WO2015187089A1 - Mth1 inhibitors for treatment of inflammatory and autoimmune conditions - Google Patents

Mth1 inhibitors for treatment of inflammatory and autoimmune conditions Download PDF

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Publication number
WO2015187089A1
WO2015187089A1 PCT/SE2015/050654 SE2015050654W WO2015187089A1 WO 2015187089 A1 WO2015187089 A1 WO 2015187089A1 SE 2015050654 W SE2015050654 W SE 2015050654W WO 2015187089 A1 WO2015187089 A1 WO 2015187089A1
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WIPO (PCT)
Prior art keywords
optionally substituted
groups selected
diamine
ring
chloro
Prior art date
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Ceased
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PCT/SE2015/050654
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English (en)
French (fr)
Inventor
Martin Scobie
Olov Wallner
Tobias Koolmeister
Karl Sven Axel VALLIN
Carl Martin HENRIKSSON
Evert Homan
Thomas Helleday
Sylvain JACQUES
Matthieu Desroses
Marie-Caroline JACQUES-CORDONNIER
Roland Julius Yu FISKESUND
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
THOMAS HELLEDAYS STIFTELSE FOR MEDICINSK FORSKNING
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THOMAS HELLEDAYS STIFTELSE FOR MEDICINSK FORSKNING
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Priority to US15/315,478 priority Critical patent/US10064869B2/en
Priority to CN201580029524.6A priority patent/CN106794181A/zh
Priority to AU2015268962A priority patent/AU2015268962A1/en
Priority to CA2948601A priority patent/CA2948601A1/en
Priority to RU2016151390A priority patent/RU2016151390A/ru
Priority to EP15802742.5A priority patent/EP3151833A4/en
Application filed by THOMAS HELLEDAYS STIFTELSE FOR MEDICINSK FORSKNING filed Critical THOMAS HELLEDAYS STIFTELSE FOR MEDICINSK FORSKNING
Priority to JP2016571095A priority patent/JP6635949B2/ja
Priority to SG11201609981RA priority patent/SG11201609981RA/en
Publication of WO2015187089A1 publication Critical patent/WO2015187089A1/en
Priority to IL249223A priority patent/IL249223A0/en
Anticipated expiration legal-status Critical
Priority to US16/120,170 priority patent/US10632125B2/en
Ceased legal-status Critical Current

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Definitions

  • the invention relates to compositions and methods for treatment, prevention and/or prophylaxis of autoimmune diseases and inflammatory (e.g. chronic inflammatory) conditions.
  • the invention relates to compositions and methods for the treatment and/or prophylaxis of common autoimmune diseases including rheumatoid arthritis, multiple sclerosis and psoriasis through inhibition of MTH1.
  • Autoimmune diseases and hyperinflammatory disorders are conditions where a mammal's immune system starts reacting against its own tissues.
  • Such conditions include, without limitation, arthritis, e.g. rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerous colitis, multiple sclerosis, lymphoproliferative diseases (e.g. those caused by Epstein Barr virus and cytomegalovirus), rejection after organ transplantation, Wegener'
  • granulomatosus psoriasis, Mb Bechterews, Behcets disease, Guillain Barre, dermatomyositis, myositis, polymyositis, primary biliary cirrhosis, anti- phospholipid syndrome, autoimmune hepatitis, autoimmune cardiomyopathy, alopecia areata, atherosclerosis, type 1 diabetes, autoimmune uveitis,
  • Methotrexate and COX-2 inhibitors In similarity to RA, the cause and pathology of autoimmune and (hyper) inflammatory conditions including MS, IBD and the majority of less prevalent autoimmune conditions, is far from understood and many patients suffer from a disease that current treatments do not have the capacity to treat or ameliorate, hence there is a great need to understand the mechanisms driving these diseases which will enable novel ways for treatments.
  • the present invention aims at providing new treatments for inflammatory and autoimmune diseases based on immunomodulatory effects that can be achieved by inhibition of the MTH1 enzyme.
  • US patent application US 2010/0016344 disclose certain 6-aryl-2,4-diamino- pyrimidines having an additional pyrimidine appendage as histamine H4 receptor modulators.
  • the compounds are claimed to be useful for the treatment of e.g. autoimmune and inflammatory disorders. Data supporting the usefulness in the treatment of inflammatory pain is presented. There is no support that the compounds would be effective in the treatment of autoimmune diseases in general.
  • the preferred 6-aryl is stated to be phenyl or 3-chlorophenyl although also 3,5-dichlorophenyl and 5-chloro-5-methoxyphenyl are exemplified. However, there is nothing that suggests that 2,3-disubstituted phenyls would be particularly advantageous.
  • the substituent on the 4-amino group contains an essential 5-trifluoromethyl-1 ,2,4- oxadiazol-3-yl group.
  • International patent application WO 2005/066839 discloses benzamides which are necessarily substituted in the 2-position by hydroxy or amino. In one case this moiety is linked to the 4-amino group of a 2,4-diamino-6-(3-pyridyl)pyrimidine. The compounds are stated to be useful in the treatment of cell prolifeartive diseases and conditions. Autoimmune or inflammatory disorders are not mentioned or suggested.
  • JP49021 147 and JP49021148 disclose certain 2-amino-4-(/V- alkylamino)-6-(pyridyl)pyrimidines claimed to be anti-inflammatory. There is however no data to support this claim. Also, all pyridines are unsubstituted and there is nothing that indicates that substituents on the pyridines would be beneficial.
  • MTH1 inhibitors have been described in Streib, M. et al. Angewandte Chemie, Int,. Ed. (2014), 52, 305-309.
  • the compounds are organometallic and are not substituted 2,4-diaminopyrimidines.
  • Chinese patent application CN 104288170 describes the natural product echinacoside as an inhibitor of MTH 1.
  • this compound is a sugar derivative and not a pyrimidine
  • the present invention aims at providing a new treatment option for autoimmune conditions and transplantation patients through pharmacologic inhibition of MTH1.
  • Diseases which may benefit from this treatment include rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerous colitis, multiple sclerosis, lymphoproliferative diseases
  • Behcets disease Guillain Barre, dermatomyositis, myositis, polymyositis, primary biliary cirrhosis, anti-phospholipid syndrome, autoimmune hepatitis, autoimmune cardiomyopathy, alopecia areata, atherosclerosis, type 1 diabetes, autoimmune uveitis, Goodpasteure's syndrome, Graves' disease, Hashimotos disease, mixed connective tissue disease, myasthenia gravis, pemphigus vulgaris, pernicious anemia, Sjogren's syndrome, giant cell arteritis, ulcerative colitis, vasculitis, Churg-Strauss syndrome, postpolio syndrome, idiopathic thrombocytopenic purpura, Peyronie disease and Dupuytren's contracture.
  • An MTH1 inhibitor (example 297) selectively kills activated T- lymphocytes while unactivated T-lymphocytes are unaffected.
  • R 2 represents hydrogen, halogen, -CN or Ci -3 alkyl optionally substituted by one or more fluoro;
  • R 3 represents -X-L-J, -Ci-i 2 alkyl optionally substituted by one or more Z 1 or heterocycloalkyl optionally substituted by one or more groups selected from Z 2 ; or R 1 represents
  • a 3- to 8-membered nonaromatic ring which ring optionally contains one or two heteroatoms and/or one or two double bonds, and which ring is optionally substituted by one or more groups selected from Y 7 ;
  • R 2 represents hydrogen, halogen, -CN or Ci -3 alkyl optionally substituted by one or more fluoro;
  • R 3 represents -X-L-J
  • R 1 is as defined herein above;
  • R 2 and R 3 are linked together to form, along with the atoms to which they are attached, a 5- to 8-membered non-aromatic ring, wherein the link formed by R 2 and R 3 is optionally substituted by one or more groups selected from Z 3 and optionally substituted by -X-L-J; X represents -Ci. 6 alkylene-, optionally substituted by one or more T 1 , or
  • L represents a single bond or -L 1 -L 2 -;
  • L 1 represents -N(R B )-, -0-, -S(0) m -, -C(0)N(R c )-, -N(R D )C(0)-, -S(0) n N(R E )-, -N(R F )S(0) n - or -N(R G )C(0)N(R H )-;
  • L 2 represents a single bond or -Ci. 6 alkylene-
  • heteroaryl contains 1 to 3 nitrogen atoms, and/or one oxygen atom and/or one or two sulfur atoms and which heteroaryl is optionally substituted by D 2 and optionally substituted by one or more groups selected from R Y ;
  • Y 1 represents hydrogen, halogen, -CN, R a , -A-C(Q)R b , -A-C(Q)N(R c )R d ,
  • Y 2 , Y 3 and Y 4 each independently represents hydrogen, halogen, R a , -A-C(Q)R b , -A-C(Q)N(R c )R d , -A-C(Q)OR e , -A-S(0) n R f , -A-S(NR 9 )(0)R h , - ⁇ -8(0) ⁇ ⁇ ) ⁇ , -A-S(0) n OR k , -B(OR') 2 , -IM3, -NO2, -OH, -OR m or -SR n ;
  • Y 5 represents halogen, R a , -A-C(Q)R b , -A-C(Q)N(R c )R d , -A-C(Q)OR e ,
  • Y 6 represents aryl or heteroaryl, both optionally substituted by one or more groups selected from halogen, -CN, R a , -A-C(Q)R b , -A-C(Q)N(R c )R d , -A-C(Q)OR e , -A-S(0) n R f , -A-S(NR 9 )(0)R h , - ⁇ -8(0) ⁇ ⁇ ) ⁇ , -A-S(0) n OR k , -B(OR') 2 , -N 3 , -N0 2 , -OH, -OR m and -SR n ;
  • Y 7 represents halogen, R a , -A-C(Q)R b , -A-C(Q)N(R c )R d , -A-C(Q)OR e , -A-S(0) n R f , -A-S ⁇ n NCR 1 ) ⁇ , -A-S(0) n OR k , -OH, -OR m , or Q;
  • A represents a single bond, -N(R')-, -C(Q)N(R J )- or -O-; each R a , R f , R h and R m independently represents Ci_ 6 alkyl optionally substituted by one or more groups selected from W 1 , heterocycloalkyl optionally substituted by one or more groups selected from W 2 or aryl or heteroaryl both optionally substituted by one or more groups selected from W 3 ; each R b , R c , R d , R e , R 9 , R', R j , R k , R 1 , R°, R p , R q , R r , R s and R l independently represents hydrogen, Ci_ 6 alkyl optionally substituted by one or more groups selected from W 1 , heterocycloalkyl optionally substituted by one or more groups selected from W 2 or aryl or heteroaryl both optionally substituted by one or more groups selected from W 3 ;
  • W 2 represents halogen, -CN, R a1 , -A 1 -C(0)R b1 , -A 1 -C(0)N(R c1 )R d1 ,
  • W 3 represents halogen, -CN, R a1 , -A 1 -C(0)R b1 , -A 1 -C(0)N(R c1 )R d1 ,
  • a 1 represents a single bond, -N(R K )- or -0-; each R a1 , R f1 and R 11 independently represents Ci_ 6 alkyl optionally substituted by one or more fluoro; each R b1 , R c1 , R d1 , R e1 , R 9 ⁇ R h1 , R i1 , R j1 , R k1 , R m1 , R n1 and R 01 independently represents hydrogen or Ci_ 6 alkyl optionally substituted by one or more fluoro; or any two R c1 and R d1 , R h1 and R i1 and/or R m1 and R n1 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which
  • Z 1 represents halogen, -CN, -A 2 -C(Q 1 )R b2 , -A 2 -C(Q 1 )N(R c2 )R d2 ,
  • Z 2 represents halogen, -CN, R a2 , -A 2 -C(Q 1 )R b2 , -A 2 -C(Q 1 )N(R c2 )R d2 ,
  • a 2 represents a single bond, -N(R L )-, -C(Q 1 )N(R M )- or -O-; each R a2 , R f2 , R i2 , R n2 and R 02 independently represents Ci -6 alkyl optionally substituted by one or more groups selected from W 4 or heterocycloalkyi optionally substituted by one or more groups selected from W 5 ;
  • R m2 represents C h alky! optionally substituted by one or more groups selected from W 4 ; each R b2 , R c2 , R d2 , R e2 , R 92 , R h2 , R j2 , R k2 , R 12 , R p2 , R q2 , R r2 , R s2 , R t2 and R u2 independently represents hydrogen, Ci -6 alkyl optionally substituted by one or more groups selected from W 4 , heterocycloalkyi optionally substituted by one or more groups selected from W 5 ; or any two R c2 and R d2 , R j2 and R k2 , R 12 and R m2 , R q2 and R r2 and/or R t2 and R u2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally
  • W 6 represents phenyl or heteroaryl, both optionally substituted by one or more groups selected from halogen and R a3 ;
  • a 3 represents a single bond, -N(R L )- or -0-; each R a3 and R f3 independently represents Ci_ 6 alkyl optionally substituted by one or more fluoro; each R b3 , R c3 , R d3 , R e3 , R 93 and R h3 independently represents hydrogen or Ci -6 alkyl optionally substituted by one or more fluoro; or
  • D 1 and D 2 represent R a4 , -A 4 -C(Q 2 )R b4 , -A 4 -C(Q 2 )N(R c4 )R d4 , -A 4 -C(Q 2 )OR e4 , -A 4 -S(0) n R M , -A 4 -S(0) n C(0)R 94 , -A 4 -S(NR h4 )(0)R i4 , -A 4 -S(0) n N(R j4 )R k4 ,
  • R c4 represents hydrogen, R a4 , -C(0)OR e4 , -S(0) n R M , -S(0) n N(R j4 )R k4 , -N(R n4 )R° 4 or -OR p4 ; each R a4 , R M and R' 4 independently represent Ci
  • each R b4 , R d4 , R e4 , R 94 , R h4 , R j4 , R k4 , R 14 , R m4 , R n4 , R 04 , R p4 , R q4 , R r4 , R s4 , R t4 , R u4 , R v4 and R w4 independently represent hydrogen, Ci.
  • a 5 represents a single bond or -N(H)-;
  • R a5 represents Ci_ 6 alkyl optionally substituted by one or more halogens;
  • T 1 represents halogen, -CN, -N(R b6 )R c6 or -OR d6 ;
  • R b6 and R c6 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring; each p and q independently represents 0, 1 or 2, provided that the sum of p and q is 0, 1 or 2; each m independently represents 0, 1 or 2; each n independently represents 1 or 2; provided that when X represents -CH 2 CH 2 -, L represents -L 1 -L 2 -, L 1 represents -N(H)- or -N(Me)-, L 2 represents a single bond and J represents 4-pyrimidinyl, and said 4-pyrimidinyl is unsubstituted or substituted with -CH 3 , -NH 2 or
  • R 1 does not represent phenyl, 3-chlorophenyl,
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. For the avoidance of doubt, solvates are also included within the scope of the invention.
  • Compounds of the invention may contain double bonds and may thus exist as E (entadel) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e.
  • a resolution for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • halo or halogen
  • fluoro chloro, bromo and iodo (for example, fluoro and chloro).
  • Ci -q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched- chain, and/or cyclic (so forming a C 3 . q -cycloalkyl group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic.
  • Part cyclic alkyl groups that may be mentioned include
  • Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C 2 . q alkenyl or a C 2 . q alkynyl group).
  • Ci -q alkylene groups (where q is the upper limit of the range) defined herein may (in a similar manner to the definition of Ci -q alkyl) be straight-chain or, when there is a sufficient number (i.e.
  • alkylene groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C 2 . q alkenylene or a C 2 . q alkynylene group).
  • Particular alkylene groups that may be mentioned include those that are straight-chained or cyclic and saturated.
  • HeterocydoalkyI groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten and, most preferably, between three and eight, e.g. a 5- or 6-membered heterocycloalkyl group). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2 . q (e.g.
  • C 4 . q heterocycloalkenyl (where q is the upper limit of the range) or a C 7 . q heterocycloalkynyl group.
  • C 2 . q heterocycloalkyl groups that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo- [3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), 1 ,3,2- dioxaborinane, 1 ,3,6,2-dioxazaborocane, 1 ,3,2 dioxaborolane, dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including 1 ,3
  • heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called "spiro"-compound.
  • the point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heterocycloalkyl groups may also be in the N- or S- oxidised form.
  • a heterocycloalkyl group is preferably a 3- to 8-membered heterocycloalkyl group (e.g. a 5- or 6-membered heterocycloalkyl group).
  • aryl when used herein, includes C 6 -io aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, be either wholly or partly aromatic.
  • C 6 -io aryl groups that may be mentioned include phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyl and the like).
  • the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system.
  • heteroaryl when used herein, includes 5- to 1 1- membered heteroaromatic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur. Such heteroaryl group may comprise one, or two rings, of which at least one is aromatic. Substituents on heteroaryl/hetero- aromatic groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl/hetero- aromatic groups may be via any atom in the ring system including (where appropriate) a heteroatom.
  • Bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which instances, the point of attachment of the polycyclic heteroaryl/heteroaromatic group may be via any ring including the benzene ring or the heteroaryl/heteroaromatic or heterocycloalkyl ring. Examples of
  • heteroaryl/heteroaromatic groups that may be mentioned include pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl and purinyl.
  • heteroaryl includes polycyclic (e.g. bicyclic) groups where all rings are aromatic, and partly aromatic groups where at least one ring is aromatic and at least one other ring is not aromatic.
  • heteroaryl groups include e.g. benzo[1 ,3]dioxolyl, benzo[1 ,4]dioxinyl,
  • Heteroatoms that may be mentioned include phosphorus, silicon, preferably boron and, more preferably, oxygen, nitrogen and sulfur.
  • formula I can thus be represented by
  • R 3 represents -X-L-J
  • X represents -(C(R A ) 2 ) P - C 2 -5heterocycloalkylene-(C(R A ) 2 ) q -
  • R A represents hydrogen
  • p represents 1
  • q repr en -(C(R A ) 2 ) P -C2-5heterocycloalkylene-(C(R A )2)q- may represent e.g.
  • formula I can then be represented by N
  • R 3 represents -X-L-J
  • L represents -L 1 -L 2 -
  • L 1 represents
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
  • the compounds of the invention also include deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
  • R represents (i)
  • Y 1 , Y 2 , Y 3 and Y 4 are as defined herein above.
  • Y 1 in particular may represent hydrogen, halogen, -CN, R a , -A-C(Q)R b ,
  • Y 2 , Y 3 and Y 4 in particular may each independently represent hydrogen, halogen, R a , -A-C(Q)R b , -A-C(Q)N(R c )R d , -A-C(Q)OR e , -A-S(0) n R f , -A-S(NR 9 )(0)R h , -A-S(0) n OR k , -B(OR') 2 , -N 3 , -N0 2 , -OH, -OR m or -SR n .
  • e presents
  • one of Y 1 , Y 2 , Y 3 and Y 4 is preferably other than hydrogen, or more preferably, two or three of Y 1 , Y 2 , Y 3 and Y 4 is other than hydrogen;
  • R 2 represents methyl, or preferably, hydrogen
  • R 3 represents -X-L-J or -Ci -6 alkyl optionally substituted by one or more Z 1 or heterocycloalkyl optionally substituted by one or more Z 2 ;
  • Y 1 represents halogen, -CN, R a or -OR m ;
  • Y 2 , Y 3 and Y 4 each independently represent hydrogen, halogen, R a , -A-C(Q)R b , -C(Q)N(R c )R d , -C(Q)OR e , -A-S(0) n R f , -8(0) ⁇ ⁇ ) ⁇ , -OH or -OR m .
  • Y 2 , Y 3 and ⁇ 4 represent hydrogen
  • Y 1 represents fluoro, chloro, -CH 3 , -CF 3 , -CN, CH 2 OH or -OCH 3 ;
  • Y 1 , Y 3 and Y 4 represent hydrogen
  • Y 1 , Y 2 and Y 4 represent hydrogen
  • -N(H)C(0)CH CH 2 , -N(H)S(0) 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 3 , -OCF 3 , -S(0) 2 CH 3 , or -S(0) 2 (4-morpholinyl);
  • R 2 represents methyl, or preferably, hydrogen
  • R 3 represents -X-L-J or -Ci -6 alkyl optionally substituted by one or more, preferably one to three, groups selected from Z 1 , or heterocycloalkyl optionally substituted by one or more, preferably one to three, groups selected from Z 2 ;
  • X represents -Ci. 6 alkylene- optionally substituted by T 1 , or
  • L represents a single bond or -L 1 -L 2 -;
  • L 1 represents -N(H)-, -0-, -S0 2 -, -C(0)N(H)-, -S(0) n N(H)- or -N(H)C(0)N(H)-;
  • L 2 represents a single bond or -Ci. 6 alkylene-;
  • J represents phenyl optionally substituted by D 1 and optionally substituted by one or more groups selected from R x , or a 5- to 10-membered monocyclic or bicyclic heteroaryl containing 1 to 3 nitrogen atoms, and/or one oxygen atom and/or one sulfur atom and which ring is optionally substituted by D 2 and optionally substituted by one or more groups selected from R Y ;
  • Z 1 represents halogen, -CN, -A 2 -C(0)R b2 , -A 2 -C(0)N(R c2 )R d2 ,
  • T 1 represents -N(R l2 )R m ;
  • a 2 represents a single bond or -N(H)-;
  • D 1 represents R a4 , -A 4 -C(Q 2 )R b4 , -A 4 -C(Q 2 )N(R c4 )R d4 , -A 4 -C(0)OR e4 , -A 4 -S(0) n R M , -A 4 -S0 2 N(R j4 )R k4 , -S0 2 OR' 4 , -N(R n4 )R° 4 , -N(H)CN, -N0 2 , -OR p4 or -SR q4 ;
  • D 2 represents R a4 , -A 4 -C(0)R b4 , -C(0)N(R c4 )R d4 , -C(0)OR e4 , -A 4 -S(0) n R M , -S(0) n N(R j4 )R k4 , -N(R n4 )R° 4 , -N0 2 , or -OR p4 ;
  • a 4 represents a single bond or -N(H)-;
  • each R x and R Y independently represent halogen, -CN, R a4 or -OR p4 ;
  • R a4 represents Ci . 6 alkyl optionally substituted by one or more groups selected from G 1 , phenyl optionally substituted by one or more groups selected from G 3 or heteroaryl optionally substituted by one or more groups selected from G 4 ;
  • R c4 represents hydrogen, R a4 or -C(0)OR e4 ;
  • R b4 and R M represent Ci _ 6 alkyl optionally substituted by one or more fluoro;
  • each, R d4 , R e4 , R j4 , R k4 , R 14 , R n4 , R 04 , R p4 , R q4 , R r4 and R u4 independently represent hydrogen or Ci -6 alkyl optionally substituted by one or more fluoro; or
  • any two R c4 and R d4 , R j4 and R k4 , and/or R n4 and R 04 are linked together to form, along with the nitrogen atom to which they are attached, a 4- to 6-membered ring; each G 1 independently represent one or more halogens;
  • each G 3 and G 4 independently represent one or more more groups selected from halogen, R a5 or -OR k5 ;
  • R a5 represents Ci_ 6 alkyl optionally substituted by one or more fluoro
  • R k5 represents hydrogen or Ci_ 6 alkyl optionally substituted by one or more fluoro; each p and q independently represents 0 or 1 , provided that the sum of p and q is 0 or 1 ; and
  • each n independently represents 1 or 2.
  • Y 1 represents fluoro and Y 2 represent fluoro, chloro, -CH 3 or -CF 3 ; or
  • Y 1 represents chloro and Y 2 represents fluoro, chloro, -CH 3 or -CF 3 ; or Y 1 represents -CH 3 and Y 2 represents fluoro, chloro, -CH 3 , -CF 3 , -CN
  • -N(H)C(0)CH CH 2 or -N(H)C(0)(4-chloro-2-hydroxyphenyl); or
  • Y 2 and Y 4 represent hydrogen
  • Y 1 represents fluoro and Y 3 represents fluoro or phenyl;
  • Y 1 represents chloro and Y 3 represents fluoro, chloro;
  • Y 1 represents -CH 3 and Y 3 represents chloro or -OCH 2 phenyl
  • Y 1 represents -OCH 3 and Y 3 represents fluoro
  • Y 2 and Y 3 represent hydrogen
  • Y 1 represents fluoro and Y 4 represents chloro, -CH 3 or -CN; or
  • Y 1 represents chloro and Y 4 represent fluoro, chloro, -CH 3 , -CF 3 or -OCH 3 ; or
  • Y 1 represents -CH 3 and Y 4 represent fluoro, chloro, -CH 3 , -CF 3 , -CN,
  • Y 1 represents -CF 3 and Y 4 represents fluoro or -CF 3 ;
  • Y 1 represents -CN and Y 4 represents chloro
  • Y 1 represents -OCH 3 and Y 4 represents fluoro, chloro, bromo, -CH 3 , -CH(CH 3 ) 2 ,
  • Y 1 and Y 4 represent hydrogen
  • Y 2 represents fluoro and Y 3 represents fluoro, chloro, -OH or -OCH 3 ; or Y 2 represents chloro and Y 3 represents fluoro or -C(0)(4-morpholinyl); or Y 2 represents -CH 3 and Y 3 represents fluoro or -OCH 3 ; or
  • Y 1 represents -OCH 3 and Y 3 represents -OH;
  • Y 1 represents-CH 2 OCH 3 and Y 3 represents (piperidin-4-yl)methoxy or
  • Y 1 and Y 3 represent hydrogen
  • Y 2 and Y 4 represent fluoro
  • Y 2 and Y 4 represent -CF 3 ; or Y 4 represents hydrogen; and Y 1 , Y 2 and ⁇ 3 represent fluoro or chloro; or
  • Y 1 and Y 2 represent chloro and Y 3 represents chloro, -OH or -OCH 3 ; or
  • Y 1 and Y 2 represent -CH 3 and Y 3 represents fluoro or -OCH 3 ; or
  • Y 1 and Y 3 represent chloro and Y 2 represents -OCH 3 ;
  • Y 2 and Y 3 represent chloro and Y 1 represents -CH 3 ; or
  • Y 2 represents hydrogen
  • Y 1 , Y 3 and Y 4 represent fluoro
  • Y 3 and Y 4 represent chloro and Y 1 represents -CH 3 ; or
  • Y 1 and Y 4 represent chloro and Y 1 represents -OCH 3 ;
  • Y 1 and Y 4 represent -CH 3 and Y 3 represents fluoro, -CH 3 or -OCH 3 ; or
  • Y 1 represents fluoro
  • Y 3 represents -CH 3 and Y 4 represents chloro
  • Y 1 represents chloro, Y 3 represents fluoro and Y 4 represents -CH 3 ; or
  • Y 1 represents chloro
  • Y 3 represents -CH 3 and Y 4 represents fluoro
  • Y 1 and Y 4 represent -CH 3 and Y 3 represents fluoro;
  • Y 1 represents -CH 3
  • Y 4 represents chloro and Y 3 represents -CF 3 or -OCH 3 ;
  • Y 1 represents hydrogen
  • Y 2 and Y 4 represent -CH 3 and Y 3 represents -OH; or
  • Y 3 represents hydrogen
  • Y 1 and E 2 represent chloro and Y 4 represents -CH 3 ;
  • R 2 represents methyl, or preferably, hydrogen
  • R 3 represents -X-L-J or Ci -6 alkyl optionally substituted by one or more, preferably one to three groups selected from Z 1 , or heterocycloalkyl optionally substituted by one or more, preferably one to three, groups selected from Z 2 ;
  • X represents Ci. 6 alkylene- optionally substituted by T 1 , or
  • L represents -L 1 -L 2 -;
  • L 1 represents -N(H)-, -0-, -S0 2 -, -C(0)N(H)-, -S(0) n N(H)- or -N(H)C(0)N(H)-;
  • L 2 represents a single bond or -Ci. 6 alkylene-
  • J represents phenyl optionally substituted by D 1 and optionally substituted by one or more groups selected from R x , or a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 3 nitrogen atoms, and/or one oxygen atom and/or one sulfur atom and which ring is optionally substituted by D 2 and optionally substituted by one or more groups selected from R Y ;
  • Z 1 represents halogen, -CN, -A 2 -C(0)R b2 , -A 2 -C(0)N(R c2 )R d2 ,
  • a 2 represents a single bond or -N(H)-;
  • D 1 represents R a4 , -A 4 -C(Q 2 )R b4 , -A 4 -C(Q 2 )N(R c4 )R d4 , -A 4 -C(0)OR e4 , -A 4 -S(0) n R M , -A 4 -S0 2 N(R j4 )R k4 , -S0 2 OR' 4 , -N(R n4 )R° 4 , -N(H)CN, -N0 2 , -0R p4 or -SR q4 ;
  • D 2 represents R a4 , -A 4 -C(0)R b4 , -C(0)N(R c4 )R d4 , -C(0)OR e4 , -A 4 -S(0) n R M , -S(0) n N(R j4 )R k4 , -N(R n4 )R° 4 , -N0 2 , or -OR p4 ;
  • a 4 represents a single bond or -N(H)-;
  • each R x and R Y independently represent halogen, -CN, R a4 or -OR p4 ;
  • R a4 represents Ci . 6 alkyl optionally substituted by one or more groups selected from G 1 , phenyl optionally substituted by one or more groups selected from G 3 or heteroaryl optionally substituted by one or more groups selected from G 4 ;
  • R c4 represents hydrogen, R a4 or -C(0)OR e4 ;
  • R b4 and R M represent Ci . 6 alkyl optionally substituted by one or more fluoro;
  • each R d4 , R e4 , R j4 , R k4 , R 14 , R n4 , R 04 , R p4 , R q4 , R r4 and R u4 independently represent hydrogen or Ci -6 alkyl optionally substituted by one or more fluoro; or
  • any two R c4 and R d4 , R j4 and R k4 , and/or R n4 and R 04 are linked together to form, along with the nitrogen atom to which they are attached, a 4- to 6-membered ring; each G 1 independently represent one or more halogens;
  • each G 3 and G 4 independently represent one or more more groups selected from halogen, R a5 or -OR k5 ;
  • R a5 represents Ci_ 6 alkyl optionally substituted by one or more fluoro
  • R k5 represents hydrogen or Ci_ 6 alkyl optionally substituted by one or more fluoro
  • T 1 represents -N(R b6 )R c6 or -OR d6 ;
  • each R b6 , R c6 and R d6 independently represents hydrogen or -Ci -6 alkyl
  • each p and q independently represents 0 or 1 , provided that the sum of p and q is 0 or 1 ;
  • each n independently represents 1 or 2.
  • Y 1 , Y 3 and ⁇ 4 represent hydrogen
  • Y 1 , Y 2 and Y 4 represent hydrogen and
  • Y 3 and Y 4 represent hydrogen
  • Y 1 represents fluoro and Y 2 represents fluoro, chloro, or -CF 3 ; or
  • Y 1 represents -CI and Y 2 represents v, -CH 3 or -CF 3 ; or
  • Y 1 represents -CH 3 and Y 2 represents chloro, -CH 3 , -CF 3 , -CN or
  • Y 2 and Y 4 represent hydrogen
  • Y 1 and Y 3 represent fluoro
  • Y 1 represents chloro and Y 3 represents fluoro or chloro;
  • Y 1 represents -CH 3 and Y 3 represents chloro
  • Y 2 and Y 3 represent hydrogen
  • Y 1 represents fluoro and Y 4 represents chloro, -CH 3 or -CN; or
  • Y 1 represents chloro and Y 4 represents fluoro, chloro, -CH 3 or -CF 3 ; or
  • Y 1 represents -CH 3 and Y 4 represent, chloro, -CH 3 , -CF 3 , -CN or
  • Y 1 represents -CF 3 and Y 4 represents fluoro or -CF 3 ;
  • Y 1 represents -CN and Y 4 represents chloro
  • Y 4 represents hydrogen
  • Y 1 , Y 2 and Y 3 represent fluoro
  • Y 1 and Y 2 represent -CH 3 and Y 3 represents fluoro; or Y 2 and Y 3 represent chloro and Y 1 represents -CH 3 ; or
  • Y 2 represents hydrogen
  • Y 1 , Y 3 and Y 4 represent fluoro
  • Y 3 and Y 4 represent chloro and Y 1 represents -CH 3 ; or
  • Y 1 and Y 4 represent -CH 3 and Y 3 represents fluoro or -CH 3 ; or
  • Y 1 represents fluoro
  • Y 3 represents -CH 3 and Y 4 represents chloro
  • Y 1 represents chloro, Y 3 represents -F and Y 4 represents -CH 3 ; or
  • Y 1 represents chloro
  • Y 3 represents -CH 3 and Y 4 represents fluoro
  • Y 1 and Y 4 represent -CH 3 and Y 3 represents fluoro;
  • Y 1 represents -CH 3
  • Y 3 represents -CF 3 and Y 4 represents chloro
  • Y 1 represents hydrogen
  • Y 2 and Y 4 represent -CH 3 and Y 3 represents -OH; or
  • Y 3 represents hydrogen
  • Y 1 , Y 2 and Y 4 represent chloro
  • Y 1 and Y 2 represent chloro and Y 4 represents -CH 3 ;
  • R 2 represents methyl, or preferably, hydrogen;
  • R 3 represents -X-L-J or -Ci -6 alkyl optionally substituted by one to three groups selected from Z 1 , or heterocycloalkyl optionally substituted by Z 2 ;
  • X represents -Ci. 6 alkylene-
  • L represents -L 1 -L 2 -;
  • L 1 represents -N(H)-, -0-, -C(0)N(H)-, -S(0) n N(H)- or -N(H)C(0)N(H)-;
  • L 2 represents a single bond
  • J represents phenyl optionally substituted by D 1 and optionally substituted by one or more groups selected from R x , or a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 3 nitrogen atoms and/or one oxygen atom and/or one sulfur atom and which ring is optionally substituted by D 2 and optionally substituted by one or more groups selected from R Y ;
  • a 2 represents a single bond or -N(H)-;
  • D 1 represents R a4 , -A 4 -C(Q 2 )R b4 , -A 4 -C(Q 2 )N(R c4 )R d4 , -A 4 -C(0)OR e4 , -A 4 -S(0) n R M , -A 4 -S0 2 N(R j4 )R k4 , -SO 2 OR 14 , -N(R n4 )R° 4 , -N(H)CN, -N0 2 , -OR p4 or -SR q4 ;
  • D 2 represents R a4 , -A 4 -C(0)R b4 , -C(0)N(R c4 )R d4 , -C(0)OR e4 , -A 4 -S(0) n R M , -S(0) n N(R j4 )R k4 , -N(R n4 )R° 4 , -N0 2 , or -OR p4 ;
  • a 4 represents a single bond or -N(H)-;
  • each R x and R Y independently represent halogen, -CN, -R a4 or -OR p4 ;
  • R a4 represents Ci -6 alkyl optionally substituted by one or more groups selected from G 1 , phenyl optionally substituted by one or more groups selected from G 3 or heteroaryl optionally substituted by one or more groups selected from G 4 ;
  • R c4 represents hydrogen, R a4 or -C(0)OR e4 ;
  • each R b4 and R M independently represent Ci -6 alkyl optionally substituted by one or more fluoro;
  • each, R d4 , R e4 , R j4 , R k4 , R 14 , R n4 , R 04 , R p4 , R q4 , R r4 and R u4 independently represent hydrogen or Ci -6 alkyl optionally substituted by one or more fluoro; or
  • any two R c4 and R d4 , R j4 and R k4 , and/or R n4 and R 04 are linked together to form, along with the nitrogen atom to which they are attached, a 4- to 6-membered ring; each G 1 independently represent one or more halogens;
  • each G 3 and G 4 independently represent one or more more groups selected from halogen, R a5 or -OR k5 ;
  • R a5 represents Ci_ 6 alkyl optionally substituted by one or more fluoro
  • R k5 represents hydrogen or Ci -6 alkyl optionally substituted by one or more fluoro
  • each n independently represents 1 or 2;
  • Y 3 and Y 4 represent hydrogen and Y 1 and Y 2 are selected from fluoro, chloro, -Me or -CF 3 ;
  • R 2 represents hydrogen;
  • R 3 represents -X-L-J or -Ci -6 alkyl optionally substituted by one or more, preferably one to three, Z
  • R 1 is 3-chloro-2-fluorophenyl, 2-chloro-3-methyl- phenyl, 3-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,3-dimethylphenyl or 2-methyl-3-trifluoromethyl;
  • R 2 represents hydrogen
  • R 3 represents -X-L-J or Ci -6 alkyl optionally substituted by one to three, Z
  • At least one, preferably two, of Y 1 , Y 2 , Y 3 and Y 4 is other than hydrogen;
  • R 2 represents hydrogen
  • R 3 represents -X-L-J
  • X represents -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -,
  • L represents -L 1 -L 2 -;
  • L 1 represents -N(H)-, -0-, -C(0)N(H)-, -S0 2 N(H)- or -N(H)C(0)N(H)-;
  • L 2 represents a single bond
  • J represents phenyl optionally substituted by D 1 and optionally substituted by one or more groups selected from R x , or a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1 to 3 nitrogen atoms, and/or one oxygen atom and/or one or two sulfur atoms and which ring is optionally substituted by D 2 and optionally substituted by R Y ;
  • R 1 represents
  • At least one, preferably two, of Y 1 , Y 2 , Y 3 and Y 4 is other than hydrogen;
  • R 2 represents hydrogen
  • R 3 represents -X-L-J;
  • X represents -CH 2 CH 2 -, -CH2CH2CH2-, -CH2CH2CH2CH2- or -cyclopropylene-;
  • L represents -L 1 -L 2 -;
  • L 1 represents -N(H)-, -0-, -C(0)N(H)-, -S0 2 N(H)- or -N(H)C(0)N(H)-;
  • L 2 represents a single bond
  • J represents phenyl optionally substituted by D 1 and optionally substituted by R x , or a 5- to 10-membered monocyclic or bicyclic heteroaryl having either 1 to 3 nitrogen atoms, one oxygen atom and/or one or two sulfur atoms and which ring is optionally substituted by D 2 and optionally substituted by R Y ;
  • R 1 represents
  • At least one, preferably two, of Y 1 , Y 2 , Y 3 and Y 4 is other than hydrogen;
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl optionally substituted by one, two or three Z 1 ; mpounds that may be mentioned when R represents
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl substituted by one, two or three groups selected from Z 1 include those where Z 1 represents fluoro, bromo, -CN, -C(0)NH 2 , -C(0)NH 2 ,
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl substituted by Z 1 ;
  • Z 1 represents heterocycloalkyi, include those where Z 1 represents
  • R 1 represents
  • At least one, preferably two, of Y 1 , Y 2 , Y 3 and Y 4 is other than hydrogen;
  • R 2 represents hydrogen or methyl
  • R 3 represents Ci-i 0 alkyl.
  • R 2 represents hydrogen and R 3 represents Ci-i 0 alkyl, include those where R 3 represents -CH 3 , -CD 3 , ethyl, 1-propyl, 2-propyl, 1-butyl, te/f-butyl, 3-pentyl, neopentyl, allyl, methallyl, 1-buten-4-yl, geranyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 2-cyclopropyl-2-ethyl, methylcyclopropyl, 2-(cyclohexen-1-yl)ethyl, bicyclo[2.2.1]hept-2-yl,
  • R 2 represents methyl include those where R 3 represents cyclopropyl.
  • R represents at least two of Y 1 , Y 2 , Y 3 and Y 4 is other than hydrogen;
  • R 2 represents hydrogen
  • R 3 represents C 2- ioalkyl. Preferred compounds that may be mentioned when R represents
  • R 2 represents hydrogen and R 3 represents C 2- ioalkyl, include those where R 3 represents ethyl, 1 -propyl, 2-propyl, 1 -butyl, te/f-butyl, 3-pentyl, neopentyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 2-cyclopropyl-2-ethyl, methylcyclopropyl, bicyclo[2.2.1]hept-2-yl, 1-noradamantyl, 1-adamantyl or 3-pinanyl.
  • R 1 represents
  • At least two of Y 1 , Y 2 , Y 3 and Y 4 is other than hydrogen;
  • R 2 represents hydrogen
  • R 3 represents C 3 .i 0 alkyl, where the alkyl is cyclic or part compounds that may be mentioned when R represents
  • R 2 represents hydrogen and R 3 represents C 3 .i 0 alkyl, where the alkyl is cyclic or part cyclic include those where R 3 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 2-cyclopropyl-2-ethyl, methylcyclopropyl,
  • R 1 represents
  • At least one, preferably two, of Y 1 , Y 2 , Y 3 and Y 4 is other than hydrogen;
  • R 2 represents hydrogen
  • R 3 represents heterocycloalkyi optionally substituted by one or two groups selected from Z 3 ;
  • Z 3 represents R a2 or -C(0)OR e2 ;
  • R a2 and R e2 represents d. 4 alkyl. compounds that may be mentioned when R 1 represents
  • R 2 represents hydrogen and R 3 represents heterocycloalkyi optionally substituted by one or two groups selected from Z 3 , include those where R 3 represents tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl or quinuclidinyl. y preferred compounds that may be mentioned when R 1 represents
  • R 2 represents hydrogen and R 3 represents heterocycloalkyi optionally substituted by one or two gropups selected from Z 3 , include those where R 3 represents tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 1-(te/f-butoxycarbonyl)azetidin-3-yl, 1-(te/f-butoxycarbonyl)-piperidin-4-yl, 1-(ethoxycarbonyl)-piperidin-4-yl or quinuclidin-3-yl.
  • R 1 is a 6-membered heteroaryl substituted by one or more groups selected from Y 5 .
  • a 6-membered heteroaryl e.g. may be pyridyl, pyrimidinyl or pyrazinyl.
  • R 1 represents (ii) a 6-membered heteroaryl substituted by one or more groups Y 5 , wherein each Y 5 is as defined herein above.
  • R 1 represents a 6-membered heteroaryl, it is substituted by one or more Y 5 ;
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl optionally substituted by one or more groups selected from Z 1 .
  • R 1 represents a 6-membered heteroaryl
  • R 1 represents pyridyl, preferably 3- or 4-pyridinyl, substituted by one or more Y 5 ;
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl
  • Y 5 represents halogen, R a , -OH or -OR m ;
  • R a and R m represents Ci -6 alkyl optionally substituted by -OH or one or more fluoro.
  • Particularly preferred compounds of formula I that may be mentioned when R 1 represents a 6-membered heteroaryl include those in which R 1 represents 3-pyridinyl substituted in the 6-position by -CH 2 OH or -OH, or in the 2-position by -CF 3 , or 4-pyridinyl substituted in the 3-position by chloro and optionally in the 2-position by -OCH 3 ;
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl.
  • R 1 represents a 6-membered heteroaryl substituted by one or more Y 5 ;
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl optionally substituted by one or more Z
  • R 1 represents a 5- to 10-membered monocyclic or bicyclic heteroaryl connected to the pyrimidine of formula I via a carbon atom of the heteroaryl ring, which heteroaryl ring is optionally substituted by one or more groups selected from Y 5 , wherein each Y 5 is as defined herein above.
  • R 1 represents a 5- to 7-membered monocyclic heteroaryl, e.g. a 5- or 6-membered heteroaryl, in particular a 5-membered heteroaryl, connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl, which heteroaryl is optionally substituted by one or more groups selected from Y 5 , wherein each Y 5 is as defined herein above.
  • R 1 represents a 5-membered heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl, said heteroaryl optionally being substituted by one or more Y 5 ;
  • R 2 represents hydrogen; and
  • R 3 represents -X-L-J or -Ci -6 alkyl optionally substituted by Z 1 ;
  • R 1 represents a 5-membered heteroaryl connected to the ring of the compound pyrimidine of formula I via a carbon atom of the heteroaryl ring
  • R 1 represents oxazolyl, pyrazolyl, thiazolyl, or preferably, furanyl, isoxazyl, pyrrolyl or thiophenyl, which heteroaryl rings are optionally substituted by one or more groups selected from Y 5 ;
  • R 2 represents hydrogen
  • R 3 represents -X-L-J
  • Y 5 represents R a , -C(0)R b , -S0 2 R f or -SOalSKR'jR';
  • X represents Ci. 6 alkylene-, e.g. -CH 2 CH 2 -;
  • L represents -L 1 -L 2 -, or preferably, a single bond
  • L 1 represents -N(H)-
  • L 2 represents a single bond
  • J represents phenyl optionally substituted in the 3-position, but preferably in the 4-position, by D 1 and optionally substituted by one or more groups selected from
  • D 1 represents -C(0)N(R c4 )R d4 , or preferably, -S0 2 R M , or -S0 2 N(R j4 )R k4 ;
  • each R x independently represent R a4 , or preferably, halogen
  • R a represents Ci -6 alkyl, preferably Cialkyl optionally substituted by one or more fluoro, but preferably Ci. e alkyl substituted by -N(H)C(0)OR e1 ; each R b and R f independently represent Ci -6 alkyl;
  • each R 1 and R j independently represent hydrogen or Ci -4 alkyl
  • R e1 represents Ci -6 alkyl
  • each R a4 and R M represents Ci -4 alkyl optionally substituted by one or more fluoro (but are preferably unsubstituted);
  • each R c4 , R d4 , R j4 and R k4 independently represents hydrogen or Ci -4 alkyl optionally substituted by one or more fluoro (but preferably unsubstituted).
  • R 1 represents a 5-membered heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl
  • R 1 represents furanyl, isoxazyl, pyrrolyl or thiophenyl which heteroaryls are optionally substituted by one or more groups selected from halogen, -CH 3 , -C(0)CH 3 , -CH 2 N(H)C(0)OC(CH 3 ) 3 or -S0 2 N(H)C(CH 3 ) 3 ;
  • R 2 represents hydrogen
  • R 3 represents -CH 2 CH 2 -J
  • J represents phenyl substituted in the 4-position by chloro, -S0 2 CH 3 or -S0 2 NH 2 .
  • R 1 represents a 5-membered heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl, which heteroaryl is optionally substituted by one or more Y 5 ;
  • R 2 represents hydrogen;
  • R 3 represents -X-L-J.
  • Other preferred compounds of formula I that may be mentioned when R 1 represents a 5-membered heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl, include those in which R 1 represents isoxazyl, oxazolyl, thiazolyl, or preferably, furanyl, pyrazolyl, pyrrolyl or thiophenyl, which heteroaryl rings are optionally substituted by one or more groups selected from Y 5 ;
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl optionally substituted by one or more groups selected from Z 1 ;
  • Y 5 represents halogen, or preferably R a ;
  • R a represents Ci -6 alkyl optionally substituted by one or more fluoro, but preferably Ci -6 alkyl substituted by -C(0)N(R c1 )R d1 or -N(R h1 )R i1 ;
  • each R c1 , R d1 , R h1 and R' 1 independently represents hydrogen or Ci_ 4 alkyl, but preferably all represent hydrogen; or
  • R h1 and R' 1 are linked together to form, along with the nitrogen atom to which they are attached, a 6-, or preferably, a 5-membered ring.
  • R 1 represents a 5-membered heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl
  • R 1 represents furanyl, pyrazolyl, pyrrolyl or thiophenyl, which heteroaryl rings are optionally substituted by -CH 3 , -CH 2 CH 2 C(0)NH 2 or -CH 2 -(1 -pyrrolidinyl);
  • R 2 represents hydrogen
  • R 3 represents C 2 . 4 alkyl optionally substituted by Z 1 ;
  • R 1 represents a 5-membered heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl, which heteroaryl is optionally substituted by one or more one or more groups selected from Y 5 ;
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl optionally substituted by one or more groups selected from Z 1 .
  • R 1 represents a 8- to 10-membered bicyclic heteroaryl, e.g. a 9- to 10-membered heteroaryl, connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl, which heteroaryl is optionally substituted by one or more groups selected from Y 5 , wherein each Y 5 is as defined herein above.
  • R 1 represents such a bicyclic heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl
  • said heteroaryl is optionally substituted by one or more groups selected from Y 5 ;
  • R 2 represents hydrogen; and R 3 represents -X-L-J or Ci -6 alkyl optionally substituted by one or more groups selected from Z 1 .
  • R 1 represents a bicyclic heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl ring, include those in which R 1 represents benzofuranyl, indazolyl, or preferably, benzothiophenyl, indolyl and quinolinyl which heteroaryls are optionally substituted by one or more groups selected from Y 5 ;
  • R 2 represents hydrogen
  • R 3 represents -X-L-J
  • each Y 5 independently represent halogen, or preferably, R a ;
  • X represents -Ci. 6 alkylene-, e.g. -CH 2 CH 2 -;
  • L represents -L 1 -L 2 - or preferably, a single bond
  • L 1 represents -0-, -N(H)-;
  • L 2 represents a single bond
  • J represents phenyl optionally substituted in the 3-position, but preferably in the 4-position, by D 1 and optionally substituted by one group selected from R x ;
  • D 1 represents -C(0)N(R c4 )R d4 or -S0 2 R M , or preferably, -S0 2 N(R j4 )R k4 ;
  • R x represents R a4 , or preferably, halogen
  • each R a4 and R M represents Ci_ 4 alkyl optionally substituted by one or more fluoro (but preferably unsubstituted);
  • each R c4 , R d4 , R j4 and R k4 independently represents hydrogen or Ci_ 4 alkyl optionally substituted by one or more fluoro (but preferably unsubstituted).
  • R 1 represents a bicyclic heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl
  • R 1 represents 3-benzothiophenyl, 4-indolyl or 5-quinolinyl, all optionally substituted by one or more chloro, fluoro, -CH 3 or -CF 3 , but preferably unsubstituted;
  • R 2 represents hydrogen
  • R 3 represents -CH 2 CH 2 -J
  • R 1 represents a bicyclic heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl, which heteroaryl is optionally substituted by one or more Y 5 ;
  • R 2 represents hydrogen;
  • R 3 represents -X-L-J.
  • R 1 represents a bicyclic heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl
  • R 1 represents 7-azaindolyl, benzofuranyl, benzothiophenyl, 2,3-dihydrobenzofuranyl, indazolyl, indolyl, isoquinolinyl, quinolinyl, and which heteroaryls are optionally substituted by one or more groups selected from Y 5 ;
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl optionally substituted by one or more groups selected from Z 1 ;
  • each Y 5 independently represent halogen, or preferably, R a or -S0 2 R f ;
  • R a represents Ci -6 alkyl optionally substituted by one or more fluoro
  • R f represents phenyl optionally substituted by halogen or Ci_ 4 alkyl optionally substituted by one or more fluoro;
  • R 1 represents a bicyclic heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl
  • R 1 represents 7-azaindol-3-yl, benzofuran-3-yl, benzothiophen-3-yl, 2,3- dihydrobenzofuran-7-yl, indazol-5-yl, indazol-6-yl, indol-3-yl, indol-4-yl, indol-5-yl, isoquinolin-4-yl, quinolin-5-yl, and which heteroaryls are optionally substituted by one or more groups selected from Y 5 ;
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl optionally substituted by one or more groups selected from Z 1 ;
  • each Y 5 independently represent fluoro, chloro, or preferably, R a or -S0 2 R f ;
  • R a represents -CF 3 , or preferably, -CH 3
  • R f represents phenyl optionally substituted in the 4-position by fluoro, or preferably by, chloro, -CH 3 or -CF 3
  • R 1 represents a bicyclic heteroaryl connected to the pyrimidine ring of the compound of formula I via a carbon atom of the heteroaryl ring, which ring is optionally substituted by one or more Y 5 ;
  • R 2 represents hydrogen;
  • R 3 represents Ci -6 alkyl optionally substituted by Z
  • R 1 represents indolyl, e.g. indol-3-yl, indol-4-yl or indol-5-yl, where the indolyls are optionally substituted in the
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl
  • Y 5 represents -S0 2 R f ;
  • R f represents phenyl optionally substituted in the 4-position by chloro, -CH 3 or -CF 3 .
  • R 1 represents (iv) -ethynyl-Y 6 , wherein Y 6 is as defined herein above.
  • Y 6 in particular may represent phenyl optionally substituted by halogen or Ci -6 alkyl optionally substituted by one or more halogens;
  • R 2 represents hydrogen
  • R 3 represents Ci -6 alkyl optionally substituted by Z Preferred compounds of formula I that may be mentioned when R 1 represents ethynyl-Y 6 include those where Y 6 represents phenyl optionally substituted by one or more halogens and/or Ci -6 alkyl optionally substituted by one or mote halogens; R 2 represents hydrogen; and
  • R 3 represents-Ci-ealkyl.
  • R 1 represents ethynyl-Y 6 ;
  • R 2 represents hydrogen
  • R 3 represents -X-L-J, or preferably, Ci -6 alkyl optionally substituted by one or more groups selected from Z 1 ;
  • R 1 represents a 3- to 8-membered nonaromatic ring, in particular a 5- to 7-membered nonaromatic ring, which ring optionally contains one or two heteroatoms and/or one or two double bonds, and which ring is optionally substituted by one or more groups selected from Y 7 .
  • R 1 when R 1 represents a 3- to 8-membered nonaromatic ring, R 1 optionally contains one or two heteroatoms, optionally contains one or two double bonds and is optionally substituted by one or more groups selected from Y 7 ;
  • R 2 represents hydrogen
  • R 3 represents -X-L-J.
  • R 1 represents a nonaromatic ring
  • R 1 is 5-7 membered nonaromatic ring optionally containing one heteroatom and/or one double bond and is optionally substituted by one or more groups selected from Y 7 ;
  • R 2 represents hydrogen
  • R 3 represents -X-L-J
  • each Y 7 independently represents R a , -C(0)R b , -C(0)OR e or -S0 2 R f ;
  • X represents -Ci. 6 alkylene-, e.g. -CH 2 CH 2 -;
  • L represents -L 1 -L 2 -, or preferably, a single bond
  • L 1 represents -N(H)- or -0-;
  • L 2 represents a single bond
  • J represents phenyl optionally substituted in the 3-position, but preferably in the 4-position, by D 1 ;
  • D 1 represents -C(0)N(R c4 )R d4 , or preferably, -S0 2 R M or -S0 2 N(R j4 )R k4 ;
  • each R a and R e independently represent Ci -6 alkyl optionally substituted by one or more fluoro;
  • each R b and R f independently represent Ci -6 alkyl optionally substituted by one or more fluoro, phenyl optionally substituted by one or more halogens and/or by one or more more R a1 , or heteroaryl optionally substituted by one or more halogens and/or by one or more R a1 ;
  • each R a1 independently represent Ci -6 alkyl optionally substituted by one or more fluoro;
  • each R c4 , R d4 , R j4 and R k4 independently represent hydrogen or Ci -4 alkyl optionally substituted by one or more fluoro (but preferably unsubstituted); and R f4 represents Ci_ 4 alkyl optionally substituted by one or more fluoro (but preferably unsubstituted).
  • Particularly preferred compounds of formula I that may be mentioned when R 1 represents a nonaromatic ring include those where R 1 is 5-7 membered and optionally contains one heteroatom and/or one double bond and is optionally substituted by one or more groups selected from Y 7 ;
  • R 2 represents hydrogen
  • R 3 represents -CH 2 CH 2 -J
  • Y 7 represents -C(0)R b , -C(0)OR e or -S0 2 R f ;
  • J represents phenyl substituted in the 4-position by -S0 2 Me or -S0 2 NH 2 ;
  • each R e independently represent Ci -6 alkyl
  • each R b and R f independently represent Ci -6 alkyl, phenyl optionally substituted by R a1 or heteroaryl optionally substituted by R a1 ;
  • each R a1 independently represent Ci -6 alkyl.
  • R 1 represents a nonaromatic ring
  • R 1 represents a 3-8 membered nonaromatic ring optionally substituted by one or more groups selected from Y 7 ;
  • R 2 represents hydrogen;
  • R 3 represents -X-L-J;
  • R 2 and R 3 are linked together to form, along with the atoms to which they are attached, a 5- to 8-membered non-aromatic ring, the link formed by R 2 and R 3 is optionally substituted by one or more Z 3 and optionally substituted by -X-L-J.
  • R 2 and R 3 are linked together to form, along with the atoms to which they are attached, a 5- to 8-membered non- aromatic ring, wherein the link formed by R 2 and R 3 is optionally substituted by one or more Z 3 and optionally substituted by -X-L-J;
  • the moiety X represents -Ci. 6 alkylene-, optionally substituted by one or more T 1 , or -(C(R A ) 2 ) P -C2-5heterocycloalkylene-(C(R A )2)q-, where the heterocycloalkylene is optionally substituted by one or more T 2 .
  • X represents -Ci. 6 alkylene-, optionally substituted by one or more T 1 .
  • X represents -C 2 . 4 alkylene-substituted by T 1 ;
  • T 1 represents -OR d3
  • R d3 represents Ci -4 alkyl, or preferably, hydrogen.
  • Particular compounds of formula I include those in which X represents -CH 2 CH(OH)-.
  • X represents -(C(R A ) 2 )p-C 2 - 5 heterocycloalkylene- (C(R A ) 2 ) q -, where the heterocycloalkylene is optionally substituted by one or more T 2 .
  • R 1 is phenyl, heteroaryl, -ethynyl-Y 6 or a 3- to 8-membered nonaromatic ring and R 2 is hydrogen and R 3 represents -X-L-J; or
  • Preferred compounds of formula I that may be mentioned include those where X
  • -CH 2 CH 2 CH 2 - preferably -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -cyclopropyl -CH 2 — CH 2 - , or more preferably, -CH 2 CH 2 -.
  • L represents a single bond. In some embodiments L represents -L 1 -L 2 -.
  • Preferred compounds of formula I include those where L 1 represents -N(R B )-, -0-, -S(0) m -, -C(0)N(R c )-, -S(0) n N(R E )-, or
  • L 2 represents a single bond. In some embodiments, L 2 represents -Ci_ 2 alkylene-, j.e. -CH 2 - and -CH 2 CH 2 -.
  • J represents
  • heteroaryl contains 1 to 3 nitrogen atoms, and/or one oxygen atom and/or one or two sulfur atoms and which heteroaryl is optionally substituted by D 2 and optionally substituted by one or more groups selected from R Y .
  • J represents (i) a 6- to 10-membered aryl, e.g. phenyl, said aryl optionally being substituted by D 1 and optionally being substituted by one or more groups selected from R x .
  • J represents (ii) a 5- to 1 1-membered monocyclic or bicyclic heteroaryl, which heteroaryl contains 1 to 3 nitrogen atoms, and/or one oxygen atom and/or one or two sulfur atoms and which ring is optionally substituted by D 2 and optionally substituted by one or more groups selected from R Y .
  • J represents (ii) a 5- to 7-membered, e.g. 5- or 6-membered, monocyclic heteroaryl, which heteroaryl contains 1 to 3 nitrogen atoms, and/or one oxygen atom and/or one or two sulfur atoms and which ring is optionally substituted by D 2 and optionally substituted by one or more groups selected from R Y .
  • J represents (ii) a 8- to 11-membered, in particular 9- or 10-membered, bicyclic heteroaryl, which heteroaryl contains 1 to 3 nitrogen atoms, and/or one oxygen atom and/or one or two sulfur atoms and which ring is optionally substituted by D 2 and optionally substituted by one or more groups selected from R Y .
  • Preferred compounds of formula I include those in which J represents phenyl substituted, preferably in the 3- or 4-position, by fluoro, chloro, bromo, -B(OH) 2 , methyl, ethyl, ethynyl, -CF 3 , -CN, -C(0)Me, -C(0)NH 2 , -C(NH)NH 2 , -C(NOH)NH 2 , -C(S)NH 2 , -C(0)N(H)Me, -C(0)NHCH(CH 3 )CH 2 OH, -C(0)N(CH 3 )propargyl, -C(0)N(H)NH 2 , -C(0)N(H)OH, -C(0)N(H)S(0) 2 Me, -C(0)OH, -CO(0)Me, -C(0)OEt, -C(0)OCH 2 CH 2 CH 3 , -C(0)OCH 2 CH(CH 3 ) 2 , -C(0)C(0)
  • particularly preferred compounds of formula I include those in which J represents phenyl substituted in the 3- or 4-position by -C(0)NH 2 , -C(0)N(H)Me, -C(0)OEt, -NHC(0)Me, -NH(CO)cyclopropyl,
  • J represents a 6-membered heteroaryl
  • J represents pyridinyl optionally substituted by D 2 and optionally substituted by one or more groups selected from R Y ;
  • D 2 represents halogen, R a4 , -A 4 -C(Q 2 )R b4 , -A 4 -C(Q 2 )N(R c4 )R d4 , -A 4 -C(Q 2 )OR e4 , -A 4 -S(0) n R f4 , -A 4 -S(0) n C(0)R 94 , -A 4 -S(NR h4 )(0)R i4 , -A 4 -S(0) n N(R j4 )R k4 ,
  • R Y represents halogen or Ci_ 3 alkyl optionally substituted by one or more fluoro.
  • J represents a 6-membered heteroaryl
  • J represents 4-pyridinyl, or preferably, 2-pyridinyl or 3-pyridinyl optionally substituted by R a4 , -C(Q 2 )N(H)R d4 , -C(0)OR e4 , -N(H)C(0)R b4 , -B(OR m4 ) 2 , -N0 2 , -N(H)S(0) n R f4 , -S(0) n R f4 , -N(R n4 )R° 4 or -OR p4 .
  • J represents a 6-membered heteroaryl
  • J represents 2-pyridinyl substituted in the 4-position by -C(0)NH 2 , -C(0)OMe or in the 5-position by -CF 3 , -C(0)NH 2 , -C(0)OH, -C(0)OEt, -N(H)C(0)Me, -N(H)C(0)N(H)C(CH 3 ) 3 ,
  • J represents a 6-membered heteroaryl
  • J represents pyrimidinyl optionally substituted by D 2 and optionally substituted by one or more groups selected from R Y ;
  • D 2 represents -A 4 -C(Q 2 )R b4 , -A 4 -C(Q 2 )N(R c4 )R d4 , -A 4 -C(Q 2 )OR e4 , -A 4 -S(0) n R f4 , -A 4 -S(0) n N(R j4 )R k4 , -A 4 -S(0) n OR 14 , -B(OR m4 ) 2 , or -N(R n4 )R° 4 ;
  • R Y represents halogen or Ci_ 3 alkyl optionally substituted by one or more fluoro.
  • Preferred compounds of formula I that may be mentioned when J represents a 6-membered heteroaryl include those in which J represents 2-pyrimidinyl or
  • J represents a 6-membered heteroaryl
  • J represents 2-pyrimidinyl substituted in the 4-position by -C(0)NH 2 , -C(0)OH, -C(0)OMe, -NH 2 , -S(0) 2 Me or -S(0) 2 NH 2 , substituted in the 5-position by -C(0)NH 2 , or 4-pyrimidinyl substituted in the 2-position by -C(0)NH 2 , -NH 2 , -S(0) 2 Me or -S(0) 2 NH 2 ; and
  • R 2 represents halogen (e.g. fluoro or chloro), or preferably, -CF 3 .
  • particularly preferred compounds of formula I that may be mentioned when J represents a 6-membered heteroaryl include those in which J represents 2-pyrimidinyl substituted in the 4-position by -S(0) 2 Me or -S(0) 2 NH 2 , or preferably by -C(0)NH 2 or -C(0)OMe.
  • J represents a 6-membered heteroaryl
  • Particular compounds of formula I that may be mentioned when J represents a 6-membered heteroaryl include those in which J represents pyrazinyl optionally substituted by D 2 ;
  • D 2 represents -A 4 -C(Q 2 )R b4 , -A 4 -C(Q 2 )N(R c4 )R d4 , -A 4 -C(Q 2 )OR e4 , -A 4 -S(0) n R M , -A 4 -S(0) n N(R j4 )R k4 , -A 4 -S(0) n OR 14 , -B(OR m4 ) 2 or -N(R n4 )R° 4 ; and
  • J represents a 6-membered heteroaryl
  • J represents 2-pyrazinyl substituted in the 6-position, or preferably in the 3- or 5-position by -S(0) 2 Me or -S(0) 2 NH 2, or preferably, by -C(0)NH 2 or -C(0)OMe.
  • J represents 1 ,3,5-triazinyl substituted by D 2 and optionally substituted by one or more groups selected from R Y .
  • J represents a 6-membered heteroaryl, in particular 1 ,3,5-triazinyl, substituted by D 2 and optionally substituted by one or more groups selected from R 2 ,
  • D 2 in particular may represent -A-C(0)R c , -A-C(0)N(R d )R e , -A-C(0)OR f ,
  • Particularly preferred compounds of formula I include those in which J represents 1 ,3,5-triazinyl substituted by -C(0)NH 2 , -C(0)OR f , -S(0) 2 R 9 , -S(0) 2 NH 2 , or in particular one or two -NH 2 .
  • J when J is a heteroaryl as defined herein above, said heteroaryl is 5-membered.
  • Particular compounds of formula I that may be mentioned when J represents heteroaryl include those in which J represents a 5-membered heteroaryl optionally substituted by D 2 ;
  • D 2 represents -A 4 -C(Q 2 )R b4 , -A 4 -C(Q 2 )N(R c4 )R d4 , -A 4 -C(Q 2 )OR e4 , -A 4 -S(0) n R M , -A 4 -S(0) n N(R j4 )R k4 , -B(OR m4 ) 2 or -N(R n4 )R° 4 ; and
  • J represents a 5-membered heteroaryl
  • J represents furanyl, imidazolyl, isoxazolyl, oxazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, pyrazolyl, 1 ,3,4- thiadiazolyl, thiazolyl, 1 ,2,3-triazolyl or thiophenyl, optionally substituted by halogen, -CH 3 , cyclopropyl, -C(0)NH 2 , -C(0)OMe, -NH 2 , -S(0) 2 Me or -S(0) 2 NH 2.
  • Particular compounds of formula I include those in which J represents a bicyclic heteroaryl optionally substituted by D 2 , and optionally substituted by one or more groups selected from R Y ;
  • D 2 represents R a4 , -A 4 -C(Q 2 )R b4 , -A 4 -C(Q 2 )N(R c4 )R d4 , -A 4 -C(Q 2 )OR e4 ,
  • Certain compounds of formula I where J represents a bicyclic heteroaryl that may be mentioned include those where the bicyclic heteroaryl is connected to L via a 5-membered ring and where the bicyclic heteroaryl is optionally substituted by D 2 and optionally substituted by one or more substituents independently selected from R Y .
  • Certain compounds of formula I where J represents a bicyclic heteroaryl that may be mentioned include those where the bicyclic heteroaryl is connected to L via a 6-membered ring and where the bicyclic heteroaryl is optionally substituted by D 2 and optionally substituted by one or more substituents independently selected from R Y .
  • Preferred compounds of formula I that may be mentioned when J represents a bicyclic heteroaryl include those where J represents benzimidazolyl,
  • the compound according to the invention is selected from the compounds of Examples 1-761.
  • a compound of the invention in another aspect of the invention the use of a compound of the invention, as hereinbefore defined, is provided for the manufacture of a medicament for the treatment of autoimmune or inflammatory conditions.
  • compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention.
  • Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.
  • prodrug of a compound of the invention we include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time, following enteral or parenteral administration (e.g. oral or parenteral administration). All prodrugs of the compounds of the invention are included within the scope of the invention.
  • certain compounds of the invention may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such.
  • Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the "active" compounds of the invention to which they are metabolised), may also be described as "prodrugs".
  • the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds, which possess pharmacological activity. It is stated herein that the compounds of the invention may be useful in the treatment of autoimmune or inflammatory conditions.
  • treatment includes treatment per se, prevention and prophylaxis.
  • the autoimmune or inflammatory conditions are selected from the group comprising: rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerous colitis, multiple sclerosis, lymphoproliferative diseases (e.g.
  • the autoimmune or inflammatory conditions are selected from rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, multiple sclerosis, rejection after organ transplantation, psoriasis and atherosclerosis. In certain embodiments of the present invention, the autoimmune or inflammatory conditions are selected from rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, multiple sclerosis, rejection after organ transplantation, and atherosclerosis. In certain embodiments of the present invention, the autoimmune or inflammatory condition is not psoriasis.
  • Compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical compositions/formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or
  • intramuscular administration and the like.
  • Compounds of the invention may be administered in the form of tablets or capsules, e.g., time-release capsules that are taken orally.
  • the compounds of the invention may be in a liquid form and may be taken orally or by injection.
  • the compounds of the invention may also be in the form of suppositories, or, creams, gels, and foams e.g. that can be applied to the skin.
  • they may be in the form of an inhalant that is applied nasally.
  • compositions/formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice. According to a further aspect of the invention there is thus provided a
  • composition/formulation including a compound of the invention, as hereinbefore defined, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • Such compositions/formulations may be of use in the treatment, prevention and/or prophylaxis of autoimmune and inflammatory conditions which benefit by inhibition of MTH1.
  • pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1 % (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
  • the invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • the present invention provides methods for the treatment of autoimmune and inflammatory conditions comprising administering a
  • Patients include mammalian (including human) patients.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient.
  • the effect may be objective (i.e.
  • test or marker measurable by some test or marker
  • subjective i.e. the subject gives an indication of or feels an effect
  • Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of autoimmune and inflammatory conditions.
  • glucocorticoids e.g. cortisone or prednisolone
  • TNF-alpha inhibitors e.g. infliximab
  • anti-CD20 e.g. rituximab
  • immunosupressants e.g. mycophenolate mofetil or azathioprine
  • antimetabolites e.g. methotrexate
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • a pharmaceutically-acceptable adjuvant, diluent or carrier Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of autoimmune diseases and inflammatory conditions, and a pharmaceutically- acceptable adjuvant, diluent or carrier;
  • the invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of autoimmune or inflammatory conditions, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
  • the two components of the kit of parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
  • Compounds of the invention may be administered at varying doses.
  • Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day.
  • the compositions typically contain between about 0.01 mg to about 2000 mg, for example between about 0.1 mg to about 500 mg, or between 1 mg to about 100 mg, of the active ingredient.
  • the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion.
  • compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • physician or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated.
  • the above- mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above- stated indications or otherwise.
  • compounds of the invention may have the advantage that they are more efficacious and/or exhibit advantageous properties in vivo.
  • Boc te/f-butoxycarbonyl HATU (1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo- [4,5-b]pyridinium 3-oxid hexafluorophosphate
  • Step 1 6-bromo-4-chloro-2H-1 ,3-benzodioxole:
  • Step 2 (7-chloro-2H-1 ,3-benzodioxol-5-yl)boronic acid:
  • Step 1 4-Bromo-2,3-dichlorophenol.
  • Step 2 1-Bromo-2,3-dichloro-4-methoxybenzene.
  • Step 3 (2,3-dichloro-4-methoxyphenyl)boronic acid.
  • Step 1 1-Bromo-3-chloro-5-methoxybenzene.
  • 1 -Bromo-3-chloro-5-fluorobenzene (1 g, 4.77 mmol, 1 equiv.) was treated at 0 °C with sodium methoxide (25 % in MeOH, 1.2 ml_, 5.71 mmol, 1.2 equiv.).
  • the reaction mixture was stirred at 100 °C for 3 h.
  • the solution was concentrated under reduced pressure, the crude product was extracted with DCM, washed with H 2 0, brine, dried over MgS0 4 and concentrated.
  • the product was obtained as a white solid (747 mg, 71 %).
  • Step 2 1 -Bromo-2,3-dichloro-5-methoxybenzene.
  • Step 3 (2,3-dichloro-5-methoxyphenyl)boronic acid.
  • Step 1 ethyl 2-ethoxy-3,4,5,6-tetrahydropyridine-3-carboxylate.
  • Step 2 2-amino-3H,4H,5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-one.
  • Step 3 4-chloro-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine.
  • 6-chloro-4-N-(1-methoxybutan-2-yl)pyrimidine-2,4-diamine 6-chloro-4-N-(1-methoxybutan-2-yl)pyrimidine-2,4-diamine.
  • n- BuOH 10 ml_
  • 1-methoxybutan-2-amine 315 mg, 3.1 mmol, 1 equiv.
  • Hunig ' s base 531 ⁇ _, 3.1 mmol, 1 equiv.
  • the reaction mixture was stirred overnight at 95 °C.
  • the solvent was removed in vacuo.
  • the crude product was diluted in EtOAc and washed with H 2 0, brine, dried over MgS0 4 and concentrated to afford the desired product as an off-white solid (592 mg, 84 %).
  • Step 1 To a suspension of 4,6-dichloropyrimidin-2-amine (500 mg, 3.05 mmol) and Hunig's base (0.80 ml_) in 2-propanol (3.0 ml_) was added tert-butyl N-(2- aminoethyl)carbamate (586 mg, 3.66 mmol) and the mixture was stirred at 150 °C for 15 min. The crude mixture was poured into NaHC0 3 (aq) and extracted three times with DCM. The combined organic layers were dried and concentrated.
  • Step 2 tert-Butyl N-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (850 mg, 2.95 mmol), (2,3-dimethylphenyl)boronic acid (532 mg, 3,55 mmol), palladium tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.030 mmol), and K 2 C0 3 (1020 mg, 7.39 mmol) were suspended in 1 ,4-dioxane (10 ml) and H 2 0 (2.0 ml). The vial was flushed with nitrogen and the resulting mixture was stirred at 90 °C for 16 h. The crude mixture was poured into NaHC0 3 (aq) and extracted three times with DCM. The combined organic layers were dried and
  • Step 3 tert-Butyl N-[2-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4- yl]amino]ethyl]carbamate (770 mg, 2.15 mmol) was dissolved in TFA (6 ml_) and the resulting mixture was stirred for 1 h at rt, after which the TFA was distilled off. Purification by column chromatography (5 ⁇ 30% MeOH [containing 1 v/v% NH4OH] in DCM) afforded 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine- 2,4-diamine (500 mg, 1.94 mmol). LCMS [M+H] + 258.
  • Step 1 A vial was charged with 4,6-dichloropyrimidin-2-amine (500 mg, 3.0 mmol) and tert-butyl N-(2-aminopropyl)carbamate (640 mg, 3.7 mmol). Then 2- propanol (3.0 ml) and Hunig's base (0.80 ml) were added and the resulting mixture was heated at 150 °C using microwave irradiation for 15 min.
  • Step 2 tert-Butyl N-[3-[(2-amino-6-chloro-pyrimidin-4-yl)amino]propyl]carbamate (790 mg, 2.6 mmol), (2,3-dimethylphenyl)boronic acid (470 mg, 3.1 mmol), palladium tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.050 mmol), and K 2 C0 3 (720 mg 5.2 mmol) were suspended in 1 ,4-dioxane (6.0 ml) and H 2 0 (1.5 ml).
  • Step 3 tert-Butyl N-[3-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4- yl]amino]propyl]carbamate (800 mg, 2.1 mmol) was dissolved in TFA and heated at reflux for 1 h. The TFA was evaporated and the crude residue was purified by column chromatography (2 ⁇ 30% MeOH [containing 1 v/v% NH 4 OH] in DCM) to afford 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (540 mg, 2.0 mmol). LCMS [M+H] + 272.
  • Tetrakis(triphenylphosphine)palladium (0) (5 mol%) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (1.00 mmol), (3- aminophenyl)boronic acid (1.3 equiv.), sodium carbonate (3.2 equiv.), 1 ,4- dioxane (4 mL) and water (1 mL) in a tube. The tube was sealed and the reaction was heated at 90°C for 5 h and then concentrated. The crude material was taken up in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, concentrated and purified by flash chromatography (0 ⁇ 15 % MeOH in DCM) to give the title compound. LCMS [M+H] + 216.
  • Tetrakis(triphenylphosphine)palladium (0) (5 mol%) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (3.00 mmol), (3-amino-2- methylphenyl)boronic acid (1.3 equiv.), sodium carbonate (3.2 equiv.), 1 ,4- dioxane (4 mL) and water (1 mL). The tube was sealed and the reaction was heated at 90°C for 5 h. The mixture was concentrated and purified by column chromatography (13% MeOH in DCM) to give the title compound.
  • Tetrakis(triphenylphosphine)palladium (0) (5 mol%) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (3.0 mmol), (5-amino-2- methylphenyl)boronic acid (1.3 equiv.), sodium carbonate (3.2 equiv.), 1 ,4- dioxane (4 mL) and water (1 mL) in a tube. The tube was sealed and the reaction was heated at 90°C for 5 h. The mixture was concentrated and purified by column chromatography (13 % MeOH in DCM) to give the title compound. LCMS [M+H] + 230.
  • Tetrakis(triphenylphosphine)palladium (0) (5 mol%) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (1.0 mmol), 4-(tetramethyl- 1 ,3,2-dioxaborolan-2-yl)aniline (1.3 equiv.), sodium carbonate (3.2 equiv.), 1 ,4- dioxane (4 ml_) and water (1 ml_) in a tube. The tube was sealed and the reaction was heated at 90°C for 5 h and then concentrated. The crude material was taken up in ethyl acetate and washed with water.
  • Step 1 A mixture of 2-(4-carboxyphenyl)ethylammonium chloride (1.0 equiv.), 4,6-dichloropyrimidin-2-amine (1.0 equiv.), diisopropylethylamine (3.2 equiv.), and 2-propanol was heated to 1 10 °C in a sealed vial for 16 h.
  • Step 2 A mixture of 4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzoic acid (1.0 equiv.), HATU (1.1 equiv.), and DMF was stirred at 20 °C for 5 min, thereafter ammonium hydroxide (3 equiv.) was added. The mixture was stirred at 20 °C for 16 h and then the mixture was diluted with NaHC0 3 and extracted with DCM x3. The combined organics were dried and purified by silica gel chromatography. [M+H] + 292.
  • Step 1 A mixture of intermediate 21 (1 equiv.), tert-butyl N-(4- aminobutyl)carbamate (1.9 equiv.), and diisopropylethylamine (2.1 equiv.) in dioxane was stirred at 150 °C in a microwave reactor for 30 min. The crude reaction mixture was then purified by preparative LC.
  • Step 2 tert-butyl N-[4-[[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4- yl]amino]butyl]carbamate was stirred in TFA at 20 °C for 1 h. The TFA was then removed and the crude residue was purified by silica gel chromatography. LCMS [M+H] + 326.
  • Step 1 A mixture of 2-amino-4,6-dichloropyrimidine (1.0 equiv.), 2-(3- nitrophenyl)ethylammonium chloride (1.3 equiv.), and diisopropylethylamine (2.5 equiv.) in 2-propanol was stirred at 100 °C in a sealed vial for 16 h. The reaction mixture was then diluted with NaHC0 3 (aq) and extracted with DCM. The crude material was then purified by silica gel chromatography.
  • Step 2 A mixture of 6-(3-chloro-2-methyl-phenyl)-N4-[2-(3- nitrophenyl)ethyl]pyrimidine-2,4-diamine (1.0 equiv.), (3-chloro-2-methyl- phenyl)boronic acid (1.2 equiv.), K 2 C0 3 (3.0 equiv.) and Pd(PPh 3 ) 4 (0.05 equiv.) in 1 ,4-dioxane and water was stirred at 90 °C for 16 h. Thereafter water was added and the mixture was extracted with DCM *3. The combined organic phases were concentrated and purified by silica gel chromatography. LCMS
  • Step 3 A mixture of 6-(3-chloro-2-methyl-phenyl)-N4-[2-(3- nitrophenyl)ethyl]pyrimidine-2,4-diamine (1.0 equiv.) and SnCI 2 H 2 0 (5.0 equiv.) was stirred in ethanol at reflux for 16 h. Then KOH (1 M) was added and the mixture was extracted with DCM *5. The organics were dried, concentrated and purified by silica gel chromatography. LCMS [M+H] + 354.
  • Step 1 A mixture of 2-amino-4,6-dichloropyrimidine (1.0 equiv.), 4-(2- aminoethyl)aniline (1.3 equiv.), and diisopropylethylamine (2.0 equiv.) in 2- propanol was stirred at 90 °C in a sealed vial for 16 h. The reaction mixture was then diluted with NaHC0 3 (aq) and extracted with DCM. The crude material was then purified by silica gel chromatography. [M+H] + 264.
  • Step 2 A mixture of N4-[2-(4-aminophenyl)ethyl]-6-chloro-pyrimidine-2,4-diamine (1.0 equiv.), (3-chloro-2-methyl-phenyl)boronic acid (1.2 equiv.), K 2 C0 3 (3.0 equiv.) and Pd(PPh 3 ) 4 (0.05 equiv.) in 1 ,4-dioxane and water was stirred at 90 °C for 16 h. Thereafter water was added and the mixture was extracted with DCM x3. The combined organic phases were concentrated and purified by silica gel chromatography. LCMS [M+H] + 354.
  • Step 1 3-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (300 mg, 1 ,4 mmol), 2- bromoacetamide (210 mg, 1 ,5 mmol), K 2 C0 3 (570 mg, 4, 1 mmol) and MeCN (15 mL) were heated in a sealed tube at 65°C overnight. The reaction was cooled and filtered. The solvent was removed in vacuo to afford 2-[3-(tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy]acetamide LCMS [M+H] + 278
  • Step 2 2-[3-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]acetamide (370 mg, 1 ,4 mmol), Nal04 (870 mg, 4,1 mmol), THF (12 ml) and water (3 ml) was stirred at r.t. for 30 min. 1 M HCI (1 mL) was added and the reaction was stirred at r.t. for 3 hours. Water (-15 mL) was added and the organic solvent was removed in vacuo. [3-(carbamoylmethoxy)phenyl]boronic acid was collected by filtration. LCMS [M+H] + 196.
  • Step 1 A mixture of 4,6-dichloropyrimidin-2-amine (1 equiv.), tert-butyl N-(2- aminoethyl)carbamate (1.2 equiv.), and diisopropylethylamine (3 equiv.) in 2- propanol was stirred at 90 °C for 16 h. The reaction mixture was then poured into water and extracted with DCM *3. The combined organics were dried (MgS0 4 ) and concentrated. The crude material was used in step 2 without further purification.
  • Step 2 The crude material from step 1 was dissolved in dioxane, then K 2 C0 2 (2 equiv.), Pd(PPh 3 ) 4 (0.05 equiv.), and (3-chloro-2-methyl-phenyl)boronic acid (1.2 equiv.) were added. The flask was flushed with N2 and the mixture was stirred at reflux for 16 h. The reaction mixture was then poured into water and extracted with DCM x3. The combined organics were dried (MgS0 4 ) and concentrated. The crude material was purified by silica gel chromatography using MeOH (0 - 9%) in DCM.
  • Step 3 The material from step 2 was dissolved in TFA and stirred at 20 °C for 2 h. The solvent was removed and the crude residue was purified by silica gel chromatography using 5 - 30% MeOH (containing 1% v/v NH 4 OH) in DCM.
  • R'X R'CO, R'S0 2 , R'OCO
  • Step 1 A mixture of the corresponding aryl halide (1.0 equiv.), N-vinylphthalimide (1.1 equiv.), Pd(OAc) 2 (0.0005 equiv.), and Et 3 N (1.2 equiv.) were dissolved in NMP and stirred at 135 °C for 16 h. The reaction mixture was cooled to room temperature and then water was added which precipitated a solid. The solid was filtered off and washed with water.
  • Step 2 In a flask, the solid from step 1 was dissolved in MeOH and then Pd/C (0.10 eqiv.) was added. The atmosphere in the flask was changed to H 2 and the resulting mixture was stirred at 60 °C for 16 - 24 h. The solution was then passed through a syringe filter and concentrated.
  • Step 3 The crude material from step 2 was dissolved in THF, and then hydrazine hydrate (1.25 equiv.) was added. The resulting mixture was stirred at reflux for 16 - 24 h. The reaction mixture was concentrated and purified by preparative LC.

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JP2016539996A (ja) * 2013-12-11 2016-12-22 バイオジェン・エムエイ・インコーポレイテッドＢｉｏｇｅｎ ＭＡ Ｉｎｃ． 腫瘍学、神経学及び免疫学におけるヒト疾患の治療に有用なビアリール化合物
US10336768B2 (en) 2014-06-13 2019-07-02 Yuma Therapeutics, Inc. Pyrimidine compounds and methods using the same
US10961254B2 (en) 2014-06-13 2021-03-30 Yuma Therapeutics, Inc. Pyrimidine compounds and methods using the same
US12011444B2 (en) 2015-11-20 2024-06-18 Idorsia Pharmaceuticals Ltd N-substituted indole derivatives as PGE2 receptor modulators
US11241431B2 (en) 2015-11-20 2022-02-08 Idorsia Pharmaceuticals Ltd N-substituted indole derivatives as PGE2 receptor modulators
US9840481B2 (en) 2016-03-22 2017-12-12 Merck Sharp & Dohme Corp. Allosteric modulators of nicotinic acetylcholine receptors
US9926285B2 (en) 2016-03-22 2018-03-27 Merck Sharp & Dohme Corp. Allosteric modulators of nicotinic acetylcholine receptors
EP3445750A4 (en) * 2016-04-18 2019-11-27 Celgene Quanticel Research, Inc. THERAPEUTIC COMPOUNDS
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US10617680B2 (en) 2017-04-18 2020-04-14 Celgene Quanticel Research, Inc. Therapeutic compounds
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US11446298B2 (en) 2017-05-18 2022-09-20 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives
US11325899B2 (en) 2017-05-18 2022-05-10 Idorsia Pharmaceuticals Ltd Benzofurane and benzothiophene derivatives as PGE2 receptor modulators
US11712438B2 (en) 2017-05-18 2023-08-01 Idorsia Pharmaceuticals Ltd Phenyl derivatives as PGE2 receptor modulators
US11839613B2 (en) 2017-05-18 2023-12-12 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives as PGE2 receptor modulators
WO2019133904A1 (en) * 2017-12-30 2019-07-04 Unity Biotechnology, Inc. Inhibitors of hsp90, pi3-kinase, proteasome, hdac, and p97 pathways for selective removal of senescent cells in the treatment of age related conditions
WO2019166639A1 (en) 2018-03-01 2019-09-06 Thomas Helledays Stiftelse För Medicinsk Forskning Substituted benzodiazoles and use thereof in therapy
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WO2025143733A1 (ko) * 2023-12-26 2025-07-03 (주)아이젠사이언스 신규한 유비퀴틴 특이적 펩티드 분해효소 1 저해제

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