2- (2H, m), 4.72 (2H, d, J= 6.0 Hz), 7.06 (5H, yl)am ino)-2-methylphenyl m), 7.35 (IH, m), 7.48 (IH, d, J= 2.4 Hz), ethanesulfonate 7.63 (IH, d, J = 2.0 Hz), 7.7 (IH, m), 8.59
(IH, s), 9.57 (2H, m).
4-((5-carbamoyl-4-((3- 3.33 (3H, s), 3.96 (2H, s), 4.73 (2H, d, J = fluorobenzyl)amino)pyrimidin-2- 6.4 Hz), 7.05 (2H, m), 7.23-7.16 (4H, m), yl)amino)-2-(2- 7.36-7.34 (IH, m), 7.49 (IH, m), 8.30 (IH, cyanoacetamido)phenyl s), 8.57 (IH, s), 9.45 (IH, m), 9.71 (IH, s), methanesulfonate 9.94 (lH, s)
5-((5-carbamoyl-4-((3- 3.32 (3H, s), 3.80 (3H, s), 4.70 (2H, d, J = fluorobenzy l)am ino)pyrimidin-2- 5.2 Hz), 7.04 (2H, i m), 7.18-7.12 (3H, m), yl)amino)-2-methoxyphenyl 7.34 (IH, m), 7.50 (IH, m), 7.8 (2H, s), methanesulfonate 8.55 (IH, s), 9.54 (2H, m).
4-((5-carbamoyl-4-((3- 3.18 (2H, s) 3.61 (2H, d, J = 6.7 Hz), 3.36 fluorobenzyl)amino)pyrimidin-2- (4H, m), 3.61 (2H, s) 4.69 (2H, d, J = 6.0 yl)amino)-2-(morpholine-4- Hz), 7.80 (7H, m), 8.56 (IH, s), 9.60 (IH, carbonyl)phenyl s), 9.80 (IH, s).
methanesulfonate
3 -((5 -carbamoyl-4-((3 - 3.32 (IH, s), 3.5 (8H, m), 4.73 (2H, d, J = fluorobenzy l)am ino)pyrimidin-2- 6.4 Hz), 6.95 (IH, m), 7.18-7.04 (3H, m), yl)amino)-5-(morpholine-4- 7.25 (IH , m), 7.38-7.33 (IH, m), 7.75 (IH, carbonyl)phenyl s), 7.86 (IH, m), 7.95 (IH, s), 8.61 (IH, s), methanesulfonate 9.62 (IH, d, J = 11.6 Hz), 9.91 (IH, s).
(R)-4-((5-carbamoyl-4-(( 1 - 1.37 (3H, t, J = 7.6 Hz), 1.49 (3H, t, J = 4 phenylethyl)amino)pyrimidin-2- Hz), 3.44 (2H, m), 5.12 (IH, m), 7.14 (2H, yl)amino)phenyl ethanesulfonate m), 7.23 (IH, d, J = 6.8 Hz), 7.32 (4H, m),
7.63 (2H, d, J = 9.2 Hz), 8.56 (IH, s)", 9.64 (2H, m).
(R)-4-((5-carbamoyl-4-(( 1 - 1.48 (3H, d, J = 8.2 Hz), 3.32 (3H, s), 5.20 phenylethyl)amino)pyrimidin-2- (IH, m), 7.21-7.16 (3H, m), 7.23 (4H, m), yl)amino)phenyl 7.60 (2H, m), 8.55 (IH, s), 9.63 (2H, m). methanesulfonate
(R)-4-((5-carbamoyl-4-((l- 1.33 (3H, m), 3.72 (3H, s), 6.52 (IH, m), phenylethyl)amino)pyrimidin-2- 6.72-6.70 (IH, m), 6.89 (IH, m), 6.96 (2H, yl)amino)-3-fluorophenyl m), 7.03-7.00 (IH, m), 7.28 (IH, m), 7.62 methanesulfonate (IH, m), 8.13 (2H, m), 10.47 (IH, m), 12.33
(lH, s).
(R)-2-acetamido-4-((5- 1.48 (3H, d, J = 6.5 Hz), 2.11 (3H, s), 3.26 carbamoyl-4-((l- (3H, s), 5.34 (IH, m), 7.19 (2H, m) 7.37- phenylethyl)amino)pyrimidin-2- 7.30 (5H, m), 7.42-7.40 (IH, m), 8.25 (IH, yl)amino)phenyl s), 8.55 (IH, s), 9.54 (IH, s), 9.64 (2H, m). methanesulfonate
(R)-2-(allylamino)-4-((5- 1.50 (3H, d, J = 6.8 Hz), 3.35 (3H, s), 3.50 carbamoyl-4-((l- (2H, m), 5.07 (IH, d, J = 17.2 Hz), 5.32 phenylethyl)amino)pyrimidin-2- (IH, t, J = 14.8 Hz), 5.64 (IH, d, J = 6.0 yl)amino)phenyl Hz), 5.75 (IH, m), 6.82 (2H, m), 7.23 (IH, methanesulfonate m), 7.31 (5H, m) 8.53 (IH, s), 9.34 (IH, s),
9.61 (lH, m).
4-((4-(benzylamino)-5- 4.68 (IH, d, J= 5.6 Hz), 7.2 (2H, d, J= 8.4 carbamoylpyrimidin-2- Hz), 7.56 (5H, m), 7.8 (2H, d, J = 8.4 Hz), yl)amino)phenyl 8.51 (IH, s), 9.7 (IH, s).
methanesulfonate
4-((4-(benzylamino)-5- 0.98 (IH, t, J= 6.4 Hz), 2.01 (IH, d, J= 7.2 carbamoylpyrimidin-2-yl)amino)- Hz), 4.68 (2H, d, J = 6 Hz), 6.90 (2H, m), 2-carbamoylphenyl 7.13 (3H, s), 7.18 (IH, s), 7.33 (4H, m), methanesulfonate 8.53 (IH, s), 9.00 (IH, s), 9.36 (IH, s), 9.49
(lH, t, J= 5.6 Hz).
4-((4-(benzylamino)-5- 0.90 (6H, m), 1.11 (3H, d, J= 6.4 Hz), 1.80 carbamoylpyrimidin-2-yl)amino)- (IH, t, J= 6.2 Hz), 2.74 (3H, d, J= 4.8 Hz), 2-(pyrrolidine- 1 -carbonyl)phenyl 3.30 (3H, m), 4.09 (IH, t, J= 5.4 Hz), 7.29 methanesulfonate (IH, d, J = 8.8 Hz), 7.71 (IH, m), 8.24 (IH, d, J= 2.4Hz), 8.32 (IH, d, J.= 3.2 Hz), 8.54 (IH, s), 9.29 (IH, d, J = 8.4 Hz), 9.77 (IH, s). .
4-((4-(benzylamino)-5- 0.90 (6H, m), 1.11 (3H, d, J= 6.4 Hz), 1.80 carbamoylpyrimidin-2-yl)amino)- (IH, t, J= 6.2 Hz), 2.74 (3H, d, J= 4,8 Hz), 2-(dimethylamino)phenyl 3.30 (3H, m), 4.09 (IH, t, J= 5.4 Hz), 7.29 methanesulfonate (IH, d, J = 8.8 Hz), 7.71 (IH, m),8.24 (IH, d, J = 2.4 Hz ), 8.32 (IH, d, J = 3.2 Hz ),
8.54 (IH, s), 9.29 (IH, d, J 8.4 Hz), 9.77 (IH, s).
5-((4-(benzylamino)-5- 0.52 (2H, m), 0.67 (2H, m), 3.31 (3H, m), carbamoylpyrimidin-2-yl)amino)- 4.71 (2H, d, J= 5.6 Hz), 7.24 (IH, m), 7.35 2-(cyclopropylcarbamoyl)phenyl (IH, m), 7.65 (IH, m), 8.02 (IH, d, J= 2H), methanesulfonate 8.24 (IH, d, J = 4.0 Hz), 8.60 (IH, s), 9.57
(IH, t, J= 5.6 Hz), 9.92 (lH, s).
2-amino-5-((4-(benzylamino)-5- 3.33 (3H, m), 4.66 (2H, m), 5.02 (2H, s), carbamoylpyrimidin-2- 6.68 (IH, d, J= 8.8 Hz), 7.24 (3H, m), 7.33 yl)amino)phenyl (4H, d, J= 6.8 Hz), 7.71 (2H, s), 8.50 (IH, methanesulfonate s), 9.30 (IH, s), 9.50 (IH, s).
3 -((4-(benzy lamino)-5 - 0.52 (2H, m), 0.68-0.65 (2H, m), 2.66 (IH, carbamoylpyrimidin-2-yl)amino)- m), 3.32 (3H, s), 4.72 (2H, d, J = 8.0 Hz), 5-(cyclopropylcarbamoyl)phenyl 7.23 (8H, m), 7.98 (IH, s), 8.24 (IH, s), methanesulfonate 8.47 (IH, d, J = 4.4 Hz), 8.59 (IH, s), 9.6- 9.5 (lH, m), 9.87 (IH, s).
3-((4-(benzylamino)-5- 3.30 (4H, m), 3.58-3.53 (7H, m), 4.71 (2H, carbamoylpyrimidin-2-yl)amino)- d, J= 5.6 Hz), 6.95 (IH, m), 7.26-7.24 (IH, 5-(morpholine-4-carbonyl)phenyl m), 7.32 (5H, m), 7.76 (IH, s), 7.98-7.97 methanesulfonate (IH, m), 8.60 (IH, s), 9.52 (IH, m), 9.90
(IH, s).
3-((4-(benzylamino)-5- 1.77 (4H, m), 3.32 (3H, s), 3.35 (2H, m), carbamoylpyrimidin-2-yl)a*mino)- 3.41 (2H, m), 4.71 (2H, d, J= 6.0 Hz), 7.03 5-(pyrrolidine- 1 -carbonyl)phenyl (IH, m), 7.24 (2H, m), 7.30 (5H, m), 7.87 methanesulfonate (2H, m), 7.98 (IH, m), 8.60 (IH, s), 9.52
(IH, m), 9.86 (IH, s).
4-((5-carbamoyl-4-((4- 3.71 (3H, s), 4.61 (2H, d, J = 5.2 Hz) 6.81 methoxybenzyl)amino)pyrimidin- (2H, d, J= 8.4 Hz), 1.31 (6H, m) 7.77 (2H, 2-yl)amino)phenyl d. J = 8.8 Hz), 8.55 (IH, s), 9.45 (IH, s), methanesulfonate 9.67 (IH. s).
4-((5-carbamoyl-4-((2,6- 3.71 (3H, s), 4.61 (2H, d, J = 5.2 Hz), 6.81 difluorobenzyl)amino)pyrimidin- (2H, d, J= 8.4 Hz), 7.14-1.31 (6H, m) 7.77
2-yl)amino)phenyl (2H, d. J = 8.8 Hz), 8.55 (IH, s), 9.45 (IH, methanesulfonate s), 9.67 (IH. s).
68. 4-((4-(benzylamino)-5- 3.40 (3H, m), 4.53 (2H, d, J= 5.6 Hz), 4.72 carbamoylpyrimidin-2-yl)amino)- (2H, d, J= 6.0 Hz), 5.27 (IH, t, J= 5.4 Hz), 2-(hydroxymethyl)phenyl 7.16 (IH, d, J = 9.2 Hz), 7.25 (IH, d, J = methanesulfonate 6.8 Hz), 7.34 (4H, m), 7.61 (IH, m), 8.05
(IH, d, J= 2.4 Hz), 8.56 (IH, s), 9.53 (IH, s), 9.68 (IH, s).
69. 4-((5 -carbamoy l-4-((3 - 3.39 (3H, s), 4.53 (2H, d, J = 5.6 Hz), 4.71 fluorobenzyl)amino)pyrimidin-2- (2H, d, J= 6.0 Hz), 5.27 (IH, t, J= 5.6 Hz), yl)amino)-2- 7.56 (7H, m), 8.02 (IH, d, J= 2.8 Hz), 8.57
(hydroxymethyl)phenyl (IH, s), 9.56 (IH, m), 9.67 (IH, s).
methanesulfonate
70. 4-((5-carbamoyl-4-((2,4- 2.20 (3H, s), 2.25 (3H, s), 3.32 (3H, s), 4.60 dimethylbenzyl)amino)pyrimidin- (2H, d, J= 6.0 Hz), 6.99 (IH, d), 7.04 (IH, 2-yl)amino)phenyl s), 7.10 (IH, d, J= 7.6 Hz), 7.71 (3H, d, J = methanesulfonate 8.8 Hz), 7.72 (IH, d, J= 7.2 Hz), 8.57 (IH, s), 9.40 (lH, s), 9.68 (lH, s).
71. 4-((4-(benzylamino)-5- 1.41 (6H, d, J= 6.8 Hz ), 3.23 (IH, s), 4.68 carbamoylpyrimidin-2- (2H, d, J= 6.0 Hz),7.13 (2H, d, J= 9.2 Hz), yl)amino)phenyl propane-2- 7.25 (2H, m ), 7.34 (4H, d, J = 4.4 Hz ), sulfonate 7.71 (2H, d, J= 9.2 Hz), 8.56 (IH, s), 9.55
(lH, s ), 9.65 (lH,s).
72. 4-((5-carbamoyl-4-((2,4- 3.32 (3H, s), 4.71 (2H, d, J = 6.0 Hz), 7.12 difluorobenzyl)amino)pyrimidin- (2H, d, J = 9.2 Hz), 7.27 (2H, d, J = 8.4 2-yl)am ino)phenyl Hz), 7.37 (IH, d, J= 2.0 Hz, J = 8.4 Hz), methanesulfonate 7.58 (2H, d, J = 8.0 Hz), 7.69 (IH, d, J =
2.0 Hz), 7.90-8.10 (IH, m), 8.59 (IH, s), 9.60 (IH, s), 9.69 (IH, s).
73. 4-((5-carbamoyl-4-((3- 1.46 (6H, d, J= 6.4 Hz) 3.78 (IH, m), 4.67 fluorobenzyl)amino)pyrimidin-2- (2H, d, J= 6.0 Hz), 7.89 (7H, m), 8.56 (IH, yl)amino)phenyl propane-2- s), 9.67 (IH, s).
sulfonate
74. (R)-3-((5-carbamoyl-4-((3- 0.90 (3H, d, J = 6.4 Hz), 0,94 (3H, d, J = methylbutan-2- 6.8 Hz), 1.13 (3H, d, J = 6.8 Hz), 1.87-1,79 yl)amino)pyrimidin-2- (IH, m), 3.35 (3H, s), 4.17-4.09 (IH, m), yl)amino)phenyl 6.94-6.91 (IH, dd, Jl = 8.0 Hz, J2 = 2.0 methanesulfonate Hz), 7.35 (IH, t, J= 8.2 Hz), 7.14 (IH, bs),
7.59 (IH, d, J = 8.0 Hz), 8.06 (IH, s), 7.80 (IH, bs), 8.54 (IH, s), 9.28 (IH, d, J = 8.4 Hz), 9.17 (lH, s).
75. (R)-5-((5-carbamoyl-4-((3- 0.9 (6H, d, J = 6.8 Hz), 1.1 (3H, d, J = 6.8 methylbutan-2- Hz), 1.8 (IH, m), 3.3 (3H, s), 4.0 (IH, m), yl)amino)pyrimidin-2-yl)amino)- 7.3 (IH, t, J = 7.2 Hz),7.4 (IH, t, J = 1.6 2-fluorophenyl methanesulfonate Hz), 8.1 (IH, d, J = 1.6 Hz), 8.5 (IH, s), 9.3
(IH, s), 9.8 (IH, s).
76. (R)-5-((5-carbamoyl-4-((3- 0.89 (6H, m), 1.1 (3H, d, J = 6.4 Hz), 1.38 methylbutan-2- (3H, t, J = 7.2 Hz), 1.8 (IH, m), 3.45 (2H, yl)amino)pyrimidin-2-yl)amino)- q, J = 4.8 Hz), 3.8 (3H, s), 4.07 (IH, m), 2-methoxyphenyl ethanesulfonate 7.11 ( 1 H, d, J = 9.2 Hz), 7.51 ( 1 H, m), 8.02
(IH, s), 8.50 (IH, s), 9.27 (IH, d, J = 8.0 Hz), 9.5 (IH, s).
77. (R)-5-((5-carbamoyl-4-((3- 0.8 (6H, m), 1.13 (3H, d, J = 8.0 Hz), 1.78 methylbutan-2- (IH, m), 3.16 (3H, s), 3.81 (3H, s), 4.1-4.07 yl)amino)pyrimidin-2-yl)amino)- (IH, m), 7.13 (IH, d, J= 9.2 Hz), 7.53 ;(1H,
2-methoxyphenyl m), 8.03 (IH, s), 8.5 (IH, s), 9.27 (IH, d, J methanesulfonate = 8.4 Hz), 9.51 (lH, s).
78. (R)-2-amino-5-((5-carbamoyl-4- 0.9 (6H, d, J = 6.8 Hz), 1.1 (3H, d, J = 6.8
((3-methylbutan-2- Hz), 1.8 (IH, m), 4.1 (IH, m), 5.0 ( 2H, s), yl)amino)pyrimidin-2- 6.7 (IH, d, J = 7.2 Hz), 7.2 (IH, q, J = 8.8 yl)amino)phenyl Hz), 7.81 (IH, s), 8.5 (IH, s), 9.2 (IH, d, J methanesulfonate = 8.4 Hz).
79. (R)-2-acetamido-5-((5- 0.9 (6H, d, J = 6.8 Hz), 1.1 (3H, d, J = 6.8 carbamoyl-4-((3 -methylbutan-2- Hz), 1.8 (IH, m), 3.2 (3H, s), 3.4 (3H, s), yl)amino)pyrim idin-2- 4.0 (IH, m), 7.5 (IH, m) 7.6 (IH, d, J= 7.2 yl)amino)phenyl Hz), 8.1 (IH, s) 8.5 (IH, s), 9.2 (IH, d, J =
methanesulfonate 7.0 Hz), 9.4 (IH, s), 9.6 (IH, s).
80. (R)-2-carbamoyl-5-((5- 0.87 (6H, m), 1.04 (3H, d, J= 6.4 Hz), 1.73 carbamoyl-4-((3 -methy lbutan^- (IH, m), 3.32 (3H, s), 3.98 (IH, m), 7.21 y amino^yrimidin^- (IH, m), 7.78 (IH, m), 8.13 (IH, m), 9.34 yl)amino)phenyl (lH, m), 10.99 (lH, s).
methanesulfonate
81. (R)-5-((5-carbamoyl-4-((3- 0.55-0.52 (2H, m), 0.69-0.65 (2H, m), 0.91 methylbutan-2- (3H, d, J = 6.8 Hz), 0.94 (3H, d, J = 6.8 yl)amino)pyrimidin-2-yl)amino)- Hz), 1.18 (3H, d, J = 6.8 Hz), 1.84-1.79 2-(cyclopropylcarbamoyl)phenyl (IH, m), 2.81-2.77 (IH, m), 3.31 (3H, s), methanesulfonate 4.17-4.12 (IH, m), 7.19 (IH, bs), 7.44 (IH, d, J = 8.8 Hz), 7.61-7.58 (IH, dd, Jl = 8.4 Hz, J2 = 2.0 Hz), 7.85 (IH, bs), 8.16 (IH, d, J = 1.6 Hz), 8.27 (IH, d, J = 4.0 Hz), 8.55 (IH, s), 9.33 (IH, d, J = 8.4 Hz), 9.89 (IH, s).
82. (R)-2-(allylcarbamoyl)-5-((5- 0.85 (6H, m), 1.13 (3H, d, J= 6.8 Hz), 1.79 carbamoy l-4-((3 -methy lbutan-2- (IH, m), 3.32 (3H, s), 3.85 (2H, d, J = 5.2 yl)amino)pyrimidin-2- Hz), 4.13 (IH, m), 5.08 (IH, m), 5.20 (IH, yl)amino)phenyl m), 5.82 (IH, m), 7.50 (IH, d, J = 8.4 Hz), methanesulfonate 7.61 (IH, d, J= 9.2 Hz), 8.19 (IH, m), 8.41
(IH, d, J= 5.6 Hz), 8.56 (IH, s), 9.33 (IH, d, J= 9.2 Hz), 9.91 (IH, s).
83. (R)-2-(benzylcarbamoyl)-5-((5- 0.90 (6H, m), 1.13 (3H, d, J= 6.4 Hz), 1.80 carbamoyl-4-((3-methylbutan-2- (IH, m), 3.17 (3H, s), 4.13 (IH, m), 4.42 yl)amino)pyrimidin-2- (2H, d, J = 6 Hz), 7.23 (IH, m), 7.31 (4H, yl)amino)phenyl m), 7.53 (IH, d, j = 9.2 Hz), 7.60 (IH, m), methanesulfonate 8.20 (IH, d , J = 1.6 Hz), 8.55 (IH, s), 8.79
(IH, t, J = 11.6 Hz), 9.32 (IH, m), 9.91 (IH, s).
84. (R)-5-((5-carbamoyl-4-((3- 0.83 (6H, m), 1.13 (3H, d, J= 6.4 Hz), 1.80 methylbutan-2- (IH, m), 3.19 (3H, s), 4.15 (IH, m), 4.41 yl)amino)pyrimidin-2-yl)amino)- (2H, d, J= 6.0 Hz), 7.13 (IH, m), 7.37 (2H, 2-((4- m), 7.53 (IH, d, J = 8.8 Hz), 7.60 (IH, m), fluorobenzyl)carbamoyl)phenyl 8.20 (IH, s), 8.55 (IH, s), 8.80 (IH, t, J = methanesulfonate 1 1.6 Hz) 9.33 (IH, d, J= 8.4 Hz), 9.92 (IH, s).
85. (R)-5-((5-carbamoyl-4-((3- 0.9 (6H, m), 1.14 (3H, d, J = 6.4 Hz), 1.80 methylbutan-2- (IH, m), 3.2 (3H, s), 4.15 (IH, m), 4.46 yl)amino)pyrimidin-2-yl)amino)- (2H, m), 6.9 (4H, m), 7.42 (IH, t, J = 7.2 2-((2- Hz), 7.63-7.53 (2H, m), 7.60 (IH, m), 8.20 fluorobenzyl)carbamoyl)phenyl (IH, d, J =1.6 Hz), 8.56 (IH, s), 8.80 (IH, t, methanesulfonate J = 5.6 Hz), 9.33 (IH, d, J = 8.8 Hz), 9.92
(IH, s).
86. (R)-5-((5-carbamoyl-4-((3- 0.88 (6H, m), 1.14 (3H, m), 1.80 (6H, m), methylbutan-2- 3.30 (3H, s), 4.14 (IH, m), 7.10 (IH, t, J = yl)amino)pyrimidin-2-yl)amino)- 14.4 Hz), 7.35 (2H, t, J = 15.6 Hz), 7.60
2-(phenylcarbamoyl)phenyl (IH, d, J = 8.4 Hz), 7.67 (3H, m), 8.24 (IH, methanesulfonate m), 8.57 (IH, s), 9.35 (IH, d, J = 8.0 Hz),
9.98 (IH, s), 10.27 (IH, s).
87. (R)-5-((5-carbamoyl-4-((3- 0.89 (m, 6H), 1.13 (3H, d, J = 6.4 Hz), 1.79 methylbutan-2- (IH, m), 2.83 (3H, s), 2.98 (3H, s), 3.29 yl)amino)pyrimidin-2-yl)amino)- (3H, s), 4.12 (IH, m), 7.21 (IH, bs), 7.30
2-(dimethylcarbamoyl)phenyl (IH, d, J = 8.4 Hz), 7.61-7.59 (IH, dd, J 1= methanesulfonate 1.6 Hz, J2 = 8.4 Hz), 7.85 (IH, bs), 8.21
(IH, d, J = 1.6 Hz), 8.55 (IH, s), 9.33 (IH, d, J= 8.4 Hz), 9.88 (lH, s).
88. (R)-5-((5-carbamoyl-4-((3- 0.85 (6H, m), 1.03 (3H, m), 1.1 1 (6H, m), methylbutan-2- 1.79 (IH, m), 2.89 (2H, m), 3.29 (3H, s), yl)amino)pyrimidin-2-yl)amino)- 3.43 (2H, m), 4.13 (2H, m), 7.28 (IH, d, J=
2-(diethylcarbamoyl)phenyl 8.4 Hz), 7.61-7.58 (IH, m), 8.22 (IH, d, J = methanesulfonate 1.6 Hz), 8.55 (IH, s), 9.33 (IH, d, J = 8.4
Hz), 9.86 (IH, s).
89. (R)-5-((5-carbamoyl-4-((3- 0.89 (6H, m), 1.13 (3H, d, J= 6.8 Hz), 1.77 methylbutan-2- (5H, m), 3.20 (2H, m), 3.32 (3H, s), 3.42 y l)amino)pyr im idin-2-yl)amino)- (2H, m), 4.02 (IH, m), 7.35 (IH, d, J = 8.4 2-(pyrrolidine- 1 -carbonyl)phenyl Hz), 7.58 (IH, m), 9.2 (IH, s), 8.55 (IH, s), methanesulfonate 9.32 (IH, d, J = 8.4 Hz), 9.87 (IH, s), 8.56
(IH, s).
90. (R)-5-((5-carbamoyl-4-((3- 0.89 (6H, m), 1.13 (3H, d, J= 6.8 Hz), 1.79 methylbutan-2- (IH, m), 3.33 (3H, s), 3.23 (2H, s), 3.46 yl)amino)pyrimidin-2-yl)amino)- (6H, m), 4.12 (IH, m), 7.18 (IH, bs), 7.33 2-(morphol ine-4-carbony l)pheny 1 (IH, d, J = 8.4 Hz), 7.63 (IH, dd, Jl = 1.6 methanesulfonate Hz, J2 = 8.4 Hz), 7.83 (IH, bs), 8.19 (IH, s), 8.55 (IH, s), 9.32 (IH, d, J = 8.4 Hz), 9.88 (lH, s).
91. (R)-5-((5-carbamoyl-4-((3- 0.22 (2H, m), 0.46 (2H, m), 0.87 (6H, m), methylbutan-2- . 1.13 (3H, d, J= 6.4 Hz), 1.79 (IH, m), 2.22 yl)amino)pyrimidin-2-yl)amino)- (3H, s), 2.27 (3H, s), 3.18 (3H, s), 4.11 (IH, 2-(cyclopropyl(2,3- m), 4.9 (2H, s), 7.08 (3H, m), 7.41 (IH, d, J dimethylbenzyl)carbamoyl)pheny = 7.6 Hz), 7.61 (IH, s), 8.26 (IH, s), 8.55 1 methanesulfonate (IH, s), 9.32 (IH, d, J = 9.2 Hz), 9.87 (IH, s).
92. (R)-3-((5-carbamoyl-4-((3- 0.55 (2H, m), 0.71-0.68 (2H, m), 0:85 (6H, methylbutan-2- m), 1.12 (3H, d, J = 6.4 Hz), 1.77 (IH, m), yl)amino)pyrimidin-2-yl)amino)- 2.82 (IH, m), 3.32 (3H, s), 4.09 (IH, m), 5-(cyclopropylcarbamoyl)phenyl 7.26 (IH, m), 8.04 (IH, m), 8.14 (IH, m), methanesulfonate 8.46 (IH, m), 8.54 (IH, s), 9.30 (IH, d, J =
8.4 Hz), 9.82 (IH, s).
93. (R)-3-carbamoyl-5-((5- 0.90 (6H, m), 1.12 (3H, d, J= 8.0 Hz), 1.75 carbamoy l-4-((3 -methylbutan-2- (IH, m), 3.41 (3H, s), 4.15 (IH, m), 7.35 yl)amino)pyrimidin-2- (IH, s), 7.47 (IH, s), 7.84 (IH, s), 8.06 (IH, yl)amino)phenyl s), 8.22 (IH, s), 8.55 (IH, s). 9.30 (IH, d, J methanesulfonate = 8.8 Hz), 9.83 (IH, s).
94. (R)-3-((5-carbamoyl-4-((3- 0.89 (6H, m), 1.12 (3H, d, J= 6.8 Hz), 1.79 methylbutan-2- (IH, m), 3.32 (3H, s), 3.37 (2H, m), 3.57
yl)amino)pyrimidin-2-yl)amino)- (6H, m), 4.0 (IH, m), 9.96 (IH, m), 7.12 5-(morpholine-4-carbonyl)phenyl (IH, m), 7.78 (2H, m), 8.01 (IH, m ), 8.55 methanesulfonate (IH, s), 9.32 (IH, d, J = 8.4 Hz), 9.88 (IH, m).
95. (R)-3-((5-carbamoyl-4-((3- 0.89 (6H, m), 1.12 (3H, d, J= 6.8 Hz), 1.78 methylbutan-2- (5H, m), 3.32 (5H, m), 3.44 (2H, m), 7.05 yl)amino)pyrimidin-2-yl)amino)- (IH, s), 7.86 (IH, s), 8.03 (IH, s), 8.55 (IH, 5-(pyrrolidine- 1 -carbohyl)phenyl s), 9.31 (IH, d, J = 8.8 Hz), 9.86 (IH, s). methanesulfonate
96. 4-((4-(allylamino)-5- 3.3 (3H, s), 4.11 (2H, t, J = 5.2 Hz), 5.13 carbamoylpyrimidin-2- (IH, dd, Jl = 1.2 Hz & J2 = 10.4 Hz), 5.21 yl)amino)phenyl (IH, dd, J7 = 1.6 Hz & J2 = 17.2 Hz), 5.95 methanesulfonate (IH, m), 7.25 (2H, d, J = 9.2 Hz), 7.85 (2H, d, J = 8.8 Hz), 8.55 (IH, s), 9.27 (IH, m), 9.68 (lH, s).
97. 4-((4-(allylamino)-5- 2.25 (3H, s), 3.40 (3H, s), 4.10 (2H, m), „carbamoylpyrimidm-2-yl)amino)- 5.11 (2H, m), 5.97 (IH, m), 7.21 (2H, d, J= 2-methylphenyl methanesulfonate 8.8 Hz), 7.59 (IH, m), 7.81 (IH, d, J = 2.4
Hz), 8.55 (IH, s), 9.29 (IH, t, J= 11.2 Hz), 9.60 (lH, s).
98. 4-((4-(allylamino)-5- 1.39 (3H, t, J = 7.6 Hz), 2.25 (3H, s), 3.53 carbamoylpyrimidin-2-yl)amino)- (2H, m), 4.11 (2H, t, J = 5.2 Hz), 5.11 (2H, 2-methylphenyl ethanesulfonate m), 5.96 (IH, m), 7.17 (IH, d, j = 8.8 Hz),
7.62-7.59 (IH, m), 7.8 (IH, d, J = 2.4 Hz), 8.55 (IH, s), 9.27 (IH, t, J= 11.2 Hz), 9.59 (IH, s).
99. 5-((4-(allylamino)-5- 1.37 (3H, m), 3.43 (2H,m), 3.80 (3H, s), carbamoylpyrimidin-2-yl)amino)- 4.21-4.09 (2H, m), 5.10 (2H, m), 5.93 (IH, 2-methoxyphenyl ethanesulfonate m), 7.12 (IH, d, J= 9.2 Hz), 7.54 (IH, m),
7.95 (IH, d, J = 2.4 Hz), 8.53 (IH, s), 9.27 (IH, m), 9.53 (IH, s).
100. 5-((4-(allylamino)-5- 3.32 (3H, s), 3.81 (3H, s), 4.09 (2H, m), carbamoylpyrimidin-2-yl)am ino)- 5.10 (2H, m), 5.93 (IH, m), 7.13 (IH, d, J=
2-methoxyphenyl 9.2 Hz), 7.54 (IH, m), 7.94 (IH, d, J = 2.4 methanesulfonate Hz), 8.53 (IH, s), 9.26 (IH, m), 9.54 (IH, s).
101. 4-((5 -carbamoy l-4-(pentan-3 - 0.87 (6H, m), 1.55 (4H, m), 3.99 (IH, d, J = ylamino)pyrimidin-2- 7.2 Hz), 7.25 (2H, d, J = 9.23 Hz), 7.86 yl)amino)phenyl (2H, d. J = 8.0 Hz), 8.52 (IH, s), 9.17 (IH, methanesulfonate s), 9.67 (lH. s).
102. 4-((5-carbamoyl-4-(pentan-3- 0.87 (6H, t, J= 7.4 Hz), 1.46 (2H, m), 1.63 ylamino)pyrimidin-2-yl)amino)- (2H, m), 3.32 (3H, t, J = 8.4 Hz), 3.97 (2H, 2-(2-cyanoacetamido)phenyl s), 4.12 ( IH, m), 7.28 (IH, d, J = 9.2 Hz), methanesulfonate 7.53 (IH, m), 8.47 (IH, d, J = 2 Hz), 8.52
(IH, s), 9.13 (IH, d, J= 8.8 Hz), 9.67 (IH, s), 9.98 (IH, s).
103. 4-((5-carbamoyl-4- 0.87 (6H, m) 1.55 (4H, m), 3.99 (IH, d, J = (isopentylamino)pyrimidin-2- 7.2 Hz), 7.25 (2H, d, J = 9.2 Hz), 7.86 (2H, yl)amino)phenyl d, J = 8.0 Hz), 8.52 (IH, s), 9.17 (IH, s), methanesulfonate 9.67 (lH. s).
104. 2-amino-4-((5-carbamoyl-4- 1.47 (7H, m), 3.85 (6H, s), 5.10 (2H, d, J = (isopentylamino)pyrimidin-2- 8.8 Hz), 5.24 (IH, d, J = 16.4 Hz), 5.87 yl)amino)phenyl (IH, s), 7.17 (IH, s), 7.29 (2H, d, J = Hz), methanesulfonate 7.87 (2H, d, J = 7.6 Hz), 8.13 (IH, s), 8.53
(IH, s), 9.18 (lH, s), 9.76 (lH, s).
105. 3-((5-carbamoyl-4- 0.89 (6H, m), 1.5-1.46 (2H, m), 1.69 (IH,
(isopentylarnino)pyrimidin-2- m), 3.32 (3H, s), 3.43(2H, m), 3.53 (8H, m), yl)amino)-5-(morpholine-4- 6.96 (IH, m), 7.13 (IH, m), 7.79 (IH, s), carbonyl)phenyl 7.79 (IH, m), 8.03 (IH, s), 8.54 (IH, s), methanesulfonate 9.14 (lH, m), 9.87 (lH, s).
106. 3 -((5 -carbamoyl-4- 0.85 (6H, m), 1.49-1.44 (2H, m), 1.64 (IH, (isopentylamino)pyrimidin-2- m), 1.82 (4H, m), 3.41(5H, m), 3.32 (3H, s), yl)amino)-5-(pyrrolidine- 1 - 7.05 (IH, s), 7.13 (IH, m), 7.81 (IH, m), carbonyl)phenyl 7.88 (IH, s), 8.03 (IH, s), 8.54 (IH, s), 9.18 methanesulfonate (IH, s), 9.85 (IH, s).
107. 2-(allylcarbamoyl)-4-((5- 1.47 (7H, m), 3.85 (6H, s), 5.10 (2H, d, J =
carbamoyl-4- 8.8 Hz), 5.24 (IH, d, J = 16.4 Hz), 5.87
(isopentylamino)pyrimidin-2- (IH, s), 7.17 (IH, s), 7.29 (2H, d, J = 6.0 yl)amirio)phenyl Hz), 7.87 (2H, d, J= 7.6 Hz), 8.13 (IH, s), methanesulfonate 8.53 (IH, s), 9.18 (IH, s), 9.76 (IH, s).
108. 4-((5-carbamoyl-4- 0.91 (6H, d, J = 6.4 Hz), 1.23 (IH, s), 1.47
(isopentylamtno)pyrimidin-2- (2H, m), 1.64 (IH, m), 3.47 (2H, m) 3.97 yl)amino)-2-(2- (2H, s), 7.27 (IH, d, J = 8.8 Hz), 7.60 (IH, cyanoacetamido)phenyl m), 8.40 (IH, s), 8.52 (IH, s), 9.14 (IH, d, J methanesulfonate = 4.4 Hz), 9.68 (IH, s), 9.98 (IH, s).
109. 3-((5-carbamoyl-4- 0.93 (6H, d, J= 6.8 Hz), 1.90 (IH, m), 3.35 (isobutylamino)pyrimidin-2- (3H, s), 6.92 (IH, m), 7.35 (IH, d, J = 8.0 yl)amino)phenyl Hz), 7.62 (IH, d, J = 8.0 Hz), 8.05 (IH, s), methanesulfonate 8.54 (IH, s), 9.35 (IH, s), 9.75 (IH, s).
110. 4-((5 -carbamoy 1-4- 0.93 (6H, d, J = 6.8 Hz), 3.1 (2H, s), 3.3 (isobutylamino)pyrimidin-2- (3H, s), 4.1 (IH, s), 7.25 (2H, d, J = 9.2 yl)amino)phenyl Hz), 7.87 (2H, d, J = 9.2 Hz), 8.5 (IH, s), methanesulfonate 9.38 (IH, s), 9.66 (IH, s).
111. 2-amino-4-((5 -carbamoy 1-4- 0.91 (6H, d, J= 6.8 Hz), 1.87 (IH, m), 2.33 (isobutylamino)pyrimidin-2- (3H, s), 5.20 (2H, s), 6.96 (IH, d, J = 8.88 yl)amino)phenyl Hz), 7.04 (IH, m), 7.17 (lH, d, J = 3 Hz), methanesulfonate 8.49 (IH, s), 9.26 (IH, s), 9.32 (IH, s).
112. 4-((5-carbamoyl-4- 0.89 (6H, d, J= 6.82 Hz), 1.9 (IH, m), 2.76
(isobutylamino)pyrimidin-2- (6H, s), 7.11 (IH, d, J = 8.8 Hz), 7.24 (IH, yl)amino)-2- d, J= 8 Hz), 7.65 (IH, s), 8.52 (IH, s), 9.38
(dimethylamino)phenyl (IH, s), 9.57 (IH, s).
methanesulfonate
113. 3-((5-carbamoyl-4- 0.85 (6H, d, J= 4.8 Hz), 1.76 (IH, m), 2.17 (isobutylamino)pyrimidin-2- (3H, s), 3.12 (2H, s), 3.44 (3H, s), 7.15 (2H, yl)amino)-2-methylphenyl m), 7.23 (IH, t, J = 7.4 Hz), 7.74 (IH, d, J methanesulfonate = 8.0 Hz), 8.45 (IH, s), 8.83 (IH, s), 9.18
(lH, s).
114. 2,6-dibromo-4-((5-carbamoyl-4- 0.91 (6H, d, J= 6.8 Hz), 1.89 (2H, m), 2.69 (isobutylamino)pyrimidin-2- (3H, s), 3.08 (2H, m), 7.72 (IH, s), 8.03 yl)amino)phenyl (IH, s), 8.73 (IH, s), 9.37 (IH, s).
methanesulfonate
115. 5 -((5 -carbamoyl-4- 0.93 (6H, d, J= 6.8 Hz), 1.92 (IH, m), 3.43 (isobutylamino)pyrimidin-2- (3H, s), 7.39 (IH, t, J = 7.2 Hz), 7.47 (IH, yl)amino)-2-fluorophenyl m), 8.15 (IH, d, J = 1.6 Hz), 8.55 (IH, s), methanesulfonate 9.36 (lH, m), 9.86 (IH, s).
116. 4-((5 -carbamoyl-4- 0.93 (6H, d, J= 6.8 Hz), 1.93 (IH, m), 3.33
(isobutylamino)pyrimidin-2- (3H, t, J = 6.2 Hz), 3.40 (3H, s), 4.55 (IH, yl)amino)-2- d, J = 5.2 Hz), 5.23 (IH, t, J = 5.6 Hz ),
(hydroxymethyl)phenyl 7.21 (IH, d, J= 8.8 Hz), 7.68 (IH, m), 8.12 methanesulfonate (IH, d, J = 2.4 Hz), 8.53 (IH, s), 9.29 (IH, s), 9.63 (IH, s).
117. 4-((5 -carbamoyl-4- 0.93 (6H, d, J = 6.8 Hz ), 1.41 (6H, d, J = (isobutylamino)pyrimidin-2- 6.8 Hz ), 1.90 (IH, m), 3.32 (2H, s), 3.68 ( yl)amino)phenyl propane-2- IH, t, J= 6.8 Hz ), 7.20 ( 2H, d, J = 9.2 Hz sulfonate ), 7.85 (2H, d, J = 8.8 Hz), 8.52 (IH, s),
9.30 (IH, s), 9.62 (1 H, s).
118. 4-((5-carbamoyl-4- 0.93 (6H, d, J= 6.8 Hz), 1.88 (2H, t, J = 6.8
(isobutylamino)pyrimidin-2- Hz), 3.38 (3H, m), 8.97 (2H, s), 7.28 (IH, d, yl)amino)-2-(2- J= 9.2 Hz), 7.56 (IH, m), 8.41 ( H, d, J= 4 cyanoacetamido)phenyl Hz), 8.53 (IH, s), 9.30 (IH, t, J = 5.2 Hz), methanesulfonate 9.68 (IH, s), 9.98 (IH, s).
119. 4-((4-(sec-butylamino)-5- 0.91 (3H, t, J= 7.6 Hz), 1.19 (3H, d, J= 6.4 carbamoylpyrimidin-2- Hz), 1.55 (2H, m), 3.32 (3H, t, J = 5.0 Hz), yl)amino)phenyl 7.26 (2H, m), 7.86 (2H, m), 8.52 (IH, s), methanesulfonate 9.12 (IH, d, J = 8,0 Hz), 9.64 (IH, s).
120. 3-((4-(sec-butylamino)-5- 0.91 (3H, t, J= 7.6 Hz), 1.19 (3H, d, J= 6.4 carbamoylpyrimidin-2- Hz), 1.55 (2H, m), 3.32 (3H, t, J = 5.0 Hz), yl)amino)phenyl 7.26 (2H, m), 7.86 (2H, m), 8.52 (IH, s), methanesulfonate 9.12 (IH, d, J = 8.0 Hz), 9.64 (IH, s).
121. 4-((5-carbamoyI-4-((2,2,2- 3.33 (3H, d, J= 7.2 Hz), 4.37 (2H, m), 7.26 trifluoroethyl)amino)pyrimidin-2- (2H, t, J= 4.4 Hz), 7.81 (2H, t, J= 6.2 Hz), yl)amino)phenyl 7.95 (IH, s), 8.63 (IH, s), 9.53 (IH, t, J= 8 methanesulfonate Hz), 9.82 (IH, s).
122. 2-amino-4-((5-carbamoyl-4- 1.14 (2H, s), 1.22 (2H, d, J = 3.6 Hz), 2.10 ((2,2,2- (2H, d, J = 10.4 Hz), 3.33 (2H, d, J = 5.2 trifluoroethyl)amino)pyrimidin-2- Hz), 4.35 (2H, d, J= 13.6 Hz), 7.00 (2H, d, yl)amino)phenyl J = 9.2 Hz), 7.28 (2H, d, / = 9.2 Hz), 7.85 methanesulfonate (2H, m), 8.49 (IH, d, J= 2.0 Hz), 8.55 (IH, s), 9.22 (IH, d, J = 7.2 Hz), 9.72 (IH, s).
123. 4-((5-carbamoyl-4-(( 1 - 0.25 (2H, m) 0.35 (2H, m), 1.10 (IH, m), cyclopropylethyl)amino)pyrimidi 1.34 (3H, m), 3.81 (IH, m), 3.3 (3H, s), n-2-y l)am ino)phenyl 7.31 (2H, d, J = 8.4 Hz), 7.89 (2H, d, J = methanesulfonate 8.0 Hz), 8.56 (IH, s), 9.21 (IH, s), 9.62
(lH, s).
124. 4-((5-carbamoyl-4-((l - 0.25 (2H, m) 0.35 (2H, m), 1.10 (IH, m), cyclopropylethyl)amino)pyrimidi 1.34 (3H, d), 3.81 (IH, m), 3.3 (3H, s), 4.5 n-2-yl)amino)-2- (2H, d, J= 5.2 Hz), 5.22 (IH, t, J= 5.6 Hz),
(hydroxymethyl)phenyl 7.21 (IH, m), 7.56 (IH, m), 8.15 (IH, s), methanesulfonate 8.51 (IH, s), 8.51 (IH, s), 9.21 (IH, d, J= 8
Hz), 9.62 (IH, s).
125. 3-((5-carbamoyl-4-((l - 0.26 (2H; m) 0.43 (2H, m), 1.23 (IH, m), cyclopropylethyl)amino)pyrimidi 1.24 (5H, t, J = 4.4 Hz), 3.41 (3H, s), 6.91 n-2-yl)amino)-5-(morpholine-4- (IH, t, J= 4.8 Hz), 7.75 (IH, s) 7.99 (IH, d, carbonyl)phenyl J = 4.5 Hz), 8.56 (IH, s) 9.21 (IH, d, J = methanesulfonate 8.0 Hz), 9.87 (IH, s).
126. 4-((5-carbamoyI-4-(( 1 - 1.21 (3H, d, J= 6.4 Hz), 3.91 (2H, s), 7.28 cyclopropylethyl)amino)pyrimidi (IH, d, J = 8.8 Hz), 7.45 (IH, d, J = 8.8 n-2-yl)amino)-2-(2- Hz), 8.45 (IH, s), 8.52 (IH, s), 9.21 (IH, d, cyanoacetamido)phenyl J= 7.6 Hz), 9.60 (IH, s), 9.99 (IH, s). methanesulfonate
127. 2-carbamoyl-4-((5-carbamoyl-4- 0.28 (2H, d, J= 4.4 Hz), 0.43 (IH, m), 1.00
(0- (IH, d, J = 8.8 Hz), 1.24 (3H, d, J = 6.8 cyclopropylethyI)amino)pyrimidi Hz), 3.72 ( IH, d, J = 7.6 Hz), 7.28 (IH, d, n-2-yl)amino)phenyl J= 9.2 Hz), 7.58 (IH, s), 7.68 (2H, m), 8.27 methanesulfonate (IH, s), 8.53 (IH, s), 9.21 (IH, d, J = 7.6
Hz), 9.73 (IH, s).
128. 2-amino-4-((5-carbamoyl-4-((l- 0.9 (6H, d, J = 6.8 Hz), 1.1 (3H, d, J = 6.8 cyclopropylethyl)amino)pyrimidi Hz), 1.8 (IH, m), 4.1 (IH, m), 5.0 (2H, s) n-2-yl)amino)phenyl 6.7 (IH, d, J = 7.2 Hz), 7.2 (IH, q, J = 8.8 methanesulfonate Hz), 7.81 (IH, s), 8.5 (IH, s), 9.2 (IH, d, J
= 8.4 Hz).
129. 4-((5 -carhamoyl-4-(( 1 - 0.27 (2H, m), 0.37 (2H, m), 0.5 (2H, t, J = 4 eye lopropy lethy l)am ino)pyrimidi Hz), 0.6 (5H, t, J = 4 Hz), 0.8 (6H, m), 1.2 n-2-yl)amino)-2- (2H, m), 1.8 (IH, m), 2.6 (IH, m), 3.3 (3H,
(cyclopropylcarbamoyl)phenyl s), 4.1 (IH, s ), 7.2 (IH, d, J = 8.2 Hz), 7.6 methanesulfonate (■IH, d, J= 8.5 Hz), 8.1 (IH, d, J= 8.3 Hz),
8.5 (IH, s), 9.4 (IH, s), 9.7 (IH. s).
130. 4-((5 -carbamoyl-4- 0.54 (2H, t, J= 3.0 Hz), 0.84 (2H, t, J= 3.4 (cyclopropylamino)pyrimidin-2- Hz), 3.32 (3H, m), 7.26 (IH, d, J= 9.2 Hz), yl)amino)phenyl 8.0 (IH, d, J = 8.8 Hz), 8.53 (IH, s), 9.75 methanesulfonate (lH, s).
131. 4-((5 -carbamoyl-4- 0.90 (6H, m), 1.12 (3H, d, J= 6.8 Hz), 1.82
(cyclopropylamino)pyrimidin-2- (IH, m), 2.75 (6H, s), 3.32 (3H, d, J = 8.8 yl)amino)-2- Hz), 4.15 (IH, m), 7.1 1 (IH, d, J= 2.4 Hz),
(dimethylamino)phenyl 7.35 (IH, m), 7.63 (IH, m), 8.52 (IH, s), methanesulfonate 9.33 (IH, d, J = 9.2 Hz), 9.50 (IH, s).
132. 3-((5-carbamoyl-4- 0.55 (2H, m), 0.86 (2H, m), 2.89 (IH, m), .
(cyclopropylamino)pyrimidin-2- 3.32 (3H, m), 6.69 (IH, m), 7.35 (IH, t, J= yl)amino)phenyl 8.2 Hz), 7.69 (IH, d, J = 8.0 Hz), 8.28 (IH, methanesulfonate s), 8.55 (IH, s), 9.15 (IH, s), 9.85 (IH, s).
133. 2-amino-5-((5-carbamoyl-4- 0.05 (2H, t, J = 2.8 Hz), 0.81 (2H, m), 2.21 (cyclopropylamino)pyrimidin-2- (IH, m), 5.05 (2H, m), 6.73 (IH, d, J = 8.8 yl)amino)phenyl Hz), 7.33 (IH, d, J= 10.8 Hz), 7.73 (IH, s), methanesulfonate 7.78 (IH, d, J = 12.8 Hz), 8.04 (IH, m),
8.51 (IH, s), 9.17 (1¾ m), 9.49 (IH, m).
134. 5 -((5 -carbamoy 1-4- 0.53 (4H, t, J = 5 Hz), 0.67 (2H, m), 0.87 (cyclopropy lam ino)py r im idin-2- (2H, d, J = 4.8 Hz), 2.78 (IH, d, J = 4 Hz), yl)amino)-2- 2.90 (IH, d, J = 3.6 Hz), 7.45 (IH, d, J =
(cyclopropylcarbamoyl)phenyl 8.8 Hz), 7.71 (IH, m), 8.25 (IH, d, J = 4.4 methanesulfonate Hz), 8.31 (IH, s), 8.56 (IH, s), 9.16 (IH, d,
J= 3.6 Hz), 9.98 (IH, s).
135. 4-((5-carbamoyl-4- 0. 1 (2H, t, J= 7.3 Hz), 0.78 (2H, t, J= 7.2
(cyclopropylamino)pyrimidin-2- Hz), 2.61 (IH, m) 3.92 (2H, s), 7.31 (IH, d, yl)amino)-2-(2- J = 8.8 Hz), 7.68 (IH, d, J = 8.7 Hz), 8.56 cyanoacetamido)phenyl (IH, s), 9.13 (IH, d, J = 3.2 Hz), 9.80 (IH, methanesulfonate s), 9.99 (IH, s).
136. 3 -((5 -carbamoyl-4- 0.54 (2H, t, J= 3.2 Hz), 0.84 (2H, m), 1.84 (cyclopropylamino)pyrimidin-2- (4H, m), 2.84 (IH, t, J = 3.2 Hz), 3.36 (2H, yl)amino)-5-(pyrrolidine- 1 - m), 3.44 (2H, m), 7.05 (IH, d, J = 1.2 Hz), carbonyl)phenyl 7.95 (IH, s), 8.25 (IH, s), 8.56 (IH, s), 9.17 methanesulfonate (IH, d, J= 3.2 Hz), 9.96 (IH, s).
137. 3 -((5 -carbamoyl-4- 0.59 (2H, m), 0.86 (2H, m), 2.91 (IH, m),
(cyclopropylamino)pyrimidin-2- 3.31 (3H, s), 3.65 (4H, m), 6.96 (IH, s), yl)amino)-5-(morpholine-4- 7.77 (IH, s), 8.33 (IH, s), 8.51 (IH, s), 9.12 carbonyl)phenyl (IH, d, J= 8.8 Hz), 9.7 (IH, s).
methanesulfonate
138. 4-((5-carbamoyl-4- 0.51 (2H, m), 0.85 (2H, t, J= 2.6 Hz), 2.94 (cyclopropylam ino)pyrim idin-2- (IH, t, J = 3.6 Hz), 3.40 (3H, s), 4.55 (IH, yl)amino)-2- d, J= 4.4 Hz), 5.20 (IH, s), 7.23 (2H, d, J=
(hydroxymethyl)phenyl 9.2 Hz), 7.86 (2H, m), 8.21 (1H, d, J = 2.4 methanesulfonate Hz), 8.53 (IH, s), 9.12 (1H, d, J = 3.6 Hz),
9.27 (IH, s).
139. 4-((5 -carbamoyl-4- 0.54 (2H, t, J= 2.8 Hz), 0.84 ( 2H, t, J= 3.4 (cyclopropylamino)pyrimidin-2- Hz), 1.41 (6H, d, J= 6.8 Hz), 2.85 (IH, d, J yl)amino)phenyl propane-2- = 4Hz), 3.67 (IH, t, J = 3.4 Hz), 7.23 (2H, sulfonate d, J = 4.6 Hz), 8.00 (IH, d, J = 9.2 Hz),
8.53 (IH, s), 9.15 (IH, d, J =3.2 Hz), 9.74 (lH, s).
140. 4-((5-carbamoyl-4- 1.25 (2H, m), 1.78 (2H, m), 2.37 (2H, m), (cyclobutylamino)pyrimidin-2- 3.33 (3H, s), 4.51 (IH, m), 7.28 (2H, d, J = yl)amino)phenyl 9.2 Hz), 7.87 (2H, d, J= 9.2 Hz), 8.53 (IH, methanesulfonate s), 9.30 (2H, d, J= 7.2 Hz), 9.67 (IH," s).
141. 4-((5 -carbamoyl-4- 1.50 (2H, m), 1.65 (4H, m), 2.03 (2H, m), (cyclopentylamino)pyrimidin-2- 3.32 (3H, m), 4.35 (IH, m), 7.25 (2H, d, J = yl)amino)phenyl 9.2 Hz), 7.88 (2H, d, J = 9.2 Hz), 8.52 (IH, methanesulfonate s), 9.20 (IH, d, J = 7.2 Hz), 9.65 (IH, s).
142. 5-((5-carbamoyl-4- 1.31 (4H, m), 1.55 (3H, m), 1.8 (5H, m), (cyclopentylamino)pyrimidin-2- 1.93 (2H, m), 3.35 (2H, m), 3.91 (3H, s), yl)amino)-2-methoxyphenyl 4.33 (IH, m), 7.15 (IH, d, J= 8.8 Hz), 7.52 ethanesulfonate (2H, d, J = 8.8 Hz), 8.00 (IH, s), 8.52 (IH, s), 9.21 (IH, d, J = 6.8 Hz), 9.45 (IH, s).
143. 4-((5 -carbamoyl-4- 1.60 (2H, m), 1.68 (2H, m), 1.82 (2H, m), (cyclopentylamino)pyrimidin-2- 1.86 (2H, m), 1.88 (2H, m), 1.98 (2H, m), yl)amino)-2-(pyrrolidine- 1 - 3.22 (2H, t, J= 6.6 Hz), 3.44 (2H, t, J= 6.6 carboriyl)phenyl Hz), 4.28 (IH, d, J= 6.8 Hz), 7.33 (IH, d, J methanesulfonate = 8.8 Hz), 7.70 (IH, m), 8.18 (IH, s), 8.53
(IH, s), 9.21 (IH, d, J = 6.8 Hz), 9.80 (IH, s).
144. 4-((5-carbamoyl-4- 0.53 (2H, m), 0.66 (2H, m), 1.46 (2H, m), (cyclopentylamino)pyrimidin-2- 1.67 (4H, m), 2.05 (2H, m), 2.79 (IH, m),
yl)amino)-2- 4.41 (IH, m), 7.45 (IH, d, 8.4 Hz), 7.60
(cyclopropylcarbamoyl)phenyl (IH, d, J = 8.4 Hz), 8.26 (2H, m), 8.55 (IH, methanesulfonate s), 9.27 (IH, d, J = 7.2 Hz), 9.92 (IH, s).
145. 4-((5 -carbamoy 1-4- 0.95 (8H, m), 3.32 (3H, s), 7.12 (2H, bs),
(cyclopentylamino)pyrimidin-2- 7.21 (2H, d, J = 9.2 Hz), 7.87 (IH, d, J = yl)amino)-2- 9.2 Hz), 8.37 (IH, s), 9.4 (IH, s).
(dimethylamino)phenyl
methanesulfonate
146. 4-((5 -carbamoy l-4-(( 1 -(5 - 1.14 (2H, s), 1.22 (2H, d, J = 3.6 Hz), 2.10 cyanopyridin-2-yl)piperidin-4- (2H, d, J = 10.4 Hz), 3.33 (2H, d, J = 5.2 yl)amino)pyrimidin-2- Hz), 4.35 (2H, d, J = 13.6 Hz), 7.00 (2H, d, yl)amino)phenyl J = 9.2 Hz), 7.28 (2H, d, J = 9.2 Hz), 7.85 methanesulfonate (2H, m), 8.49 (IH, d, J = 2 Hz), 8.55 (IH, s), 9.22 (IH, d, J = 7.2 Hz), 9.72 (IH, s).
147. 4-((5-carbamoyl-4- 1.21 (2H, m), 1.41 (2H, m), 1.67 (2H, m), ((cyclopentylmethyl)amino)pyrim 1.89 (2H, m), 2.22 (IH, m), 3.51 (5H, s), idin-2-yl)amino)phenyl 7.28 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = methanesulfonate 8.0 Hz), 8.51 (IH, s), 9.40 (IH, s), 9.85
(IH, s).
148. 4-((5-carbamoyl-4-(((tetrahydro- 1.2 (2H, m), 1.6 (2H, m), 1.9 (IH, m), 3.2 2H-pyran-4- (2 H, m), 3.9 (2H, m), 7.2 (2H, d, J = 9.0 yl)methyl)amino)pyrimidin-2- Hz) 7.7 (2H, d, J = 9.0 Hz), 8.5 (IH, s), 9.2 yl)amino)phenyl (IH, d, J= 4.8 Hz), 10.0 (IH, s).
methanesulfonate
149. 4-((5 -carbamoyl-4- 0.46 (3H, m) 0.51 (2H, m), 0.81 (2H, m), ((dicyclopropylmethyl)amino)pyr 1.02 (2H, m), 3.43 (3H, s), 3.61 (IH, m), imidin-2-yl)amino)phenyl 7.2 (2H, d, J= 8.4 Hz), 7.77 (2H, d, J = 8.4 methanesulfonate Hz), 8.51 (IH, s), 9.2 (IH, d, J = 8.8 Hz),
9.7 (IH, s).
150. 4-((5 -carbamoy 1-4- 0.28 (6H, m), 0.43 (2H, m), 1.03 (2H, m), ((dicyclopropylmethyl)amino)pyr 3.43 (3H, s), 3.63 (IH, d, J = 8.8 Hz), 4.54
itnidin-2-yl)amino)-2- (2H, d, /= 5.7 Hz), 5.21 (IH, t, J= 5.6 Hz),
(hydroxymethyl)phenyl 7.12 (IH, m), 8.12 (IH, d. J= 2.3 Hz), 8.51 methanesulfonate (lH, s), 9.17 (lH, s), 9.67 (lH. s).
151. 4-((5-carbamoyl-4- 0.48 (2H, m), 0.51 (4H, m), 0.61 (2H, m),
((dicyclopropylmethyl)amino)pyr 0.67 (2H, m), 1.1 (2H, m), 2.71 (IH, m), imidin-2-yl)amino)-2- 3.51 (IH, t, J = 9.2 Hz), 7.28 (IH, d, J= 8.8
(cyclopropylcarbamoyl)phenyl Hz), 7.56 (IH, m), 8.15 (IH, s), 8.36 (IH, d, methanesulfonate J = 8.0 Hz), 8.53 (IH, s), 9.21 (IH, d, J =
8.8 Hz), 9.71 (IH, s) .
152. 4-((5 -carbamoyl-4- 0.30 (6H, m), 0.42 (2H, m), 1.04 (2H, d, J =
((dicyclopropylmethyl)amino)pyr 8.0 Hz), 1.09 (IH, m), 3.61 (IH, d, J = 8.0 imidin-2-yl)amino)-2-(2- Hz), 3.98 (2H, s), 7.28 (IH, d, J = 9.2 Hz), cyanoacetamido)phenyl 7.45 (IH, d, J = 8.8 Hz), 8.37 (IH, s), 8,52 methanesulfonate (IH, s), 9.26 (IH, d, J = 7.2 Hz), 9.63 (IH, s), 9.97 (IH, s).
153. (R)-2-((5-carbamoyl-4-((3- 0.55 (6H, m), 1.27-1.25 (3H, m), 1.89 (IH, methylbutan-2- m), 3.20 (3H, s), 4.14 (IH, m), 5.54 (2H, s), yl)amino)pyrimidin-2- 7.10-7.05 (IH, m), 7.28 (IH, m), 7.38-7.32 yl)amino)phenyl (IH, m), 8.25 (IH, d, J= 8.4 Hz), 8.42 (IH, methanesulfonate m), 8.88 (IH, m).
154. (R)-2-((5-carbamoyl-4-((3- 1-0.8 (6H, m), 1.1 (3H, d, J = 6.4 Hz), 1.78 methylbutan-2- (IH, m), 2.3 (IH, s), 3.37 (3H, s), 4.02-3.94 yl)amino)pyrimidin-2-yl)amino)- (IH, m), 7.13 (IH, d, J = 8.4 Hz), 7.3 (IH, 5-methylphenyl methanesulfonate s), 7.91 (IH, 4, J= 8.0 Hz), 8.45 (2H, d, J =
1.6 Hz), 9.19 (IH, d, J= 8.0 Hz).
155. (R)-4-((5-carbamoyl-4-((l - 1.47 (3H, d, J= 6.8 Hz), 5.12 (IH, m), 6.87 phenylethyI)amino)pyrimidin-2- (2H, d, J= 9.2 Hz), 7.21 (IH, m), 7.27 (4H, yl)amino)phenyl 4- m), 7.47 (2H, m), 7.56 (2H, m), 7.93 (2H, fluorobenzenesulfonate m), 8.54 (IH, s), 9.65 (2H, m).
156. (R)-4-((5-carbamoyl-4-(( 1 - 1.45 (3H, d, J= 6.8 Hz), 5.00 (IH, m), 6.77 phenylethyl)amino)pyrimidin-2- (2H, d, J= 9.2 Hz), 7.18 (IH, m), 7.24 (4H,
yl)amino)phenyl m), 7.43 (2H, d, J = 9.2 Hz), 7.66 (2H, m), benzenesulfonate 7.86 (4H, m), 8.52 (1H, s), 9.58 (2H, m)
157. (R)-4-((5-carbamoyl-4-((l- 1.24 (6H, m), 1.46 (3H, d, J= 6.8 Hz), 3.05 phenylethyl)amino)pyrimidin-2- (1H, m), 5.02 (1H, m), 6.79 (2H, d, J = 8.8 yl)amino)phenyl 4- Hz), 7.18 (3H, m), 7.42 (2H, m), 7.57 (2H, isopropylbenzenesulfonate d, J = 8.4 Hz), 7.78 (2H, d, J = 8.4 Hz),
8.54 (1H, s), 9.59 (2H, m).
158. (R)-4-((5-carbamoyl-4-(( 1 - 1.47 (3H, d, J = 7.2 Hz), 2.42 (3H, s), 5.12 phenylethyl)amino)pyrimidin-2- (1H, t, J = 13.6 Hz), 6.80 (2H, d, J = 9.2 yl)amino)phenyl 3- Hz), 7.18 (4H, m), 7.26 (2H, m), 7.43 (2H, methylbenzenesulfonate d, J = 8.8 Hz), 7.55 (5H, m), 8.54 (lH, s),
9.64 (2H, m).
159. (R)-4-((5-carbamoyl-4-(( 1 - 1.46 (3H, d, J = 7.2 Hz), 5.13 (1H, m), 6.82 phenylethyl)amino)pyrimidin-2- (2H, d, J = 9.2 Hz), 7.20 (1H, m), 7.29 (2H, yl)amino)phenyl 4- m), 7.46 (2H, d, J= 8.8 Hz), 7.69 (2H, d, J (trifluoromethoxy)benzenesulfon = 8.0 Hz), 8.02 (2H, m), 8.54 (1H, s), 9.65 ate (2H, m).
160. 4-((5-carbamoyl-4-((2-chloro-6- 3.29 (3H, s), 4.84 (2H, d, 2H, J = 5.2 Hz); fluorobenzyl)amino)pyrimidin-2- 7.10 (1H, bs), 7.25-7.27 (3H, m), 7.28-7.31 yl)amino)phenyl (2H, m); 7.70 (1H, bs), 7.87-7.90 (2H, m), methanesulfonate 8.56 (1H, s), 9.51 (1H, s), 9.75 (1H, s).
It will be appreciated that while preparing any of these compounds 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 quantity of active component, that is, the compounds of formula (1) 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.
In one aspect, the present invention pertains to methods of treating a JAK- associated disease or disorder in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. A JAK- associated disease can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the JAK, including over expression and/or abnormal activity levels. A JAK-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating JAK activity.
Examples of JAK-associated diseases include diseases involving the immune system including, for example, organ transplant rejection (e.g., allograft rejection and graft versus host disease). Further examples of JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, or autoimmune thyroid disorders. Further examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, atopic dermatitis and rhinitis. Further examples of JAK-associated diseases include viral diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV). Further examples of JAK-associated diseases or conditions include skin disorders such as atopic dermatitis, psoriasis (for example, psoriasis vulgaris), skin sensitization, and the like. Further examples of JAK- associated diseases are those involving IL-6 pathways including Castleman's disease, Kaposi's sarcoma, and others. Further examples of JAK-associated diseases or conditions include immune reactions (such as diarrhea, skin irritation, skin rash, contact dermatitis or allergic contact sensitization) caused by certain therapeutics in some patients. Further examples of JAK-associated diseases include hyperpropliferative disorders including polycythemia vera, essential thrombocytopenia, myeloid metaplasia with myelofibrosis, and the like. In further embodiments, the JAK-associated disease is cancer such as, for example, prostate, renal, hepatocellular, pancreatic, gastric, breast, lung, cancers of the head and neck, glioblastoma, leukemia, lymphoma or multiple myeloma.
As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response associated with such treatment with a JAK inhibitors as are well known, in a tissue, system, animal, individual or human.
One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-inflammatory agents, and/or immunosuppressants can be used in combination with the compounds of the present invention for treatment of JAK- associated diseases, disorders or conditions. For example, a JAK inhibitor used in combination with a chemotherapeutic in the treatment of multiple myeloma may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects. Examples of additional pharmaceutical agents used in the treatment of multiple myeloma, for example, can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and velcade. Additive or synergistic effects are desirable outcomes of combining a JAK inhibitor of the present invention with an additional agent. Furthermore, resistance of multiple myeloma cells to agents such as dexamethasome may be reversible Upon treatment with a JAK inhibitor of the present invention. The agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
When employed as pharmaceuticals, the compounds described herein can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophuialmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial^ subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or
intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
In vitro JAK inhibition was performed using in vitro Fluorogenic Substrate Assay and IC50 values of most of the compounds tested were below 30 nM.
The compounds were tested for their efficacy and safety as follows.
In vitro JAK inhibition assay
JA 2 and JAK3 inhibition assay may be performed as described in
WO2008031594 with minor modifications as are well within the scope of a skiled person. JAK2 and JAK3 kinases are used as GST-JAK-3(811- 1124), and GST-JAK- 2(808-1 132) respectively.
JAK-2 or JAK-3 enzymatic activity is determined using a time-resolved fluorescence energy transfer technology. The phosphorylation of a synthetic biotinylated peptide substrate (Acetate-GGEEEEYFELVKKK (Biotin)-CONH2) by either JAK-2 or JAK-3 in the presence of ATP is quantified using Europium labeled anti phosphotyrosine antibody and Streptavidin- Allophycocyanin Both JAK-2 and JAK-3 enzymes used in these assays contain the kinase domain (JH-1 domain) of the full length proteins and are used as glutathione S-transferase (GST) fusion proteins.
Inhibitors are dissolved in dimethylsulfoxide (DMSO). Dilutions are prepared in 90% DMSO followed by additional dilutions steps as required to perform an 8-point concentration- response.
The reaction mix consists of 5 \iL of diluted compound, 10 μ1_ of assay buffer and 5 μ1_ of enzyme dilution. After incubation . for 60 minutes at room temperature the reaction is stopped by the addition of EDTA. For detection of the product anti- phosphotyrosine antibody and Streptavidin-APC are added and after 60 minutes the samples are measured in an EnVision 2102 Multilabel Reader (Perkin Elmer, Inc., Wellesley, MA, USA, in the following mentioned as "PerkinElmer") with excitation wavelength of 320nm and emission at 665nm.
Example. No. JAK3 IC50 (nM) JAK2 ICso (nM)
1 6.9 47.5
2 153.2 736
3 23.6 185
4 12.0 26.8
5 5.6 22.1
6 11.8 ND
12 5.6 ND
13 2.9 9.2
19 6.69 38.8
20 6.01 ND
21 9.7 ND
34. 22.6 46.8
36 19.3 57.2
37 8.7 18.9
39 25 97.9
48 8.4 14.3
67 15.4 67.5
68 ND 53.3
' 69 23.2 157.4
78 4.1 16.3
94 22 29.6
95 6 48.3
111 5.0 23.9
124 20.8 50.9
134 34 92.8
140 37.3 63.8
Claims
We claim
Compound of the general formula (I),
(I)
or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein R] represents optionally substituted groups selected from (C3-C8) cycloalkyl, aralkyl, heteroaralkyl, (C1-C6)alkyl, (C2-C4)alkenyl, and (C2- C4)alkynyl; R2 represents optionally substituted groups selected from (Cr C6)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C8) cycloalkyl, aryl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from N, O or S; R3 at each occurrence independently represents hydrogen, halogen, nitro, cyano, -(CH2)r-C(0)R4, -(CH2)r-C(0)OR4, - N(R 2 , -NH(CH2)r-C(0)R4i - NHCCHyr-CCO Rt, -NH(CH2)r-S(0)2OR4 wherein -r' represents an integer from 0-2; R4 at each occurrence independently represents hydrogen, optionally substituted groups selected from (Ci-C6)alkyl, (C2-C4)alkenyl, and (C2- C4)alkynyl; or the group NR5R6 wherein R5 and Re independently represents hydrogen, optionally substituted groups selected from (C1-C6)alkyl, (C2- C4)alkenyl, (C2-C )alkynyl, (C3-C8) cycloalkyl, aryl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from N, O or S, or R5, R<5 together with N can form a 4-7 membered ring, which may be optionally substituted and which may optionally further contain one or more heteroatoms selected from N, O or S; 'X' represents O; 'm' represents an integer from 0-4.
2. The compound of formula (I) as claimed in claim 1 or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof represented by the following formula
(I)
wherein all the symbols are as defined in claim 1.
3. The compound of formula (I) as claimed in claim 1 or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof represented by the following formula
o
wherein all the symbols are as defined in claim 1.
4. The compound of formula (I) as claimed in claim 1 or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof represented by the following
wherein all the symbols are as defined in claim 1.
5. The compound of formula (I) as claimed in claim 1 or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof represented by the following formula
wherein all the symbols are as defined in claim 1.
The compound of any one of the preceding claims, wherein, the moiety
is selected from the group comprising of
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
(S)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methoxyphenyl methanesulfonate;
(R)-2-amino-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (dimethylamino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- fluorophenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl ethanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl propane-2 -sulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl 2,2,2-trifluoroethanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methylphenyl ethanesulfonate;
(R)-2-acetamido-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
(R)-2-(allylamino)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methylphenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- hydroxyphenyl methanesulfonate;
(R)-methyl 5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)- 2-((methylsulfonyl)oxy)benzoate;
(R)-4-((5-carbamoyI-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methoxyphenyl ethanesulfonate;
(R)-2-carbamoyl-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (methylcarbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-((2- fluorobenzyl)carbamoyl)phenyl methanesulfonate;
(R)-2-(benzylcarbamoyl)-4-((5-carbamoyl-4-((3-methylbutan-2- yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-(((R)-3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (((R)- 1 -phenylethyl)carbamoyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(((R)-3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-(((S)- l-phenylethyl)carbamoyl)phenyl methanesulfonate;
(R)-4-((5 -carbamoyl-4-((3 -methy lbutan-2-yl)am ino)pyrim idin-2-y l)am ino)-2- ((pyridin-3-ylmethyl)carbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyi-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)aniino)-2-((4- fluorobenzyl)carbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (phenylcarbamoyl)phenyl methanesulfonate;
(R)-2-(allylcarbamoyl)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin- 2-yl)amino)phenyl methanesulfonate;
(R)-2-(5-((5-carbamoyl-4-(((R)-3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-
2- ((methylsulfonyl)oxy)benzamido)propanoic acid;
(R)-methyl 2-(5-((5-carbamoyl-4-(((R)-3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)-2-((methylsulfonyl)oxy)benzamido)propanoate;
4-((5-carbamoyl-4-(((R)-3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-(((S)-
3- methylbutan-2-yl)carbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (dimethylcarbamoyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (pyrrolidine-l-carbonyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)aniino)pyrimidin-2-yl)amino)-2- (piperidine-l-carbonyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (moφholine-4-caΓbonyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
(R)-3 -((5 -carbamoyl-4-((3 -methy lbutan-2-yl)amino)pyrim idin-2-yl)amino)-5 - (hydroxymethyl)phenyl methanesulfonate;
(S)-4-((5-carbamoyl-4-(( 1 -hydroxy-3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(S)-4-((4-((l-amino-3-methyl-l-oxobutan-2-yl)amino)-5-carbamoylpyrimidin-2- yl)amino)phenyl methanesulfonate;
(S)-4-((5 -carbamoyl-4-(( 1 -cyano-2-methy lpropyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((2-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((4-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
2- amino-4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)-2-methylphenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)-2-methylphenyl ethanesulfonate;
4- ((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyI methanesulfonate;
5- ((5-carbamoyl-4-((3-fiuorobenzyl)amino)pyrimidin-2-yl)amino)-2- methoxyphenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fίuorobenzyl)amino)pyrimidin-2-yl)amino)-2-(mo holine- 4-carbonyl)phenyl methanesulfonate;
3- ((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)-5-(mo holine-
4- carbonyl)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2-yl)amino)phenyl ethanesulfonate;
(R)-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2-yl)amino)-3- fluorophenyl methanesulfonate;
(R)-2-acetamido-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-2-(allylamino)-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-carbamoylphenyl methanesulfonate;
4-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-(pyrrolidine- 1 - carbonyl)phenyl methanesulfonate;
4- ((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-(dimethylamino)phenyl methanesulfonate;
5- ((4-(benzylamino)-5-carbamoylpyrimidin-2-yI)amino)-2- (cyclopropylcarbanioyl)phenyl methanesulfonate;
2- amino-5-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl methanesulfonate;
3- ((4-(benzylamino)-5-carbamoylpyrimidin-2-yI)amino)-5- (cyclopropylcarbamoyl)phenyl methanesulfonate;
3-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-5-(morpholine-4- carbonyl)phenyl methanesulfonate;
3- ((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-5-(pyrrolidine-l- carbonyl)phenyl methanesulfonate;
4- ((5-carbamoyl-4-((4-methoxybenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((2,6-difluorobenzyl)amino)pyrimidin-2^yl)amino)phenyl methanesulfonate;
4-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-(hydroxymethyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-((2,4-dimethylbenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((4-(benzylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl propane-2- sulfonate;
4-((5-carbamoyl-4-((2,4-difluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((3-fluorobenzyl)amino)pyrimidin-2-yl)amino)phenyl propane- 2-sulfonate;
(R)-3-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- fluorophenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methoxyphenyl ethanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- methoxyphenyl methanesulfonate;
(R)-2-amino-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-2-acetamido-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-2-carbamoyl-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yi)amino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
(R)-2-(allylcarbamoyl)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin- 2-yI)amino)phenyl methanesulfonate;
(R)-2-(benzylcarbamoyl)-5 -((5 -carbamoy l-4-((3 -methylbutan-2- yl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-((4- fluorobenzyl)carbamoyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyI-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2-((2- fluorobenzyl)carbamoyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (phenylcarbamoyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (dimethylcarbamoyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (diethylcarbamoyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (pyiTolidine-l-carbonyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-2- (moφholine-4-carbonyl)phenyl methanesulfonate;
(R)-5-((5-carbamoyl-4-((3-methylbutan-2-yI)amino)pyrimidin-2-yl)amino)-2- (cyclopropyl(2,3-dimethylbenzyl)carbamoyl)phenyl methanesulfonate;
(R)-3-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-5- (cyclopropylcarbamoyl)phenyl methanesulfonate;
(R)-3-carbamoyl-5-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
(R)-3-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-5- (moφholine-4-carbonyl)phenyl methanesulfonate;
(R)-3-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-5- (pyrrolidine- 1 -carbonyl)phenyl methanesulfonate;
4-((4-(allylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((4-(allylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-methylphenyl methanesulfonate;
4- ((4-(allylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-methylphenyl ethanesulfonate;
5- ((4-(allylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-methoxyphenyl ethanesulfonate;
5-((4-(allylamino)-5-carbamoylpyrimidin-2-yl)amino)-2-methoxyphenyl methanesulfonate;
4-((5-carbamoyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-(pentan-3-ylamino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
4-((5-carbamoyl-4-(isopentylamino)pyrimidin-2-yl)amino)phenyl
methanesulfonate;
2- amino-4-((5-carbamoyl-4-(isopentylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
3- ((5-carbamoyl-4-(isopentylamino)pyrimidin-2-yl)amino)-5-(morpholine-4- carbonyl)phenyl methanesulfonate;
3-((5-carbamoyl-4-(isopentylamino)pyrimidin-2-yl)amino)-5-(pyrrolidine-l- carbonyl)phenyl methanesulfonate
2-(allylcarbamoyl)-4-((5-carbamoyl-4-(isopentylamino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-(isopentylamino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
3- ((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)phenyl
methanesulfonate;
4- ((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)phenyl
methanesulfonate;
2- amino-4-((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4- ((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)-2- (dimethylamino)phenyl methanesulfonate;
3- ((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)-2-methylphenyl methanesulfonate;
2,6-dibromo-4-((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
5- ((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)-2-fluorophenyl methanesulfonate;
4- ((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)phenyl propane-2- sulfonate;
4-((5-carbamoyl-4-(isobutylamino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
4-((4-(sec-butylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl methanesulfonate;
3- ((4-(sec-butylamino)-5-carbamoylpyrimidin-2-yl)amino)phenyl methanesulfonate;
4- ((5-carbamoyl-4-((2,2,2-trifluoroethyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
2-amino-4-((5-carbamoyl-4-((2,2,2-trifluoroethyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-(( 1 -cyclopropylethyl)amino)pyrimidin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
3- ((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2-yl)amino)-5- (mo holine-4-carbonyl)phenyl methanesulfonate;
4- ((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
2-carbamoy l-4-((5 -carbamoyl-4-(( 1 -cyclopropylethyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
2- amino-4-((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((l-cyclopropylethyl)amino)pyrimidin-2-yl)anvino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4- ((5-carbamoyl-4r(cyclopropylamino)pyrimidin-2-yl)amino)-2- (dimethylamino)phenyl methanesulfonate;
3- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
2- amino-5-((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
5- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
4- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
3- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-5-(pyrrolidine-l- carbonyl)phenyl methanesulfonate;
3- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-5-(mo holine-4- carbonyl)phenyl methanesulfonate;
4- ((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(cyclopropylamino)pyrimidin-2-yl)amino)phenyl propane-2- sulfonate;
4-((5-carbamoyl-4-(cyclobutylamino)pyrimidin-2-yl)amino)phenyl
methanesulfonate; ;
4- ((5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-yl)amino)phenyl
methanesulfonate;
5- ((5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-yl)amino)-2-methoxyphenyl ethanesulfonate;
4-((5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-yl)amino)-2-(pyrrolidine-l- carbonyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-yl)amino)-2- (dimethylamino)phenyl methanesulfonate;
4-((5-carbamoyl-4-(( 1 -(5 -cyanopyridin-2-yl)piperidin-4-yl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((cyclopentylmethyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrimidin-2- yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((dicyclopropylmethyl)amino)pyrimidin-2-yl)amino)phenyl methanesulfonate;
4-((5-carbamoyl-4-((dicyclopropylmethyl)amino)pyrimidin-2-yl)amino)-2- (hydroxymethyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-((dicyclopropylmethyl)amino)pyrimidin-2-yl)amino)-2- (cyclopropylcarbamoyl)phenyl methanesulfonate;
4-((5-carbamoyl-4-((dicyclopropylmethyl)amino)pyrimidin-2-yl)amino)-2-(2- cyanoacetamido)phenyl methanesulfonate;
(R)-2-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)aminp)phenyl methanesulfonate;
(R)-2-((5-carbamoyl-4-((3-methylbutan-2-yl)amino)pyrimidin-2-yl)amino)-5- methylphenyl methanesulfonate;
(R)-4-((5-carbamoyl-4-(( 1 -phenylethyl)amino)pyrimidin-2-yl)amino)phenyl 4- fluorobenzenesulfonate;
(R)-4-((5-carbamoyl-4-((l-phenylethyl)amino)pyrimidin-2-yl)amino)phenyl benzenesulfonate;
(R)-4-((5-carbamoyl-4-(( 1 -phenylethyl)amino)pyrimidin-2-yl)amino)phenyl 4- isopropylbenzenesulfonate;
(R)-4-((5 -carbamoy l-4-(( 1 -pheny lethyl)amino)pyrimidin-2-y l)amino)phenyl 3 - methylbenzenesulfonate;
(R)-4-((5-carbamoyl-4-(( 1 -phenylethyl)amino)pyrimidin-2-yl)amino)phenyl 4- (trifluoromethoxy)benzenesulfonate;
4-((5-carbamoyl-4-((2-chloro-6-fluorobenzyl)amino)pyrirnidin-2-yl)arnino)phenyl methanesulfonate.
9. A pharmaceutical composition which comprises a compound as claimed in any one of claims 1 to 8, together with a pharmaceutically acceptable carrier.
10. A compound as claimed in any one of claims 1 to 8, for use as a medicament.
11. A compound as claimed in claim 10, for use in the treatment or prophylaxis of a condition associated with a disease or disorder associated with JAK inhibition.
12. Use of a compound as claimed in any one of claims 1 to 8, for the manufacture of a medicament for the treatment or prophylaxis of a condition associated with a disease or disorder associated with JAK inhibition.
13. A method for the treatment or prophylaxis of a disease or disorder associated with JAK inhibition in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound as claimed in any one of claims 1 to 8 or a composition as claimed in claim 9.
14. A compound as claimed in claim 11, a method as claimed in claim 13, or a use as claimed in claim 12, wherein the condition associated with a disease or disorder associated with JAK inhibition is selected from the group consisting of inflammatory disease, immune-related disease, autoimmune disease and cardiovascular disease.
15. The method of claim 13, wherein said JAK kinase is selected from the group
consisting of JAK1, JAK2, JAK3 and TYK2.
16. The method of claim 15, wherein said JAK kinase is JAK1, JAK2, JAK3 and
TYK2 or combinations thereof.
17. The method of claim 13, wherein said inflammatory disease, immune-related
disease, autoimmune disease is selected from the group consisting of rheumatoid
arthritis, osteoarthritis, irritable bowel disease (IBD), asthma, chronic obstructive pulmonary (COPD), Crohn's disease, psoriasis, multiple sclerosis (MS) and organ transplants.
18. The compound as claimed in any preceding claims in combination with a second medicament which provides either an additional or synergistic effect in the treatment of diseases as claimed earlier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2227MU2011 | 2011-08-08 | ||
| IN2227/MUM/2011 | 2011-08-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013054351A1 true WO2013054351A1 (en) | 2013-04-18 |
Family
ID=47553311
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2012/000538 WO2013054351A1 (en) | 2011-08-08 | 2012-08-03 | Heterocyclic compounds |
Country Status (2)
| Country | Link |
|---|---|
| AR (1) | AR087487A1 (en) |
| WO (1) | WO2013054351A1 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015069310A1 (en) * | 2013-11-07 | 2015-05-14 | Bristol-Myers Squibb Company | Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses |
| WO2015123453A1 (en) * | 2014-02-14 | 2015-08-20 | Portola Pharmaceuticals, Inc. | Pyridazine compounds as jak inhibitors |
| US9382246B2 (en) | 2013-12-05 | 2016-07-05 | Pharmacyclics Llc | Inhibitors of Bruton's tyrosine kinase |
| CN106478465A (en) * | 2016-10-18 | 2017-03-08 | 天津力生制药股份有限公司 | A kind of synthetic method of olsalazine sodium important intermediate hydride |
| JP2019513778A (en) * | 2016-04-15 | 2019-05-30 | エピザイム，インコーポレイティド | Amine-substituted aryl or heteroaryl compounds as EHMT1 and EHMT2 inhibitors |
| JP2019518796A (en) * | 2016-06-27 | 2019-07-04 | ライジェル ファーマシューティカルズ， インコーポレイテッド | 2,4-Diamino-pyrimidine compounds and methods of making and using said compounds |
| CN110734427A (en) * | 2018-07-20 | 2020-01-31 | 北京赛特明强医药科技有限公司 | Alkenyl-containing pyrimidine formamide compound, composition and application thereof |
| WO2022135430A1 (en) * | 2020-12-22 | 2022-06-30 | InventisBio Co., Ltd. | Heteroaryl compounds, preparation methods and uses thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003074515A1 (en) * | 2002-03-01 | 2003-09-12 | Smithkline Beecham Corporation | Diamino-pyrimidines and their use as angiogenesis inhibitors |
| EP1518855A1 (en) * | 2002-06-28 | 2005-03-30 | Yamanouchi Pharmaceutical Co. Ltd. | Diaminopyrimidinecarboxa mide derivative |
| WO2007085833A2 (en) * | 2006-01-26 | 2007-08-02 | Astrazeneca Ab | Pyrimidine derivatives |
| WO2008009458A1 (en) * | 2006-07-21 | 2008-01-24 | Novartis Ag | 2, 4 -di (arylaminio) -pyrimidine-5-carboxamide compounds as jak kinases inhibitors |
| US20080255172A1 (en) * | 2007-04-16 | 2008-10-16 | Hutchison Medipharma Enterprises Limeted | Pyrimidine derivatives |
| WO2009145856A1 (en) * | 2008-04-16 | 2009-12-03 | Portola Pharmaceuticals, Inc. | 2, 6-diamino-pyrimidin- 5-yl-carboxamides as syk or jak kinases inhibitors |
| WO2010129802A1 (en) * | 2009-05-06 | 2010-11-11 | Portola Pharmaceuticals, Inc. | Inhibitors of jak |
| WO2011060295A1 (en) * | 2009-11-13 | 2011-05-19 | Genosco | Kinase inhibitors |
-
2012
- 2012-08-03 WO PCT/IN2012/000538 patent/WO2013054351A1/en active Application Filing
- 2012-08-08 AR ARP120102897A patent/AR087487A1/en not_active Application Discontinuation
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003074515A1 (en) * | 2002-03-01 | 2003-09-12 | Smithkline Beecham Corporation | Diamino-pyrimidines and their use as angiogenesis inhibitors |
| EP1518855A1 (en) * | 2002-06-28 | 2005-03-30 | Yamanouchi Pharmaceutical Co. Ltd. | Diaminopyrimidinecarboxa mide derivative |
| WO2007085833A2 (en) * | 2006-01-26 | 2007-08-02 | Astrazeneca Ab | Pyrimidine derivatives |
| WO2008009458A1 (en) * | 2006-07-21 | 2008-01-24 | Novartis Ag | 2, 4 -di (arylaminio) -pyrimidine-5-carboxamide compounds as jak kinases inhibitors |
| US20080255172A1 (en) * | 2007-04-16 | 2008-10-16 | Hutchison Medipharma Enterprises Limeted | Pyrimidine derivatives |
| WO2009145856A1 (en) * | 2008-04-16 | 2009-12-03 | Portola Pharmaceuticals, Inc. | 2, 6-diamino-pyrimidin- 5-yl-carboxamides as syk or jak kinases inhibitors |
| WO2010129802A1 (en) * | 2009-05-06 | 2010-11-11 | Portola Pharmaceuticals, Inc. | Inhibitors of jak |
| WO2011060295A1 (en) * | 2009-11-13 | 2011-05-19 | Genosco | Kinase inhibitors |
Cited By (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2014347275B2 (en) * | 2013-11-07 | 2017-12-07 | Bristol-Myers Squibb Company | Alkyl-amide-substituted pyridyl compounds useful as modulators of IL-12, IL-23 and/or IFNalpha responses |
| EA033272B1 (en) * | 2013-11-07 | 2019-09-30 | Бристол-Маерс Сквибб Компани | Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses |
| KR20160071475A (en) * | 2013-11-07 | 2016-06-21 | 브리스톨-마이어스 스큅 컴퍼니 | Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses |
| EP3590926A1 (en) * | 2013-11-07 | 2020-01-08 | Bristol-Myers Squibb Company | Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses |
| KR102186633B1 (en) | 2013-11-07 | 2020-12-03 | 브리스톨-마이어스 스큅 컴퍼니 | Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses |
| CN106660960A (en) * | 2013-11-07 | 2017-05-10 | 百时美施贵宝公司 | Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses |
| WO2015069310A1 (en) * | 2013-11-07 | 2015-05-14 | Bristol-Myers Squibb Company | Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses |
| JP2017512749A (en) * | 2013-11-07 | 2017-05-25 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Alkyl-amide-substituted pyridyl compounds useful as modulators of IL-12, IL-23 and / or IFN alpha response |
| US9663467B2 (en) | 2013-11-07 | 2017-05-30 | Bristol-Myers Squibb Company | Alkyl-amide-substituted pyridyl compounds useful as modulators of IL-12, IL-23 and/or IFNα responses |
| US9987266B2 (en) | 2013-11-07 | 2018-06-05 | Bristol-Myers Squibb Company | Alkyl-amide-substituted pyridyl compounds useful as modulators of IL-12, IL-23 and/or IFNα responses |
| US9656988B2 (en) | 2013-12-05 | 2017-05-23 | Pharmacyclics Llc | Inhibitors of Bruton's tyrosine kinase |
| US9382246B2 (en) | 2013-12-05 | 2016-07-05 | Pharmacyclics Llc | Inhibitors of Bruton's tyrosine kinase |
| US9834548B2 (en) | 2014-02-14 | 2017-12-05 | Portola Pharmaceuticals, Inc. | Pyridazine compounds as JAK inhibitors |
| WO2015123453A1 (en) * | 2014-02-14 | 2015-08-20 | Portola Pharmaceuticals, Inc. | Pyridazine compounds as jak inhibitors |
| JP7420847B2 (en) | 2016-04-15 | 2024-01-23 | エピザイム，インコーポレイティド | Amine-Substituted Aryl or Heteroaryl Compounds as EHMT1 and EHMT2 Inhibitors |
| JP2019513778A (en) * | 2016-04-15 | 2019-05-30 | エピザイム，インコーポレイティド | Amine-substituted aryl or heteroaryl compounds as EHMT1 and EHMT2 inhibitors |
| JP2022081606A (en) * | 2016-04-15 | 2022-05-31 | エピザイム，インコーポレイティド | Amine-substituted aryl or heteroaryl compounds as EHMT1 and EHMT2 inhibitors |
| JP7041070B2 (en) | 2016-04-15 | 2022-03-23 | エピザイム，インコーポレイティド | Amine-substituted aryl or heteroaryl compounds as EHMT1 and EHMT2 inhibitors |
| JP2019518796A (en) * | 2016-06-27 | 2019-07-04 | ライジェル ファーマシューティカルズ， インコーポレイテッド | 2,4-Diamino-pyrimidine compounds and methods of making and using said compounds |
| JP7065840B2 (en) | 2016-06-27 | 2022-05-12 | ライジェル ファーマシューティカルズ， インコーポレイテッド | 2,4-Diamino-pyrimidine compound and method for producing and using the compound |
| US11524955B2 (en) | 2016-06-27 | 2022-12-13 | Rigel Pharmaceuticals, Inc. | 2,4-diamino-pyrimidine compounds and method for making and using the compounds |
| CN106478465B (en) * | 2016-10-18 | 2018-08-24 | 天津力生制药股份有限公司 | A kind of synthetic method of olsalazine sodium important intermediate hydride |
| CN106478465A (en) * | 2016-10-18 | 2017-03-08 | 天津力生制药股份有限公司 | A kind of synthetic method of olsalazine sodium important intermediate hydride |
| CN110734427B (en) * | 2018-07-20 | 2021-01-15 | 北京赛特明强医药科技有限公司 | Alkenyl-containing pyrimidine formamide compound, composition and application thereof |
| CN110734427A (en) * | 2018-07-20 | 2020-01-31 | 北京赛特明强医药科技有限公司 | Alkenyl-containing pyrimidine formamide compound, composition and application thereof |
| WO2022135430A1 (en) * | 2020-12-22 | 2022-06-30 | InventisBio Co., Ltd. | Heteroaryl compounds, preparation methods and uses thereof |
| CN114981262A (en) * | 2020-12-22 | 2022-08-30 | 益方生物科技(上海)股份有限公司 | Heteroaryl compounds, their preparation and use |
| CN115160297A (en) * | 2020-12-22 | 2022-10-11 | 益方生物科技(上海)股份有限公司 | Heteroaryl compounds, their preparation and use |
Also Published As
| Publication number | Publication date |
|---|---|
| AR087487A1 (en) | 2014-03-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2013054351A1 (en) | Heterocyclic compounds | |
| US10336711B2 (en) | Prolyl hydroxylase inhibitors | |
| JP6791979B2 (en) | Nitrogen-containing heterocyclic compounds, production methods, intermediates, compositions and applications | |
| ES2394472T3 (en) | Quinazolin-oxime derivatives as hsp90 inhibitors | |
| CA2866852C (en) | Solid forms of an epidermal growth factor receptor kinase inhibitor | |
| CN107428754B (en) | Bicyclic quinazolinone derivatives | |
| JP6474068B2 (en) | 2-Aminopyrimidine compounds and drug compositions and uses thereof | |
| JP5637562B2 (en) | Novel pyrrolinone derivative and pharmaceutical composition containing the same | |
| AU2004283751B2 (en) | p70S6 kinase modulators and method of use | |
| KR100910333B1 (en) | Quinazoline derivative having tyrosine kinase inhibitory activity | |
| CN101258149B (en) | Thiazole derivatives and use thereof | |
| ZA200402796B (en) | N-substituted hydroxypyrimidinone carboxamide inhibitors of hiv integrase | |
| JP2009525337A (en) | 4-Aryl-2-amino-pyrimidines or 4-aryl-2-aminoalkyl-pyrimidines as JAK-2 modulators and methods of use | |
| AU2018226922B2 (en) | Urea-substituted aromatic ring-linked dioxane-quinazoline and -linked dioxane-quinoline compounds, preparation method therefor and use thereof | |
| JP2022553351A (en) | Improved Methods, Kits, Compositions, and Dosing Regimens for the Use of Heterocyclic Inhibitors of ERK1 and ERK2 | |
| CN103534241A (en) | Fak inhibitor | |
| NZ545459A (en) | Quinazoline analogs as receptor tyrosine kinase inhibitors | |
| CA2689607A1 (en) | Kinase inhibitor compounds | |
| EP3181553A1 (en) | Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof | |
| JP2007517007A (en) | Pyrimidine with Tie2 (TEK) activity | |
| CA3232128A1 (en) | Pyridine derivative and use thereof | |
| JP4993205B2 (en) | Pyrimidine derivatives having tyrosine kinase inhibitory action | |
| CN103880822A (en) | 2,4,6-trisubstituted pyrimidine compounds containing 1,2,3-triazole, preparation method and application thereof | |
| TW202045506A (en) | Pyrazole compound | |
| AU2018337138B2 (en) | 2-substituted pyrazole amino-4-substituted amino-5-pyrimidine formamide compound, composition, and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12813532 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 12813532 Country of ref document: EP Kind code of ref document: A1 |