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Definitions

• Atherosclerosis is regarded as a chronic inflammatory disease, which develops in response to injury of the vessel wall and is characterized by the complex development of an occlusive and prothrombotic atheroma.
• the pathogenesis of this lesion generally involves endothelial dysfunction (reduced bioavailable NO) 5 adhesion molecule expression, adhesion and infiltration of leukocytes, cytokine and growth factor generation, accumulation of foam cells, expansion of extracellular lipid and matrix, activation of matrix metalloproteases (MMPs) and proliferation of vascular smooth muscle cells.
• endothelial dysfunction reduced bioavailable NO
• adhesion and infiltration of leukocytes adhesion and infiltration of leukocytes
• cytokine and growth factor generation accumulation of foam cells
• expansion of extracellular lipid and matrix activation of matrix metalloproteases (MMPs) and proliferation of vascular smooth muscle cells.
• MMPs matrix metalloproteases
• rheumatoid arthritis rheumatoid arthritis
• osteoarthritis endotoxemia and/or toxic shock syndrome
• other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis.
• IL-I, TNF and other cytokines affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important as critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
• TGF- ⁇ transforming growth factor beta
• This invention also relates to a method of inhibiting the production of IL-I in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) and (Ia), (II) and (Ha), (III) and (Ilia),
• G 3 is CH 2 ;
• Rl is C(Z)N(Ri C)(CRl 0R20)vRb, C(Z)O(CRi ⁇ R2 ⁇ ) V Rb,
• Rl ' is independently selected at each occurrence from halogen, C 1.4 alkyl, halo- substituted-Ci-4 alkyl, cyano, nitro, (CRioR2 ⁇ )v'NRdRd% (CRi0R20)v'C(O)Ri2, SR 5 , S(O)R 5 , S(O) 2 R 5 , or (CRl ⁇ R2 ⁇ )v'ORl3;
• Rj 1 is selected from an optionally substituted C 1 -I 0 alkyl, -CH 2 -C(O)-CH 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C(O)N(R 1 OOCH 2 -CH 2 -, -CH 2 -
• R 2 ' is hydrogen, C 1-1 Q alkyl, C 3-7 cycloalkyl, C ⁇ . ⁇ cycloalkylalkyl, aryl, arylC ⁇ io alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or a heterocyclylCi_!o alkyl moiety, and wherein each of these moieties, excludmg hydrogen, may be optionally substituted 1 to 4 times, independently, by Ci-I 0 alkyl, halo-substituted C 1-1 Q alkyl, C 2-1 Q alkenyl, C 2-1 Q alkynyl, C3_ 7 cycloalkyl, C3 -7 cycloalkylC 1-1 Qalkyl, C5_7cycloalkenyl, C5.7 cycloalkeiiyl C 1 -1 Q alkyl, halogen, -C(O), cyano, nitro, aryl, aryl C 1
• C3_7cycloalkyl C ⁇ . ⁇ cycloalkyl Ci-io alkyl; an unsubstituted or substituted aryl, or arylCl-4 alkyl; an unsubstituted or substituted heterocyclic, or heterocyclic Ci-4 alkyl; an unsubstituted or substituted heteroaryl, or heteroCi-4 alkyl, and wherein these aryl, heterocyclic, and heteroaryl containing moieties are substituted one to two times independently at each occurrence by halogen; Ci _ 4 alkyl, hydroxy; hydroxy substituted Ci_4 alkyl;
• R5 and R25 together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; and wherein these moieties, excluding hydrogen, are optionally substituted 1 to 4 times, independently at each occurrence by halogen; hydroxy; hydroxy substituted Ci-ioalkyl; Ci_io alkoxy; halosubstituted Cl -10 alkoxy; Ci .4 alkyl; halosubstituted C1-4 alkyl; SR5, S(O)Rs, S(O)2Rs; C(O)RJ; C(O)ORJ; C(O)NR4'Ri4'; NR4-C(0)Ci_ioalkyl; NR4-C(O)aryl; NR4'Ri4 ⁇ ; cyano; nitro; Ci-io alkyl; C3_7cycloalkyl; C3_7cycloalky
• Rd and Rd' are each independently selected at each occurrence from hydrogen, Ci_4 alkyl, C3_5 cycloalkyl, C3.5 cycloalkylCi_4alkyl, or the Rd and Rd' together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 5 to 6 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9', and wherein the Rd and Rd' moieties which are Cl .4 alkyl, C ⁇ .gcycloalkyl, C3_6cycloalkylCi-4 alkyl, and the Rd and Rd' cyclized ring are optionally substituted, 1 to 4 times, independently at each occurrence by halogen; halosubstituted Ci .4 alkyl; hydroxy; hydroxy substituted Ci_4alkyl; C1-4 alkoxy; Ci_4alkyl; halosubstituted C1-4 alkoxy; S(O)mR
• Z is independently selected at each occurrence from oxygen or sulfur,
• v is 0 or an integer having a value of 1 to 2.
• v' is 0 or an integer having a value of 1 or 2.
• Ci_ioalkyl Ci_io alkoxy, such as methoxy or ethoxy; halosubstituted Ci_io alkoxy; ORg , such as methoxy, ethoxy or phenoxy; SR5, S(O)Rs, S(O)2R5, such as methylthio, methylsulfmyl or methyl sulfonyl; C(O)RJ; C(O)ORJ; C(O)NR4"RI4"; cyano; nitro; NR15R25; -Z'-(CRioR2 ⁇ )s-Z'-; Ci-ioalkyl; C3_7cycloalkyl or a C3_7cycloalkylCi_io alkyl group, such as cyclopropyl, or cyclopropyl methyl, or cyclopropylethyl, etc.; halosubstituted Ci-io alkyl, such CF2CF2H,
• R] 3 is a phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 2,4-diflurophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3- chlorophenyl, 4-chloro ⁇ henyl, 3-chloro-4-fluorophenyl, 4-methyl-3-fluoro ⁇ henyl, 4- trifluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-ethoxyphenyl, 4- methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-thiomethylphenyl, 4- acetylphenyl, 4-dimethylaminophenyl, biphenyl, 4'-fluorobiphenyl, 4-sulfonamindo- 2-methylphenyl, 3-phenyloxyphenyl, benzyl, or phenethyl.
• Rb is a pheny
• m is independently selected at each occurrence from 0 or an integer having a value of 1 or 2.
• R4 and Ri 4 are each independently selected at each occurrence from hydrogen, optionally substituted Ci-io alkyl, optionally substituted C3_7cycloalkyl, optionally substituted C 3_7cycloalkylCi-4 alkyl, optionally substituted aryl or optionally substituted aryl-Ci-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic Cl .4 alkyl, or R4 and Ri 4 together with the nitrogen to which they are attached may form an optionally substituted heterocyclic ring of 4 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or nitrogen.
• the R3 moieties are optionally substituted 1 to 4 times, independently at each occurrence by halogen, nitro, Cl -.4 alkyl, halo-substituted C 1.4 alkyl, C 2 .4 alkenyl, C 2 -4alkynyl, C3_ 6 cycloalkyl, C3_6cycloalkylCi_4 alkyl, C 5 .
• R3 moieties are optionally substituted independently, one or more times, suitably 1 to 4 times, independently at each occurrence by the R3 optional substituent is independently selected from halogen, C 1 .40 alkyl, (CR 10 R 2 O) n OR 6 , (CR 10 R 2 O) n NR 16 R 26 , or halo-substituted C 1 -10 alkyl.
• the optional substituents are independently selected at each occurrence from halogen, C 1 -1 Q alkyl, hydroxy, C 1 -1 Q alkoxy, cyano, nitro, amino, or halosubstituted C 1-1 O alkyl.
• the R3 substituents are selected independently from halogen, such as fluorine, chlorine, bromine or iodine, or C 1 -1 Q alkyl, such as methyl.
• the R3 moieties are selected from an optionally substituted C 1-1 O alkyl, optionally substituted C3_ 7 cycloalkyl, optionally substituted C3_7cycloalkylalkyl, or an optionally substituted aryl.
• the R3 moiety is selected from an optionally substituted C 1 -10 alkyl, or an optionally substituted aryl.
• R3 is an optionally substituted phenyl.
• R3 is a phenyl ring substituted one or more times by independently at each occurrence by fluorine, chlorine, hydroxy, methoxy, amino, methyl, or trifluoromethyl.
• R3 is a 2,6-difluorophenyl.
• R3 is an aryl moiety, it is a phenyl ring.
• the phenyl ring is optionally substituted, independently at each occurrence, one or more times, suitably 1 to 4 times by halogen, C 1.4 alkyl, or halo-substituted-Ci-4 alkyl.
• the phenyl ring may suitably be substituted in the 2, 4, or 6-position, or di- substituted in the 2,4- position, or 2,6-position, such as 2-fluoro, 4-fluoro, 2,4- difluoro, 2,6-difluoro, or 2-methyl-4-fluoro; or tri-substituted in the 2,4,6-position, such as 2,4,6-trifluoro.
• Ri 6 and R26 are each independently selected at each occurrence from hydrogen, or Cl -4 alkyl; or the Ri 6 and R26 together with the nitrogen which they are attached form an unsubstituted or substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9'.
• Xi is N(Ri 1), O, S(O) m , or CRI QR 2 O-
• Xi is N(Ri i), or O.
• R] ⁇ is independently selected at each occurrence from hydrogen, or Ci-4 alkyl.
• R2 is independently selected from hydrogen, optionally substituted Cl-IO alkyl, optionally substituted C3_ ⁇ cycloalkyl, optionally substituted C3_7cycloalkylalkyl, optionally substituted aryl, optionally substituted arylCi _ ⁇ Qz3ky ⁇ , optionally substituted heteroaryl, optionally substituted heteroarylC ⁇ _ ⁇ Q alkyl, optionally substituted heterocyclic, optionally substituted heterocyclylCi_i ⁇ alkyl moiety; or R2 is the moiety (CR 10 R20)q'Xl(CRl0R20)qC(A 1 )(A 2 )(A3), or (CR 1O R2 ⁇ )q'C(Ai)(A 2 )(A3).
• Rf is independently selected at each occurrence from hydrogen, Cj _i ⁇ alkyl, aryl, aryl Ci_i ⁇ alkyl, heteroaryl, heteroaryl Ci_i ⁇ alkyl, heterocyclic, or a heterocyclic Ci_i ⁇ alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted.
• the heterocyclic containing moiety is suitably selected from tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (including oxidized versions of the sulfur moiety), aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-l-pyrrolidinyl, 3-oxo-l- pyrrolidinyl, l,3-benzdioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino and thiomorpholino (including oxidized versions of the sulfur moiety).
• R 2 is an optionally substituted piperidinyl or piperazinyl ring.
• R 2 when R 2 is an optionally substituted heterocyclic or heterocyclic alkyl ring the ring is substituted one or mores times independently by an optionally substituted heterocyclic, heterocyclic alkyl, aryl, arylalkyl, alkyl, (CRioR 2 o)n NR e R e' > or (CRi o R 2 ⁇ )n N ( R l 00C(Z)OR 7 .
• the second heterocyclic ring is suitably selected from an optionally substituted tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (including oxidized versions of the sulfur moiety), aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-l-pyrrolidinyl, 3- oxo-1 -pyrrolidinyl, l,3-benzdioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, diazepine, morpholino or thiomorpholino (including oxidized versions of the sulfur moiety).
• R.2' is an optionally substituted heterocyclic, or a heterocyclylCj.io alkyl
• the ring is selected from tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (including oxidized versions of the sulfur moiety), aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-l-pyrrolidinyl, 3-oxo-l-pyrrolidinyl, 1,3- benzdioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, diazepine, hexahydro-1-H-azepine, morpholino or thiomorpholino (including oxidized versions of the sulfur moiety).
• a 1 is an optionally substituted C 1 -10 alkyl, heterocyclic, heterocyclic C 1 -I 0 alkyl, heteroaryl, heteroaryl C 1-1 O alkyl, aryl, or aryl C 1- 1 Q alkyl.
• a 2 is an optionally substituted C 1 -1 O alkyl, heterocyclic, heterocyclic C 1 -10 alkyl, heteroaryl, heteroaryl C 1 -10 alkyl, aryl, or aryl C 1-10 alkyl.
• A3 is hydrogen or is an optionally substituted C 1 -10 alkyl.
• Rl4 are not cyclized. In another embodiment neither R4 and R14 is hydrogen.
• the X substituent is an optionally substituted l,4'-bipiperin-l 'yl ring, a 4-amino-l- piperidinyl, or a 2,2,6,6-tetramethyl-4-piperidinyl)amino.
• R3 is a 2,6-difluoro phenyl
• Ri ' is independently selected at each occurrence from hydrogen, fluorine, or methyl
• g is 1 or 2
• Ri is selected from C(Z)N(Rl ⁇ ')(CRl ⁇ R2 ⁇ )vRb >
• Rb moiety is Ci-io alkyl or an optionally substituted aryl, preferably propyl or 4-fluorophenyl, or optionally substituted heteroaryl, preferably thiazolyl
• X is (CH2) n N(R2')(R2") > and n is 0.
• Another embodiment of the invention is the genus of compounds of formula (Ic), a subgenus of compounds of Formula (I) and (Ia) wherein Ri is C(Z)N(Ri O')(CRl ⁇ R2 ⁇ )vRb > and Rb is an optionally substituted heteroaryl, an optionally substituted heteroaryl Ci_io alkyl, optionally substituted heterocyclic and optionally substituted heterocyclic Ci_io alkyl.
• the remaining groups are the same as enumerated above for Formula (I) and (Ia).
• Ri ' is independently selected hydrogen, halogen, Ci-4 alkyl, or halo-substituted-Ci-4 alkyl. In another embodiment, Ri ' is independently selected from hydrogen, fluorine, chlorine, methyl, or CF3. In one embodiment when Ri ' is substituted on the phenyl ring in the ortho position, and a second Ri ' moiety is also substituted on the ring, then preferably the second substitution is not in the other ortho position. In one embodiment of the invention, g is 1 or 2.
• R7', R77 and R77" are each independentlyselcted from hydrogen, C 1- 6 alkyl-group, C 2-6 alkenyl-group, C 4-6 cycloalkyl-C 0 - 6 alkyl-group, N(C 0-4 alkyl)(C O -4 alkyl)-Cl-4 alkyl-N(C 0-4 alkyl)-group, -N(C 0-4 alkyl)(C 0-4 alkyl) group, C , -3 alkyl-CO ⁇ -C 0-4 alkyl-group, C 0 - 6 alkyl-O-C(O)— C 0 .
• B is -C 1-6 alkyl-, -C 0-3 alkyl-O-C 0-3 alkyl-, -C 0-3 alkyl-NH-C 0-3 alkyl-, -C 0-3 alkyl-NH-C 3 .
• E 2 is CH 2 , CHR 77 , C(OH)R 77 NH, NR 77 , O, S, -S(O)-, or -S(O) 2 -.
• Rl ' is independently selected at each occurrence from halogen, Cl -4 alkyl, halo- substituted-Ci-4 alkyl, cyano, nitro, (CR 10 R 20 ) V 5 NRdRd', (CRioR2 ⁇ )v'C(0)Ri2, SR5, S(O)Rs, S(O)2R5, or (CRioR2 ⁇ )v'ORl3;
• Rj 5 is hydrogen, Ci_io alkyl, 03.7 cycloalkyl, 03.7 cycloalkyl CI_IQ alkyl, aryl, arylCi.i ⁇ alkyl, heteroaryl, heteroarylCi_i Q alkyl, heterocyclic, or heterocyclylCi_io alkyl moiety, which moieties, excluding hydrogen, may all be optionally substituted;
• Rq and Rq' are independently selected at each occurrence from hydrogen, Ci_i 0 alkyl, C3_7cycloalkyl, C3_7cycloalkylCi_ 10 alkyl, 05.7 cycloalkenyl, C 5.7 cycloalkenyl-C i_i ⁇ alkyl, aryl, arylCi_i 0 alkyl, heteroaryl, heteroarylCi_ 10 alkyl, heterocyclic, or a heterocyclylCi_i 0 a ⁇ yl moiety, wherein all of the moieties except for hydrogen, are optionally substituted, or Rq and Rq' together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring of 5 to 7 members, which ring may contain an additional heteroatom selected from oxygen, nitrogen or sulfur; R2 is hydrogen, Ci_io alkyl, C3..7 cycloalkyl, C3.7 cycloalkylalkyl, aryl, arylC
• R 2 ' is hydrogen, Ci_io alkyl, C3J7 cycloalkyl, C3_ ⁇ cycloalkylalkyl, aryl, arylCj.jo alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or a heterocyclylCi_io alkyl moiety, and wherein each of these moieties, excluding hydrogen, maybe optionally substituted;
• R2" is hydrogen, CJ.JQ alkyl, C3.7 cycloalkyl, C3..7 cycloalkylalkyl, aryl, arylCj.io alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or a heterocyclylCj.io a ⁇ yl moiety, and wherein these moieties, excluding hydrogen, may be optionally; or wherein R 2 " is the moiety (CRioR 2 o)tXl(CRl ⁇ R
• a ⁇ is an optionally substituted CJ. ⁇ Q alkyl, heterocyclic, heterocyclic Cj.10 alkyl, heteroaryl, heteroaryl Cj.10 alkyl, aryl, or aryl CJ.JQ alkyl;
• A2 is an optionally substituted Ci_io alkyl, heterocyclic, heterocyclic Cj_io alkyl, heteroaryl, heteroaryl Cj. ⁇ Q alkyl, aryl, or aryl C j . JQ alkyl;
• R3 is a Ci_io alkyl, C3_ ⁇ cycloalkyl, C3_ ⁇ cycloalkyl Ci_io alkyl, aryl, arylCi_io alkyl, heteroaryl, heteroarylC ⁇ . ⁇ Q alkyl, heterocyclic or a heterocyclylC ⁇ .
• R4 and Ri4 are each independently selected at each occurrence from hydrogen, C]_4 alkyl, C3_7 cycloalkyl, C3_7 cycloalkylCi_4alkyl, aryl, aryl-Ci-4 alkyl, heterocyclic, heterocyclic Ci_4 alkyl, heteroaryl or a heteroaryl Ci .4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or the R4 and Ri 4 together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or nitrogen; R4' and Rl 4' are each independently selected at each occurrence from hydrogen or
• R5 is independently selected at each occurrence from hydrogen, Cl -.4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR4'Ri4% excluding the moieties SR5 being SNR4'Ri4' j S(O ⁇ Rs being SO2H and S(O)Rs being SOH;
• R9' is independently selected at each occurrence from hydrogen, or Ci .4 alkyl
• RlO and R20 ⁇ e independently selected at each occurrence from hydrogen or Ci_4alkyl
• Rl 2 is independently selected at each occurrence from hydrogen, Ci_4 alkyl, halo- substituted C 1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3_7 cycloalkyl, C3_7cycloalkylCi-4 alkyl, C5-.7 cycloalkenyl, Cs- ⁇ cycloalkenyl Cl .4 alkyl, aryl, arylCi_4 alkyl, heteroaryl, heteroarylCi-4 alkyl, heterocyclyl, or a heterocyclylCi-4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• Z is independently selected at each occurrence from oxygen or sulfur; and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
• G4 is CH
• R 2 ' is hydrogen, C 1 -10 alkyl, C3.7 cycloalkyl, C3.7 cycloalkylalkyl, aryl, arylC ⁇ io alkyl, heteroaryl, heteroarylC ⁇ io alkyl, heterocyclic, or aheterocyclylC ⁇ o alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• Rl 3 is independently selected at each occurrence from hydrogen, C 1.4 alkyl, halo- substituted Ci_4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3_7 cycloalkyl, C3-7cycloalkylCi-4 alkyl, C5-7 cycloalkenyl, Cs. ⁇ cycloalkenyl Ci-4 alkyl, aryl, arylCi_4 alkyl, heteroaryl, heteroarylCi-4 alkyl, heterocyclyl, or a heterocyclylCi-4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; Rd and Rd' are each independently selected from hydrogen, Cl _4 alkyl, C3.6 cycloalkyl, C3.6 cycloalkylCi ⁇ alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or Rd and Rd' together with the nitrogen which they are attached
• Another aspect of the invention are compounds of the formula:
• G5 and G6 are independently selected from nitrogen or CH; Rl is C(Z)N(Ri ⁇ ')(CRl ⁇ R2 ⁇ )vRb, C(Z)O(CRi O R2 ⁇ )vRb,
• Rl ' is independently selected at each occurrence from halogen, C].4 alkyl, halo- substiruted-Ci-4 alkyl, cyano, nitro, (CRloR2 ⁇ )v'NRdRd%
• Rb is hydrogen, Ci_io alkyl, C3J7 cycloalkyl, C ⁇ . ⁇ cycloalkyl Ci_io alkyl, aryl, arylCi_ioalkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or heterocyclylCi_io alkyl moiety, which moieties, excluding hydrogen, may all be optionally substituted;
• X is R 2 , OR 2% S(O) 1n R 2 ', (CH 2 ) n 'N(R 10 ')S(O) m R 2 ', (CH 2 VN(R 10 0C(O)R 2 >,
• Rq and Rq' are independently selected at each occurrence from hydrogen, Ci -1 Q alkyl, C 3 . ⁇ cycloalkyl, C3_7cycloalkylCi_ioalkyl, 05.7 cycloalkenyl, C 5.7 cycloalkenyl-C i_ioalkyl, aryl, arylCi.io alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or a heterocyclylCi_io alkyl moiety, wherein all of the moieties except for hydrogen, are optionally substituted, or Rq and Rq' together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring of 5 to 7 members, which ring may contain an additional heteroatom selected from oxygen, nitrogen or sulfur;
• R 2 is hydrogen, CI_I Q alkyl, 03.7 cycloalkyl, 03.7 cycloalkylalkyl, aryl, arylC
• R 2 is the moiety (CR 10 R 2 0)q'Xl (CRi oR2 ⁇ )qC(Ai)(A 2 )(A 3 ), or
• R 2 ' is hydrogen, C 1 -1 Q alkyl, C 3 .7 cycloalkyl, C 3 .7 cycloalkylalkyl, aryl, arylCj.jo alkyl, heteroaryl, heteroarylC ⁇ Q alkyl, heterocyclic, or aheterocyclylC ⁇ Q alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• a 1 is an optionally substituted C 1 -1 Q alkyl, heterocyclic, heterocyclic C 1-1 Q alkyl, heteroaryl, heteroaryl Ci - 1 O alkyl, aryl, or aryl C 1- 1 O alkyl;
• a 2 is an optionally substituted C 1- IQ alkyl, heterocyclic, heterocyclic C 1 -1 Q alkyl, heteroaryl, heteroaryl Ci_io alkyl, aryl, or aryl Ci_io alkyl;
• a 3 is hydrogen or is an optionally substituted Ci _i Q alkyl;
• R 3 is a Ci_io alkyl, C 3 _7 cycloalkyl, C 3 _7 cycloalkyl Ci - 1 Q alkyl, aryl, arylC ⁇ jQ alkyl, heteroaryl, heteroarylCj.jo alkyl, heterocyclic or a heterocyclylC ⁇ Q alkyl moiety, and wherein each of these moieties may be optionally substituted;
• R4 and R 1 4 are each independently selected at each occurrence from hydrogen, C 1 .4 alkyl, C 3 .7 cycloalkyl, C 3 .7 cycloalkylC ⁇ alkyl, aryl, aryl-Ci-4 alkyl, heterocyclic, heterocyclic C 1 .4 alkyl, heteroaryl or a heteroaryl C 1 .4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or the R4 and Ri 4 together with the nitrogen which they are
• R5 is independently selected at each occurrence from hydrogen, Cl -4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR4'Ri4', excluding the moieties SR5 being
• SNR4'Ri4' 5 S(O)2R5 being SO2H and S(O)Rs being SOH;
• R9' is independently selected at each occurrence from hydrogen, or Cl .4 alkyl
• R] 1 is independently selected at each occurrence from hydrogen or Ci-4alkyl
• Another aspect of the invention are compounds of the formula:
• Gi and G2 are independently selected from nitrogen or CH: G 3 is CH 2 ; G 4 is CH; one of G5, G6, G7 and G8 is nitrogen and the others are CH; Rl is C(Z)N(Ri 0')(CRl0R20)vRb, C(Z)O(CRi ⁇ R2 ⁇ ) V Rb,
• Ri ' is independently selected at each occurrence from halogen, Cl-4 alkyl, halo- substituted-Ci_4 alkyl, cyano, nitro, (CRioR2 ⁇ )v'NRdRd%
• X is R 2 , OR 2 ', S(O) 1n R 2 ', (CH 2 )n'N(R 10 ')S(O) m R 2 ' 5 (CH 2 VN(R 10 OC(O)R 2 ',
• R 2 is the moiety (CR 1 O R 2 o) q 'Xi (CR 1 O R 2 o) q C(A 1 )(A 2 )(A 3 ), or
• R 2 ' is hydrogen, C 1-10 alkyl, C ⁇ . ⁇ cycloalkyl, C3.7 cycloalkylalkyl, aryl, 8TyIC 1-10 alkyl, heteroaryl, heteroarylC ⁇ . ⁇ 0 alkyl, heterocyclic, or a heterocyclylC ⁇ . ⁇ Q alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• R 2 " is hydrogen, C 1-10 alkyl, C3_7 cycloalkyl, 03.7 cycloalkylalkyl, aryl, arylC 1 - 10 alkyl, heteroaryl, heteroarylC ⁇ io alkyl, heterocyclic, or a heterocyclylCi_i 0 alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally; or wherein R 2 » is the moiety (CRioR 2 ⁇ )t x l(CRl ⁇ R
• Ai is an optionally substituted Ci-IQ alkyl, heterocyclic, heterocyclic CI_I Q alkyl, heteroaryl, heteroaryl C 1 -1 O alkyl, aryl, or aryl C 1-10 alkyl;
• a 2 is an optionally substituted C 1-10 alkyl, heterocyclic, heterocyclic C 1 - I 0 alkyl, heteroaryl, heteroaryl C 1 - I 0 alkyl, aryl, or aryl Ci-I 0 a ⁇ yl;
• A3 is hydrogen or is an optionally substituted CI_IQ alkyl
• R.3 is a C ⁇ io alkyl, C3.7 cycloalkyl, C-$_ ⁇ cycloalkyl C ⁇ _ ⁇ Q alkyl, aryl, arylC ⁇ io alkyl, heteroaryl, heteroarylCi_io alkyl heterocyclic or a heterocyclylCi-io alkyl moiety, and wherein each of these moieties may be optionally substituted
• R4 and Ri 4 are each independently selected at each occurrence from hydrogen, C 1.4 alkyl, C ⁇ . ⁇ cycloalkyl, C ⁇ -I cycloalkylCj ⁇ alkyl, aryl, aryl-Ci-4 alkyl, heterocyclic, heterocyclic Ci -4 alkyl, heteroaryl or a heteroaryl Ci_4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or the R4
• RlO' is independently selected at each occurrence from hydrogen or Ci_4alkyl
• Rl 2 is independently selected at each occurrence from hydrogen, C 1.4 alkyl, halo- substituted C1.4 alkyl, C 2 -4 alkenyl, C2-4 alkynyl, C3-.7 cycloalkyl,
• Gj and G2 are nitrogen: G3 is CH 2 ; G 4 is CH;
• G5 and G6 are nitrogen; and Gl and G8 are CH;
• Rl is C(Z)N(Ri0')(CRl0R20)vRb, C(Z)O(CRi 0 R 2 0)vRb,
• Rl' is independently selected at each occurrence from halogen, Ci .4 alkyl, halo- substituted-Ci_4 alkyl, cyano, nitro, (CRioR 2 ⁇ )v'NRdRd%
• Rb is hydrogen, Ci_io alkyl, C ⁇ - - ⁇ cycloalkyl, C3.7 cycloalkyl CI _I Q alkyl, aryl, arylCi_ioalkyl, heteroaryl, heteroarylCi.io alkyl, heterocyclic, or heterocyclylCi_io alkyl moiety, which moieties, excluding hydrogen, may all be optionally substituted;
• XI is N(Ri i), O, S(O) m , or CR10R20;
• Rh is selected from an optionally substituted Ci-io alkyl, -CH 2 -C(O)-CH 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C(O)N(Ri O ')CH 2 -CH 2 -,
• R 2 is hydrogen, Cj.io alkyl, 03,7 cycloalkyl, C3.7 cycloalkylalkyl, aryl, arylCi_io alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or a heterocyclylCi_io alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or R 2 is the moiety (CRi O R 2 ⁇ )q'Xl(CRloR 2 ⁇ )qC(Ai)(A 2 )(A 3 ), or
• R 2 ' is hydrogen, C ⁇ io alkyl, C3_7 cycloalkyl, C3.7 cycloalkylalkyl, aryl, alkyl, heteroaryl, heteroarylCj.iQ alkyl, heterocyclic, or a heterocyclylCi_io alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• R 2 » is hydrogen, Ci_io alkyl, C3..7 cycloalkyl, C3..7 cycloalkylalkyl, aryl, alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or a heterocyclylCi_io alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally; or wherein R 2 " is the moiety (CR l o R 2 o)tXl(CRl ⁇
• Ci_io alkyl is an optionally substituted Ci_io alkyl, heterocyclic, heterocyclic C ⁇ . ⁇ Q alkyl, heteroaryl, heteroaryl Ci_io alkyl, aryl, or aryl C ⁇ . ⁇ Q alkyl;
• A3 is hydrogen or is an optionally substituted Cj.io alkyl
• R3 is a Ci_io alkyl, C3_ ⁇ cycloalkyl, 03.7 cycloalkyl Cj_]() alkyl, aryl, arylCi_]o alkyl, heteroaryl, heteroarylC ⁇ _ ⁇ Q alkyl, heterocyclic or a heterocyclylC ⁇ . ⁇ Q alkyl moiety, and wherein each of these moieties may be optionally substituted; R4 and R14 are each independently selected at each occurrence from hydrogen, C 1.4 alkyl, C3J7 cycloalkyl, C3_7 cycloalkylCi_4alkyl, aryl, aryl-Ci-4 alkyl, heterocyclic, heterocyclic Ci -4 alkyl, heteroaryl or a heteroaryl Ci .4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or the R4 and Ri 4 together with the nitrogen which they are attached form an optional
• R5 is independently selected at each occurrence from hydrogen, Ci .4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR4'Ri4', excluding the moieties SR5 being
• SNR4'Ri4' 5 S(O) 2 R5 being SO 2 H and S(O)Rs being SOH;
• Ro,' is independently selected at each occurrence from hydrogen, or Cl .4 alkyl;
• RlO and R 2 O are independently selected at each occurrence from hydrogen or
• Rl 3 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, halo- substituted Cl _4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3..7 cycloalkyl, C3-7cycloalkylCi-4 alkyl, C5-7 cycloalkenyl, C5-7cycloalkenyl Ci-4 alkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi_4 alkyl, heterocyclyl, or a heterocyclylCi _4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; Rd and Rd' are each independently selected from hydrogen, Ci_4 alkyl, C3.6 cycloalkyl, C ⁇ - ⁇ cycloalkylCi ⁇ alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or Rd and Rd' together with the nitrogen which they
• m is independently selected at each occurrence from 0 or an integer having a value of l or 2;
• q is 0 or an integer having a value of 1 to 10;
• q' is 0, or an integer having a value of 1 to 6;
• t is an integer having a value of 2 to 6;
• v is 0 or an integer having a value of 1 or 2;
• v' is independently selected at each occurrence from 0 or an integer having a value of
• G 3 is CH 2 ;
• G 4 is CH;
• G6 and G8 are nitrogen; and G5 and G7 are CH; Ri is C(Z)N(Ri ⁇ ')(CRl ⁇ R2 ⁇ )vRb, C(Z)O(CR] ⁇ R2 ⁇ ) V Rb,
• Rj 3 is hydrogen, C]_io alkyl, 03.7 cycloalkyl, 03.7 cycloalkyl Ci_i 0 alkyl, aryl, arylCi_ioalkyl, heteroaryl, heteroarylCi_i() alkyl, heterocyclic, or heterocyclylC i_io alkyl moiety, which moieties, excluding hydrogen, may all be optionally substituted;
• X is R 2 , OR 2 ', S(O) 1n R 2 ', (CH 2 ) n 'N(R 10 ')S(O) m R 2S (CH 2 ) n 'N(Ri 0 OC(O)R 2 ',
• Rq and Rq' are independently selected at each occurrence from hydrogen, CJ.JO alkyl, C3_7cycloalkyl, C3_7cycloalkylCi_i 0 alkyl, C 5 _7 cycloalkenyl, C 5 _7 cycloalkenyl-C i_i O alkyl, aryl, arylCi_i 0 alkyl, heteroaryl, heteroarylC ⁇ io alkyl, heterocyclic, or a heterocyclylCi_i 0 alkyl moiety, wherein all of the moieties except for hydrogen, are optionally substituted, or Rq and Rn' together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring of 5 to 7 members, which ring may contain an additional heteroatom selected from oxygen, nitrogen or sulfur;
• R2 is hydrogen, C 1 -1 Q alkyl, C3_7 cycloalkyl, C 3 _7 cycloalkylalkyl,
• R 2 is the moiety (CR 1 QR 20 ⁇ X 1 (CR 1 QR 2 O) 01 C(A 1 XA 2 XA 3 ), or (CR 1 OR 2 OVC(Ai)(A 2 )(A 3 );
• R 2 ' is hydrogen, C 1 -1 Q alkyl, C 3 _7 cycloalkyl, C 3 _ ⁇ cycloalkylalkyl, aryl, arylC ⁇ o alkyl, heteroaryl, heteroarylC ⁇ o alkyl, heterocyclic, or a heterocyclylC ⁇ Q alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• R 2 » is hydrogen, C 1-1 Q alkyl, C3.7 cycloalkyl, C3-7 cycloalkylalkyl, aryl, arylC ⁇ Q alkyl, heteroaryl, heteroarylC ⁇ Q alkyl, heterocyclic, or a heterocyclylC ⁇ Q alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally; or wherein R 2 » is the moiety (CR 1O R2 ⁇ )tX 1 (CR 1 oR 2 o) q C(A 1 )
• a 1 is an optionally substituted C 1-1 O alkyl, heterocyclic, heterocyclic C 1 -1 Q alkyl, heteroaryl, heteroaryl C 1-1 O alkyl, aryl, or aryl C 1 -1 Q alkyl;
• a 2 is an optionally substituted C 1-1 Q alkyl, heterocyclic, heterocyclic C 1- IQ alkyl, heteroaryl, heteroaryl C 1 -1 O alkyl, aryl, or aryl C 1-1 Q alkyl;
• a 3 is hydrogen or is an optionally substituted C 1 -1 Q alkyl
• R5 is independently selected at each occurrence from hydrogen, C 1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR4'Ri4', excluding the moieties SR5 being SNR4'Ri A ⁇ S(O) 2 Rs being SO 2 H and S(O)Rs being SOH;
• Rep is independently selected at each occurrence from hydrogen, or Ci_4 alkyl
• R ⁇ 0 and R 2 Q are independently selected at each occurrence from hydrogen or Ci_4alkyl
• Rj 0' is independently selected at each occurrence from hydrogen or Ci-4alkyl
• Rl l is independently selected at each occurrence from hydrogen or C 1 _4alkyl
• Rl 2 is independently selected at each occurrence from hydrogen, C 1.4 alkyl, halo- substituted C 1-4 alkyl, C 2 _4 alkenyl, C 2 -4 alkynyl, C3.7 cycloalkyl, C3_7cycloalkylCi-4 alkyl, C5-7 cycloalkenyl, Cs_7cycloalkenyl Cl -4 alkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi-4 alkyl, heterocyclyl, or a heterocyclylCi_4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• Rl 3 is independently selected at each occurrence from hydrogen, C 1.4 alkyl, halo- substituted Ci-4 alkyl, C 2 -4 alkenyl, C 2 _4 alkynyl, C3.7 cycloalkyl, C3-7cycloalkylCi_4 alkyl, C5-7 cycloalkenyl, Cs_7cycloalkenyl Ci .4 alkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi_4 alkyl, heterocyclyl, or a heterocyclylC 1-4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; Rd and Rd' are each independently selected from hydrogen, Ci-4 alkyl, C ⁇ - ⁇ cycloalkyl, C ⁇ - ⁇ cycloalkylCi_4alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or Rd and Rd'
• m is independently selected at each occurrence from 0 or an integer having a value of l or 2;
• q is 0 or an integer having a value of 1 to 10;
• q' is 0, or an integer having a value of 1 to 6;
• t is an integer having a value of 2 to 6;
• v is 0 or an integer having a value of 1 or 2;
• v' is independently selected at each occurrence from O or an integer having a value of l or 2;
• Z is independently selected at each occurrence from oxygen or sulfur; and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
• Another aspect of the invention are compounds of the formula:
• Ri ' is independently selected at each occurrence from halogen, Ci .4 alkyl, halo- substituted-Ci-4 alkyl, cyano, nitro, (CR l ⁇ R2 ⁇ )v 'NRdRdS (CRioR2 ⁇ )v'C(0)Ri2, SR5, S(O)R 5 , S(O) 2 Rs, or (CRi ⁇ R2 ⁇ )v'ORl3;
• R ⁇ is hydrogen, Ci_io alkyl, 03.7 cycloalkyl, 03.7 cycloalkyl CI_J O alkyl, aryl, arylCi_ioalkyl, heteroaryl, heteroarylCi_io alky
• R 2 is the moiety (CR lo R 2 o) q 'Xi(CRioR2 ⁇ )qC(A 1 )(A 2 )(A 3 ), or
• R 2 ' is hydrogen, CI _IQ alkyl, C 3 _7 cycloalkyl, C 3 _7 cycloalkylalkyl, aryl, arylCi_io alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or a heterocyclylCi_io alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• R 2 » is hydrogen, Ci_io alkyl, C 3 _7 cycloalkyl, C 3 _7 cycloalkylalkyl, aryl, arylCi_io alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or a heterocyclylCi_io alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally; or wherein R 2 » is the moiety (CRi oR2 ⁇ )tXl (CRl O R 2 ⁇ )q c ( A l)(A 2 )(A 3 ); Ai is an optionally substituted Ci_io alkyl, heterocyclic, heterocyclic CI_I Q alkyl, heteroaryl, heteroaryl Ci_io alkyl, aryl, or aryl Ci_io alkyl; A 2 is an optionally substituted Ci_io alkyl, heterocyclic, heterocyclic Ci_io alkyl,
• a 3 is hydrogen or is an optionally substituted Ci_io alkyl
• R 3 is a C i_ 10 alkyl, C 3 j ⁇ cycloalkyl, C 3 .7 cycloalkyl C ⁇ io alkyl, aryl, arylC ⁇ io alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic or a heterocyclylCi_io alkyl moiety, and wherein each of these moieties maybe optionally substituted;
• R4 and Ri 4 are each independently selected at each occurrence from hydrogen, Cl -4 alkyl, C 3 _7 cycloalkyl, C 3 _7 cycloalkylCi_4alkyl, aryl, aryl-Ci.4 alkyl, heterocyclic, heterocyclic Ci .4 alkyl, heteroaryl or a heteroaryl C 1.4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or the R4 and Ri 4 together with the nitrogen which they are attached form
• Rg' is independently selected at each occurrence from hydrogen, or C 1.4 alkyl
• RlO and R20 are independently selected at each occurrence from hydrogen or Ci_4alkyl
• Rl 1 is independently selected at each occurrence from hydrogen or Ci_4alkyl
• Rl 3 is independently selected at each occurrence from hydrogen, Ci -4 alkyl, halo- substituted Ci_4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-.7 cycloalkyl,
• m is independently selected at each occurrence from 0 or an integer having a value of l or 2;
• q is 0 or an integer having a value of 1 to 10;
• q' is 0, or an integer having a value of 1 to 6;
• t is an integer having a value of 2 to 6;
• v is 0 or an integer having a value of 1 or 2;
• v' is independently selected at each occurrence from 0 or an integer having a value of
• Z is independently selected at each occurrence from oxygen or sulfur; and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
• Another aspect of the invention are compounds of the formula:
• G3 is CH 2 ;
• G4 is CH;
• G6 and G7 are nitrogen; G5 and G8 are CH; Ri is C(Z)N(RlC)(CRl 0R20)vRb, C(Z)O(CRi ⁇ R2 ⁇ ) V Rb,
• Rl ' is independently selected at each occurrence from halogen, Cl -4 alkyl, halo- substituted-Ci_4 alkyl, cyano, nitro, (CRioR2 ⁇ )v'NRdRd% (CRioR20)v'C(0)Ri2, SRs, S(O)R 5 , S(O) 2 R 5 , or (CRi 0 R2 ⁇ )v'ORl3;
• Rfo is hydrogen, C 1 -1 Q alkyl, C3.7 cycloalkyl, C3..7 cycloalkyl C 1 -1 O alkyl, aryl, arylC 1 -10 alkyl, heteroaryl, heteroarylC 1-10
• Rq and Rq' are independently selected at each occurrence from hydrogen, C 1 -10 alkyl, C3_ycycloalkyl, C3_7cycloalkylC 1 _ 10 alkyl, C5..7 cycloalkenyl, C 5.7 cycloalkenyl-C 1-10 alkyl, aryl, 3TyIC 1- 1 Q alkyl, heteroaryl, heteroarylC 1-10 alkyl, heterocyclic, or a heterocyclylC ⁇ 10 alkyl moiety, wherein all of the moieties except for hydrogen, are optionally substituted, or Rq and Rq' together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring of 5 to 7 members, which ring may contain an additional heteroatom selected from oxygen, nitrogen or sulfur; R 2 is hydrogen, C 1 -10 alkyl, 03.7 cycloalkyl, C3.7 cycloalkylalkyl
• R 2 ' is hydrogen, C 1 -10 alkyl, C 3- 7 cycloalkyl, C3..7 cycloalkylalkyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1 - 10 alkyl, heterocyclic, or a heterocyclylC 1 -10 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• R 2 " is hydrogen, C 1 -10 alkyl, C3.7 cycloalkyl, C3_7 cycloalkylalkyl, aryl, arylC ⁇ Q alkyl, heteroaryl, lieteroarylC 1 - 10 alkyl, heterocyclic, or a heterocyclylC 1 - 10 alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally; or wherein R 2 » is the moiety (CR 1 OR 2 O) 1 X 1 (CR 1 0R 2 ⁇ qC(
• a 1 is an optionally substituted C 1-1 Q alkyl, heterocyclic, heterocyclic C 1 -1 Q alkyl, heteroaryl, heteroaryl C 1 -1 O alkyl, aryl, or aryl C 1 -1 Q alkyl;
• a 2 is an optionally substituted C 1 -1 O alkyl, heterocyclic, heterocyclic C 1-1 O alkyl, heteroaryl, heteroaryl C 1-10 alkyl, aryl, or aryl C 1 -1 Q alkyl;
• A3 is hydrogen or is an optionally substituted Ci_io alkyl;
• R3 is a Cj.10 alkyl, 03.7 cycloalkyl, C3J7 cycloalkyl CJ.JO alkyl, aryl, arylCj.io alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic or a heterocyclylCi-io alkyl moiety, and wherein each of these moieties may be optionally substituted;
• R4 and Ri 4 are each independently selected at each occurrence from hydrogen, C 1.4 alkyl, C$- _ ⁇ cycloalkyl, C3..7 cycloalkylCi_4alkyl, ary
• R5 is independently selected at each occurrence from hydrogen, Cl -4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR4'Rl4', excluding the moieties SR5 being SNR4'Ri4' j S(O)2R5 being SO2H and S(O)Rs being SOH; R9' is independently selected at each occurrence from hydrogen, or Cl .4 alkyl;
• RlO and R20 are independently selected at each occurrence from hydrogen or Ci_4alkyl
• Rl 3 is independently selected at each occurrence from hydrogen, Cl -4 alkyl, halo- substituted Ci_4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3_7cycloalkylCi-4 alkyl, C5.7 cycloalkenyl, C5-7cycloalkenyl Ci_4 alkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi_4 alkyl, heterocyclyl, or a heterocyclylC 1-4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; Rd and Rd' are each independently selected from hydrogen, Cl -4 alkyl, cycloalkyl, C ⁇ - ⁇ cycloalkylC ⁇ alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or Rd and Rd' together with the nitrogen which they are attached form an optional
• m is independently selected at each occurrence from 0 or an integer having a value of l or 2;
• q is 0 or an integer having a value of 1 to 10;
• q' is 0, or an integer having a value of 1 to 6;
• t is an integer having a value of 2 to 6;
• v is 0 or an integer having a value of 1 or 2;
• v' is independently selected at each occurrence from 0 or an integer having a value of
• Z is independently selected at each occurrence from oxygen or sulfur; and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
• Another aspect of the invention are compounds of Formula (A) and (Al):
• Gi, and G 2 are independently nitrogen;
• G 3 is CH 2 ;
• G 4 is CH;
• Y is C(R x )(R 2 ), C(O), N(R 2 ), N(R w )C(R y )(R z ), oxygen, OC(Ry)(R 2 ), S(0)m, or
• R x is hydrogen, C 1-2 alkyl, N(R V ) 2 , hydroxy, thio, C ⁇ _2 alkoxy, or S(O) 1n C 1 _2alkyl;
• Ry is hydrogen or C ⁇ j ⁇ alkyl;
• R w is hydrogen or C 1 _2 alkyl
• R v is independently selected from hydrogen or C alkyl
• Rl is C(Z)N(Ri O')(CRlOR2O)vRb, C(Z)O(CRi O R2 ⁇ ) V Rb, N(Rio')C(Z)(CRioR2O)vRb, N(Ri O ')C(Z)N(Rl ⁇ ')(CRl ⁇ R2 ⁇ )vRb, or
• Rl ' is independently selected at each occurrence from halogen, C 1.4 alkyl, halo- substiruted-Ci-4 alkyl, cyano, nitro, (CR 1 O R 2 ⁇ )v'NRdRd% (CRioR20)v'C(0)Ri2, SR 5 , S(O)R 5 , S(O) 2 R 5 , or (CRi 0 R2 ⁇ )v'ORl3;
• Rb is hydrogen, Ci_io alkyl, C ⁇ . ⁇ cycloalkyl, 03.7 cycloalkyl C 1-1 Q alkyl, aryl, arylCi_ioalkyl, heteroaryl, heteroarylC ⁇ o alkyl, heterocyclic, or heterocyclylCi_io alkyl moiety, which moieties, excluding hydrogen, may all be optionally substituted;
• X I is N(Ri 1), O, S(O) 1n , or CRi 0 R 2 O;
• Rq and Rq' are independently selected at each occurrence from hydrogen, C 1-10 alkyl, C ⁇ .ycycloalkyl, C3_7cycloalkylC 1 . 1 oalkyl, C 5 _7 cycloalkenyl, C 5 _7 cycloalkenyl-C j. ⁇ alkyl, aryl, arylC ⁇ o alkyl, heteroaryl, heteroarylC ⁇ Q alkyl, heterocyclic, or a heterocyclic 4 0 alkyl moiety, wherein all of the moieties except for hydrogen, are optionally substituted, or Rq and Rq' together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring of 5 to 7 members, which ring may contain an additional heteroatom selected from oxygen, nitrogen or sulfur;
• R 2 is hydrogen, C 1-10 alkyl, 03.7 cycloalkyl, 03.7 cycloalkylalkyl, aryl, arylC 1 -10 alkyl, heteroaryl, heteroarylC ⁇ . ⁇ Q alkyl, heterocyclic, or a heterocyclylC ⁇ . ⁇ Q alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or R 2 is the moiety (CRi O R2 ⁇ )q'Xl (CRi ⁇ R2 ⁇ )qC(Ai)(A 2 )(A 3 ), or
• R 2 ' is hydrogen, Ci_io alkyl, C ⁇ . ⁇ cycloalkyl, C ⁇ . ⁇ cycloalkylalkyl, aryl, arylC ⁇ io alkyl, heteroaryl, heteroary!Ci_io alkyl, heterocyclic, or a heterocyclylCi_io alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• R 2 » is hydrogen, Ci_io alkyl, C3.7 cycloalkyl, C3.7 cycloalkylalkyl, aryl, arylCi_io alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or a heterocyclylCi_iQ alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally; or wherein R 2 » is the moiety (
• Ai is an optionally substituted CI_IQ alkyl, heterocyclic, heterocyclic Ci_io alkyl, heteroaryl, heteroaryl CI_IQ alkyl, aryl, or aryl Ci_io alkyl;
• a 2 is an optionally substituted CI_IQ alkyl, heterocyclic, heterocyclic CI _I Q alkyl, heteroaryl, heteroaryl CI_IQ alkyl, aryl, or aryl Ci_io alkyl;
• A3 is hydrogen or is an optionally substituted CI_IQ alkyl;
• R4' and R 14' are each independently selected at each occurrence from hydrogen or Ci_4 alkyl, or R4' and R14' together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members, which ring optionally contains an additional heteroatom selected from NR9 ' ;
• R5 is independently selected at each occurrence from hydrogen, C 1.4 alkyl, C 2 -4 alkenyl, C2-4 alkynyl or NR4'Ri4', excluding the moieties SR5 being SNR4'Ri4' ; S(O) 2 R5 being SO 2 H and S(O)Rs being SOH; Ro.' is independently selected at each occurrence from hydrogen, or Cl -4 alkyl; Rio and R 2 Q are independently selected at each occurrence from hydrogen or
• Ci_4alkyl Rl 0' is independently selected at each occurrence from hydrogen or Ci_4alkyl; Rl ⁇ is independently selected at each occurrence from hydrogen or Ci-4alkyl;
• Rl 2 is independently selected at each occurrence from hydrogen, Cl -4 alkyl, halo- substituted Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylCi_4 alkyl, C5-7 cycloalkenyl, Cs. ⁇ cycloalkenyl C 1.4 alkyl, aryl, arylCi .4 alkyl, heteroaryl, heteroarylCi .4 alkyl, heterocyclyl, or a heterocyclylCi-4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• Rl 3 is independently selected at each occurrence from hydrogen, Cl -4 alkyl, halo- substituted Cl -4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3_ ⁇ cycloalkyl, C3_7cycloalkylCi-4 alkyl, C5-7 cycloalkenyl, C5_7cycloalkenyl Cl -4 alkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi -4 alkyl, heterocyclyl, or a heterocyclylCi-4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; Rd and Rd' are each independently selected from hydrogen, C1.4 alkyl, C3.6 cycloalkyl, C ⁇ - ⁇ cycloalkylCi _4alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or Rd and Rd' together with the nitrogen
• Z is independently selected at each occurrence from oxygen or sulfur; and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
• the present invention is directed to novel compounds of Formula (A) and
• Formula (Al), or a pharmaceutically acceptable derivative thereof As will be readily recognized, the difference between compounds of Formula (A) and Formula (Al), and that of Formula (I) and (Ia) lies in the linker Y.
• the respective R ⁇ , R 2 , and R3, etc. terms are the same for both groups. For purposes herein, everything applicable to Formula (I) is also applicable to Formula (A) unless otherwise indicated.
• Another aspect of the invention are compounds of Formula (B) and (Bl):
• G 1 , and G 2 are independently nitrogen;
• G 3 is CH 2 ;
• G 4 is CH
• R x is hydrogen, C i_ 2 alkyl, N(R V )2 > hydroxy, thio, C i_ 2 alkoxy, or S(0) m C]_2 alkyl;
• Rb is hydrogen, Cj.10 alkyl, C3.7 cycloalkyl, 03.7 cycloalkyl Ci 40 alkyl, aryl, arylCi_ioalkyl, heteroaryl, heteroarylCi_iQ alkyl, heterocyclic, or heterocyclylC 1 -10 alkyl moiety, which moieties, excluding hydrogen, may all be optionally substituted;
• X is R 2 , OR 2 ', S(O) 1n R 2 ', (CH 2 )n'N(Rio')S(0) m R 2 ', (CH 2 ) ⁇ N(R 10 ')C(O)R 2 >,
• R n is selected from an optionally substituted C 1 -10 alkyl, -CH 2 -C(O)-CH 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C(O)N(R 10 OCH 2 -CH 2 -, -CH 2 -N(R 10 OC(O)CH 2 -, -CH 2 -CH(OR 10 O-CH 2 -, -CH 2 -C(O)O-CH 2 -CH 2 -, or -CH 2 -CH 2 -O-C(O) CH 2 -;
• Rq and Rq' are independently selected at each occurrence from hydrogen, C 1 -10 alkyl, C 3- 7cycloalkyl, C3_7cycloalkylC 1 _ 10 alkyl, C5.7 cycloalkenyl, C5.7 cycloalkenyl-C 1 -10 alkyl, aryl, 8TyIC 1-10 alkyl
• R 2 is the moiety (CR 1 0R 20 VX 1 (CR 1 0R 2 ⁇ qC(A 1 )(A 2 )(A 3 ), or
• a 3 is hydrogen or is an optionally substituted C 1 -10 alkyl
• R3 is a C ⁇ io alkyl, C- ⁇ . ⁇ cycloalkyl, C ⁇ -I cycloalkyl CI ⁇ Q alkyl, aryl, arylCi_io alkyl, heteroaryl, heteroarylCj_io alkyl, heterocyclic or a heterocyclylC ⁇ io a ⁇ yl moiety, and wherein each of these moieties may be optionally substituted
• R-4 and Ri 4 are each independently selected at each occurrence from hydrogen, Cl .4 alkyl, C3_7 cycloalkyl, CT 1 -J cycloalkylCi_4alkyl, aryl, aryl-Ci-4 alkyl, heterocyclic, heterocyclic Cl -.4 alkyl, heteroaryl or a heteroaryl Ci_4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be
• R4 1 and Ri4' are each independently selected at each occurrence from hydrogen or Ci_4 alkyl, or R4' and Ri 4' together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members, which ring optionally contains an additional heteroatom selected from NR9 ' ;
• R5 is independently selected at each occurrence from hydrogen, Ci .4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR4'Rl4', excluding the moieties SR5 being
• Rl O' is independently selected at each occurrence from hydrogen or Ci-4alkyl
• Rl 1 is independently selected at each occurrence from hydrogen or Ci-4alkyl
• Rl 2 is independently selected at each occurrence from hydrogen, C 1.4 alkyl, halo- substituted C 1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3.7 cycloalkyl,
• Rd and Rd' are each independently selected from hydrogen, Cl-4 alkyl, C3.6 cycloalkyl, C3-6 cycloalkylCi_4alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or Rd and Rd' together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 5 to 6 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NRo. 5 ; g is 0 or an integer having a value of 1 , 2, 3, or 4; n' is independently selected at each occurrence from 0 or an integer having a value of
• m is independently selected at each occurrence from 0 or an integer having a value of l or 2;
• q is 0 or an integer having a value of 1 to 10;
• q' is 0, or an integer having a value of 1 to 6;
• t is an integer having a value of 2 to 6;
• v is 0 or an integer having a value of 1 or 2;
• v' is independently selected at each occurrence from 0 or an integer having a value of l or 2;
• Z is independently selected at each occurrence from oxygen or sulfur; and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
• linker Y may be present in a similar manner in the same position for all of the remaining formulas, Formula's (III) and (Ilia), (IV) and (IVa), (V) and (Va), (VI), (VIa-VIi), etc., herein.
• G 1 , G 2 are independently nitrogen or CH, but G 1 , and G 2 are not both nitrogen;
• G 3 is CH 2 ;
• G 4 is CH;
• Rl is C(Z)N(Ri0')(CRl0R20)vRb, C(Z)O(CRi O R2 ⁇ )vRb,
• Rl ' is independently selected at each occurrence from halogen, Ci_4 alkyl, halo- substituted-Ci-4 alkyl, cyano, nitro, (CRioR2 ⁇ )v'NRdRd% (CRioR20)v'C(0)Ri2, SR5, S(O)R 5 , S(O) 2 R5, or (CRi 0 R2 ⁇ )v'ORl3;
• R ⁇ j is hydrogen, C 1 -1 O alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl Ci_io alkyl, aryl, arylCi_ioalkyl, heteroaryl, heteroarylCi_i ⁇ alkyl
• X I is N(R 1 i), O, S(O) m , or CR 10 R 2 O; Rh is selected from an optionally substituted Cl -10 alkyl, -CH 2 -C(O)-CH 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C(O)N(Ri o')CH 2 -CH 2 -, -CH 2 -N(RiOOC(O)CH 2 -, -CH 2 -CH(OR 10 0-CH 2 -, -CH 2 -C(O)O-CH 2 -CH 2 -, or -CH 2 -CH 2 -O-C(O) CH 2 -; Rq and Rq' are independently selected at each occurrence from hydrogen, Ci_io alkyl, C3_7cycloalkyl, C3_7cycloalkylCi_ 1 oalkyl, C5.7 cycloalkenyl, C
• R 2 ' is hydrogen, CI_I Q alkyl, C3..7 cycloalkyl, C3_7 cycloalkylalkyl, aryl, arylC ⁇ o alkyl, heteroaryl, heteroarylC j . i Q alkyl, heterocyclic, or a heterocyclylC i . i Q alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• R 2 " is hydrogen, Ci -1 O alkyl, C3_7 cycloalkyl, C3.7 cycloalkylalkyl, aryl, arylCj_jo alkyl, heteroaryl, heteroarylCj ⁇ Q alkyl, heterocyclic, or a heterocyclylC J.IQ alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally; or wherein R 2 " is the moiety (CR 1 QR 2 o) t Xi(CRioR 2 o)qC(Ai)(A 2 )(A3);
• a 1 is an optionally substituted Ci -1 O alkyl, heterocyclic, heterocyclic C 1 -1 Q alkyl, heteroaryl, heteroaryl Ci_io alkyl, aryl, or aryl CI_IQ alkyl;
• a 2 is an optionally substituted Ci-IQ alkyl, heterocyclic, heterocyclic C 1 -1 Q alkyl, heteroaryl, heteroaryl Ci_io alkyl, aryl, or aryl C 1 -1 Q alkyl;
• R9' is independently selected at each occurrence from hydrogen, or C1-4 alkyl
• Rj 0 and R20 are independently selected at each occurrence from hydrogen or Ci-4alkyl
• RlO' is independently selected at each occurrence from hydrogen or Ci_4alkyl
• Rj2 is independently selected at each occurrence from hydrogen, C1-.4 alkyl, halo- substituted C 1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3.7 cycloalkyl,
• Rl 3 is independently selected at each occurrence from hydrogen, C 1.4 alkyl, halo- substituted Ci _4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-.7 cycloalkyl, C3_7cycloalkylCi-4 alkyl, C5-7 cycloalkenyl, C5_7cycloalkenyl Ci_4 alkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi-4 alkyl, heterocycly
• Rd and Rd' are each independently selected from hydrogen, Cl -.4 alkyl, C3.6 cycloalkyl, C3.6 cycloalkylCi_4alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or Rd and Rd' together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 5 to 6 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9'; g is 0 or an integer having a value of 1, 2, 3, or 4; n' is independently selected at each occurrence from 0 or an integer having a value of
• m is independently selected at each occurrence from 0 or an integer having a value of l or 2;
• q is 0 or an integer having a value of 1 to 10;
• q' is 0, or an integer having a value of 1 to 6;
• t is an integer having a value of 2 to 6;
• v is 0 or an integer having a value of 1 or 2;
• v' is independently selected at each occurrence from 0 or an integer having a value of 1 or 2;
• Z is independently selected at each occurrence from oxygen or sulfur; and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
• the X term may also be the B-Non-Ar-cyc moiety as disclosed above.
• the X term may also be the X moiety as disclosed in WO 2004/073628, published September 2004, Boehm et al., whose disclosure is incorporated by reference herein.
• the template containing the Gj and G2 moieties will have a numbering system that allows for different (R 1 and R 1 ') substituents on the phenyl, the pyridyl and pyrimidine ring at the C 4 position of the pharmacophore; the X term at the C 2 position and the R 3 substituent in the N 8 position.
• Formula (VIII) and (Villa) the difference is in the allowance of the G 1 and G 2 moieties to be carbon or nitrogen, independently.
• the remaining compounds of Formulas (II) and (Ha), (III) and (Ilia), (IV) and (IVa), (V) and (Va), (VI) and (VIa-VIi) may also have the same pharmacophore template of:
• Ri ' is independently selected at each occurrence from halogen, Ci .4 alkyl, halo- substituted-Ci-4 alkyl, cyano, nitro, (CR l()R2 ⁇ )v 'NRdRdS (CRl ⁇ R2 ⁇ )v'C(0)Ri2, SR 5 , S(O)R 5 , S(O) 2 R 5 , or (CRi ⁇ R2 ⁇ )v'ORl3;
• R ⁇ j is hydrogen, CI_IQ alkyl, C3_ ⁇ cycloalkyl, 03.7 cycloalkyl C ⁇ io alkyl, aryl, arylCi_ioalkyl, heteroaryl,
• X is R 2 , OR 2% S(O) 1n R 2 ', (CH 2 ) n 'N(R 10 ')S(O) m R 2 ', (CH 2 VN(R 10 ')C(O)R 2 >,
• XI is N(Ri 1), O, S(O) m , or CR 10 R 20 ; Rh is selected from an optionally substituted Ci-io alkyl, -CH2-C(O)-CH2-, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -C(O)N(RIoOCH 2 -CH 2 -, -CH 2 -N(R 10 OC(O)CH 2 -, -CH 2 -CH(OR 1 OO-CH 2 -, -CH 2 -C(O)O-CH 2 -CH 2 -, or -CH 2 -CH 2 -O-C(O)CH 2 -; Rq and Rq' are independently selected at each occurrence from hydrogen, C 1-1 Q alkyl, C3 ⁇ cycloalkyl, C3_7cycloalkylC 1 .
• R 2 is hydrogen, C 1- 1 Q alkyl, 03.7 cycloalkyl, 03.7 cycloalkylalkyl, aryl, arylC ⁇ Q alkyl, heteroaryl, heteroarylC ⁇ Q alkyl, heterocyclic, or aheterocyclylC ⁇ Q alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or
• R 2 is the moiety (CR 1 oR 2 o)q'X 1 (CR lo R 2 o) q C(A 1 )(A 2 )(A 3 ), or
• R 2 ' is hydrogen, C 1 -1 Q alkyl, C3.7 cycloalkyl, C3_7 cycloalkylalkyl, aryl, arylC ⁇ Q alkyl, heteroaryl, heteroarylC ⁇ _ ⁇ Q alkyl, heterocyclic, or a heterocyclylC ⁇ 1 Q alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• R 2 » is hydrogen, C 1-1 Q alkyl, C3_7 cycloalkyl, 03.7 cycloalkylalkyl, aryl, 8TyIC 1 -1 Q alkyl, heteroaryl, heteroarylC ⁇ 1 Q alkyl, heterocyclic, or a heterocyclylCj ⁇ Q alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally; or wherein R 2 » is the moiety (CR 1 oR 2O )tXl (CR 1 ⁇ R
• Rg' is independently selected at each occurrence from hydrogen, or C] .4 alkyl
• Rj 0 and R 2 O are independently selected at each occurrence from hydrogen or Ci-4alkyl
• Rj 0' is independently selected at each occurrence from hydrogen or Ci-4alkyl
• RJ i is independently selected at each occurrence from hydrogen or Ci_4alkyl
• Rl 2 is independently selected at each occurrence from hydrogen, Cl -4 alkyl, halo- substituted Ci -4 alkyl, C 2 _4 alkenyl, C 2 -4 alkynyl, C3-.7 cycloalkyl, C3_7cycloalkylCi-4 alkyl, C5-7 cycloalkenyl, C5_7cycloalkenyl Ci .4 alkyl, aryl, arylCi_4 alkyl, heteroaryl, heteroarylCi-4 alkyl, heterocyclyl, or a heterocyclylC i_4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
• Rl 3 is independently selected at each occurrence from hydrogen, Cl -4 alkyl, halo- substituted Ci -4 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, C3.7 cycloalkyl,
• m is independently selected at each occurrence from 0 or an integer having a value of l or 2;
• q is 0 or an integer having a value of 1 to 10;
• q' is 0, or an integer having a value of 1 to 6;
• t is an integer having a value of 2 to 6;
• v is 0 or an integer having a value of 1 or 2;
• v' is independently selected at each occurrence from 0 or an integer having a value of l or 2;
• Z is independently selected at each occurrence from oxygen or sulfur; and a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
• the present invention covers all combinations of particular and preferred groups described hereinabove. It is also to be understood that the present invention encompasses compounds of formula (I) in which a particular group or parameter, for example R5, R ⁇ , R9, Rio > ⁇ l 1 > Rl2> ⁇ 13 ⁇ P' n > or ⁇ 1> G ⁇ c - mav occur more than once. In such compounds it will be appreciated that each group or parameter is independently selected from the values listed. When any variable occurs more than one time in a Formula (as described herein), its definition on each occurrence is independent of its definition at every other occurrence.
• Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically derivatives.
• salts and solvates of compounds of the invention which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable.
• salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.
• pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, solvate or prodrug e.g. ester, of a compound of the invention, which upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof.
• pharmaceutically acceptable derivatives are salts, solvates, esters, carbamates and phosphate esters.
• pharmaceutically acceptable derivatives are salts, solvates and esters.
• pharmaceutically acceptable derivatives are salts and esters, in particular salts.
• the compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
• suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.
• a pharmaceutical acceptable salt may be readily prepared by using a desired acid or base as appropriate.
• the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
• Salts of the compounds of the present invention may, for example, comprise acid addition salts resulting from reaction of an acid with a nitrogen atom present in a compound of formula (I). Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
• Pharmaceutically acceptable base salts include ammonium salts such as a trimethylammonium salt, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.
• ammonium salts such as a trimethylammonium salt
• alkali metal salts such as those of sodium and potassium
• alkaline earth metal salts such as those of calcium and magnesium
• salts with organic bases including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.
• solvates refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
• solvents for the purpose of the invention may not interfere with the biological activity of the solute.
• suitable solvents include water, methanol, ethanol and acetic acid.
• the solvent used is a pharmaceutically acceptable solvent.
• suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid.
• Prodrugs are any covalently bonded carriers that release a compound of formula (I) in vivo when such prodrug is administered to a patient.
• Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
• Prodrugs include, for example, compounds of this invention wherein hydroxy or amine groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy or amine groups.
• representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of formula (I).
• esters may be employed, such as methyl esters, ethyl esters, and the like. Esters may be active in their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
• halogen such as fluorine, chlorine, bromine or iodine
• hydroxy such as hydroxy substituted Ci_ioalkyl
• Ci-io alkoxy such as methoxy or ethoxy
• halosubstituted Ci-io alkoxy S(0)m alkyl, such as methyl thio, methylsulfinyl or methyl sulfonyl; a ketone (-C(O)), or an aldehyde (-C(O)Rg>), such as C(0)Ci_io alkyl or C(O)aryl
• Rg' is hydrogen, Ci_io alkyl, C3-.7 cycloalkyl, heterocyclyl, heterocyclyl Ci_ioalkyl, aryl, arylCi-i ⁇ alkyl, heteroaryl or heteroarylCi_io alkyl, (and wherein
• Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include salts formed with both organic and inorganic acids or bases.
• Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifiuoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, alkyl sulphonic acid derivatives, such as methanesulphonic, or ethanesulphonic, arylsulphonic acid derivatives , such as p-toluenesulphonic, m-toluenesulphonic, benzenesulphonic, camphor sulphonic, 4-chlorobenzenesulphonic, 4-bromobenzenesulphonic, 4- phenyl
• pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
• Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
• alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, sec-butyl, tert- butyl or t-butyl and hexyl and the like.
• alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and containing at least one double bond.
• C2-6alkenyl means a straight or branched alkenyl containing at least 2, and at most 6, carbon atoms and containing at least one double bond.
• alkenyl as used herein include, but are not limited to ethenyl, 2- propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3- methylbut-2-enyl, 3-hexenyl, l,l-dimethylbut-2-enyl and the like.
• alkoxy refers to straight or branched chain alkoxy groups containing the specified number of carbon atoms.
• Cj.galkoxy means a straight or branched alkoxy containing at least 1 , and at most 6, carbon atoms.
• alkoxy as used herein include, but are not limited to, methoxy, ethoxy, propoxy, ⁇ ro ⁇ -2-oxy, butoxy, but-2-oxy, 2-methylprop-l-oxy, 2-methylprop- 2-oxy, pentoxy and hexyloxy.
• cycloalkyl refers to cyclic radicals, such as a non- aromatic hydrocarbon ring containing a specified number of carbon atoms.
• C3_7cycloalkyl means a non-aromatic ring containing at least three, and at most seven, ring carbon atoms.
• Representative examples of "cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and the like.
• alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like.
• aryl is used herein to mean phenyl, naphthyl, and indene.
• heteroaryl ring refers herein to mean a monocyclic five- to seven- membered unsaturated hydrocarbon ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur.
• heteroaryl rings include, but are not limited to, furyl, pyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, oxathiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and uracil.
• fused aromatic rings include, but are not limited to, indolyl, isoindolyl, indazolyl, indolizinyl, azaindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, purinyl, and phthalazinyl.
• heterocyclic rings is used herein to mean a monocyclic three- to seven-membered saturated or non-aromatic, unsaturated hydrocarbon ring containing at least one heteroatom selected from nitrogen, oxygen, sulphur or oxidized sulphur moieties, such as S(0)m, and m is 0 or an integer having a value of 1 or 2.
• heterocyclic rings shall also refer to fused rings, saturated or partially unsaturated, and wherein one of the rings may be aromatic, or heteroaromatic.
• Each of the fused rings may have from four to seven ring atoms.
• heterocyclyl groups include, but are not limited to, the saturated or partially saturated versions of the heteroaryl moieties as defined above, such as tefrahydropyrrole, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (including oxidized versions of the sulfur moiety), azepine, diazepine, aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-l-pyrrolidinyl, 3-oxo-l- pyrrolidinyl, l,3-benzdioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino and thiomorpholino (including oxidized versions of the sulfur
• arylalkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean a Cl -4 alkyl (as defined above) attached to an aryl, heteroaryl or heterocyclic moiety (as also defined above) unless otherwise indicated.
• sulfinyl is used herein to mean the oxide S(O) of the corresponding sulfide, the term “thio” refers to the sulfide, and the term “sulfonyl” refers to the fully oxidized S (0)2 moiety.
• aroyl is used herein to mean C(O)Ar, wherein Ar is as phenyl, naphthyl, or aryl alkyl derivative such as defined above, such group include but are not limited to benzyl and phenethyl.
• alkanoyl is used herein to mean C(O)C]-IO alkyl wherein the alkyl is as defined above.
• the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
• substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
• the present invention covers all combinations of particular and preferred groups described hereinabove. It is also to be understood that the present invention encompasses compounds of formula (I) in which a particular group or parameter, for example R5, Rg, Rg, RJQ, RJ ⁇ , R ⁇ 5 Rl3, n > m, or t, etc. may occur more than once. In such compounds it will be appreciated that each group or parameter is independently selected from the values listed. When any variable occurs more than one time in a Formula (as described herein), its definition on each occurrence is independent of its definition at every other occurrence.
• Cis (E) and trans (Z) isomerism may also occur.
• the present invention includes the individual stereoisomers of the compounds of the invention and where appropriate, the individual tautomeric forms thereof, together with mixtures thereof.
• the compounds of Formula (I) and (Ia), (II) and (Ha), (III) and (Ilia), (IV) and (IVa), (V) and (Va), (VI), (VIa-VIi), (VIII), (Villa), (IX), (IXa), (A), (Al), (B), and (Bl), may be obtained by applying the synthetic procedures described herein.
• (Ia), (II) and (Ha), (III) and (Ilia), (IV) and (IVa), (V) and (Va), (VI), (VIa-VIi), (VIII), (Villa), (IX), (IXa) 5 (A), (Al), (B), and (Bl) may be prepared by applying standard techniques for functional group inter-conversion, well known in the art. For instance: C(O)NR4Ri4 from CO2CH3 by heating with HNR4R14 in CH3OH with or without catalytic or stoichiometric metal cyanide or Aluminum trimethyl, e.g.
• OC(O)R6 from OH with e.g., ClC(O)Rg in bases such as triethylamine and pyridine; NRio-C(S)NR4Ri4 from NHR10 with an alkylisothiocyanate, or thiocyanic acid and ClC(S)NR4Ri4; NRioC(0)OR6 from NHRi 0 with an alkyl or aryl chloroformate; NRioC(0)NR4H from NHRlO by treatment with an isocyanate, e.g.
• acetone NR10SO2R7 from NHRlO by treatment with CISO2R7 by heating in bases such as pyridine; NRi OC(S)Re from NRi oC(0)R6 by treatment with Lawesson's reagent [2,4-t ⁇ (4-methoxyphenyl)- 1 ,3,2,4-dithiadiphosphetane-2,4-disulfide]; NRi 0SO2CF3 from NHRio with triflic anhydride and base wherein Re, RlO ? R4 and Ri 4 are as defined in Formula (I) herein.
• Precursors of the groups Ri, R2 and R3, can be other Ri, R2 and R3, e t c groups that may be interconverted by applying standard techniques for functional group interconversion.
• a moiety is a halo substituted Ci_io alkyl
• Ci_ioalkylNH2 compound can be converted to the corresponding CI .J Q alkylN3 derivative by reacting with a suitable azide salt, and thereafter if desired can be reduced to the corresponding Ci_ioalkylNH2 compound, which in turn can be reacted with RyS(0)2X' wherein X' is halo (e.g., chloro) to yield the corresponding c l-l0 alk yMHS(0)2R7 compound.
• Ci_iQ-alkyl Alternatively wherein the moiety is a halo-substituted Ci_iQ-alkyl it can be reacted with an amine R4R14NH to yield the corresponding Ci_iQ-alkylNR4Ri4 compound, or can be reacted with an alkali metal salt of R7SH to yield the corresponding Ci_iQalkylSR7 compound.
• hydroxyl protecting groups include ether forming groups such as benzyl, and aryl groups such as fert-butoxycarbonyl (Boc), silyl ethers, such as t- butyldimethyl or t-butyldiphenyl, and alkyl ethers, such as methyl connected by an alkyl chain of variable link, (CRioR2 ⁇ )n- Amino protecting groups may include benzyl, aryl such as acetyl and trialkylsilyl groups. Carboxylic acid groups are typically protected by conversion to an ester that can easily be hydrolyzed, for example, trichloethyl, tert-butyl, benzyl and the like. Pharmaceutically acid addition salts of compounds of the various Formulas described herein may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid in the presence of a suitable solvent.
• Boc fert-butoxycarbonyl
• silyl ethers such as t
• Leaving groups LG, described as Leaving group 1 (LGl) & LG2
• Leaving group 1 (LGl) & LG2) in Scheme I 5 and elsewhere can be independently selected from -Cl, -Br, -I, or -OTf and these groups can be installed through the transformation of another functional group (e.g. -OH) by following the methods well known in the art (e.g., treatment of the -OH compound with POCl 3 ).
• Method A is for conversion of 1 to 2.
• Treatment of 1 with an amine R 3 NH 2 in the presence of an olefin forming agent, such as bis(2,2,2-trifluoroethyl)- (methoxycarbonylmethyl)-phosphonate or an acylating agent, such as acetic acid anhydride, meldrums acid or acetyl chloride affords compound 2.
• an olefin forming agent such as bis(2,2,2-trifluoroethyl)- (methoxycarbonylmethyl)-phosphonate
• an acylating agent such as acetic acid anhydride, meldrums acid or acetyl chloride affords compound 2.
• olefin forming reagent bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate is used
• alternative cyclization reagents include, but are not limited to bis(2,2,2- trifluoroethyl)-(ethoxycarbonylmethyl)phosphonate, bis(2,2,2-trifluoroethyl)- (isopropoxycarbonyl-methyl)phosphonate, (diethoxy-phosphoryl)-acetic acid methyl ester, (diisopropoxy-phosphoryl)-acetic acid methyl ester, (diphenyloxy-phosphoryl)- acetic acid methyl ester, (diethoxy-phosphoryl)-acetic acid ethyl ester, (diisopropoxy- phosphoryl)-acetic acid ethyl ester, or (diphenyloxy-phosphoryl)-acetic acid ethyl ester.
• reaction solvents can be various organic solvents, such as chloroform, methylene chloride, acetonitrile, toluene, DMF, or n-methylpyrrolidine, DCM, THF, toluene, DMSO, or combinations thereof. While the reaction shows triethylamine as a base, suitable alternative bases can include, but are not limited to pyridine, diisopropyl ethyl amine, or pyrrolidone, or combinations thereof.
• the reaction temperature of this particular step in the reaction scheme can be varied from room temperature to > 100 0 C, i.e. reflux temperature of the solvent. Alternatively, this reaction process step may be performed under suitable microwave conditions.
• Method B is for the installation of group -X [e.g., 2 to 3, 6 to (Ia), or 5 to 4]. This may or may not require first conversion of sulfide (-SMe) to sulfoxide (-SOMe) or sulfone (-SO 2 Me). This conversion can be achieved using meta- chloroperoxybenzoic acid (mCPBA) in high yield and purity. Suitable oxidation methods for use herein include use of one or two equivalents of meta- chloroperoxybenzoic acid (mCPBA) or Oxone ® to afford either the sulfoxides or sulfones or a mixture of both.
• group -X e.g., 2 to 3, 6 to (Ia), or 5 to 4].
• This conversion can be achieved using meta- chloroperoxybenzoic acid (mCPBA) in high yield and purity.
• mCPBA meta- chloroperoxybenzoic acid
• Oxone ® Oxone ®
• Oxidation of the sulfides to sulfoxides or sulfones can also be effected by OsO 4 and catalytic tertiary amine N-oxide, hydrogen peroxide, hydrogen peroxide/NaWO4, and other peracids, oxygen, ozone, organic peroxides, potassium and zinc permanganate, potassium persulfate, and sodium hypochlorite.
• the subsequent displacement of sulfone group -SO 2 Me (likewise, all displacement reactions mentioned below may be achieved using the sulfide -SMe or sulfoxide - SOMe) requires a suitable nucleophile (e.g., amine, alcohol) containing the unit -X.
• Displacements with amines were usually done with an excess of amine in N- methylpyrrolidine (Barvian et al., J. Med. Chem. (2000), 4606-4616). A wide range of primary amines underwent this reaction with excellent yields. In some cases (e.g., in O-displacement) an anion of the nucleophile was prepared with base (usually sodium hydride) in DMF (or DMSO) and then added to the sulfone. Yields for these reactions were usually lower.
• Analogs containing sulfones as the X substituents may be displaced with sodium alkoxide in the alcohol, or alternatively reactive alkoxide or phenoxide nucleophiles that may be generated from the alcohol or phenol with a suitable base such as sodium, NaH or sodium bistrimethylsilyl amide in a polar aprotic solvent such as DMSO, or run as a neat reaction.
• the sulfone may be displaced with carbon nucleophiles.
• Suitable carbon nucleophiles include, but not limited to aryl Grignard reagents, alkyl Grignard reagents or related organometallics such as organo lithium, zinc, tin, copper or boron. These reactions may, in some cases, require transition metal catalysis such as with Pd or Ni catalysts.
• Method C is for coupling with appropriate aryl groups to convert 3 to compounds with Formula (Ia) (or 2 to 6).
• This transformation may be achieved using, but not limited to boronic acids (e.g., ClA) under Suzuki cross-coupling conditions, employing a palladium catalyst, such as tetrakis(triphenylphosphine) ⁇ alladium(O).
• boronic acids e.g., ClA
• a palladium catalyst such as tetrakis(triphenylphosphine) ⁇ alladium(O).
• the cross-coupling may be performed using aryl or heteroaryl organozinc, (e.g., aryl/heteroaryl-ZnBr, aryl/heteroaryl-ZnCl, aryl/heteroaryl-Zn- Rl), organocopper, [e.g., (aryl/heteroaryl)2-CuLi], organotin [e.g., aryl/heteroaryl-
• Method D is for coupling of 2 (or 3 or 7) with an aryl group whose structure has a suitable precursor (e.g., acidic group -CO 2 H, ester group -CO 2 Me) to the final substituent R 1 in Formula (Ia).
• a suitable precursor e.g., acidic group -CO 2 H, ester group -CO 2 Me
• This transformation may be achieved using, but not limited to boronic acids (e.g., DlA) or protected acids (e.g., DlC, DIE) under Suzuki coupling conditions, (THF/H2O, and K2CO3) employing a palladium catalyst, such as tetrakis(triphenylphosphine) palladium(O). If desired, these Suzuki coupling reactions may be run under microwave conditions.
• the boronic acid (Dl A or DIE) or ester can be synthesized either by the palladium catalyzed coupling of an aryl halide and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane or the transmetalation of an aryl halide with a Grignard reagent, e.g., isopropylmagnesium bromide followed by a trialkylborate (e.g., triethylborate) in a suitable solvent like THF.
• a Grignard reagent e.g., isopropylmagnesium bromide followed by a trialkylborate (e.g., triethylborate) in a suitable solvent like THF.
• Rj, Rj Q, and R20 is as defined for compounds of Formula (I) herein; and r is an integer having a value of 2 to 6.
• the coupling conditions include the use of appropriate solvents.
• solvents include, but are not limited to dioxane, THF, DMF 5 DMSO, NMP, acetone, water, or a combination or a mixture thereof.
• the solvent is THF/H2O, or dioxane/H2 ⁇ .
• the coupling conditions also include the presence of catalytic amount of catalysts and these catalysts include, but not limited to tetrakis(triphenylphosphine)- palladium (0), PdCl2, Pd(OAc)2, (CH3CN)2PdC12, Pd(dppf)2, or [1,1 '- bis(diphenylphosphino)-ferrocene]-dichloropalladium(II).
• catalysts include, but not limited to tetrakis(triphenylphosphine)- palladium (0), PdCl2, Pd(OAc)2, (CH3CN)2PdC12, Pd(dppf)2, or [1,1 '- bis(diphenylphosphino)-ferrocene]-dichloropalladium(II).
• the coupling reaction may or may not require the presence of a base.
• Suitable bases include, but are not limited to NaHCC>3, KHCO3, Na2CO3, K2CO3, KOAc or combination or mixture thereof.
• the base is K2CO3 and KOAc.
• the coupling reaction may or may not require heating.
• the heating can be carried out with a regular oil bath or microwave irradiations and the temperature can be varied from room temperature to > 100 0 C, i.e. reflux temperature of the solvent.
• the coupling reaction may or may not require a sealed reaction vessel and the internal pressure can be varied from one atmosphere to 100 atmospheres.
• aryl or heteroaryl boronic acid or ester intermediates containing the R] moiety used in the Suzuki coupling reactions may or may not be commercially available and they can be prepared by utilizing proper methods in the literature known to those with appropriate training. Examples of these methods include, but not limited to palladium catalyzed coupling of an aryl halide and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi-l,3,2-dioxaborolane or the transmetalation of an aryl halide with a Grignard reagent, e.g., isopropylmagnesium bromide followed by a trialkylborate (e.g., triethylborate) in a suitable solvent.
• a Grignard reagent e.g., isopropylmagnesium bromide followed by a trialkylborate (e.g., triethylborate) in a suitable solvent.
• solvents include, but not limited to CH2C12, chloroform, CH3CN, benzene, THF, hexane, ethyl ether, tert-butyl methyl ether, DMSO, DMF, toluene, n-methyl-pyrrolidine, dioxane.
• the reaction temperature can be varied from -78 °C to >100 °C, i.e. reflux temperature of the solvent.
• this reaction process step may or may not be performed under suitable microwave irradiation conditions.
• This reaction may or may not require a sealed reaction vessal and the internal pressure can be varied from one atmosphere to 100 atmospheres.
• the cross-coupling may be performed using aryl or heteroaryl organozinc, organocopper, organotin (e.g., DlB), or other organometallic reagents
• DID e.g., DID
• a protected precursor e.g.,DlC, DID, DIE
• This coupling reaction may be performed utilizing aryl or heteroaryl organozinc (e.g., Aryl-ZnBr, Ri-ZnCl, Aryl -Zn- Aryl), organocopper [e.g., (Aryl) 2 - CuLi], organotin (e.g., Aryl-Sn(CH 3 ) 3 , Aryl -Sn(CH2CH 2 CH2CH3) 3 ], or other organometallic reagents to afford the cross-coupling product.
• organozinc e.g., Aryl-ZnBr, Ri-ZnCl, Aryl -Zn- Aryl
• organocopper e.g., (Aryl) 2 - CuLi
• organotin e.g., Aryl-Sn(CH 3 ) 3 , Aryl -Sn(CH2CH 2 CH2CH3) 3
• organometallic reagents e.g., aryl or heteroaryl
• organozinc e.g., Aryl-ZnBr, Ri-ZnCl, Aryl -Zn- Aryl
• organocopper e.g., (Aryl) 2 - CuLi
• organotin e.g., Aryl -Sn(CH 3 ) 3 , Aryl -Sn(CH2CH 2 CH2CH 3 ) 3
• organometallic reagent is not commercially available, they can readily be prepared by utilizing proper methods, known in the literature.
• Such solvents include, but are not limited to dioxane, THF, methylene chloride, chloroform, benzene, hexane, ethyl ether, tert-butyl methyl ether or a combination or a mixture thereof.
• the coupling reaction may, or may not, require the presence of catalytic amount of a catalyst.
• catalysts include, but are not limited to tetrakis(triphenylphosphine)palladium (0), PdCl 2 , Pd(OAc) 2 , (CH 3 CN) 2 PdCl 2 ,
• the reaction temperature can be varied from -78 0 C to >100 0 C, i.e. reflux temperature of the solvent.
• this reaction process step may be performed under suitable microwave irradiation conditions, if needed.
• This reaction may, or may not, require a sealed reaction vessel and the internal pressure can be varied from one atmosphere to 100 atmospheres.
• Method E is for the transformation of the suitable precursor (e.g., acidic group -COOH in 4, 5, 9, 11, 15, 16, 17, or 18) to the final substituent R 1 .
• This type of transformations can be achieved by utilizing well-established strategies in the art.
• the transformation may be done in one step (such as coupling with amines HN(Rio')R-b under standard coupling conditions e.g. EDC/HOBT/ET3N in CH3CN; coupling with alcohol, HORj, under standard coupling conditions, e.g.
• DCC DCC, DMAP in DCM to form esters or reduction to alcohol
• step e.g., Curtuis rearrangement to form isocyanates followed by urea formation with amines or acid chloride formation followed by addition of an amine, HN(Ri O')Rb or an alcohol, HORb pl us a non-nucleophilic base, e.g. DIPEA in an aprotic solvent like DCM.
• This conversion may require a deprotection step to install the precursor at first (e.g., hydrolysis Of-CO 2 Me with LiOH/THF/water to prepare -COOH).
• bases include but are not limited to pyridine, diisopropyl ethylamine or pyrrolidine, which may also be used in an appropriate organic solvent, including but not limited to THF, diethyl ether, DCM, DMF, DMSO, toluene or dioxane.
• Method G is for cyclization of 8 to 9. It may be achieved by mixing compound 8 with an olefin forming agent (e.g., Wittig reagents) or amide forming agent (e.g.,. acid, acid chloride, ester) or an agent with both potential reactivities such as bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)-phosphonate, bis(2,2,2- trifluoroethyl)-(ethoxycarbonylmethyl)phosphonate, bis(2,2,2-trifluoroethyl)- (isopropoxycarbonylmethyl)phosphonate, (diethoxy-phosphoryl)-acetic acid methyl ester, (diisopropoxy-phosphoryl)-acetic acid methyl ester, (diphenyloxy-phosphoryl)- acetic acid methyl ester, (diethoxy-phosphoryl)-acetic acid ethyl ester, (diisopropoxy- phosphoryl)-ace
• reaction solvent can be DCM, THF, toluene, DMSO or DMF.
• protected group (-CO 2 Me in 8) may or may not be hydrolyzed. Either output may be utilized to the advantage of expanding structure-activity-relationship (SAR) studies.
• the hydrolysis can be achieved by mixing with LiOH in THF/water. A different protecting group at this position (e.g., tert-butyl) may require a different de-protection method (e.g., treatment with TFA).
• Preparation of compounds with Formula (I) may also be achieved through compound 2, which in turn may be constructed from aldehyde 1 as shown in Scheme 4. Suitable methods from Methods A-H can be utilized to furnish appropriate conversions in Scheme 4.
• Preparation of compounds with Formula (I) may also be achieved through compound 2, which in turn may be constructed from aldehyde 1 as shown in Scheme 5. Suitable methods from Methods A-H can be utilized to furnish appropriate conversions in Scheme 5.
• the starting material 1-Scheme 7 may be obtained from the commercially available 4,6-dihydroxy-2-methylmercaptopyrimidine by known literature procedures, such as those noted in Santilli et al., J. Heterocycl. Chem. (1971), 445- 53, wherein POCl 3 and DMF are used.
• the intermediate 2-Scheme 7 was produced by two different routes. In the first route, coupling of dichloro aldehyde 1-Scheme 7with aryl amines in the presence of NaH in DMSO (Santilli et al., J. Heterocycl. Chem. (1971), 445-53) afforded the desired compound 2-Scheme 7 along with imine 13-Scheme 7. The imine was converted to aldehyde 2-Scheme 7 by treatment with aqueous HCl in THF.
• Conversion of 1-Scheme 7 to 2-Scheme 7 may also be achieved using triethylamine and the desired amine in chloroform at room temperature for 10 minutes.
• the reaction was very effective for a range of alkyl amines (78-95 % yield).
• For aryl amines elevated temperatures (reflux) and longer reaction time (24 hours) were necessary for reaction completion.
• Use of the base could be omitted when 3 or more equivalent of amine were used.
• Other suitable bases include but are not limited to pyridine, diisopropyl ethylamine or pyrrolidine, which may also be used in an appropriate organic solvent, including but not limited to THF, diethyl ether or dioxane.
• the nitrile 9-Scheme 7 was prepared in three steps from the aldehyde 1-Scheme 7 (Santilli et al., J. Heterocycl. Chem. (1971), 445-53). Coupling of dichloro nitrile 9-Scheme 7 with aryl amines in the presence of NaH in DMSO afforded the desired compound 10-Scheme 7.
• Other suitable bases such as pyridine, diisopropyl ethylamine, or sodium may also be used in an appropriate organic solvent such as THF, DMF or dioxane.
• Production and use of the nitrile 9- Scheme-I may also be found in PCT/USOl/06688, filed March 2, 2001 whose disclosure is incorporated herein by reference in its entirety.
• Aldehyde 2-Scheme 7 was coupled to arylboronic acids under Suzuki coupling conditions, using a palladium catalyst, such as tetrakis(triphenylphosphine) palladium(O), to afford good to excellent yields of 3-Scheme 7.
• a palladium catalyst such as tetrakis(triphenylphosphine) palladium(O)
• the bi- aryl coupling reaction of 2-Scheme 7 may be performed using aryl or heteroaryl organozinc, organocopper, organotin, or other organometallic reagents known to afford bi-aryl cross-coupling products such as 3-Scheme 7 [see for example Solberg, J.; Undheim, K. Acta Chemica Scandinavia 1989, 62-68].
• Displacement of the chlorine in 2-Scheme 7 may also be achieved with nitrogen nucleophiles [for related animations see US patent 3,631,045 and 3,910,913], sulphur nucleophiles, [see Tumkevicius, S. Liebigs Ann. 1995, 1703-1705], oxygen nucleophiles, or alkyl nucleophiles.
• 3-Scheme 7 was then converted to pyridopyrimidinone 5-Scheme 7 by one of three procedures.
• the first procedure used the Wittig reaction, as modified by Horner- Emmons, converting 3-Scheme 7 to 4-Scheme 7.
• the aldehyde 3- Scheme 7 was treated with a suitable phosphorus ylide, such as triethyl phosphonoacetate or methyl diethylphosphonoacetate, to give the olefin intermediate 4-Scheme 7.
• the reaction was performed under reflux, in a suitable base, such as sodium hydride, sodium methoxide, or sodium hydroxide, and in a suitable organic solvent such as diethyl ether, dioxane or ethanol.
• the conversion of 3-Scheme 7 to 4-Scheme 7 may also be performed using the Peterson olefmation reaction, or an aldol-based olefmation reaction that utilizes acetic anhydride, malonic acid and its monoalkyl esters, or ethyl acetate. Heating of 4-Scheme 7 in toluene at 220 0 C in a sealed tube (Matyus et al.
• the third procedure involved acetylation of 3-Scheme 7, followed by the intramolecular aldol condensation, promoted by an acetylating agent (such as acetic anhydride, acetyl chloride, or a ketene) and a suitable base (such as pyridine, diispropyl ethylamine, or pyrrolidine), to generate 5-Scheme 7 in a very good yield.
• an acetylating agent such as acetic anhydride, acetyl chloride, or a ketene
• a suitable base such as pyridine, diispropyl ethylamine, or pyrrolidine
• R3 is an arylalkyl, or heteroarylalkyl substituent it is not clear that the reaction will form the key intermediate of Formula (VII), as shown below (3a- Scheme 8), which may optionally be isolated, as shown in Scheme 8 below.
• Compounds of Formula (VII) are preferably not isolated but further reacted with a base or with heat to cyclize into 5-Scheme-7. The first and second procedures should be utilized for all other R3 moieties.
• Oxidation of the sulfide 5-Scheme 7 to the sulfone 6-Scheme 7 was performed using mef ⁇ -chloroperoxybenzoic acid (mCPBA) in high yield and purity.
• mCPBA mef ⁇ -chloroperoxybenzoic acid
• Suitable oxidation methods for use herein include use of one or two equivalents of mef ⁇ -chloroperoxybenzoic acid (mCPBA) or Oxone ® to afford either the sulfoxides or sulfones.
• Oxidation of the sulfides to sulfoxides or sulfones can also be effected by OsO 4 and catalytic tertiary amine N-oxide, hydrogen peroxide, other peracids, oxygen, ozone, organic peroxides, potassium and zinc permanganate, potassium persulfate, and sodium hypochlorite.
• Displacements of the sulfones 6-Scheme 7 to the final products 7-Scheme-7 were usually done with an excess of amine in N-methylpyrrolidine (Barvian et al., J. Med. Chem. (2000), 4606-4616). A wide range of primary amines underwent this reaction with excellent yields. In some cases (in O-displacement or sulfonamide formation) an anion of the nucleophile was prepared with base (usually sodium hydride) in dimethylformamide and then added to the sulfone. Yields for these reactions were usually lower.
• sulfone of analogs of Formula (I) compounds with ethanolamine, in NMP occurred in 30 min. at 65° C, while a more hindered amine such as tris(hydroxymethyl)-aminomethane may require elevated temperatures and extended reaction times (80° C over a 24 hour reaction time).
• the sulfone can also be displaced by a primary or secondary amine with an additional non-nucleophilic base (e.g. DIPEA) in aprotic solvents like DCM, CH3CN, NMP, and at varying temperatures depending upon the nucleophilicity of the amine.
• DIPEA additional non-nucleophilic base
• the sulfone may also be displaced with a substituted arylamine, or heteroarylamine at elevated temperatures, sometimes requiring formation of the aryl or heteroarylamine anion with sodium hydride, or other suitable base, in DMSO.
• the sulfoxide analogs of Formula (I) compounds may be readily displaced with aluminum salts of aryl or heteroaryl amines as previously described in the patent literature (WO 99/32121).
• sulfone and sulfoxide analogs of Formula (I) and (Ia) may be displaced with aryl or heteroaryl or alkyl thiols or alkyl or aryl or heteroaryl alcohols.
• analogs of (I) containing sulfones as the X substituents may be displaced with sodium alkoxide in the alcohol, or alternatively reactive alkoxide or phenoxide nucleophiles may be generated from the alcohol or phenol with a suitable base such as sodium, NaH or sodium bistrimethylsilyl amide in a polar aprotic solvent such as DMSO, or run as a neat reaction.
• sulfones related to Formula (I) and (Ia) may be displaced with carbon nucleophiles such as aryl or alkyl Grignard reagents or related organometallics such as organo lithium, zinc, tin or boron.
• transition metal catalysis such as with Pd or Ni catalysts.
• Transition metal catalysis such as with Pd or Ni catalysts.
• Displacement of related 2- pyrimidine sulfones with cyanide, malonate anions, unactivated enolates, or heterocyclic C nucleophiles such as 1-methylimidazole anion, by the generation of the anion with NaH or other suitable base in THF also has precedent (see for example, Chem Pharm Bull. 1987, 4972-4976.).
• analogs of Formula (I) and (Ia) compounds wherein X is an alkyl sulfone may be displaced with the anion of 1 -methyl imidazole, generated by treatment of 1 -methyl imidazole with n-butyl lithium in a solvent such as THF at temperatures of about -70°, to afford the C- alkylated product substituted on the imidazole C-2.
• compounds of Formulas (I), (Ia), (II) and (Ha) wherein X is R.2 or NHS(O)mR.2 may be obtained from compounds of 6-Scheme 7 by displacement of the sulfone using the appropriate "X" functionality as defined in Formula (I) and (Ia).
• Suitable oxidation methods for use herein include use of an oxidant such as one or two equivalents of met ⁇ -chloroperoxybenzoic acid or Oxone ® to afford either the sulfoxides or sulfones.
• Oxidation of the sulfides to sulfones may also be effected by OsO 4 and catalytic tertiary amine N-oxide.
• Other methods for sulfide oxidation include the use of hydrogen peroxide, other peracids, oxygen, ozone, organic peroxides, potassium and zinc permanganate, potassium persulfate, and sodium hypochlorite.
• 8-Scheme 7 can be also prepared by heating the trans ester 4-Scheme 7 in alcohol in the presence of the corresponding sodium alkoxide. The yield of this reaction was very high for primary alcohols, but longer reaction times were required for secondary alcohols. Sodium alkoxides may be easily prepared from corresponding alcohol and base, such as sodium or sodium hydride.
• Reduction of trans ester 4-Scheme 7 with SmI 2 gives the reduced analogue 11-Scheme 7.
• This reduction can be also done in the presence of other reducing agents such as hydrogen gas, lithium in liquid ammonia, magnesium or sodium borohydride in the appropriate organic solvent such as THF, ethanol or diethyl ether.
• Cyclization of the ester 11-Scheme 7 can be done utilizing sodium methoxide in methanol to give reduced analogue 12-Scheme 7.
• Other organic bases, such as sodium, sodium ethoxide or TEA can be used in an appropriate organic solvent such as methanol, ethanol or dioxane.
• the product 12-Scheme 7 can be also obtained by heating ester 11-Scheme 7 to 150 0 C in an appropriate organic solvent, such as toluene, xylene or isopropanol.
• Scheme 9 The preparation can be achieved by reacting compound 16 (for A or B) or 3 (for Al or Bl) with another reagent with appropriate structures as shown in Scheme 9 employing Method I.
• Method I is for the substitution of -LG 2 with appropriate compound containing the structural unit of -Y-H. This can be achieved by heating the reaction mixtures in appropriate solvents.
• the heating method can be selected from either a regular oil bath or microwave irradiations.
• Solvents can be CH 2 Cl 2 , DMSO, DMF, toluene, benzene, CH 3 CN or NMP.
• the reaction may or may not require the presence of bases.
• An example of the base can be selected from, but not limited to triethyl amine, diisopropyl ethyl amine, NaH, n-BuLi, tert-Bul ⁇ , tert-BuOK, Li 2 CO3,
• This transformation may also require the presence of catalytic amount of catalysts containing transition metals (e.g., Pd, Cu, Ni, or W). These catalysts include, but not limited to Pd/C, Pd(PPh 3 ) 4 and PdCl 2 .
• catalysts include, but not limited to Pd/C, Pd(PPh 3 ) 4 and PdCl 2 .
• Rl is an aryl ring substituted as defined in compounds of Formula (I) and (II) inclusive;
• R3 is an C]_io alkyl, C 3.7 cycloalkyl, C 3.7 cycloalkylalkyl, aryl, arylCi_io alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic, or aheterocyclylCj.io alkyl moiety, which moieties are optionally substituted;
• R ⁇ 2' is a C ⁇ . iQ alkyl, aryl, heteroaryl, or arylalkyl;
• m is 0 or an integer having a value of 1 or 2; and
• Rg is a Cj.4 alkyl.
• Rg is a Ci_4 alkyl, and more preferably methyl.
• m is 0 or an integer having a value of 1 or 2. More preferably m is 0 or 2.
• R3, Rj 2' j m an d Rg are as defined for Formula (VII) above;
• Rl is a ring substituted as defined in compounds of Formula (III).
• R3, Ri2'j m and Rg are as defined for Formula (VII) above;
• Rl is a ring substituted as defined in compounds of Formula (V).
• R3, R12', m and Rg are as defined for Formula (VII) above;
• R3 is an optionally substituted CJ.J O alkyl, C3_7 cycloalkyl, C3_7 cycloalkylalkyl, or aryl.
• R3 optional substituents are independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
• Rl is as defined above for Formula (I) and (II) compounds, and R3, Rg, and m is an optionally substituted aryl or heteroaryl moiety, as defined for Formula (VII) compounds.
• Rl is defined above for Formula (III) to (VI) compounds, and R3, Rg, and m is an optionally substituted aryl or heteroaryl moiety, as defined for Formula (VII) compounds.
• Another aspect of the invention are compounds of Formula (C) and (Cl):
• LG2 is chlorine, bromine, iodine, or O-S(O)2CF3;
• R3 is a Ci_io alkyl, C3.7 cycloalkyl, C ⁇ . ⁇ cycloalkyl CJ. ⁇ Q alkyl, aryl, aryl Cj. JO alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic or a heterocyclylCi_io alkyl moiety, and wherein each of these moieties may be optionally substituted, and is as defined for compound of Formula (I) and (Ia) herein.
• Gl, G2, G3, G4 and X are as described for compounds Formula (I) and (Ia) herein;
• LG2 is chlorine, bromine, iodine, or O-S(O)2CF3;
• R3 is a Ci_io alkyl, C3..7 cycloalkyl, C3.7 cycloalkyl C ⁇ io alkyl, aryl, aryl Cj _ 10 alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic or a heterocyclylCi_io alkyl moiety, and wherein each of these moieties may be optionally substituted (and are as defined for compounds of Formula (I) and (Ia) herein).
• Gl, G2, G3, G4, Rj and (R-i)g are as described for compounds of Formula (I) and (Ia) herein; m is 0 or an integer having a value of 1 or 2; Rg is a C i.ioalkyl;
• LG2 is chlorine, bromine, iodine, or O-S(O)2CF3;
• R3 is a Ci_io alkyl, C3..7 cycloalkyl, C3..7 cycloalkyl CJ_IQ alkyl, aryl, aryl C]_]Q alkyl, heteroaryl, heteroarylCi_io alkyl, heterocyclic or a heterocyclylCi_io alkyl moiety, and wherein each of these moieties maybe optionally substituted (as defined for compounds of Formula (I) and (Ia) herein).
• RL Rl % g > and R3 are as defined for Formula (II) herein.
• CDCI3 is deuteriochloroform
• DMSO-d ⁇ is hexadeuteriodimethylsulfoxide
• CD3OD or MeOD
• Heating of reaction mixtures with microwave irradiations was carried out on a Smith Creator (purchased from Personal Chemistry, Forboro/MA, now owned by Biotage), a Emrys Optimizer (purchased from Personal Chemistry) or an Explorer (provided by CEM Discover, Matthews/NC) microwave.
• the title compound was prepared by following the procedure in Example 1 d trom N-(cyclopropylmethyl)-3-(8-(2,6-difluorophenyl)-2-methyl sulfone-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylbenzamide and 1,1 -dimethyl ethyl A- amino- 1 -piperidinecarboxylate.
• Example 7c The title compound was prepared as described in Example 7c from 6-chloro- iV- ⁇ 3-[8-(2,6-difluoro ⁇ lienyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3- J]pyrimidin-4-yl]-4-methylphenyl ⁇ -3- ⁇ yridinecarboxamide and m-CPBA: LC-MS m/z 582 (M+H)+, 2.30 min (ret time).
• Example 18 The title compound was prepared as described in Example Id from 6-chloro- iV- ⁇ 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3- c?]pyrimidm-4-yl]-4-methylphenyl ⁇ -3-pyridinecarboxamide and (lH-imidazol-2- ylmethyl)amine dihydrochloride: LC-MS m/z 599 (M+H) + , 1.92 min (ret time).
• Example 18 Example 18
• the benzoic acid (1.54 g, 0.01 mol) is dissolved in trifluoroniethanesulfonic acid (10 mL) and cooled to about 0 0 C.
• NIS (2.25 g. 0.01 mol) is added in several portions over a 6 h period while maintaining the reaction temperature at about 0 0 C.
• the mixture is allowed to warm to rt. overnight.
• the reaction mixture is then poured over ice and extracted with ethyl acetate (3x).
• the organic layers are washed (Na 2 SaO 5 ) and concentrated.
• the material is carried on crude.
• the title compound was prepared from 3-[8-(2,6-difluoro ⁇ henyl)-2- (methylthio)-7-oxo-7,8-dihydropyrido[2,3-(i]pyrimidin-4-yl]-4-methylbenzoic acid and 4-fluoroaniline by following the General Procedure for EDC couplings as disclosed in the general experimental section above. Crude reaction mixture was purified via flash chromatography (EtOAc:Hexanes, 2:1) to afford the title compound (0.125 g, 34%).
• the title compound (0.105 g, 79%) was prepared by following the General Procedure for sulfide oxidations, as disclosed above.
• the title compound is prepared by following the General Procedure for Sulfoxide/Sulfone/sulfone displacement as disclosed above. Concentrated reaction mixture is purified via reversed-phase HPLC to give the desired compound as a white solid (43 mg, 39%): LC-MS m/z 576 (M+H) + , 1.89 min (ret time). HPLC (254nm) indicates 90% pure.
• the borate ester (0.683 g, 2.27 mmol), chloride (0.768 g, 2.27 mmol), K 2 CO 3 (0.941 g, 6.81 mmol) and tetrakistriphenylphosphine palladium (131 mg, 0.11 mmol) are dissolved in dioxane / water (3:1) and heated at reflux for about 4 h. The reaction mixture is then taken up in ethyl acetate and washed with water, brine and dried with Na 2 SO 4 . The concentrated mixture was purified via flash chromatography to give the desired product (0.6 g, 55%).
• the title compound is prepared according to the General Procedure for sulfide oxidation, as disclosed above. It is concentrated to give the desired product as a yellow powder (0.3 g, 49%).
• the title compound is prepared according to the General Procedure for Sulfoxide/Sulfone/Sulfone Displacement, as disclosed above.
• the concentrated reaction mixture is precipitated with DMSO / water, and filtered.
• the desired product is obtained as a white solid (m.p. 326.3-327.9) 95% pure by.HPLC (55 mg, 45%): LC-MS m/z 587 (M+H) + , 1.74 min (ret time).

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