ZA200700314B - Fused ring heterocycle kinase modulators - Google Patents

Fused ring heterocycle kinase modulators Download PDF

Info

Publication number
ZA200700314B
ZA200700314B ZA200700314A ZA200700314A ZA200700314B ZA 200700314 B ZA200700314 B ZA 200700314B ZA 200700314 A ZA200700314 A ZA 200700314A ZA 200700314 A ZA200700314 A ZA 200700314A ZA 200700314 B ZA200700314 B ZA 200700314B
Authority
ZA
South Africa
Prior art keywords
unsubstituted
substituted
membered
heteroaryl
aryl
Prior art date
Application number
ZA200700314A
Inventor
William D Arnold
Gosberg Andreas
Li Zhe
Ruo W Steensma
Mark E Wilson
Original Assignee
Sgx Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sgx Pharmaceuticals Inc filed Critical Sgx Pharmaceuticals Inc
Publication of ZA200700314B publication Critical patent/ZA200700314B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

FUSE RING HETERQCYCLE= KINASE MODU_TLATORS
CROSS-REFERENCES TO REEATED APPLICATIONS
[0001] This application claims the benefit of US. Provisional Patent =Application No. 60/591,778, fileed July 27, 2004, U.S. Provisional Patent Application No. 60/591,886, filed
July 27, 2004, a—nd U.S. Provisional Patent Application No. 60/680,091 -, filed May 11, 2005, each of which iss incorporated herein by reference in its entirety for all pourposes.
BACKGROUND OF T HE INVENTION
[0002] Mamr malian protein kinases are important regulators of cellul ar functions.
Because dysfurctions in protein kinase activity nave been associated with several diseases and disorders, gorotein kinases are targets for dru_g development.
[0003] The tyrosine kinase receptor, FMS-like tyrosine kinase 3 (FL_T3), is implicated in cancers, including leukemia, such as acute myel oid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplasia. About oxe-quarter to one-third of AML patients } have FLT3 muntations that lead to constitutive activation of the kinase and downstream signaling path—ways. Although in normal humars, FLT3 is expressed mmainly by normal myeloid and 1=ymphoid progenitor cells, FLT3 iss expressed in the leuk—emic cells of 70-80% of patients witch AML and ALL. Inhibitors that: target FLT3 have been reported to be toxic to leukemic ceslis expressing mutated and/or comstitutively-active FLTC3. Thus, there is a need to develop potent FLT3 inhibitors that may be used to treat dise=ases and disorders such as leukemia. :
[0004] The Abelson non-receptor tyrosine ki nase (c-Abl) is involve=d in signal transduction, via phosphorylation of its substrate proteins. In the cell, c-Abl shuttles between the cytoplasm and nucleus, and its activity is normally tight®y regulated through a number of divverse mechanisms. Ab] has been implicated in the contmrol of growth-factor and integrin signaling, cell cycle, cell differentiation and neurogenesis, agpoptosis, cell adhesion, cytoskeletal sstructure, and response to DNA d=amage and oxidative stress.
[0005] The c-Abl protein contains approximately 1150 amino-acic3 residues, organized into a N-terminal cap region, an SH3 and an S-H2 domain, a tyrosine= kinase domain, a nuclear local ization sequence, a DNA-bindings domain, and an actin—binding domain.
[0006] Chmronic myelogenous leukemia (CML) is associated with sthe Philadelphia chromosomaza] translocation, between chromossomes 9 and 22. This t=ranslocation generates an aberrant fFusion between the ber gene and tthe gene encoding c-Abol. The resultant Ber-
Ab] fusion protein has constitutively active tyrosine-kinase activity. The elevated kinase activity is reported to be the priamary causative factor of CML, and 3s responsible for cellular transformation, loss of growth-factor dependence, and cell Proliferation.
[0007] The 2-phenylaminopyximidine compound imatinib (also referred to as STI-571,
CGP 57148, or Gleevec) has been identified as a specific and potent inhibitor of Ber-Abl, as well as two other tyrosine kinasses, c-kit and platelet-derived growtkn factor receptor.
Imatinib blocks the tyrosine-kixaase activity of these proteins. Imatinib has been reported to be an effective therapeutic agent for the treatment of all stages of CML. However, the majority of patients with advarmced-stage or blast crisis CML suffer a relapse despite continued imatinib therapy, due to the development of resistance to the drug. Frequently, the molecular basis for this resistance is the emergence of imatinib -resistant variants of the kinase domain of Ber-Abl. Thie most commonly observed underlying amino-acid substitutions include Glu255Y.ys, Thr315lle, Tyr293Phe, and Met 51 Thr. [0008) MET was first identified as a transforming DNA rearrangement (TPR-MET) in a human osteosarcoma cell line that had been treated with N-methyk-N'-nitro- nitrosoguanidine (Cooper et aX. 1984). The MET receptor tyrosines kinase (also known as hepatocyte growth factor receptor, HGFR, MET or c-Met) and its ligand hepatocyte growtkn factor ("HGF") have numerous biological activities including the stimulation of proliferation, survival, differentiation and morphogenesis, branching tubulogenesis, cell motility and invasive growth. Pathologically, MET has been imp licated in the growth, invasion and metastasis of many different forms of cancer includi ng kidney cancer, lung cancer, ovarian cancer, liver cancer and breast cancet. Somatic, Activating mutations in
MET have been found in hunan carcinoma metastases and in spostadic cancers such as papillary renal cell carcinoma. The evidence is growing that MET is one of the long-sought oncogenes controlling progression to metastasis and therefore a very interesting target. In addition to cancer there is evidence that MET inhibition may hav=e value in the treatment Of various indications including: Listeria invasion, Osteolysis assoc-iated with multiple myeloma, Malaria infection, diabetic retinopathies, psoriasis, ancl arthritis.
[0009] The tyrosine kinase RON is the receptor for the macrophage stimulating protein and belongs to the MET family of receptor tyrosine kinases. Likse MET, RON is implicated in growth, invasion and metastasis of several different forms of «cancer including gastric cancer and bladder cancer.
[0010] The Aurora family of serine/theronine kinase sis essential for mitotic progression.
Expression and activity of the Arurora kinases are tigh. tly regulated during the cellcycle. A variety of proteinss having roles in cell division have been identified as Aurora kinase substrates. Based. on the known function of the Auror=a kinases, inhibition of thesir activity is believed to disrupst the cell cycle and block proliferation and therefore tumor cell viability.
Harrington et al., Nature Medicine, advanced publicat=ion online (2004).
[0011] 3-Phospehoinositide-dependent kinase 1 (PDIK1) is a Ser/Thr protein kinase that can phosphorylate and activate a number of kinases ir the AGC kinase super fammily, including Akt/PXZB, protein kinase C (PKC), PKC-reRated kinases (PRK 1 and PRK2), p70 ribobsomal S6-kanase (S6K1), and serum and glucocorticoid-regulated kinase CSGK). The first identified PXDK 1 substrate is the proto-oncogene Akt. Numerous studies Imave found a high level of activated Aktina large percentage (30-60%) of common tumor types, including melanoma and breast, lung, gastric, prostatze, hematological and ovamrian cancers.
The PDK 1/Akt signaling pathway thus represents an. attractive target for the deevelopment of small molecule inhibitors that may be useful in the treatment of cancer. Feldman et al., JBC
Papers in Press. Published on March 16, 2005 as Maanuscript M501367200.
[0012] Because kinases have been implicated in nmumerous diseases and con_ditions, such as cancer, there is a need to develop new and potent protein kinase inhibitors sthat can be used for treatment. The present invention fulfills theese and other needs in the art. Although certain protein Rcinases are specifically named herein, the present invention is not limited to inhibitors of these kinases, and, includes, within its scope, inhibitors of related protein kinases, and inkibitors of homologous proteins.
BRIEF DESCRIPTION OF “THE DRAWINGS
[0013] Figure 1 shows the wild-type ABL numbe=ring according to ABL ex—on Ia.
BRIEF SUMMARY OF TIE INVENTION
[0014] It has been discovered that, surprisingly, fused ring heterocycle conmpounds of the present invention may be used to modulate kinase activity and to treat diseas. es mediated by kinase activity". These novel fused ring heterocycles kinase modulators are described in detail below. In addition, inhibitory activities of selected compounds are dissclosed herein.
[0015] In ome aspect, the present invention provi des a fused ring heterocycle kinase modulator having the formula:
H op
N
RA 2
LR? O.
[0016] In Formula (I), L' and L? are independently a bond, -S(O)s-, -O-, -NH-= unsubstituted C,-«Cs alkylene, or unsubstituted 2 to 5 membered heteroalkylene. The symbol n is an ingeger from 0 to 2. R! and R? are indepeendently substituted or umsubstituted cycloalkyl, substi tuted or unsubstituted heterocycloalky/l, substituted or unsubsti tuted heteroaryl, or sub»stituted or unsubstituted aryl. In somes embodiments, R'isnot substituted or unsubstituted pyrrolyl. In other embodiments, 1! is Tot unsubstituted 2 to 5 rmembered heteroalkylene when R and R? are both unsubstituted gohenyl. In other embodir nents, L' is not -S(0);- where R? is unsubstituted piperazinyl.
[0017] In anotkaer aspect, the present invention provi des a fused ring heterocy=cle kinase modulator (also weferred to herein as a "compound of tthe present invention") having the formula: .
H
Na N
R2_ J PY 12” °N
L1-R? 1m).
[0018] In Forrmula (ID), IL}, 14 R!, and R? are as deff ned above in the discussi_on of
Formula (I).
[0019] In another aspect, the present invention prov ides a fused ring heterocye/cle kinase modulator (also referred to herein as a "compound of the present invention”) h=aving the formula: , H
Na N,
R2_ I Py N 12 N
L1-R! (mm).
[0020] In Formula am, L!, L% R}, and R? are as de=fined above in the discus.sion of
Formula (I).
[0021] In anowther aspect, the present invention provsides methods of modulat=ing protein kinase activity wsing the fused ring heterocycle kinases modulators of the present invention.
W 0 2006/015124 PCT/US2005/026734
The method includes contacting the protein kinase with a fused rings heterocycle kinase modclulator.
[0022] In another aspect, the pressent invention provides methods of treating a disease meciiated by kinase activity (kinase mediated disease or disorder) iim a subject (e.g. mamymals, such as humans) in need of such treatment. The method includes administesxing to the subject a therapeutically effe=ctive amount of a fused ring heteerocycle kinase mo=dulator of the present invention —
[0023] In another aspect, the pre sent invention provides a pharm aceutical compositio=n including a fused ring heterocycle kinase modulator in admixture vith a pharmaceuticaally acceptable excipient.
DETAILED DESCRIPTION OF THE INVENATION Definitions
[0024] Abbreviations used herein have their conventional meaning within the chemiecal . an. d biological atts. [0 025] Where substituent group sare specified by their conventi-onal chemical formualae, written from left to right, they equally encompass the chemically Edentical substituents that w ould result from writing the stru_cture from right to left, e.g., -CFL,0- is equivalent to -OCH;-. [(®026] The term "alkyl," by itse=If or as part of another substitue=nt, means, unless otherwise stated, a straight (i.e. uzbranched) or branched chain, om cyclic hydrocarbon _ raadical, or combination thereof, which may be fully saturated, mowno- or polyunsaturat-ed and czan include di- and multivalent readicals, having the number of cambon atoms designated (i.e.
C,-Co means one to ten carbons)». Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylimethyl, homologs an.d isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsatumrated a_lkyl group is one having one or more double bonds or triple bon_ds. Examples of ’ wnsaturated alkyl groups include, but are not limited to, vinyl, 2-joropenyl, crotyl, 2- issopentenyl, 2-(butadienyl), 2,4-poentadienyl, 3-(1,4-pentadienyl)_, ethynyl, 1- and 3- propynyl, 3-butynyl, and the highher homologs and isomers. Alksyl groups which are 1_imited t © hydrocarbon groups are terme d "homoalkyl".
[0027] The term "alkylene" by itself or as part of another substinient means a divale=nt radical derived from an alkyl, as exemmplified, but not limited, by —CCH,CH,CH,CH,-, -CH,CH=CHCH,-, —-CH,C=CCH,-, and -CH,CH,CH(CH,CH,CH=)CH;-. Typically, an alkyl (or alkylene) group will have ficom 1 to 24 carbon atoms, withn those groups having 10 ox fewer carbon atoms being preferrezd in the present invention. A “lower alkyl" or "leower alkylene" is a shorter chain alkyl or alkylene group, generally havimng eight or fewer c=arbon atoms. [©0028] The term "heteroalkyl," by itself or in combination with amnother term, means=s, wnless otherwise stated, a stable strasght or branched chain, or cycl ic hydrocarbon radical, or combinations thereof, consisting of zat least one carbon atoms and &at least one heteroatom selected from the group consisting o £0, N, P, Si and S, and wherein the nitrogen, sul: fur, and phosphorus atoms may optional 1y be oxidized and the nitroger heteroatom may
Optionally be quaternized. The hetewoatom(s) O, N, P and S and S—i may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is att=ached Ce to the remainder of the molecule. Examples include, but are not li—mited to, -CH,-CH _»-O-
CHa, -CH,-CH,-NH-CHj, -CH,-CH 2-N(CH3)-CHi, -CH,-S-CH>~CZHs, -CH,-CHp,-S(&0)-
CH, -CH,-CH,-S(0),-CH3, -CB=C H-0-CHj, -Si(CHj3)3, -CH2-CE=1=N-OCHj, -CH=C_H-
IN(CH;)-CH3, O-CHj3, -O-CH,-CH3, and —CN. Up to two or three Bheteroatoms may b e consecutive, such as, for example, -€CH,-NH-OCH3 and ~CH,-O-S8i(CH3)s. Similarly=, the tem "heteroalkylene"” by itself or as part of another substituent me=ans a divalent radiecal derived from heteroalkyl, as exempl ified, but not limited by, -CH,;—CH,-S-CH;-CH,- and -
CH,-S-CH,-CH,-NH-CH,-. For heteroalkylene groups, heteroator=ms can also occupy= either or both of the chain termini (e.g., allxyleneoxo, alkylenedioxo, alkyyleneamino, alkylenediamino, and the like). StilK further, for alkylene and hete—roalkylene linking _groups, no orientation of the linking group iss implied by the direction in w—hich the formula ozf the
Linking group is written. For examp le, the formula —C(O)OR'- rep- resents both -C(OWOR'-. and -R'OC(0)-. As described above, heteroalkyl groups, as used Therein, include thosse groups that are attached to the remainder of the molecule through =a heteroatom, such as -
C(O)R', -C(O)NR', -NRR, -OR’, -S R|, and/or -SO;R'. Where "heteroalkyl" is recitec,
Followed by recitations of specific heteroalkyl groups, such as -NRRR' or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundarmt or mutually exclusive.
Rather, the specific heteroalkyl grovaps are recited to add clarity. Whus, the term
"heteroalkyw1" should not be interpreted herein as excluding specific hete=roalkyl groups, such as -NR'R" «or the like.
[0029] T he terms "cycloalkyl" and "hetero cycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of " alkyl” and "heteroalk=y!", respectively. Additionally, for heterocycloalkyl, a heteromatom can occupy the position at which the heterocycle is attached to the remainder of the mowlecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cy=clohexenyl, 3- cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1 —(1,2,5,6-tetrahydropyridyl), 1 —piperidinyl, 2-piperidinyl, =3-piperidinyl, 4- morpholiryl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yT4, tetrahydrothien-2- yl, tetrahy~drothien-3-yl, 1 —piperazinyl, 2-piperazinyl, and the like. Time terms "cycloalk-ylene" and "heterocycloalkylene" refer to the divalent derivatives of cycloalkyl and heteraocycloalkyl, respectively.
[0030]. The terms "halo" or "halogen," by themselves or as part of arother substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and po lyhaloalkyl. For example, the term "halo(C;-Cy)alky!" is mean to include, but not be limited to, trifluorormethyl, 2,2,2-trifluorcethyl, 4-chlorobutyl, 3-bromopropyl, amd the like.
[0031] The term "aryl" means, unless otherwise stated, a polyunsati rated, aromatic, hydrocar=bon substituent which can be a simgle ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently. The term "heter-oaryl" refers to aryl groups (=or rings) that contain from one to four heteroatoms (in each s-eparate ring in the case of multigple rings) selected from N, O, and S, wherein the nitrogen aned sulfur atoms are optional ly oxidized, and the nitrogen atorn(s) are optionally quaternizzed. A heteroaryl group czan be attached to the remainder of the molecule through a car~bon or heteroatom.
Non-limmiting examples of aryl and hetero aryl groups include phenyl, 1-naphthyl, 2- naphthy=1, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- imidazoolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, =5-oxazolyl, 3- isoxazo-lyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiamzolyl, 2-furyl, 3-furyl , 2-thien=yl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-poyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, S-isoquinolyl, 2- quinoxaalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituernts for each of above noted aryl and heteroaryl ring systems are selected from the groups of acceptable subsstituents described below. The terms "arylene" and "heteroarylene” refer tc the divalent radiczals of ar-yl and heteroaryl, respectively.
[032] For brevity, the term "ary”1" when used in combination w=ith other terms (e.53., ar-yloxo, arylthioxo, arylalkyl) includes both aryl and heteroaryl rings as defined abowve.
T hus, the term "arylalkyl" is meant to include those radicals in winich an aryl group 3s attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl” and the like) inclimding those alkyl groups in which a carbon atom (e.g., 2 methylene growip) has been replaced by, for example, an oxygen atom (e.g. , phenoxymethyl, 2-pyridyloxy=methyl, 3-(1- maphthyloxy)propyl, and the like). However, the term "haloaryl,” ' as used herein is mmeant to cover only aryls substituted with one or more halogens.
[0033] Where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific mamber of rmembers (e.g. "3 to 7 membered” ), the term "member" referrers to a carbon or hete=roatom.
E0034] The term "oxo" as used Therein means an oxygen that is double bonded to -a carbon atom. f0035] Each of above terms (e. £2. "alkyl," "heteroalkyl," "cycloalkyl, and *heterocycloalkyl”, "aryl," "heteroaryl" as well as their divalent —radical derivatives ) are “meant to include both substituted. and unsubstituted forms of the= indicated radical.
Preferred substituents for each type of radical are provided belo=w. Co
[0036] Substituents for alkyl, heteroalkyl, cycloalkyl, heteroc=ycloalkyl monovaleent and divalent derivative radicals (including those groups often referre=d to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloamlkyl, cycloalkenyl... and heterocycloalkenyl) can be one or more of a variety of groups seelected from, but n_ot limited to: -OR', =O, =NR', =N-OR', -NIRR", -SR’, -halogen, -SiR'R"R™", -OC(O)R, -C(O-)R, -CO,R',-C(O)NR'R", -OC(O)NRR", -NR"C(O)R', -NR-C(O)NCR"R", -NR"C(O)YOOR',
NR-C(NRR")=NR", -S(O)R’, —=S(O):R/, -S(O);NRR", -NRSO=;R’, -CN and -NO= in a number ranging from zero to (2rm'+1), where m' is the total number of carbon atormns in such radical. R', R", R" and R" each preferably independently refer to hydrogen, substituted or :msubstituted heteroalkyl, substi tuted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary=1 (e.g., aryl substitented with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thiomalkoxy groups, or arylalkyl groups. When a compound of the invention includes more thar one R group, for ~example,
WNO 2006/015124 PCT/US2005/026794 each of the R groups is independently selected as are each R', R", R""" and R"" groups when moore than one of these groups is present, When R' and R" are attach- ed to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, &G-, or 7-membered ring.
Foor example, -NR'R" is meant to include, but not be limited to, 1-pymrolidinyl and 4- meorpholinyl. From the above discussion of substituents, one of skill. in the art will urderstand that the term "alkyl" is meant to include groups including carbon atoms bound to gr-oups other than hydrogen groups, such as haloalkyl (e.g., -CF3 ancl -CH,CF3) and acyl (e.g, -C(O)CHs3, -C(O)CF3, -C(O) CH,OCHj, and the like). [©037] Similar to the substituents described for alkyl radicals abosve, exemplary suabstituents for aryl and heteroary1 groups ( as well as their divalentz derivatives) are varied amd are selected from, for example: halogen, -OR', -NR'R", -SR', -h:alogen, -SiR'R"R", -@C(O)R!, -C(O)R', -COR!, -C(O)NR'R", -OC(O)NRR", NR"C(O)R!, -NR'-C(O)NR"R",
NR"C(O)OR!, -NR-C(NRR"R"")=NR"", -NR-C(NR'R")=NR", -SCO)R’, -S(O)R’, - S(O)NRR", -NRSO;R', -CN and -NO,, -R', -N3, -CH(Ph),, fluorc(C,-Cy)alkoxo, and fFluoro(C;-Cq)alkyl, in 2 number ranging from zero to the total number of open valences on aaromatic ring system; and where R’, R", R™ and R"" are preferably independently selected
From hydrogen, substituted or unsubstituted alkyl, substituted or upmsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for ex—ample, each of the R groups is independently selected as are each R', R", R™ and R"" gr oups when more than one «of these groups is present.
[0038] Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR")-U-, wherein T and U are independently -NR-, - 0-, -CRR'- or a single bond, and q is an integer of from 0 to 3. Al ternatively, two of the substituents on adjacent atoms ofaryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CHz)-B-, wherein A and B are indespendently -CRR'-, -O-, -
NR-, -§-, -8(0)-, -S(0)z~, -S(O) 2NR'"- or a single bond, and r is an__ integer of from 1to 4.
One of the single bonds of the mew ring so formed may optionally~ be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CR=2R")-X'-(C'R")4-, Where s and d are independently integers of from 0 to 3, and X' is =O-, -N_R"-, -S-, -S(O)-, -8(0);-, or~ -S(O);NR'-. The substituents R,R', R" and R" are preferably inclependently selected from hydrogen, substituted o-r unsubstituted alkyl, substitute=d or unsubstituted cyclosalkyl, substituted or unsubstituted heterocycloalkyl, substitut-ed or unsubstituted aryl, and substituted or unsubstit-uted heteroaryl.
[0039] As used hereim, the term "heteroatom" or "rirag heteroatom" is meant to include oxygen (0), nitrogen (IN), sulfur (S), phosphorus (P), 2and silicon (Si).
[0040] An "aminoalksyl" as used herein refers to an zamino group covalently bound to an alkylene linker. The asmino group is -NRR", wherein R' and R" are typically selected from hydrogen, substituted or unsubstituted alkyl, substituteed or unsubstituted hetemoalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyc=loalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0041] A "substituerat group,” as used herein, meanss a group selected from the following moieties:
[0042] (A) -OH, -INH,,-SH, -CN, -CF3, -NO,, ox eo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitute=d cycloalkyl, unsubstitcated heterocycloalkyl, unsubstituted aryl, w_nsubstituted heteroaryl, and
[0043] (B) alkyl, Ineteroalkyl, cycloalkyl, heteroc_ycloalkyl, aryl, and hete=roaryl, substituted with at least one substituert selected from:
[0044] @) oxo, -OH, -NH,, -SH, -CN, -CF;, -NO, halogen, unsumbstituted alkyl, unsubstituted heteroalkyl, unswbstituted cycloalkyl, ursubstituted heterocycloalkyl, unsubstitutead aryl, unsubstituted heteroaryl, and
[0045] (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, znd heteroaryl, substituted with at least one siabstituent selected from=
[0046] (a) oxo, -OH, -NHa, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, urmsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, un:substituted aryl, unsubstituted heteroar—yl, and [0047) (b) alkyl, heteroalkyl, cyc loalkyl, heterocycloalkywl, aryl, or heteroaryl, substituted with at least one substistuent selected from oxo, -OH, -NH;, -SH, -CN, -CF3, -NOa, halogen, unsubstituted alkyl, urasubstituted heteroalkyl., unsubstituted cycloalkyl, unsubstituted heterocyclo alkyl, unsuabstituted aryl, and unsubstituted heteroaryl. [0048) A “size-limited substituent" or size-linnited substituent group," as Lased herein means a grosup selected from all of the substituents described above for a "sutostituent group," wherein each substituted or unsubstituted alkyl is a substituted or unssubstituted Ci-
Cao alkyl, ezach substituted or unsubstituted heteroalkyl is a substituted or unssubstituted 2 to member=ed heteroalkyl, each substituted or unsubstituted cycloalkyl is a suabstituted or unsubstituted Cs-Cs cycloalkyl, and each substituated or unsubstituted heteroc=ycloalkyl is a substituted or unsubstituted 4 to 8 membered het erocycloalkyl.
[0049] A_ "lower substituent" or " lower substi tuent group,” as used hereina means a group selected from all of the substituents described above for a "substituent groups," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C;-Cg alky1, each substituted _ or unsubstituted heteroalkyl is a substituied or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or um nsubstituted Cs-
C; cycloallikyl, and each substituted or unsubstituted heterocycloalkyl is a su™bstituted or unsubstituated 5 to 7 membered heterocycloalkyl .
[0050] The compounds of the present invention may exist as salts. The present invention includes suach salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citmrates, fumarates, tartrates (eg (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates., benzoates and salts with amino acids such as glutamic acid. These salts may be prepared ty methods known to those skilled in art. Also included are base =addition salts such as so dium, potassium, calcium, ammonium, organic amino, or magnes=ium salt, or a similar salt. When compounds of the present irxvention contain relatively bzasic functionaB ities, acid addition salts can be obtained by contacting the neutral form of such compouncis with a sufficient amount of the desired acid, either neat or in a Suitable inert solvent. Fxamples of acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, caxbonic, monohydrogencarbownic, phosphoric, monohydmrogenphosphoric, dihydrogenphosphoic, sulfuric, monohydrogen_sulfuric, hydriodic , or phosphorous acids and the like, as well as the salts derived orgganic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fimmaric, lactic, mandelic_, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanaesulfonic, and the like. Also included are salts of amino acids such as arginate amnd the like, and salts of i organic acids like glucuronic or gal actunoric acids and the like. Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compoumids to be converted into either base or acid addition salts .
[0051] The neutral forms of the compounds are preferably rege=nerated by contactinge the salt with a base or acid and isolatirag the parent compound in the conventional manner—. The parent f=omm of the compound diffe=rs from the various salt forms in certain physical properties, such as solubility in po lar solvents.
[0052] Certain compounds of th_e present invention can exist i-n unsolvated forms ass well as solvated forms, including hydrated forms. In general, the sol-vated forms are equivalent to unsowlvated forms and are encormpassed within the scope of thme present invention. Certain compownds of the present invention may exist in multiple crystalline or amorphous f=orms.
In general, all physical forms are equivalent for the uses contenplated by the present invention and are intended to be ovithin the scope of the present- invention.
[0053] Certain compounds of thie present invention possess a-symmetric carbon atcoms (optical or chiral centers) or doubsle bonds; the enantiomers, raccemates, diastereomers, tautoners, geometric isomers, ste=reoisometric forms that may oe defined, in terms o absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for ammino acids, and individual isomers are encompassed within the scope of the present inven_tion. The compoundss of the preserat invention do not include those which are known in art sto be too unstable to synthesize and/or isolate. The pr-esent invention is meant to ineclude compounds in r—acemic and optically pure forms. Optically active (R)- and (S)-, or (D)=- and (L)-isomers maay be prepawed using chiral synthons o r chiral reagents, or resolved 1asing conventional techniques.
Wher the compounds described herein contain olefinic bonds or other centers of ge=ometric asymmetry, and unless specified otherwise, it is intended that —the compounds inclucle both E and ZZ geometric isomers.
[00548] The term "tautomer," ams used herein, refers to one of ~ two or more structur al isomers which exist in equilibriwam and which are readily conwerted from one isomezric form to an«other.
[0055] It will be apparent to Cone skilled in the art that certaiin compounds of this invention may exist in tautomeric forms, all such tautomeric forms of tkae compounds being \ovithin the scope of the invention.
[0056] Unless otherwise stated, structures depicted herein ares also meant to include =all stereochemical forms of the structure; i.e., theR and S configurations for each asymimeetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastercosmeric mixtures of the present comgpounds are within the scope of the invention.
[0057] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched ato-ms.
For example, compounds harving the present structures except for the replacement of za hydrogen by a deuterium or tritium, or the replacement of a caarbon by BC. or C-en—riched carbon are within the scope of this invention.
[0058] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such c-ompounds. For example, the compounds may be radiolabeled with radioactive isotopes, su ch as for example tritium CH), jodine-125 (21) or carbon—14 (**C). All isotopic variations of the compounds of the present : invention, whether radioactive or not, are encompassed withimn the scope of the present : invention. {00591 The term "pharmaceutically acceptable salts” is me=ant to include salts of active compounds which are prepared with relatively nontoxic acids or bases, depending om the particular substituent moieties found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base ad dition salts can be obtained by contacting the neutral form of such compounds with a suffiecient amount of the desired base, either neat orin a suitable inert ssolvent. Examples of pharmaceutically acceptable base addition salts include sodiwum, potassium, calcium, ammonium, organic amine, or magnesium salt, or a similar ssalt. When compounds of the present invention contain relatively basic functionalities, aci d addition salts can be obtained by contacting the neutral Form of such compounds with a sufficient amount of the d_esired acid, either neat or in a suitable inert solvent. Examples of poharmaceutically accepizrable acid addition salts include those derived from inorganic acic3s like hydrochloric, hydrobromic, nitric, carbonic, monohydro gencarbonic, phosphoric, monohydrogenphosphori<, dihydrogenphosphoric, sulfuric, monohydrogensulfuric_, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatfively nontoxic organic acids like acetic, propionic, isobutyric, mamleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfcamic, and the like. Also included are salts of amino acids suck as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids anmd the like (see, for example, Bemge et al., "Pharmaceutical Salts", Powrnal of Pharmaceutical” Science, 1977, 66, 1-19). Certain specific compounds of the pxresent invention contain beoth basic and acidic functionalities that allow the compounds to be converted into eithe=x base or acid addition salt. s.
[0060] In .addition to salt forms, the present imvention provides compotands, which are in a prodrug forrm. Prodrugs of the compounds described herein are those commpounds that readily undergo chemical changes under physiological conditions to proide the compounds of the presemt invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical xnethods in an ex vivo envmronment. For example, prodrugs can be slowly converted to the compounds of the pressent invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
[0061] The terms "a," "an," or "a(n)", when used in reference to a group of substituents Co "herein, meaan at least one. For example, where a compound is substitute=d with "an" alkyl or aryl, the coempound is optionally substituted with at least one alkyl and/or at least one aryl.
Moreover, where a moiety is substituted with an R substituent, the grou—p may be referred to as "R-subs—tituted." Where a moiety is R-subs tituted, the moiety is substituted with at least one R subsstituent and each R substituent is optionally different.
[0062] IDescription of compounds of the present invention are limiteda by principles of chemical tonding known to those skilled in tke art. Accordingly, where a group may be substitute by one or more of a number of substituents, such substitutiomns are selected so as to comply with principles of chemical bondirag and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable u-nder ambient conditions, such as acqueous, neutral, and sever=al known physiological conditions. For example, a heterocycloalkyl or heteroarye/] is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding k=nown to those skilled in the art thereby avoiding inherently vamstable compounds.
[0063] “The terms "treating" or "treatment" in reference to a particulamr disease includes prevention of the disease.
[0064] ~The symbol ww denotes the point of attachment of a moiety <o the remainder of the molecule.
WO 2006/015124 PCT/US2005/026794
L Fused Ring Heterocycle Kinase Modulators
[0065] In one aspect, the present inveration provides a fused ring hesterocycle kinase modllulator (also referred to herein as a "compound of the present inve=ntion") having the formula:
H
9
N
RE 2 ~~
L1-R! @.
[0066] In Formula (I), L! and I? are independently a bond, -S(O)q- , -O-, -NH-, substituted or unsubstituted C;-Cs alkylene, or substituted or unsubstituted 2 to S membered hete=roalkylene. In some embodiments, LL! and 1? are independently =a bond, -S(O)y-, -O-, -NBX -, unsubstituted C;-Cs alkylene, or unsubstituted 2 to S membere=d heteroalkylene. The symLbol n is an integer from 0 to 2. R' and R? are independently subsstituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted hete=roaryl, or substituted or unsubstituted aryl.
[0067] In some embodiments, R' is not substituted or unsubstituted pyrrolyl. In other embodiments, L! is not unsubstituted 2 to 5 membered heteroalkylen e when R! and R? are botla unsubstituted phenyl. In other embodiments, L! is not -S(O),- vevhere R? is unstabstituted piperazinyl. :
[00638] In some embodiments, R! is not substituted or unsubstitutec3 5-membered hetesroaryl. In other embodiments R' is substituted or unsubstituted €-membered heteroaryl, subsstituted or unsubstituted heterocycloalkyl, substituted or unsubstistuted aryl, or substituted or unsubstituted heteroaryl. R' may also be a substituted or unsubstituted 6- membered heteroaryl, or substituted or unsubstituted aryl.
[0069] In other embodiments, L! is not unsubstituted 2 to 5 membe=red heteroalkylene whe=nR' and R? are both unsubstituted aryl. In other embodiments, I__' is not unsubstituted 2 to 5 membered heteroalkylene when R! and R? are both substituted o—r unsubstituted phenyl.
In other embodiments, L! is selected frorn a bond, -S(0);-, -O-, -NH—, and unsubstituted C,-
Cs aslkylene. In other embodiments, n is O or 1. In other embodimenrts, L! is selected from a boned, -O-, -NH-, and unsubstituted C,-Cs alkylene.
[0070] In some embodiments, L' is not -S(O),- where R? is substituted or un substituted piperazinyl. In other embodiments, L! is not -S(O)=- where R? is unsubstituted heterocycloalkyl. In other embodiments, L! is not —S(O),- where R' is substitu_ted or unsubstituted hetexrocycloalkyl. In other embodime=nts, nis 0 or 1. In other embodiments,
L! is not -S(O),- where L? is a bond.
[0071] Insome embodiments, R? is not an unsubsstituted 6-membered hetero-cycloalkyl.
In other embodiments, R? is not a substituted or unsubstituted 6-membered heterocycloalkyl. In other embodiments, R? is selected from substituted or unsubstituted heteroaryl, substiguted or unsubstituted S-membere«d heterocycloalkyl, substitu _ted or unsubstituted aryl, and substituted or unsubstituted cycloalkyl. R? may also be substituted or unsubstituted cycloalkyl, substituted heterocyclamalkyl, substituted or unsubstituted heteroaryl, or subestituted or unsubstituted aryl.
[0072] Insome embodiments, R! is not substitute=d or unsubstituted isoxazolyl where R*is unsubstituted pyr-idinyl. In other embodiments, R! is not substituted or unsubstituted isoxazolyl where L'isabond or -CH,-. In other ermbodiments, R! is not substituted or unsubstituted iso=azolyl. In other embodiments, R_!is not a 4-subsituted isoxaszolyl. In other embodiments, R' is not a 5-yl-isoxazolyl. In other embodiments, R! is mot a 4- subsituted-5-yl-isoxazolyl. In other embodiments, R' is not an isoxazolyl subsstituted with a fluoro-substitutec aryl.
[0073] L! and XL? may independently be a bond, —S(O)q-, -O-, -NH-, or unsubostituted C;-
Cs alkylene. In s ome embodiments, L! and L* are abond. In other embodime=nts, L' or L? is a bond.
[0074] R'may be a substituted or unsubstituted cycloalkyl, substituted or ursubstituted heterocycloalkyl_, substituted or unsubstituted 5- or~ 6-membered heteroaryl, ox— substituted or unsubstituted ary-1 R! may also be a substituted or- unsubstituted 6-membered_ heteroaryl, or substituted or unssubstituted aryl.
[0075] In other embodiments, R! is (1) unsubstit-uted C3-C; cycloalkyl; (2) vansubstituted 3 to 7 membered h_eterocycloalkyl; (3) unsubstituted heteroaryl; (4) unsubstituted aryl; (5) substituted C3-C— cycloalkyl; (6) substituted 3 to 7 membered heterocycloalky~]; (7) substituted aryl; «or (8) substituted heteroaryl. Ins ome related embodiments, (5) and (6) are substituted with =an oxo, -OH, -CF3, -COOH, cyano, halogen, R!'-substituted or unsubstituted C1—Cio alkyl, R''-substituted or unsubstituted 2 to 10 memberedk. heteroalkyl,
WOR 2006/015124 PCT/US2005/026794
R'' —gcubstituted or unsubstituted C3-C; cycloalkyl, R''-substituted or unsubstituted 3 to 7 merbered heterocycloalkyl, R'Z sub stituted or unsubstituted aryl, IR *-substituted or unswubstituted heteroaryl, -L2-C(X)IR’, -L'2-0R?, -L'>-NR*'R*”, or -L'2-S(0).R". X'is =S, =0, or=NR"’, wherein RY isH, -OR'"!, R''-substituted or unswubstituted C;-Cio alkyl,
RY —gsubstituted or unsubstituted 2 to 10 membered heteroalkyl, R!! substituted or unsubstituted Cs-C; cycloalkyl, R''_ substituted or unsubstituted 3 t-o 7 membered heteerocycloalkyl, R'2-substituted or ~unsubstituted aryl, or R'>-subs-tituted or unsubstituted heteeroaryl. R'! is hydrogen or R'!-substitued or unsubstituted C;~Cio alkyl. The symbol rm is ean integer from O to 2.
[0076] In other related embodiments, (7) and (8) are substituted ~with an -OH, -CF5, -Ca@O0H, cyano, halogen, R''-substigtuted or unsubstituted C;-C;g alkyl, R''-substituted or uns=substifuted 2 to 10 membered het-eroalkyl, R''-substituted or unsubstituted C;-C- cycloalkyl, R'-substituted or unsubstituted 3 to 7 membered heter-ocycloalkyl, RZ sulbstituted or unsubstituted aryl, R' “substituted or unsubstituted Aneteroaryl, L2CXHRT,-
L'=.0R®, -L'*NR°'R*?, or -L'2-S(OC»).R". L'2 is a bond, unsubstituted C;-Cq alkylene, or= un_substituted heteroalkylene. X! amd m are as defined above. [0%077] R’ is hydrogen, R''-substi tuted or unsubstituted Ci-C1o &lkyl, R'!-substituted or umm substituted 2 to 10 membered heteroalkyl, R!!-substituted or urmsubstituted C3-C; cy~cloalkyl, R!'!-substituted or unsubostituted 3 to 7 membered hetestocycloalkyl, RZ substituted or unsubstituted aryl, R 12 substituted or unsubstituted heteroaryl, “OR”! or .
NJRR™. R7', R™, and R" are inciependently hydrogen, R!l-sub stituted or unsubstituted
C—4-Cyo alkyl, R!!-substituted or unssubstituted 2 to 10 membered Ineteroalkyl, R!!-substitutted or— unsubstituted C3-C cycloalkyl, ZR"! -substituted or unsubstituted 3 to 7 membered hesterocyclo alkyl, R"2-substituted o T unsubstituted aryl, or R'%-subostituted or unsubstituted he=teroaryl. R" and R” are optionally joined with the nitrogen to which they are attached to form an R''-substituted or unsubst-ituted 3 to 7 membered heterocycloalkyl, or R2- substituted or unsubstituted heteroaryl. [D078] R%, R®! and R* are indep endently hydrogen, -CF;, R'!-ssubstituted or unsubstitu_ted
C1-Cio alkyl, R'-substituted or un substituted 2 to 10 membered heteroalkyl, R'!-substitu_ted o-r unsubstituted Cs-C; cycloalkyl, R!'-substituted or unsubstitute=d 3 to 7 membered h_eterocycloalkyl, R'2.substituted or unsubstituted aryl, R! 2 substituted or unsubstituted heteroaryl, -C(XDRY, or -S(0).R®!. X*is=S, =0, or =NR'®. R *®is R"!-substituted or unsubstituted C;-C alkyl, R!'-substituted or unsubstituted 2 to 10 member-ed heteroalkyl,
R''-substitu ted or unsubstituted C3-C7 cycloalkyl, R!!-substituted or unsubsstituted 3 to 7 membered Ieterocycloalkyl, R'%-substituted or unsubstituted aryl, or R'2-sumbstituted or unsubstituted heteroaryl. The symbol w is ara integer from 0 to 2. R%! and TR” are optionally j=oined with the nitrogen to which €hey are attached to form an R_''-substituted or unsubstituted 3 to 7 membered heterocycloal kyl, ox R!2_substituted or unsumbstituted heteroaryl.
[0079] R_®' is hydrogen, R''-substituted or unsubstituted C1-Cio alkyl, R! !-substituted or unsubstituted 2 to 10 membered heteroalkyl, R''-substituted or unsubstitut-ed C3-Cq cycloalkyl R''-substituted or unsubstituted 3 to 7 membered heterocycloa_lkyl, R'*- substituted. or unsubstituted aryl, R'*-substituted or unsubstituted heteroar=yl, or NRIRSE,
[0080] R=¥'! and R®' are independently hy-drogen, R!'-substituted or unsubstituted C;-Cio alkyl, R!!- substituted or unsubstituted 2 to L ( membered heteroalkyl, R''—substituted or unsubstitu_ted Cs-C; cycloalkyl, R!'-substitumted or unsubstituted 3 to 7 me=mbered heterocycLoalkyl, R!2.substituted or unsubstituted aryl, or R!2-substituted or unsubstituted heteroaryl . R®Y and R¥'? are optionally joiraed with the nitrogen to which_ they are attached to form ar R''-substituted or unsubstituted 3 to 7 membered heterocycloamlkyl, or RY substituted or unsubstituted heteroaryl.
[0081] Mn some embodiments, R®¥ and R* 6 are optionally joined with th_e atoms to which they are a_ttached to from a substituted or umsubstituted heterocycloalky! eor substituted or unsubstituted heteroaryl. In other embodincients, R®" and R'¢ are optionaally joined with the atoms to ~which they are attached to from a substituted or unsubstituted heeterocycloalkyl or substitute=d or unsubstituted heteroaryl. In other embodiments, R®! and R=* are optionally joined wi_th the atoms to which they are att ached to from a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In other embwodiments, R¥! and
R® are o-ptionally joined with the atoms to which they are attached to from a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl .
[0082] R'is hydrogen, R'-substituted <r unsubstituted C;-Cso alkyl, “R''-substituted or unsubstituted 2 to 10 membered heteroalkyl, R!l-substituted or unsubstistuted C3-C; cycloalkyl, R'!-substituted or unsubstitute d 3 to 7 membered heterocycleoalkyl, R'- substituted or unsubstituted aryl, R'>-subs-tituted or unsubstituted heteroaryl, or NR''R'®?,
R19! and. R!®? are independently hydrogen , R''-substituted or unsubstituted C,-Cio alkyl,
R''-substitutecd or unsubstituted 2 to 10 membered heteroalkyl, R!!-sulostituted or unsubstituted &C;-C; cycloalkyl, R'_ substituted «or unsubstituted 3 to 7 membered heterocycloallecyl, R'2-substituted or unsubstitute=d aryl, or R*2-substitutted or unsubstituted heteroaryl. R™° and R'® are optionally joined vith the nitrogen to which they are attached to form an R'™® -substituted or unsubstituted 3 to 7 membered heterocyc=loalkyl, or R'% substituted or unsubstituted heteroaryl. (0083] R'is oxo, -OH, -COOH, -CF3, -OCF, -CN, amino, halogerm, R"*-substituted or unsubstituted 2 to 10 membered alkyl, R"-subsstituted or unsubstituted 2 to 10 membered heteroalkyl, R= P-substituted or unsubstituted C.-C cycloalkyl, R"-sulostituted or unsubstituted 3 to 7 membered heterocycloalky~l, R“-substituted or ursubstituted aryl, or
R'*-substitutezd or unsubstituted heteroaryl.
[0084] R'? is-OH, -COOH, amino, halogen, -CF3, -OCF3, -CN, R'3.substituted or unsubstituted 2 to 10 membered alkyl, R!3-sub stituted or unsubstitute=d 2 to 10 membered heteroalkyl, IR 3-substituted or unsubstituted C =-C7 cycloalkyl, R!*-su_bstituted or unsubstitutecl 3 to 7 membered heterocycloalkyl, R “substituted or unsubstituted aryl, or
R“-substitut ed or unsubstituted heteroaryl.
[0085] R'? is oxo, -OH, -COOH, amino, haleogen, -CFs, -OCF3, -CIN, unsubstituted C;-Co alkyl, unsubsstituted 2 to 10 membered heteroa_lkyl, unsubstituted C3- C7 cycloalkyl, unsubstitutecd 3 to 7 membered heterocycloallc yi, unsubstituted aryl, munsubstituted . heteroaryl. ‘
[0086] R'“ is -OH, -COOH, amino, halogen , -CF3, -OCF3, -CN, urasubstituted C;-Cia alkyl, unsub stituted 2 to 10 membered heteroalkyl, unsubstituted C3—Cy cycloalkyl, unsubstitute d 3 to 7 membered heterocycloalleyl, unsubstituted aryl, unsubstituted heteroaryl.
[0087] In some embodiments, R! is (1), (2) 4), (5,) (6), or (7) (i.e=. unsubstituted C3-C; cycloalkyl, munsubstituted 3 to 7 membered he-terocycloalkyl, unsubstituted aryl, substituted
C;-C7 cyclo alkyl, substituted 3 to 7 memberead heterocycloalkyl, or substituted aryl, respectively). In some embodiments, where IR! is (3), or (8), then thse heteroaryl is a 6- membered kneteroaryl.
[0088] W here R! is (7) or (8) (i.e. substituted aryl or substituted h_eteroaryl), (7) and (8) may be sub stituted with an -OH, -CF3, -OCF =, halogen, unsubstitutezd C;-Cio alkyl,
unsubstituted 2 to 10 menmbered heteroalkyl, unsubstituted Cs-Cr cycloalkyl, unsubstituted 3 to 7 membered heterocycsloalkyl, unsubstituted aryl, unsubstituted heteroaryl, or -L'2-OR®.
In a related embodiment. , L'2 is a bond. In other related embodiments, (7) and (8) may be substituted with an -OCHEL, -OCF3, -CHs, -CFs, -OCH, CH, halogen, or cycloproOpyloxy.
[0089] R’may be: (1) unsubstituted C3-C; cycloalkyl; (2) unsubstituted 3to7 membered heterocycloalkyl; (3) un_substituted heteroaryl; (4) unsubstituted aryl; (5) substitwuted C3-C7 cycloalkyl; (6) substitut-ed 3 to 7 membered heterocycloalkyl; (7) substituted aryl; or (8) substituted heteroaryl. Mn some related embodiments, (5) mand (6) are substituted with an oxo, -OH, -CF3, COO, cyano, halogen, R*'-substituted or unsubstituted C-C po alkyl, RZ- substituted or unsubstitmuted 2 to 10 membered heteroalkyl, R2'-substituted or ursubstituted
Ci1-Cy cycloalkyl, R2-swubstituted or unsubstituted 3 to 7 membered heterocyclo alkyl, R*2 substituted or unsubstit—uted aryl, or RZ_substituted or unsubstituted heteroaryl, 12%
COAR?, -L2-0RY, -L? 2NR¥'R%, or 12.S(0)RS. X*is =S,=0, or=NR", wherein RY is
H, -OR'", R2_substitu—ted or unsubstituted C;-Cyo alkyl, RR?! -substituted or unstabstituted 2 to 10 membered hetero alkyl, R*'-substituted or unsubstitt ated C3-C; cycloalkyl, RL substituted or unsubstit-uted 3 to 7 membered heterocyclo alkyl, R%-substituted or unsubstituted aryl, or R=? substituted or unsubstituted het eroaryl. R'is Hor R¥- substituted or unsubstisuted C;-Cio alkyl. The symbol q is an integer from Oto 2.
[0090] In other relatesd embodiments, (7) and (8) are swbstituted with an OH, -CF3, -
COOH, cyano, haloger, R*'-substituted or unsubstituted C,-Cio alkyl, R*'-subsstituted or oo unsubstituted 2 to 10 nmembered heteroalkyl, R2'-substitumted or unsubstituted C3-C; cycloalkyl, R2?!'-substituted or unsubstituted 3 to 7 membeered heterocycloalkyl, R*2% substituted or unsubsti_tuted aryl, R*-substituted or unsulbstituted heteroaryl, LC R2.CEOR?, - 12.0R%, -L22-NR'R5=2 or -L*-S(0);R’. L* is a bond, tansubstituted C-Cyo alkylene or unsubstituted heteroallkylene. X° and q are as defined above.
[0091] R® is hydrogeen, R*'-substituted or unsubstituteci C;-Cyg alkyl, R?!-subostituted or unsubstituted 2 to 10 rmembered heteroalkyl, R2l.substitiated or unsubstituted Cs-C; cycloalkyl, R*-substistuted or unsubstituted 3 to 7 membwered heterocycloalkyl , R?- substituted or unsubst-ituted aryl, R?-substituted or unsubstituted heteroaryl, -aOR*, or
NR¥R®. R* and R>-> are optionally joined with the nitrogen to which they amre attached to form an R%!-substitute=d or unsubstituted 3 to 7 membere=d beterocycloalkyl, or= R*- substituted or unsubstzituted heteroaryl.
[0092] RR’, R™2 and R* are independently hydrogen, R*-substituted or unsubstituted C,-
Cio alkyl, R*-suabstituted or unsubstituted 2 to 10 membered heteroalkyl, MR! substituted or unsubstituted C=-Cy cycloalkyl, R*'-substituted or unsubstituted 3 to 7 membered heterocycloalky™1, R22_substituted or unsubstituted aryl, or R?2_substituted eor unsubstituted heteroaryl.
[0093] R* R® !and R* are independently hydrogen, -CF3, R*'-substitute=d or unsubstituted
C1-Cyg alkyl, R='.substituted or unsubstituted 2 to 10 membered heteroalk=yl, R*!-substituted or unsubstituted Cs-C cycloalkyl, R*! substituted or unsubstituted 3 to 7 —membered heterocycloalksesl, R?-substituted or unsubstituted aryl, RZ substituted or unsubstituted heteroaryl, CCXHRY, or -S(O)R*. R’! and R > are optionally joined wisth the nitrogen to which they are attached to form an R?!_substituated or unsubstituted 3 to 7 membered heterocycloalk=y], or R* substituted or unsubstituted heteroaryl.
[0094] X*is =S, =O, or =NR'®, wherein R'® is R*'-substituted or unsub stituted Ci-Cio alkyl, R?'-subsstituted or unsubstituted 2 to 10 membered heteroalkyl, R*' substituted or unsubstituted C3-Cy cycloalkyl, R?! substituted or unsubstituted 3 to 7 membered heterocycloalk=y]), RZ_gubstituted or unsubstituted aryl, or R?*?-substituted_. or unsubstituted heteroaryl. Thee symbol v is an integer from 0 to 2.
[0095] R* is: hydrogen, R2!-substituted or unsubstituted C;-Cio alkyl, RR -substituted or unsubstituted 2= to 10 membered heteroalkyl, R 2 substituted or unsubstitmited C3-C7 cycloalkyl, R2! _substituted or unsubstituted 3 to 7 membered heterocyclosalkyl, R* substituted or Lansubstituted aryl, R*%_substituted or unsubstituted heteroa yl, or NRR*Z,
R*! and R"? aare independently selected from hydrogen, R?'.substituted or unsubstituted
C;-Cyp alkyl, R=2_substituted or unsubstituted 2 to 10 membered heteroalkyl, R*'-substituted or unsubstitutesd C3-C; cycloalkyl, R?!-substituted or unsubstituted 3 to 7 membered heterocycloalk=yl, R?*2-substituted or unsubstituted aryl, or R* substituted or unsubstituted heteroaryl. R?* and R*? are optionally joined with the nitrogen to whickn they are attached to form an R*' —substituted or unsubstituted 3 to 7 membered heterocyclo. alkyl, or R%- substituted or mansubstituted heteroaryl.
[0096] In some embodiments, R*' and R'® are optionally joined with tine atoms to which they are attach_ed to from a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted Heteroaryl. In other embodiments, R*!! and R'® are optionally joined with the atorns to whiclia they are attached to from a substituted or unsubstituted haeterocycloalkyl or substituted or unsubstituted heteroaryl. In other embodiments, R* and R* aree optionally joined with the atomms to which they are attached to freom a substituted or unsumbstituted heterocycloalkyl om substituted or unsubstituted heteroaryl. In other embodinents, R*'! and
R are optionally Ji oined with the atoms to which they are attached to from a =substituted or unsubstituted heter-ocycloalkyl or substituted or unsubstituted heteroaryl.
[0097] R® is hydrogen, R*'-substituted or unsubstitvated Ci-Cyo alkyl, R?'-stabstituted or unsubstituted 2 to 10 membered heteroalkyl, R*!-subsstituted or unsubstituted C3-C; cycloalkyl, R?!-sulostituted or unsubstituted 3 to 7 me=mbered heterocycloalky=1, R* substituted or unsumbstituted aryl, R*?-substituted or umsubstituted heteroaryl, sor -NRS'R®,
RS! and R% are hyedrogen, R*'-substituted or unsubsti tuted C;-Cio alkyl, R?!-ssubstituted or unsubstituted 2 to 10 membered heteroalkyl, R%'-subsstituted or unsubstituted C3-Cs cycloalkyl, R?'-sulbstituted or unsubstituted 3 to 7 me=mbered heterocycloalky}, R%- substituted or unsiabstituted aryl, or R?2.substituted ox unsubstituted heteroarssl. R® and R®? are optionally join ed with the nitrogen to which they are attached to form an “R!-substituted or unsubstituted 3 to 7 membered heterocycloalkyl, oer R?-substituted or unswubstituted heteroaryl.
[0098] R?' is ox=o, -OH, -COOH, -CF3, -OCFj, -CNJ, amino, halogen, R*-smubstituted or unsubstituted 2 to 10 membered alkyl, RZ -substitutead or unsubstituted 2 to 1 0 membered . heteroalkyl, R®-sUibstituted or unsubstituted C3-Cy cycloalkyl, R™-substitute=d or unsubstituted 3 to 7 membered heterocycloalkyl, R**—substituted or unsubstituted aryl, or
R**-substituted or unsubstituted heteroaryl.
[0099] R? is -O=H, -COOH, amino, halogen, -CF3, -OCF3, -CN, R?*-substistuted or unsubstituted 2 to 10 membered alkyl, R**-substitute«d or unsubstituted 2 to 1 0 membered heteroalkyl, R*-su_ibstituted or unsubstituted C3-C7 cycloalkyl, R*-substitute- d or unsubstituted 3 to 7 membered heterocycloalkyl, R** substituted or unsubstit=uted aryl, or
R?*-substituted or unsubstituted heteroaryl.
[0100] R? is ox_o, -OH, -COOH, amino, halogen, —CFs, -OCF3, -CN, unsubstituted C;-Cyo alkyl, unsubstitute=d 2 to 10 membered heteroalkyl, unsubstituted C;-C; cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, uns ubstituted aryl, unsubsti_tuted heteroaryl.
[0101] Ris -OwH, -COOH, amino, halogen, -CFs, -OCFs, -CN, unsubstitu_ted Ci-Cio alkyl, unsubstitute=d 2 to 10 membered heteroalkyl, unsubstituted C3-C; cycloalkyl,
unsubstituted 3 to 7 nembered heterocycloalkyl, unsubstituted aryl, unsubstitt ted heteroaryl.
[0102] In some embodiments, R%is (1), (3), (4), (5,) (6), (7), or (8) (Le. unsubstituted Cs-
C; cycloalkyl, unsubsstituted heteroaryl, unsubstituted aaryl, substituted C3-C; cycloalkyl, substituted 3 to 7 memmnbered heterocycloalkyl, substitumted aryl, or substituted “heteroaryl, respectively). R? ma-y also be (3), (4), (7), or (8). In o-ther embodiments, R? iss (7) or (8).
[0103] In some embodiments, where R?is (7) and (83), then (7) and (8) are substituted with an -L2-COC)RS, -L2-0R?, -L2NR*'R%, -L2-C (NH)-NR*R*, or -L2—S(O){R".
[0104] In some em bodiments, R®is -NR*2R®. x3 may be =0 or =NR!. R® may be _NRS'R®. R* may bes -C(O)R* or -S(O)R*'. R* maybe -NR*'R*"2. [01 05] In other em bodiments where R%is (7) and (8D), then (7) or (8) may bes substituted with an -OH, -CF;, -«COQOH, amino, halogen, unsubsti—tuted 2 to 10 membered heteroalkyi, unsubstituted C3-C7 eycloalkyl, unsubstituted 3 to 7 rrmembered heterocycloallkyl, unsubstituted aryl, ursubstituted heteroaryl, or -L*-Ca(X*)R’. X’ may be =O.
[0106] R® may be mmsubstituted C;-Cjo alkyl, unsub stituted 2 to 10 membered heteroalkyl, unsubstituted C;3-C; cycloalkyl, unsubstituted 3 to 7 naxembered heterocycloallkyl, unsubstituted aryl, umnsubstituted heteroaryl, or NRZER®. R*? and R* may inedependently be hydrogen, R2?!.sulbostituted or unsubstituted C;-C io alkyl, R*'-substituted or— unsubstituted 2 to 10 membered hesteroalkyl, R2!-substituted or unsiabstituted C3-C; cycloal kyl, rR? substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R%-substitute=d or unsubstituted aryl, om R%-substituted or unsubstituted heteroaryl. R*? and R*>= are optionally joined with the nitro_gen to which they are attached to form an R%'-substitutecq or unsubstituted 3 to 7 mmembered heterocycloalkyl, or R_Z.-substituted or unsubsstituted heteroaryl.
[0107] In another eembodiment where R%is (7) or (8), then (7) and (8) may be substituted with unsubstituted 2 to 10 membered heteroalkyl, or —12.C(O)R’. L? may toe a bond. R® may be NR¥?R¥, R=* and R® may independently be hydrogen, R2'-substitutted or unsubstituted C,-Cio alkyl, R?! substituted or unsubst=ituted 2 to 10 memberead heteroalkyl,
R*!-substituted or urasubstituted C3-C; cycloalkyl, R?! substituted or unsubsti_tuted 3 to 7 membered heterocycloalkyl, RZ-substituted or unsubstituted aryl, or R?-sub stituted or unsubstituted heteroaryl. R* and R* are optionally jeoined with the nitrogen to which they
) are attacThed to form an R*'-substituted or unsubstituted 3 to 7 membered hesterocycloalkyl, or R%-suabstituted or unsubstituted heteroaryl.
[0108] In some embodiments, R! is a substituted or unsubstituted fused rirng aryl or substitut .ed or unsubstituted fused ring heteroaryl. In other embodiments, R= is substituted or unsubestituted indolyl, substituted or unsubstituted quinolinyl, or substitut-ed or unsubsti—tuted benzodioxolyl. R* may be a substituted or unsubstituted fusecq ring aryl or substituted or unsubstituted fused ring heteroaryl. R! may be a substituted cor unsubstituted indolyl, =substituted or unsubstituted quinolinyl, or substituted or unsubstitut ed benzodicoxolyl.
[0109] Rand R? may independently be a substituted or unsubstituted hydlantoinyl, substitut ed or unsubstituted dioxolanyl, substituted or unsubstituted dioxany~1, substituted or unsubsti—tuted trioxanyl, substituted or unsubstituted tetrahydrothienyl, subst_ituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydrothiopwhenyl, substitut ed or unsubstituted tetrahydropyranyl, substituted or unsubstituted Co tetrahydmrothiopyranyl, substituted or unsubstituted pyrrolidinyl, substituted =or unsubstituted morpholino, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrazolyl, substitut- ed or unsubstituted furanyl, substituted or unsubstituted imidazolyl, substituted or unsubstistuted isoxazolyl, substituted or unsubstituted oxadiazolyl, substitute=d or unsubstistuted oxazolyl, substituted or unsubstituted pyridyl, substituted or umnsubstituted pyrazyl, substituted or unsubstituted pyrimidy1, substituted or unsubstituted —pyridazinyl, substituteed or unsubstituted thiazolyl, substituted or unsubstituted isothioazolyl, substituted or unsub stituted triazolyl, substituted or unsubstituted thienyl, substituted or— unsubstituted triazinyl.. substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted tetrazolyl.
[0110] In another embodiment, the compound of the present invention is amny one of the compourds of Tables 1-18 or 20, and/or of the methods 2-61 in the Examples section below.
[0111] In another aspect, the present invention provides a fused ring hetereocycle kinase modulator (also referred to herein as a "compound of the present invention" )e having the formula:
Ne N
RA I hw; 2” °N
L-R! I.
[0112] In Formula (II), LL? R! and R? are as defined above in the discussion of
Formula (I).
[0113] In another aspect, the present im vention provides a fused rirng heterocycle kinase modulzator (also referred to herein as a "compound of the present inv—ention") having the formul a:
Ne N.
RZ, 2 I pe N
L-R? (III) -
[0114]; In Formula (III), L!, 1.2, R!, ana R? are as defined above in_ the discussion of
Formumla (I). [01158 In some embodiments, each substituted group described atoove in the compounds of Formulae (I)-(ITI) is substituted with at least one substituent grou—p. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, ssubstituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl. ,, substituted alkylene, and/or— substituted heteroalkylene, described above in the compounds of Formulae (I)-(III) are sullbstituted with at least one substituent group. In other embodiments, at least one or all of thesse groups are substituted with at least one size-limited substiti_aent group.
Alterrmatively, at least one or all of these groups are substituted with. at least one lower substi—tuent group.
[01167] In other embodiments of the compounds of Formulae (D-II), each substituted or unsubstituted alkyl is a substituted or urnsubstituted C;-Cy alkyl, ea_ch substituted or unsubstituted heteroalkyl is a substituted] or unsubstituted 2 to 20 mmembered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsu_bstituted C.-Cs cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a s-ubstituted or unsubsstituted 4 to 8 membered heterocyrcloalkyl, each substituted o»r unsubstituted alkylene is a substituted or unsubstituted C;-Czo alkylene, and/or each substi_tuted or unsubstituted hetercalkylene is a substituted or unsubstituted 2 to 20 membered hneteroalkylene.
: [0117] Alternatively, each substituted or unsubstituted alkyl iss a substituted or unsubstituted C;-Cs alkyl, each substituted or unsubstituted hete=roalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or Linsubstituted cycloalky® is a substituted or unsubstituted Cs—C; cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 member—ed heterocycloalkyl, ea=ch substituted or unsubstituted alicylene is a substituted or unsubsti_tuted C;-Cs alkylene, amnd/or : each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene. }
Exemplary Syntheses
[0118] The compounds of the invention are synthesized by arn appropriate combinatieon of generally well known synthetic methods. Techniques useful in synthesizing the compounds of the invention are both readil y apparent and accessible to thosse of skill in the relevan. t art.
The discussion below is offered to illustrate how, in principle, to gain access to the compounds claimed under this invention and to give details on certain of the diverse methods available for use in assembling the compounds of the mnvention. However, th_e discussion is not intended to define or limit the scope of reactios nis or reaction sequence=s that are useful in preparing the compounds of the present invention. The compounds of thi s invention may be made by the procedures and techniques disclosed in the Examples se=ction below, as well as by known or ganic synthesis techniques. In Sechemes 1,2 and 3, L!, RR! 12, and R? are as defined above. :
[0119] The key intermediates for the synthesis of 3,5-disubst-ituted 1 H-pyrazolo{3,4— blpyndine derivatives are 5-br-omo-1H-pyrazolo[3,4-b]pyridine and 5-bromo-3-iodo-1 H- pyrazolo{3,4-b]pyridine. The dodine and/or bromine substituermts on sp>-hybridized, aromatic carbon atoms present in these building blocks offer m_imerous synthetic possibilities for functionalizatt on of either position. A great va_riety of such synthetic methods exists and these procedures are generally well known and familiar to someones with skill in the art and include, by means of example and not limitamtion: transition metal catalyzed processes, most notably processes utilizing palladiun—, iron, nickel or copper catalysts, as well as metal-halogen exchange reactions, most notably such procedures introducing lithium or magnesium, and subsequent reaction of the transient or isolated_ organometallic derivative with an electrophile of suitable react=ivity either directly or v~ia transmetallation to fine tune tlae reactivity of the organometallic species.
HN— \ HN— \
ES NTR
P L
Br Br
[0120] Using such rmethods, introduction of different Substituents on the 3- and S-position of the 1H-pyrazolo[3,4-b]pyridine core can be accompli shed by introducing a chosen substituent at the S-position starting from 5_bromo- 1 H-poyrazolo[3,4-blpyridine armd subsequent halogenation, especially iodination, at positi on 3 of the 1H-pyrazolo[3-,4- blpyridine core to enable the use of the aforementioned methods to introduce another substituent of choice at that position. Alternatively, sone of the methods outlined above may be utilized to selectively functionalize 5-bromo-3-i_ odo-1H-pyrazolo[3,4-b]pyridine at the 3-position by selectively reacting with the iodo subsstituent over the bromo sutostituent. 1t is generally well known and familiar to someone with skill in the art, that a variety of palladium catalysts axe known and readily available or accessible which will exhi bit higher reaction rates with aromatic iodo substituents as compared to aromatic bromo substituents and such catalysts may be utilized under suitable conditions to effect selective iodine substitution.
[0121] 5-bromo-1F1-pyrazolo[3,4-b]pyridine or a dermvative containing an appreopriate protecting group may also be functionalized at the 3-pomsition via various electrophilic aromatic substitution reactions that are generally well kknown and familiar to sommeone with skill in the art, such zs FRIEDEL-CRAFTS-acylation.
[0122] The substituents introduced on either position in such fashion may either represent fully elaborated compounds, such as those claimed uncer this invention, or they mmay contain functional groups, such as, for example and without limitation, amines, carboxylic acids or esters, nitriles, olefins or halogens, either free -or bearing suitable protecting groups, which in turn may be utilized as starting material in generally well known synthetic transformations to synthesize compounds that are clairmned under this invention.
[0123] Suitably functionalized pyrazolo[3,4-b]pyridine derivatives, particularly 5-bromo- 1 H-pyrazolo[3,4-b]pyridine and 5-bromo-3-iodo-1H-p= yrazolo[3,4-b]pyridine, useful in synthesizing compounds of the present invention can toe prepared as outlined in sScheme 1 from commercially available 5-bromo-2-fluoropyridin_e. 5-Bromo-2-fluoropyricline can be selectively functionalized at the 3-position by the gene=rally well known selective metallatiosn of 2-flucropyridines in a manner ressembling general methoeds described in
Schlosser, M., Organometallics in Synthesis, Z2nd. ed., Wiley-VCH, 20 02; Clayden, I,
Organoliehiums: Selectivity for Synthesis, Pergamon, 2002; and Mongmn et al., Te etrahed=ron (2001) 57, 4059-4090. Thus, metallation may be accomplished by tresatment with a suit=able, non-nuclesophilic strong base (e.g. lithium di-i.so-propylamide or lithivom 2,2,6,6- tertramethhylpiperidide) in an aprotic solvent (e.g. THF, hexanes, ether or mixtures there=of) at low termperature, typically —78°C or below.
[0124] The unpurified metallated intermedizate can be converted to the corresponding 3- carbaldelnyde 2 by treatment with a formylatirg reagent such as DMF, N-formyl-N- methylammiline, N-formylmorpholine, N-formylpiperidine or ethyl formmate. Reaction of the carbaldelnyde with hydrazine or a suitable hyclrazine derivative (e.g. h-ydrazine-tert- butylcartazate, or a soluble organic or inorgamnic salt derived from hycdrazine such as hydrazin_e hydrochloride) either directly or upon protection of the aldeshyde using a suit able protecting group (e.g. acetal) will provide access to 5 -bromo-1H-pyra_zolo[3,4-b]pyridimne.
Introduc-tion of a suitable group at the 3-position for further elaboration can be accompl-ished via methods generally well known in the art, such as arm electrophilic arommatic substitut jon (e.g. bromination or iodination). Thus, the iodide 4 is accessible from 3 by treatmermt with suitable reagents, such as N-iowdosuccinimide, iodine monochloride or icdine, under cosnditions facilitating such transformation. Other examples of functionalization via electrophilic aromatic substitution are, by me=ans of example and not “limitation, FRIEDE=L-
CRAFTS—acylation using functionalized acyl Inalides such as, for example, bromoacetyl chloride , acryloyl chloride or trichloroacetyl chloride in the presence of aluminum trichloride in dichloromethane at ambient termperature or below. As wwill be appreciate. d by the skill-ed artisan, the products of such react®ons may be utilized as s tarting materials for the synt¥hesis of certain heterocyclic compoumds.
[0125] Alternatively, the metallated intermediate derived from dep—rotonation of S-br—omo- 2-fluoroe pyridine can be transmetallated under suitable conditions to #orm an organocuprate reagent (c.f. Lipshutz, B., Organometallics imi Synthesis, 2nd. ed., Wiley-VCH, 2002).
Reaction of the cuprate generated in such fashion with an acyl halides gives access to ketones of the general structure 5, which cam be cyclized by reaction with hydrazine om a soluble organic or inorganic salt derived frorm hydrazine (e.g. hydrazine hydrochlorides) to afford thhe corresponding 3-substituted 5-bro-mo-1H-pyrazolo[3 ,4-b]yridines of the ge=neral structur-€ 6.
Scheme 1
I CHO ji 1 1
NTO NT a . NTT b—r—B
Br Br 2 Lo3 Br 4
F 0 5 og — WJ * 4 R ZZ
Br 3 Br 6
[0126] Elaboration of halides 3, 4 or 6 can be readily accomplished by gene=rally well known rrethods, such as those outlined in Scheme 2 below. For example, metal catalyzed cross comupling reactions may be employed using various known transition me=tal compounds : (e.g. compounds derived from palladium, iron or nickel). Examples of such t-ransformations can be £ound in the following references: Diederich, F., Stang, P.J. — Metal-ccatalyzed Cross- couplin_g Reactions, Wiley-VCH, 1998; Beller, M., Transition Metals for Organic
Synthes~is, Wiley-VCH, 1998; Tsuji, J., Palladium Reagents and Catalysts, W¥iley-VCH, 1%, & 2" cads., 1995, 2004; Fuerstner, A, et al., J.Am.Chem.Soc. (2002) 124, 138-56; and Bolm,
C., et all, Chem.Rev. (2004) 104, 6217. Other useful methods involve the co nversion ofa bromin-e or iodine substituent into a metal or metalloid substituent (e.g. orgarmoboron, organo Mithium, organotin, organosilicon, organozinge, organocopper or organcomagnesium compound) using generally well known methods (e.g. metal halogen exchange and, as appropxriate or required, subsequent transmetallation using soluble and reactive compounds of boroe1, magnesium, zinc, tin, silicon or copper; for representative examples of such methocJology see: Schlosser, M., Organometallics in Synthesis, 2nd. ed., Wil_ey-VCH, 2002.).. Organometallic derivatives obtained in such fashion may itself be of "use in transition metal catalyzed coupling reactions with aromatic or olefinic halide=s or triflates, or, if smfficiently reactive, be reacted directly with suitable electrophiles, sucTh as, for example, certain organic halides, MICHAEL-acceptors, oxiranes, aziridines, a"ldehydes, acyl halidess, or nitriles.
[0127] Selective functionalization at either the 3- or S-position may require different strategie=s depending on the nature of the transformations utilized to iratroduce functionalities at either position, especially the sequence of functionalization at eithe=r position. Thus, it may be 2advantageous or necessary to achieve functionalization at the 3-position prior to function_alization of the 5-position in some cases while the opposite approach may be required in other cases, depending on the nature of the specific group:sto be introduced, the methodss required to accomplish such transformations, or the inherent= selectivity of the methodss utilized. For example, some reactants, such as for example =some boronic acids or their est ers that are electron deficient (e.g. contain one or more electr-on withdrawing substituents or that represent derivatives of certain heterocyclic syste: ms) and/or contain one or more substituents ortho to the boron-carbon bond may require the use of highly active palladitmm catalysts (such as those menti oned in Vilar, R., Christman_, U. — Angew. Chem. (2005) 717, 370; Littke, A.F., Fu, G. — Angew. Chem. (2002) 114, 43250.) and more forcing conditions, such as higher temperatures and/or longer reaction times. Such conditions may not be conducive to achieving appreciable selectivities in reactions o f 5-bromo-3-iodo-1H- pyrazol o[3,4-b]pyridine. Hence, in such cases, it may be advantageous to avoid selectivity issues amltogether by sequential substitution of bromine in 5-bromo-1_H- pyrazolo[3,4- blpyrid-ine, iodination at the 3-position and subsequent introduction eof the second substitizuent at position 3 utilizing the methods detailed above. Gener—ally, when substitution of the Imalogen atom at either position require conditions that involve= highly reactive catalysis or reagents under conditions that generally do not favor hig=h levels of selectivity between the two halogen atoms present in 5-bromo-3-iodo-1H- pyra_zolo[3,4-b]pyridine, it may be= advantageous to resort to this sequential approach.
[0128] It will also be appreciated that protection of reactive group:-s within LL 12 R and/or TR as well as the pyrazolo[3,4-b] pyridine scaffold, (e.g. the proton at position 1), with a suitable protecting group may be advantageous or required. For example it was found t=o be advantageous in some cross-coupling reactions to protect the nitrogen at position 1 of the 1H-pyrazolo[3,4-b]pyridine scaffold by introduction of either a (2- trimettm ylsilylethoxy)-methyl or (2-methoxy-ethoxy)methyl group at= that position.
Introduaction and removal of these protecting groups could be conveniently accomplished by methods well known in the chemical literature. The compounds obtzained by any of the aforermentioned methods may contain functional groups, either free or protected, that can be further elaborated by generally well known methods.
i [0129] A more detailed description of the utilization of cross-coupling proceduares in the synthesis of the coxmpounds claimed under this inventi_on is illustrated in Scheme= 2: X! and
X? are selected frorm, but not limited to, halogen, boromnic acid or ester, trifluorobeorate salt, organomagnesium,. organozinc, or organotin. With resspect to the introduction of individual residues -L'-R! or —L2-R? such transformations, as outMined above, can be achieveed via standard halogen cross-coupling methodologies.
Scheme 2 "en Bs L! Ne L! HNN L!
Tr Fr gh
PP ZF ZF x2 x2 Lx ] L2p2
NT NT NT NX
CE Ce x2 LE p LZ oo Lea
[0130] Coupling s of the corresponding bromide or ieodide (X', X* = Br, I) witha suitable reagents such as boronic acids and boronates, organobworaunes, organostannanes, crganozinc compounds, organomagnesium compounds, olefins or terminal alkynes (either p urchased or obtained via generally well known protocols) can be carried out in the presence of a suitable transition metal catalyst (e.g. palladium compounds). The coupling may optionamlly be performed in the pxresence of ligands such as phosphin_es, diphosphines, Ardueng=o-type heterocyclic carberes or arsines. Organic or inorganics bases (e.g. tertiary or secondary amines, alkaline carbonates, bicarbonates or phosphates) and/or other well knowra additives (e.g. lithium chloride, copper halides or silver salts) may be utilized to assist or amccelerate such transformations. .
[0131] These cross coupling reactions may be carrie=d out in suitable solvents such as
THF, dioxane, dims ethoxyethane, diglyme, dichloromes=thane, dichloroethane, ace tonitrile,
DMF, N-methylpyxrrolidone, water, or mixtures of ther—eof at temperatures rangin_g from 25 °C to 200 °C using. The temperature may optionally toe maintained with heatings, conventional heatirag or microwave irradiation. In the case of the 3-iodo-5-brom_o-1H-
pyrazolo[3,4-&pyridine, the selective or prefere=ntial substitution of the ido substituent over the bromo substituent is possible under gernerally less forcing conditions, such as lower temperature a-nd shorter reaction times using a ssuitable transition metal catalyst. Selective . functionalizat-ions of di- or oligohalogen composunds by means of transition metal catalyzed transformations are well precedented in the chemical literature: see for example Ji, J., et al.
Org.Lett (20083) 5, 4611; Bach, T., et al., J.Org. Chem (2002) 67, 5789, Andamczyk, M. et.al,
Tetrahedron (2003) 59, 8129.
[0132] This methodology may be extended to the incorporation of non carbon based nucleophiles «e.g. alcohols, thiols, primary or secondary amines) that ma.y optionally contain suitable protecting groups of alcohols, thiols or amines. Examples of such groups can be found in Greene, T., et al., Protective Groups in Organic Synthesas, 3rd ed., John
Wiley & Sons, 1999. Exemplary methods of pmrotection are described in Ley, S., et al,
Angew. Chem . (2003) 115, 5558; Wolfe, J., et a_l., Acc. Chem.Res. (1998) 31, 805; Hartwig,
Acc.Chem.Re=s. (1998) 31, 852; Navarro, O., et al.,J Org.Chem. (2004) 69,3173, Ji, J., et al,,
Org. Lert (2003) 5, 4611. The compounds obtamned by such methods carx be further elaborated by~ well known methods to obtain otTher compounds of the present invention.
[0133] In ssome cases it may be advantageouss to achieve cross-couplin gs to carbon or non- carbon atoms. by first converting the respective halogen derivative into the corresponding organometallic derivative (e.g., a boronic acid or ester, trifluoroborate salt, organomagnessium, organozine or organotin corrnpound). Such compoun ds are accessible by means of substituting the halide moiety with arm appropriate metal or metalloid. Any functional groups present (e.g. the ring nitrogera in position 1 of the pyra=zolo[3,4- b]pyridine), rmay need to be protected by a suitable protecting group ("PCG"). See Greene, et al, 1999.
[0134] Intreoduction of such metals or metalloids can be achieved by generally well- known methods, such as metallation using metals or a metal-halogen exchange reaction.
Useful metals for metallation include alkaline cor alkaline earth metals or activated forms of such metals. Suitable reagents for use in metal—halogen exchange reactions include organolithiurm or organomagnesium compound. s (e.g. n-butyllithium, zerz-butyllithium or iso-propylma_gnesium chloride or bromide). Sumbsequent transmetalation. reactions of the organometallic intermediate may be performed as needed with a suitable soluble and reactive meta_l compound such as magnesium chloride, magnesium bromide, tri-n-butyltin chloride, trimethyltin chloride, trimethyl borate, triethyl borate, tri-iso-propyl bor-ate, zinc triflate or zinc chloride. Introduction of a boronic acid pinacol ester can be conveeniently achieved by reacting “the halogen derivative directly with bis(pinacolato)diboron in the presence of dichloro[ 1,1 ' bis(diphenylphosphino)ferrocsene]palladium(r) and sui—table bases (e.g. potassium or soclium acetate) in solvents such as IOMSO, DMF, DMA or N— methylpyrrolidone at. temperatures ranging from 80-160 °C. Conventional heatimng or microwave irradiation may be employed to maintain the appropriate temperature (for literature precedent of similar transformations, see Ishiiyama, T., et al., J. Org. C=hem. (1995) 60, 7508.).
[0135] Methods fos: conversion of the boronic acid pinacol ester obtained by thhis method into other boronic ac=id derivatives such as boronic aci«ds, boronates, or trifluoroloorate salts are generally well kriown. As will be apparent to the skilled artisan, such organ-ometallic derivatives may be watilized in cross-coupling reactions similar to those describe=d above in the case of halogen containing derivatives of pyrazolos[3,4-b]pyridine. Such cotplings can be effected utilizing suitable coupling partners, such as aromatic, heteroaromatic halides or olefinic reagents uncer conditions identical or evidently similar and/or related tc the methods described ambove.
[0136] Other methods may utilize the reactivity of Organometallic derivatives generated from halogen contak ning derivatives of pyrazolo[3,4-BJpyridine by any of the methods described above. Foor example, derivatives containing alkaline or alkaline earth metals (e.g. organolithium, orga nomagnesium or organozinc com pounds) may be employed in direct couplings to a ranges of other electrophilic coupling p=artners such as, for examp- le, activated olefins (MICHAEL-a cceptors), aldehydes, nitriles, arormatic nitro compounds, caarboxylic acid derivatives, oxiraness, aziridines, organic disulfides or= organic halides. Such transformations are generally well kznown in the art (for reactions with aromatic nitro compouneds, see for example Sapountziss, L, et al, J. Am. Chem. Soc. (2002) 124, 9390.).
[0137] The synth etic strategies utilized to access 3, 5-disubstituted 1H-pyrrols=o[2,3- b]pyrazine derivatiwes are closely related to the strategies described above for 1H- pyrazolo[3,4-b]pyradine derivatives, with the main di fference relating to the synthesis of the 1 H-pyrrolo[2,3-b]peyrazine scaffold itself. The key irtermediates utilized are 3 -substituted 5-iodo-1H-pyrrolo[_2,3-b]pyrazine derivatives and 5-Tbromo-1H-pyrrolo[2,3-b]oyrazine itself.
Se w
Br i
[0138] The general synthetic strategies to access 3,5-disubmstituted 1 H-pyrazolo[_ 3,4- b]pyridine derivatives from 5-bsromo-1H-pyrazolo[3,4-b]pyr-idine outlined above wwill also pertain to accessing 3,5-disubsstituted 1H-pyrrolo[2,3-b]pyr=azine derivatives fromm 5-bromo- 1H-pyrrolo[2,3-b]pyrazine and 3-substituted S-iodo-1H-pyrr—olo[2,3-b]pyrazine derivatives.
However, the exact conditions —for otherwise similar or identical transformations may very well be different for 1 H-pyrrolc(2,3-b]pyrazine derivatives =and optimization depe=nding on the scaffold utilized may be recguired.
[0139] S-Bromo-1H-pyrrolo[ 2,3-b]pyrazine is accessible wia regioselective
SONOGASHIRA-coupling of 3-armino-2,6-dibromo-pyrazine with trimethylsilylacet—ylene (see
Adamczyk,M., et al. — Tetrahedron (2003) 59, 8129.), N-acylation, and subsequer—t cyclization using -n-butylammonium fluoride (for precedentc of this reaction pleas e see ‘W02004/032874A2). Starting from commercially available= 3-amino-2,6-dibromeo- pyrazine, 5-bromo-3-trimethylssilanylethynyl-pyrazin-2-ylan—ine can be obtained ty reaction with trimethylsilylacetylene in the presence of a palladium c=atalyst, such as tetrakis(triphenylphosphino)pallladium(0) and a catalytic ameount of a copper co-c=talyst, such as copper(I)-iodide in a mIxture of DMF and a basic ter-tiary organic amine, such as triethylamine at elevated temperatures. Acetylation with acetyl chloride in pyridimne at 20- 60 °C gives access to N-(5-brormo-3-trimethylsilanylethynyl—pyrazin-2-yl)-acetammide and subsequent cyclization with tetmra-n-butylammonium fluorides in THF under reflux affords 5- ‘bromo-1H-pyrrolo[2,3-b]pyraz-ine.
[0140] Introduction of a suitable group at the 3-position for further elaboration can be accomplished via methods gene=rally well known in the art, ssuch as an electrophili ¢ aromatic substitution (e.g. bromination oer iodination). Thus, 5-bromaw-3~iodo-1H-pyrrolo[2=,3- blpyrazine is accessible from 5—bromo-1H-pyrrolo{2,3-b]pyxazine by treatment with suitable reagents, such as N-iodlosuccinimide, iodine monochloride or iodine, unde=r conditions facilitating such trarmsformation.
[0141] Other examples of furactionalization via electrophil ic aromatic substituticon are, by tueans of example and not limi ation, FRIEDEL-CRAFTS-acylaation using functionalized acyl halides such as, for example, br-omoacetyl chloride, acryloyl chloride or trichloroa.cetyl chloride in the presence off aluminum trichloride in dichlorommathane at ambient temperature or below. As will be appreeciated by the skilled artisan, the —products of such re. actions either represent compounds clairmed under this invention or may toe utilized as startirmg materials for the synthesis of such ¢ ompounds, most notably certain Feterocyclic compo unds.
[0142] Further elaboration of halide D (X*=Br, I) as well as selective sequertial substitution of both halogeen substituents in 5_bromo-3-iodo-1 H-pyrrolo[2,3-b_Jpyrazine can be readily accomplished boy generally well known methods such as, for exampole, sequential metal catalyzed cross coupling reactions may be employed using various known transition metal compounds (e.g. commpounds derived from palladium, iron or nickel). FZxamples of such transformations can be found in the following references: Diederich, F., sStang, P.J. —-
Metal-catalyzed Cross-comupling Reactions, Wiley-VCH, 1 998; Beller, M., Treansition
Metals for Organic Synth esis, Wiley-VCH, 1998; Tsuji, J. Palladium Reagerals and
Catalysts, Wiley-VCH, 1 =t & 27 eds., 1995, 2004; Fuerstrer, A., et al, J.Am. Chem.Soc. (2002) 124, 13856; and F8olm, C., et al., Chem.Rev. (2004 ) 104, 6217. The g-eneral methods known in the ch-emical literature and familiar to s omeone with skill 1_n the art are essentially the same mettnods as those described above for similar or identical transformations utilizing 1H-pyrazolo[3,4-b]pyridine derinvatives.
[0143] As was discusse=d for 1H-pyrazolo[3,4-b]pyridiness the skilled artisar will appreciate that selective sfunctionalization at either the 3- or S-position may reaquire different strategies depending on the nature of the transformations Latilized to introduce functionalities at either position, especially the sequence of functionaliza—tion at either position. Thus, it may be advantageous or necessary to achieve functionaliz ation at the 3-positizon prior to functionalization of the S-position in some cases while thes opposite approach may be required in other cases, depending on the nature of the spe=cific groups to be i-niroduced, the methods required to accomplish such transformations, or #&the inherent selectiwwity of the methods utilized.
[0144] In the case of tine 3-iodo-5-bromo-1H-pyrrolo[2, 3-blpyrazine, the sslective or preferential substitution - of the iodo substituent over the bromo substituent is possible under generally less forcing co nditions, such as lower temperatumre and shorter reaction times using a suitable transition metzal catalyst. Selective functionaliz ations of di- or olig=ohalogen compounds by means of” transition metal catalyzed transformations are well porecedented in
’ the chemical litesrature: see for example Ji, J., et al. Org.Lett (2003) 5, 4611; MBach, T., et al,
J. Org.Chem (20 02) 67, 5789, Adamczyk, M. et.al ., Tetrahedron (2003) 59, 8129. [0145) In the case of halide D (X*=Br, I) other 1aseful methods may involves the conversion of a “bromine or iodine substituent into a metal or metalloid substituent (e.g. organoboron, or ganoithium, organotin, organosiliecon, 0rganozinc, organocopoper or organomagnesitam compound) using generally we=1l known methods (e.g. metal halogen exchange and, a .s appropriate or required, subsequ_ent transmetallation using =soluble and reactive compoiands of boron, magnesium, zinc, tin, silicon or copper; for representative examples of suc-h methodology see: Schlosser, M. , Organometallics in Syntieesis, 2nd. ed.,
Wiley-VCH, 20 02). Organometallic derivatives cebtained in such fashion mamy itself be of use in transition metal catalyzed coupling reactioras with aromatic or olefinic- halides or triflates, or, if stafficiently reactive, be reacted directly with suitable electropkniles, such as, for example, cer-tain organic halides, MICHAEL-ac «ceptors, oxiranes, aziridine s, aldehydes, acyl halides, or mitriles. Again, the general metho-ds known in the chemical Literature are essentially the same as those described above for ssimilar or identical transformations utilizing 1H-pyr—azolo[3,4-b]pyridine derivatives.
[0146] In cert=ain such transformations, it may b e advantageous or required to introduce one or more suiable protecting groups, in order to temporarily substitute aciedic protons, such as, for exarmple, the hydrogen atoms attachecd to nitrogen or oxygen, as -meeded, and in particular the hy~drogen atom in position 1 of the I_H-pyrrolo[2,3-b]pyrazine =scaffold, by methods well krown in the chemical literature (¢f— T.W.Greene, P.G.M.Wutss — Protective
Groups in Orga nic Synthesis, 3rd ed., John Wiley— & Sons, 1999). {0147} The creoss-coupling methodology descritmed above may be extended to the incorporation ofS non-carbon based nucleophiles (e.g. alcohols, thiols, primar—y or secondary amines) that may optionally contain suitable protecting groups of alcohols, thiols or amines,
Examples of such groups can be found in Greene, T., et al., Protective Groupos in Organic
Synthesis, 3rd ecl,, John Wiley & Sons, 1999. Exemplary methods of protect ion are described in Len, S., et al., Angew. Chem. (2003) 7715, 5558; Wolfe, J., et al., _Ace. Chem. Res. (1998) 31, 805; Hartwig, Acc.Chem.Res. (1998) 3_1, 852; Navarro, O., et al... .0rg.Chem. (2004) 69,3173 , Ji, J, et al,, Org.Leit (2003) 5, 4611. The compounds obtai—ned by such methods can be further elaborated by well known methods to obtain other compounds of the present invention. In some cases, direct substitutieon of the 5-iodo or 5-bromeo substituent in
1H-pyrrolo[2,3-b]pyrazine with ar amine, alcohol or thiol may be successfully accomplished at ambient or elevated temperatures in the presermce of weak acids , such as, for example, acetic acid, or a strorg, non-nucleophilic base, such as, for exampl-e, sodium hydride either in neat amine, alcohol or thiol, respectively or inm a suitable aprotic solvent, such as, for example, DMF, NMP=, DMSO, or acetonitrile.
Scheme 3
NH Pi 2 NH si] Pe
Br ZZ ~ NH = Si x ST NT beh Ne r
Br Br
HN HINT HN) HN
N ~7 \ NV N XN 5 _ \ x kL _N IN ZN _N R ~ Ng
Br Br /f X X2=Br, 1 2,
NH, O NH OMe
Or —— a R “ R?! i B | Cc 2
WSN Ve y Loose
NH LN
A l :
[0148] An alternative method for the synthesis of 3,5-disubmstituted LH-pyrrolo[2,3- b]pyrazine derivatives was deve=loped, starting from methyl 2=-amino-3-pyrazimnecarboxylate, incorporation of an iodine atom on the 5-position to give met"hyl 2-amino-5-ioedo-3- pyrazinecarboxylate can be ach# eved by various known meth_ods, such as reaction with N- jodosuccinimide in ethanol at re=flux. The halogenated ester Obtained by such means may then be hydrolized by standard mmethods. For example, treatrmnent with lithium hydroxide in
THE-water mixtures at ambient temperature affords the corresponding acid.
[0149] Synthesis ofa ketone intermediate B can be emchieved by treating the corresponding WEIN_REB-amide A (3-amino-6-iodo-py-razine-2-carboxylic acid methoxy- methyl-amide) or its hydrochloride salt with a suitable= organometallic species. for example, using an organomag-nesium or organolithium compound. (for examples of the —use of N- methoxy-N-methylazmides (Weinreb Amides) in keton_e synthesis, see S.Nam, SM. Weinreb — Tetrahedron Lett. 1981, 22,3815.) 3-Amino-6-iodo—pyrazine-2-carboxylic amcid methoxy- methyl-amide (A) is- accessible by condensation of thes parent acid with N,O- dimethylhydroxylanmine using standard methods for ammide-formation, either bey prior activation of the acied or in sifu or via direct condensat jon. Methods and reage=nts for both transformations are described in the chemical literatur—e and well known to sor-neone skilled in the art, such as in_ the case of direct methods using suitable coupling reagents such as, but not limited to, PyB(OP, HBTU or HATU.
[0150] The organeometallic reagents required for the= introduction of a ketone residue LR! in B can be obtained either commercially or synthesized by various methods cescribed mn the literature, such as, but not limited to the GRIGNAR D-reaction of organic cha lorides, . bromides, or iodides, with magnesium (cf. J. March — Advanced Organic Che=mistry, 3rd ed., John Wiley & Sons, 1992), metal-halogen excharage reactions of organic bromides or iodides using suitabele organolithium or organomagne sium compounds such a_s, but not limited to, n-butylli—thium, zerz-butyllithium or iso-prospylmagnesium chloride or bromide (e.g. J.Clayden — Omganolithiums: Selectivity for Synr=hesis, Pergamon, 2002; A.Boudier, i
L.O.Bromm, M.Lotrz, P.Knochel- Angew. Chem. Int. _Ed. (2000) 39, 4414.) o= deprotonation of sufficiently acidi_c compounds, such as for examples pyrimidines, pyraziness, 2-chloro- or 2-fluoropyridines u sing a suitable base, such as for example lithium N,N-diiscopropylamide or lithium 2,2,6,6-testramethylpiperidide (cf. J.Claydem — Organolithiums: Sel-ectivity for
Synthesis, Pergamo n, 2002; A. Turck, N.P1é, F.Mongi n, G.Quéguiner — Tetrahedron (2001) 57,4489; F.Mongin_, G.Quéguiner — Tetrahedron (2001) 57,4059). In certaira such transformations, it mmay be advantageous or required €o introduce one or more suitable protecting groups, #n order to temporarily substitute acidic protons (e.g. the h_ydrogen atoms attached to nitroger or oxygen) as needed, by methods well known in the chemical literature (¢f. T.W.Greene, P_G.M.Wuts — Protective Groups ira Organic Synthesis, 3rd_ ed., John
Wiley & Sons, 199 9).
[0151] Conversionof the ketone intermediate B tos the methoxyvinyl deriv=ative C can be achieved by several known methods but is most conveniently carried out via a WITTIG-
reaction (cf. B.ES Maryanoff, AB.Reitz — Chen. Rev. (1989) 89, 8«63) using an ylid generated from commercially available metoxymethyltriphenylp_hosphonium chloride and a suitable base, for example, but not limited to, a strong organometallic base such as, but not limited to, a nom-nucleophilic amide such as the lithium, sodium or potassium salt of bis(trimethylsil yl)amine.
[0152] Subse=quent cyclization of the resulting olefin C, which «can be utilized in either th e
E- or Z-form om a mixture of these both forms, can be achieved urder general acid catalysis conditions to a—fford 3-substituted 1H-5-iodo-pyrrolo[2,3-b]pyraz mines. Such methods may utilize strong imorganic or organic acids, such as sulfuric acid, perchloric acid, hydrochloriec acid, trifluoronmethanesulfonic acid or tri flusoroacetic acid in suitamble solvents (e.g. THF, dioxane, dieth=y! ether, dimethoxyethane, di_glyme, dichloromethane, dichloroethane or chloroform, water, methanol, or ethanol, or mixtures thereof) at temperatures ranging froma 0°C to 160°C. A similar cyclization has be en described by Sakammoto ef al., Heterocycles . (1992), 34(12)e, 2379-84. There the authorss describe the convers—ion of 2-nitro-3-(2- ethoxyvinyl)p—yridine to the parent pyrrolo[ 2,3-b]pyridine. Form_ation of the vinyl group was reported t- o be achieved via a STILLE-coupling of the 3-bronmo analog with tributyl-2- ethoxyvinylst=annane.
[0153] The utility of 3-substituted 1H-5-modo-pyrrolo[2,3-b]py~razines in the synthesis of compounds cl aimed under this invention will be obvious to someone skilled in the art base=d on the methods described above. One of skill will immediately winderstand that the synthetic metkniods described herein, including the Examples section below, may be used and/or elaborzated to obtain the compounds of Formulae (I), (ID, and/or (II).
A. Protecting Groups
[0154] The term "protecting group” refemrsto chemical moieties that block some or all i reactive moieties of a compound and prevent such moieties fron participating in chemica 1 reactions unti 1 the protective group is removed, for example, those moieties listed and described in MC. W. Greene, P.G.M. Wuts, Protective Groups in (Organic Synthesis, 3rd ed.
John Wiley &= Sons (1999). It may be adv antageous, where different protecting groups ate employed, thaateach (different) protective group be removable toy a different means.
Protective groups that are cleaved under totally disparate reaction conditions allow differential resmoval of such protecting groups. For example, protective groups can be removed by acid, base, and hydro genolysi s. Groups such as trit=yl, dimethoxytrityl, acetal and terr-butyldimethiylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protectzed with Cbz groups, which aare removable by hydro genolysis, and Fmoc groups, which amre base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labi_le groups such as, without limitation, methyl, ethyl, and acetyl in the presence of anmines blocked with acid labille groups such as ferr- butyl carbamate or with carbamates t™hat are both acid and base stzable } but hydrolytically removable.
[0155] Carboxylic acid and hydroxy reactive moieties ~may also be blocked with hydrolyticaily removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups suck as
Fmoc. Carboxylic acid reactive moieties may be blocked with oxidatively-removabke protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may. be blocked with fluoride labile silyl carbamates.
[0156] Allyl blocking groups are useful in the presences of acid- and base- protectixag groups since the former are stable and can be subsequent=ly removed by metal or pi-a cid catalysts. For examraple, an allyl-blocked carboxylic acid can be deprotected with a palladium(0)-cataly zed reaction in the presence of acid l=abile t-butyl carbamate or baase- labile acetate amines protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attach ed to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
[0157] Typical bYocking/protecting groups include, burt are not limited to the followwving moieties:
H> Hap 0
HC?" HC” Hy ’
Hs lo) allyl Bn Cbz alloc Me
HsC_ Hs AN / 0 : / 0) (HsC)sC™ (HCC > slg A «CHg)eC” TT t-butyl TBDMS Teoc Bos (0)
Hl, oo
C— Oo HC
O° ee A
HsCO CY pMB trityl acetyl
Fmoc . 11. Methods of Inhibiting Kinases
[0158] In anether aspect, the present inventi on provides methods of mo=dulating protein kinase activity using the fused ring heterocyclee kinase modulators of the goresent invention.
The term "modulating kinase activity," as usecd herein, means that the activity of the protein kinase is incre=ased or decreased when contacteed with a fused ring heterocycle kinase modulator of tThe present invention relative to ~the activity in the absence Of the fused ring heterocycle kimase modulator. Therefore, the present invention provides a method of modulating preotein kinase activity by contacting the protein kinase with = fused ring heterocycle kinase modulator of the present iravention (e.g. the compouncls of any one of
Formulae (I)-CIID).
[0159] In arm exemplary embodiment, the fmsed ring heterocycle kinase= modulator inhibits kinase activity. The term "inhibit," as used hesrein in reference to kinase activity, means that the kinase activity is decreased when contacteed with a fused ring heteroc-ycle kinase modulator relative to the activity in the absen ce of the fused ring heteroc-ycle kinase modulator. Therefore, the present invention &urther provides a method o-f inhibiting protein kinase activitsy by contacting the protein kinasse with a fused ring heteroc-ycle kinase modulator of -the present invention.
[0160] In certain embodiments, the protein kinase is a protein tyrosine= kinase. A protein tyrosine kinasse, as used herein, refers to an exzyme that catalyzes the ph_osphorylation of tyrosine residues in prroteins with a phosphate donors (e=.g. a nucleotide phosphate donor such as ATP). Proteimn tyrosine kinases include, for example, Abelson tyrosine kinases ("Ab") (e.g. c-Abl anad v-Abl), Ron receptor tyrosine k-inases ("RON"), Met receptor tyrosine kinases ("MEST"), Fms-like tyrosine kinases ("¥FLT") (e.g. FLT3), srac-family tyrosine kinases (e.g. lyn, CSK), and p21-activated kinaase-4 ("PAK"), FLT3 5 aurora kinases, B-lymphoid tyrosine kinases ("Bk"), cyclin-dependent kinases ("CLOK") (e.g.
CDK 1and CDKS5), sr-c-family related protein tyrosine kzinases (e.g. Fyn kinasse), glycogen synthase kinases ("G=SK") (e.g. GSK3a and GSK38), lymphocyte protein tyrosine kinases : ("Lck"), ribosomal Se6 kinases (e.g. Rsk1, Rsk2, and Rssk3), sperm tyrosine kinases (e.g.
Yes), and subtypes amd homologs thereof exhibiting tyrosine kinase activity— In certain embodiments, the protein tyrosine kinase is Abl, RON MET, PAK, or FLT. In other embodiments, the protein tyrosine kinase is a FLT3 or Abl family member.
[0161] In some em bodiments, the kinase is selected from Abelson tyrosines kinase, Ron : receptor tyrosine kin:ase, Met receptor tyrosine kinase, Fms-like tyrosine kinmase-3, Aurora kinases, p21-activate=d kinase-4, and 3-phosphoinositicle-dependent kinase-1 .
[0162] In another embodiment, the kinase is a mutart kinase, such as a mutant Bcer-Abl kinase, FLT3 kinase or aurora kinases. Useful mutant Bcr-Abl kinases inclu ade those having at least one of the following clinically isolated mutatiosns: M244V, L.248V, €5250E, G250A,
Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T3151, T"315N, T3154,
F317V, F317L, M34-3T, M351T, E355G, F359A, F359V, V379], F382L, L 387M, H396P,
H396R, S417Y, E45 9K and F486S. In some embodiments, the mutant Abl kinase has a
T3151 mutation. Thee numbering system denoting the position of the amino acid mutation above the well know=n wild-type ABL numbering accosrding to ABL exon Iam. See
Deininger, M., et al., Blood 105(7), 2640 (2005). The numbering system is reproduced in
Figure 1. In some ermbodiments, the mutant Ber-Abl kkinase includes at leasst one of the mutations listed abo~ve and has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence of Figure 1. In some embodiments , the mutant Ber-
Abl kinase includes at least one of the mutations listecd above, has a sequence identity to
Figure 1 as discussead above, and includes at least 50, “100, 150, 200, 250, 300, 350, 400, 450. 500, 550, 600, a550, 700, 750, 800, 850, 900, 950, 1000, 1050, or 1100 amino acids.
[0163] In some encibodiments, the kinase is homologous ta a known kinasse (also referred to herein as a "homologous kinase"). Compounds andl compositions useful for inhibiting
WOB 2006/015124 PCT/US2005/0267" 94 the b iological activity of homologous kinases may be initially scree=ned, for example, irm bind#ing assays. Homologous enzym es comprise an amino acid sequence of the same le=ngth that ms at least 50%, at least 60%, at Least 70%, at least 80%, or at le=ast 90% identical to= the amiro acid sequence of full length known kinase, or 70%, 80%, or 90% homology to tine knowvn kinase active domains. Hom ology may be determined using, for example, a PS 1
BLAST search, such as, but not limi ted to that described in Altschial, et al., Nuc. Acids Rec. 25:3 389-3402 (1997). In certain embodiments, at least 50%, or at Meast 70% of the sequmence is aligned in this analysis. Other tools for performing the= alignment include, for exarple, DbClustal and ESPript, which may be used to generate thhe PostScript version of the ;alignment. See Thompson et al. _ Nucleic Acids Research, 28:2 919-26, 2000; Goue=t, et al., aBioinformatics, 15:305-08 (1999). Homologs may, for examp le, have a BLAST E=- vale of 1 x 10° over at least 100 armino acids (Altschul et al., Nuc=leic Acids Res., 25:3389- 402 (1997) with FLT3, Ab}, or another known kinase, or any functzional domain of FL™I3,
Abl , or another known kinase. [01e34] Homology may also be determined by comparing the active site binding poclket of the enzyme with the active site bind ing pockets of a known kinase . For example, in homologous enzymes, at least 50%, 60%, 70%, 80%, or 90% of thee amino acids of the molecule or homolog have amino acid structural coordinates of a Clomain comparable in size to tHhe kinase domain that have a root mean square deviation of thes alpha carbon atoms of up to about 1.54, about 1.254, about L A, about 0.754, about 0.54, and or about 0.25A. : [01e65] The compounds and compositions of the present invention are useful for inhSbiting kinsase activity and also for inhibitirag other enzymes that bind AT®P. They are thus useful for the treatment of diseases and disorders that may be alleviated oy inhibiting such A_TP- bineding enzyme activity. Methods of determining such ATP binding enzymes includes those known to those of skill in the art, those discussed herein relating teo selecting homolog=ous enzzymes, and by the use of the database PROSITE, where enzymes containing signatv ares, seq uence patterns, motifs, or profiles of protein families or domaimns may be identified. [01.66] The compounds of the present invention, and their derivatives, may also be wused as kin_ase-binding agents. As binding agents, such compounds and d_erivatives may be b=ound to =a stable resin as a tethered substrate for affinity chromatography applications. The cornpounds of this invention, and their derivatives, may also be mmodified (e.g., radiol=abelled or affinity labeled, etc.) in order to utilize them in the investigation of enzyme= or polypeptide characterization, structure, and/or functio=n.
[0167] In an exemplary embodiment, the fused rings heterocycle kinase modilulator of the present invention is a kinase inhibitor. In some embo=diments, the kinase inhiWbitor has an
ICs, of inhibition cownstant (K;) of less than 1 micromeolar. In another embodimment, the kinase inhibitor has an ICs or inhibition constant (K;)) of less than 500 micror-molar. In another embodiment, the kinase inhibitor has an ICs or K; of less than 10 micsromolar. In another embodiment, the kinase inhibitor has an ICso or Kj of less than 1 micromolar. In another embodiment, the kinase inhibitor has an ICs or K; of less than 500 n=anomolar. In another embodiment, the kinase inhibitor has an ICsp or K; of less than 10 naraomolar. In another embodiment, the kinase inhibitor has an ICso or K; of less than 1 nanomolar.
III. Methods of Treatment
[0168] In another aspect, the present invention prowides methods of treatine a disease. mediated by kinase activity (kinase-mediated disease or disorder) in a subject= (e.g. mammals, such as lmumans). By "kinase-mediated"” or "kinase-associated" diseases is meant diseases in which th=e disease or symptom can be alleviated by inhibiting kinamse activity (e.g. where the kina=se is involved in signaling, media tion, modulation, or regmulation of the disease process). By "diseases" is meant diseases, or disease symptoms. The= method includes administer®ng to the subject an effective amount of a fused ring hetezxcycle kinase modulator of the present invention (e.g. the compoun_ds of any one of Formul_ae (I)~(III)).
[0169] Examples of kinase associated diseases incl ude cancer (e.g. leukemia, tumors, and metastases), allergy, asthma, obesity, inflammation (e.g. inflammatory diseas. es such as inflammatory airways disease), hematological disords=ers, obstructive airways disease, asthma, autoimmun-e diseases, metabolic diseases, infection (e.g. bacterial, viral, yeast, fungal), CNS diseasses, brain tumors, degenerative neural diseases, cardiovascular diseases, and diseases associzated with angiogenesis, neovascul arization, and vasculoge=nesis. In an exemplary embodinment, the compounds are useful fo-r treating cancer, includ=ing leukemia, and other diseases owr disorders involving abnormal cesli proliferation, such as myeloproliferative clisorders.
[0170] More spec ific examples of cancers treated with the compounds of tle present invention include breast cancer, lung cancer, melanorma, colorectal cancer, bl adder cancer,
ovarian cancer, prostate cancer, renal cancer, squamouss cell cancer, glioblastoma, pancreatic cancer, Kaposi's sarcoma, multiple myeloma, and leukemia (e.g. myelo®d, chronic myeloid, acute lymphoblastic, chronic lymphoblastic, Hodgkins, and other leukemias and hemat-clogical cancers).
[0171] Other speci fic examples of diseases or disorders for which treatment by the compounds or compeositions of the invention are useful for treatment or preventior include, but are not limited to transplant rejection (for example, kidney, liver, heart, lung, islet cells, pancreas, bone marre©w, cornea, small bowel, skin allo grafts or xenografts and otlmer transplants), graft vs. host disease, osteoarthritis, rheurmatoid arthritis, multiple scMerosis, diabetes, diabetic retinopathy, inflammatory bowel dissease (for example, Crohn's disease, ulcerative colitis, an_d other bowel diseases), renal disease, cachexia, septic shock , lupus, myasthenia gravis, osoriasis, dermatitis, eczema, sebo 1thea, Alzheimer's disease,
Parkinson's disease, stem cell protection during chemotherapy, ex vivo selection «or ex vivo purging for autologous or allogeneic bone marrow transplantation, ocular disease, retinopathies (for exxample, macular degeneration, dia~betic retinopathy, and other retinopathies), corneal disease, glaucoma, infections (for example bacterial, viral or fungal), heart diseasse, including, but not limited to, re=stenosis.
IV. Assays
[0172] The comp ounds of the present invention mamy be easily assayed to determine their ability to modulate protein kinases, bind protein kina=ses, and/or prevent cell growth or proliferation. Some examples of useful assays are presented below.
A. Kinase Inhibition and Binding Assase’s
[0173] Inhibitiorn of various Kinases is measured b= methods known to those osf ordinary skill in the art, such as the various methods presente] herein, and those discussed in the
Upstate KinasePro filer Assay Protocols June 2003 publication.
[0174] For exanmple, where in vitro assays are perf=ormed, the kinase is typical ly diluted to the appropriate coracentration to form a kinase soluti on. A kinase substrate and phosphate donor, such as ATP, is added to the kinase solution. The kinase is allowed to tr=ansfer a phosphate to the k-inase substrate to form a phosphomylated substrate. The form ation of a phosphorylated substrate may be detected directly bZy any appropriate means, such as radioactivity (e.g. [v-*2P-ATP]), or the use of detect=able secondary antibodies (e.g. ELISA).
Alternatively, the formation of = phosphorylated substrate maay be detected using any= appropriate technique, such as the detection of ATP concentr=ation (e.g. Kinase-Glo®D assay system (Promega). Kinase intmibitors are identified by detecting the formation of a phosphorylated substrate in the- presence and absence of a tesst compound (see Exampples section below).
[0175] The ability of the conpound to inhibit a kinase in a_ cell may also be assayed using methods well known in the art. For example, cells containin_g a kinase may be contacted with an activating agent (such as a growth factor) that activates the kinase. The amount of intracellular phosphorylated stabstrate formed in the absence and the presence of the= test compound may be determined by lysing the cells and detecting the presence phosphmorylated substrate by any appropriate method (e.g. ELISA). Where tlhe amount of phosphorylated substrate produced in the presence of the test compound is decreased relative to the amount produced in the absence of the= test compound, kinase inhibition is indicated. More detailed cellular kinase assays are discwussed in the Examples section below.
[0176] To measure the bind=ing of a compound to a kinases, any method known to those of ordinary skill in the art may bee used. For example, a test ki—t manufactured by Disceoverx (Fremont, CA), ED-Staurospcorine NSIP™ Enzyme Bindings Assay Kit (see U.S. Patent No. 5,643,734) may be used. Kinzase activity may also be assayed as in U.S. Patent 6,589,950, issued July 8, 2003.
[0177] Suitable kinase inhibitors may be selected from thee compounds of the inv—ention through protein crystallographic screening, as disclosed in, for example Antonysan—y, et al.,
PCT Publication No. WO030 87816A1, which is incorporat=e herein by reference ina its entirety for all purposes.
[0178] The compounds of t-he present invention may be computationally screene d to assay and visualize their ability to bind to and/or inhibit various Ixinases. The structure rmnay be computationally screened witha plurality of compounds of the present invention t© determine their ability to binc to a kinase at various sites. Such compounds can be= used as targets or leads in medicinal «chemistry efforts to identify, for example, inhibitors of potential therapeutic importance (Travis, Science, 262:1374,1993). The three dimensional structures of such compound s may be superimposed on a three dimensional repres-entation of kinases or an active site or= binding pocket thereof to assess whether the compovand fits spatially into the representati_on and hence the protein. In this screening, the qualisty of fit of
: such entities or compounds to the binding pocket may be judged either by shape complementarity or by” estimated interaction energy (Meg, et al., J. Comp. Chen. 13:505-24, 1992).
[0179] The screening of compounds of the present inve=ntion that bind to and/or Tmodulate kinases (e.g. inhibit or activate kinases) according to this invention generally invol=ves consideration of two factors. First, the compound must toe capable of physically aad structurally associating, either covalently or non-covalen_tly with kinases. For exarmple, covalent interactions may be important for designing irre=versible or suicide inhibiteors of a protein. Non-covalent molecular interactions important mn the association of kinasees with the compound include hydrogen bonding, ionic interactions, van der Waals, and hydrophobic interactions. Second, the compound must bwe able to assume a conformmation and orientation in relation to the binding pocket, that allcaws it to associate with kirmases.
Although certain portions of the compound will not directly participate in this asso-ciation with kinases, those poxtions may still influence the overa=1l conformation of the mo_lecule and may have a significant impact on potency. Conform._ational requirements inclumde the overall three-dimensio nal structure and orientation of thes chemical group or compound in relation to all or a portion of the binding pocket, or the spacing between functional groups of a compound comprising several chemical groups that -directly interact with kinas=ses.
[0180] Docking programs described herein, such as, fomr example, DOCK, or GO=LD, are used to identify compounds that bind to the active site armd/or binding pocket. Compounds may be screened agairast more than one binding pocket o fthe protein structure, or rnore than one set of coordinates for the same protein, taking into account different molecular— dynamic conformations of the protein. Consensus scoring may theen be used to identify the compounds that are the best fit for the protein (Charifsorm, P.S. et al., J Med. Chem=. 42: 5100-9 (1999)). Data obtained from more than one prote=in molecule structure may also be scored according to the methods described in Klingler et al., U.S. Utility Applicaticon, filed
May 3, 2002, entitled *'Computer Systems and Methods #For Virtual Screening of
Compounds." Compounds having the best fit are then ototained from the producer of the chemical library, or synthesized, and used in binding assaays and bioassays.
[0181] Computer modeling techniques may be used to assess the potential modulating or binding effect of a chemical compound on kinases. If co-mputer modeling indicates a strong interaction, the molecule may then be synthesized an_d tested for its ability ®o bind to kinases and affect (by inhibiting or activating) its activity.
[0182] Modulating: or other binding compounds of" kinases may be computationally evaluated by means Of a series of steps in which chemical groups or fragmeents are screened and selected for their ability to associate with the individual binding pocke=ts or other areas of kinases. This process may begin by visual inspec=tion of, for example, thhe active site on the computer screen based on the kinases coordinates. Selected fragments or chemical groups may then be positioned in a variety of orientations, or docked, wittmin an individual binding pocket of kinases (Blaney, J.M. and Dixon, J.S., Perspectives in IDJrug Discovery and Design, 1:301, 1993). Manual docking may be accomplished using software such as
Insight II (Accelrys, San Diego, CA) MOE (Chemical Cornputing Group, Inc., Montreal,
Quebec, Canada); ard SYBYL (Tripos, Inc., St. Lowmis, MO, 1992), followed by energy minimization and/or= molecular dynamics with stanciard molecular mechanics force fields, such as CHARMM (Brooks, et al., J. Comp. Chem. 4: 187-217, 1983), ANMBER (Weiner, ef al, J. Am. Chem. Soc. 106: 765-84, 1984) and C? MIMFF (Merck Molecular Force Field; -
Accelrys, San Diego, CA). More automated dockirg may be accomplishesd by using programs such as D- OCK (Kuntz ez al., J. Mol. BioZ., 161:269-88, 1982; IDOCK is available from University of «California, San Francisco, CA); AUTODOCK (Goodssell & Olsen,
Proteins: Structure, Function, and Genetics 8:195-22202, 1990; AUTODOCZK is available from Scripps Resea rch Institute, La Jolla, CA); GORLD (Cambridge Cryst allographic Data
Centre (CCDC); Joes et al., J. Mol. Biol. 245:43-53, 1995); and FLEXXC (Tripos, St. Louis,
MO; Rarey, M., et zal, J. Mol. Biol. 261:470-89, 19996). Other appropriates programs are described in, for ex_ample, Halperin, et al.
[0183] During se lection of compounds by the ab -ove methods, the efficiency with which that compound may bind to kinases may be tested -and optimized by computational evaluation. For ex=ample, a compound that has bee=n designed or selected. to function as a kinases inhibitor mmay occupy a volume not overlapping the volume occu pied by the active site residues when the native substrate is bound, however, those of ordinary skill in the art will recognize that there is some flexibility, allowi ng for rearrangement of the main chains and the side chainss. In addition, one of ordinary sMkill may design compomunds that could exploit protein reamrangement upon binding, such =as, for example, resulting in an induced
Gt. An effective kinase inhibitor may demonstrates a relatively small difference in energy between its bound and free states (i.e., it must hav-e a small deformation energy of binding and/or low comformational strain upon binding). Thus, the most efficient kinasse inhibitors should, for ex ample, be designed with a deformation energy of binding of not greater than kcal/mol, rot greater than 7 kcal/mol, not greater than 5 kcal/mol, or not greater than 2 kcal/mol. Kirase inhibitors may interact with the Jprotein in more than one corformation that is similar in overall binding energy. In those cases, the deformation energy of binding is taken to be the difference between the energy of the free compound and the average energy of the conformations observed when the in hibitor binds to the enzyme.
[0184] Specific computer software is available i: the art to evaluate compoumnd deformation e=nergy and electrostatic interaction. Examples of programs designed for such uses include: Gaussian 94, revision C (Frisch, Gaussian, Inc., Pittsburgh, PA. ©1995);
AMBER, ver-sion 7. (Kollman, University of California at San Francisco, ©20802);
QUANTA/CIHARMM (Accelrys, Inc., San Diego , CA, ©1995); Insight II/Disscover (Accelrys, Inec., San Diego, CA, ©1995); DelPhi (Accelrys, Inc., San Diego, CCA, ©1995), and AMSOL (University of Minnesota) (Quanturra Chemistry Program Exchamnge, Indiana
University). These programs may be implemented, for instance, using a computer workstation, as are well known in the art, for exarmple, a LINUX, SGI or Sun ~workstation.
Other hardware systems and software packages will be known to those skilled in the art.
[0185] Those of ordinary skill in the art may ex press kinase protein using romethods known in the art, anc the methods disclosed herein. The mative and mutated kinase peolypeptides described hemrein may be chemically synthesized im whole or part using technieques that are well known i_n the art (see, e.g., Creighton, Proteixs: Structures and Molecular Principles,
W.H. Freemzan & Co., NY, 1983).
[0186] Gere expression systems may be used for the synthesis of native anc3 mutated polypeptides . Expression vectors containing the rative or mutated polypeptide coding sequence anc appropriate transcriptional/translational control signals, that are known to those skilled in the art may be constructed. These methods include in vitro re~combinant
DNA technicjues, synthetic techniques and in vivo recombination/genetic recommbination.
See, for exarmple, the techniques described in Sambrook ef al., Molecular Cloning: A
Laboratory Nedanual, Cold Spring Harbor Laboratory, NY, 2001, and Ausubel et al, Current
Protocols in “Molecular Biology, Greene Publishirg Associates and Wiley Interscience, NY, 1989.
[0187] Host-expression vector sy/stems may be used to express kinase. These inclimde, but are not Immited to, microorganisms such as bacteria transformed vith recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression veectors containing thee coding s-equernce; yeast transforme d with recombinant yeast expression vectors containing the codizxng sequence; insect cell systems infected with recombinant virus expression —vectors (e.g., baculovirus) containing the coding sequence; plant cell systcems infected with recombinant virus expression vect-ors (e.g., cauliflower mosaic vis, CaMV; tobacco mosaic wirus, TMV) or transforme=d with recombinant plasmid expression vectors (e. g,Ti plasmid) containing the coding secjuence; or animal cell systems.. The protein may a_1so be expresse=d in human gene therapy systems, including, for exampl-e, expressing the prootein to augment the amount of the proteirm in an individual, or to express. an engineered therapeutic protein. The expression elements of these systems vary in their strength and specificities.
[0188] Specifically designed vectors allow the shuttling of DNA between hosts suech as bacteria—yeast or bacteria-animal cells. An appropriately constructed expression vector may contain: an origin of replication feor autonomous replication in heost cells, one or moe selectab~ le markers, a limited number of useful restriction enzymee sites, a potential for high copy mu_mber, and active promoters. A promoter is defined as a MDNA sequence that directs
RNA polymerase to bind to DNA. and initiate RNA synthesis. A. strong promoter is one that causes mRNAs to be initiated at lxigh frequency.
[0189] The expression vector nr ay also comprise various elemeents that affect trans=cription and trammslation, including, for exa-mple, constitutive and inducibl_e promoters. These= element=s are often host and/or vector dependent. For example, vvhen cloning in bacterial systemss, inducible promoters suck as the T7 promoter, pL of bac=teriophage A, plac, php, ptac (ptzxp-lac hybrid promoter) armd the like may be used; when cloning in insect celT] systemss, promoters such as the ba_culovirus polyhedrin promoter may be used; when cloning in plant cell systems, promoters derived from the genome of plat cells (e.g., heat smock promote=ts; the promoter for the stall subunit of RUBISCO; the promoter for the "chlorophyll a/b binding protein) ovr from plant viruses (e.g., the 3555S RNA promoter of
CaMV; the coat protein promoter of TMV) may be used; when —loning in mammali=an cell systemss, mammalian promoters (e.g. metallothionein promoter) or mammalian viral promoters, (e.g., adenovirus late promoter; vaccinia virus 7.5K poromoter; SV40 prommoter; bovine —papilloma virus promoter; and Epstein-Barr virus promoter) may be used.
[0190] Various methods may be used to introduce the vector into host cells, for example, transformation, ®ransfection, infection, protoplast fusion, and electroporatiomn. The expression vector-containing cells are clonally propagated and individually= analyzed to determine wheter they produce the appropriate polypeptides. Various selection methods, including, for example, antibiotic resistance, may be used to identify host c=ells that have been transforme=d. Identification of polypeptide expressing host cell cloness may be done by several means, i_ncluding but not limited to immumological reactivity with &anti- kinase antibodies, and —the presence of host cell-associated activity.
[0191] Expresssion of cDNA may also be performed using in vitro produ~ced synthetic mRNA. Synthestic mRNA can be efficiently translated in various cell-free systems, including but noot limited to wheat germ extracts and reticulocyte extracts, as well as efficiently transslated in cell-based systems, inclucling, but not limited, to microinjection into frog oocytes.
[0192] To demtermine the cDNA sequence(s) that yields optimal levels off activity and/or protein, modifiesd cDNA molecules are constructed. A non-limiting example of a modified cDNA is where= the codon usage in the cDNA has been optimized for the Imost cell in which the cDNA will be expressed. Host cells are transformed with the cDNA n—olecules and the levels of kinases RNA and/or protein are measure d.
[0193] Level. s of kinase protein in host cells are quantitated by a variety of methods such as immunoaffirity and/or ligand affinity techniques, kinase-specific affinity beads or specific antibodies are used to isolate 35S-methiomine labeled or unlabeled protein. Labeled or unlabeled protein is analyzed by SDS-PAGE. Unlabeled protein is dete=cted by Western blotting, ELIS AA or RIA employing specific antibodies.
[0194] Follo=wing expression of kinase in a rec ombinant host cell, polypeptides may be recovered to proovide the protein in active form. Several purification proceedures are available and suitable for use. Recombinant kinase may be purified from cell lysates or from condition. ed culture media, by various combinations of, or individual application of, fractionation, or chromatography steps that are kznown in the art.
[0195] In adedition, recombinant kinase can be separated from other cell ular proteins by use of an immuwno-affinity column made with monoclonal or polyclonal a—ntibodies specific for full length —nascent protein or polypeptide fra gments thereof. Other affinity based purification techniques known in the art may also be used.
[0 196] Alternatively, the polypeptides may be recovered from a Hhost cell in an unfolded, in active form, e.g., from inclusion bodies of bacteria. Proteins recovered in this form may be solubilized using a denaturant, e.g., guanidinium hydrochloride, and then refolded into ara active form using methods known to those skilled in the art, such &as dialysis.
B. Cell Growth Assays [©197] A variety of cell growth assays are known in the art and =are useful in identifying fiased ring heterocycle compounds (i.e. "test compounds") capable= of inhibiting (e.g. resducing) cell growth and/or proliferation. [®0198] For example, a variety of cells are known to require specific kinases for growth and/or proliferation. The ability of such a cell to grow in the pres=ence of a test compound may be assessed and compared to the growth in the absence of the test compound thereby iudentifying the anti-proliferative properties of the test compound. One common method of’ t his type is to measure the degree of incorporation of label, such as tritiated thymidine, into= the DNA of dividing cells. Alternatively, inhibition of cell prolifeeration may be assayed by letermining the total metabolic activity of cells with a surrogate rmarker that correlates with cell number. Cells may be treated with a metabolic indicator in the presence and absence Of fhe test compound. Viable cells metabolize the metabolic indicat=or thereby forming a letectable metabolic product. Where detectable metabolic produ_ct levels are decreased in athe presence of the test compound relative to the absence of the teest compound, inhibition eof «cell growth and/or proliferation is indicated. Exemplary metabol ic indicators include, for example tetrazolium salts and AlamorBlue® (see Examples secti_on below). “V. Pharmaceutical Compositions and Administration
[0199] In another aspect, the present invention provides a phar-maceutical composition including a fused ring heterocycle kinase modulator in admixtures with a pharmaceutically acceptable excipient. One of skillin the art will recognize that tie pharmaceutical compositions include the pharmaceutically acceptable salts of th-e fused ring heterocycle kinase modulators described above.
[0200] In therapeutic and/or diagnostic applications, the comp ounds of the invention cam be formulated for a variety of modes of administration, includinge systemic and topical or localized administration. Techniques and formulations generally may be found in
Remington: The Science and Practice of Pharmacy (20™ ed.) Lippincott, Williams &
Wilkins (2000).
[0201] The compounds according to the invention are effective ov=er a wide dosage range.
For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are e=xamples of dosages that may be used. A most preferable dosage is 10 to 30 mg per day. Thes exact dosage will depend upon the route of administration, the form in which the cormpound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
[0202] Pharmaceutically acc eptable salts are generally well known to those of ordinary skill in the art, and may include, by way of example but not limitat=ion, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate, carbonate, citrate, cdetate, edisylate, estolate, esylate, fimarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrab=amire, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lact-obionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate {embonate), pantothenate, phosphate/ diphosphate, polygalacturonate, salicylates, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts may be found in, for example, Remington: The Science and Practice of Pharmacy (20" ed.)
Lippincott, Williams & Wilkins (2000). Preferred pharmaceutical ly acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrat=e, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamosate (embonate), phosphate, salicylate, succinate, sulfate, or tartrate.
[0203] Depending on the specific conditions being treated, suchm agents may be formulate into liquid or solid dosage forms and administered systemically om locally. The agents may be delivered, for example, in a timed- or sustained- low release fosm as is known to those skilled in the art. Techniques for formulation and administration ray be found in
Remington: The Science and Practice of Pharmacy (20™ ed.) Lippincott, Williams &
Wilkins (2000). Suitable routes may include oral, buccal, by inh=alation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articular, inmtra —sternal, intra-synoviall,
intra- hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.
[0204] For injection, the agents of thes invention may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution,
Ringer's solution, or physiological salirme buffer. For such transmuco -sal administration, penetrants appropriate to the barrier to Tbe permeated are used in the formulation. Such penetrants are generally known in the a rt.
[0205] Use of pharmaceutically acceptable inert carriers to formul ate the compounds herein disclosed for the practice of the “invention into dosages suitable for systemic admi nistration is within the scope of th. ¢ invention. With proper chowice of carrier and suitable manufacturing practice, the commpositions of the present invention, in particular, those formulated as solutions, may be &xdministered parenterally, such as by intravenous injection. The compounds can be formmulated readily using pharmac=eutically acceptable carri ers well known in the art into dosages suitable for oral administ—ration. Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and #he like, for oral ingestion by a patient to be treated.
[02006] For nasal or inhalation delivery, the agents of the inventiora may also be formulated by methods known to those of skill in the art, and may irclude, for example, bu_t not Limited to, examples of solubilizing, diluting, or dispersing substances such as, saline, pres ervatives, such as benzyl alcohol, =absorption promoters, and flu_orocarbons.
[02007] Pharmaceutical compositions suitable for use in the presermt invention include com positions wherein the active ingreclients are contained in an effective amount to achiev—e its imatended purpose. Determination o fthe effective amounts is well within the capability of thos e skilled in the art, especially in light of the detailed disclosure provided herein.
[0208] In addition to the active ingrezdients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising exccipients and auxiliaries which facilitate processing of the active compounds into preparatiomns which can be used phaxmaceutically. The preparations foxmulated for oral administration may be in the form =of tabl ets, dragees, capsules, or solutions .
[0209] Pharmaceutical preparations for oral use can be obtained oy combining the actives compounds with solid excipients, opti-onally grinding a resulting maxture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, te obtain tablets or dragee= cores. Suitable excipients are, in particular, fillers such as sugsars, including lact=ose, sucrosse, mannitol, or sorbitol; cellulose preparations, for example, mmaize starch, wheat= starch_, rice starch, potato starch, gelatin, gum tragacanth, methyl celBulose, hydro=xypropylmethyl-cellulose, sodium carboxymethyl-cellulose (CMC), and/or polyvanylpyrrolidone (PVP: povidone). If desired, disintegrating age=nts may be added, such as the cross- linked polyvinylpyrrolidone, agar, or alginic acid or a s-alt thereof such ass sodiumm alginate.
[02108] Dragee cores are provided with suitable coatings. For this purpose, concentr—ated sugar solutions may be used, which may optionally contain gum ara_bic, talc, polyv-inylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacqu_er solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or piggments may Woe added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [021M] Pharmaceutical preparations tha t can be used orally include push-fit capsule-s made of ge latin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as g=lycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture witha filler such as lactose, binders such as starches, and/or lubricants such as t=alc or magnesium stear.ate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid. polysethylene glycols (PEGs). In addition , stabilizers may be added (021 2] Depending upon the particular condition, or disease state, to be treated or prev-ented, additional therapeutic agents, which are normally admirqistered to treat or prevent that ~condition, may be administered together with the inhibitors of this invention. Foor exarmple, chemotherapeutic agents or othmer anti-proliferative agent=s may be combine -d with the i nhibitors of this invention to treat proliferative diseases and ca_ncer. Examples o-f known chemotherapeutic agents include. but are not limited to, adr-iamycin, dexamet=hasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, inter—ferons, and platintam derivatives. [02M 3] Other examples of agents the irahibitors of this invention —may also be comb-ined with include, without limitation, anti-inflammatory agents such as corticosteroids, T_INF bloc=kers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasala=zine; immunomodulatory and_ immunosuppressive agents such as cyclosporin, tacrolimus, rapam w/cin, mycophenolate mo=fetil, interferons, corticosteroids, cyclophophamide, azathioprine, ana d sulfasalazine; neurotrophic factors such as acetyicholinesterase inhibitors, MAQ inhitoitors, interferons, ant3-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian =agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, Gliuretics, nitrates, calecium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood dis-orders such as corticosteroids, anti-leukemic agents, and growth facstors; agents for tresating diabetes such as insulin, insulin analogues, alpha glucosidase inhibitors, biguanides, ancl insulin sensitizers; and agents for treating immunodeficiency disor: ders such as gamma globulin.
[0214] These additional agents may be administered separately, as p=art of a multiple dossage regimen, from the inhibitor-containing composition. Alternativ =ely, these agents may be part of a single dosage form, mix ed together with the inhibitor in a single composition.
[0215] The present invention is not to be limited in scope by the exemmplified ermm bodiments, which are intended as illustrations of single aspects of thre invention. Indeed, vamrious modifications of the invention in addition to those described herein will become apparent to those having skill in the art from the foregoing description Such modifications ‘are intended to fall within the scope of the invention. Moreover, any o=ne or more features of any embodiment of the invention may be combined with any one or more other features of any other embodiment of the invention, without departing from the =scope of the invention. For example, the fused ring heterocycle kinase modulators described in the
Fu_sed ring heterocycle kinase modulators section are equally applicabMe to the methods of tre atment and methods of inhibiting kinases described herein. Referen=ces cited throughout thi_s application are examples of the level of skill in the art and are hereby incorporated by reference herein in their entirety for all purposes, whether previously specifically . incorporated or not.
EXAMPLES
[02167] The following examples are offered to illustrate, but not. to limit the claimed inven®tion. The preparation of embodiments of the present invention is described in the following examples. Those of ordinary skill in the art will undersstand that the chemical reacti ons and synthesis methods provided may be modified to prespare many of the other comp-ounds of the present invention. "Where compounds of the pmresent invention have not been exemplified, those of ordinary skill in the art will recognize that these compounds maay be precpared by modifying synthesis methods presented herein, ard by using synthesis metheods known in the art.
Syntlesis of the compounds:
Methaod 1:
F F HN oN HN-T 0 Step 1 or Step 2 Sy _Step3 y 7 4 7 HCI 7
Bor Br Br Br /
HN-N SEM. SEMIN Q
S=tep 4 (y Step 5 of Step 6 ry 0
L LL
Br Br Ber
SEMN-N ¢ MY q. \ N™ {)
Step 7 Sav Step 8 = —_— > -—_— oo gq 3
A= OH O
Step 1: Synthesis of 5-bromo-2—fluoro-pyridine-3-carbaledehyde. [02M7] A solution of lithium di-iso-propylamine (5 mL, 35 mmmol) in anhydrous THF @o mL)» was cooled to 78 °C under nitrogen and z-butyl lithium (22.5 M in hexanes, 12 mL, 30 mm _ol) was added. The mixture was then stirred at —78 °C for 15 min before 5-bromo-2- fluosTo-pyridine (5 g, 28 mmol) was added. The resulting mixtu_re was then stirred at —=78 °C for 0 min. N-formylpiperidine (4 mL, 36 mmol) was added vesry rapidly to the suspensi~on at — 778 °C and the mixture stirred vigorously for 60 sec. The rezaction was immediately
) quenched by the addition of a 10 % (w/v) aqueous solution of cilitric acid. The mixture was warmed to room temperature and distributed between water and dichloromethane. The aqueous phase was extracted. three times with dichloromethane and the organic phases were combined, dried over sodium sulfate, filtered and concentrated. Crystallization of the crude= product from cyclohexane afforded 5-bromo-2-fluoro-pyridine— 3-carbaldehyde (2.993 g, 52% yield) as pale beige flaky crystals. "H-NMR (500 MHz, des-DMS0) 510.07 (s, 1H), 8.70 (dd, 1H), 8.55 (dd, 1H). MS: m/z 236, 238 [MNa'], 204, 2206 [MH"], 176, 178 [MH- co".
Steps 2 and 3: Synthesis of 5-bromo-1H-pyrazolo[3,4-b] pyridine.
[0218] 5-bromo-2-fluoro-pyridine-3-carbaldehyde (13.66 g, 656.96 mmol), pinacol (8.75 g, 74.0 mmol) and para-toluen esulfonic acid monohydrate (1.50 =, 7.89 mmol) were placed in a flask equipped with a DEA N-STARK-condenser and dissolved in anhydrous benzene (400 mL). The mixture was heated to reflux and solvent distilled of =f until the distillate remains clear and the remaining vollame was approximately 200 ml. Tle mixture was diluted with ethyl acetate (300 mL) and washed with a saturated aqueous somlution of sodium bicarbona-te and brine, then dried over sodium sulfate, filtered and concentr—ated. The resulting residue was dissolved in a mixture of ethanol (400 mL) and di-iso-propoyl-ethyl-amine (25 mL).
Anhydrous hydrazine (15 ml, 0.48 mol) was then added and th. resulting mixture was stirred under reflux conditions for 4 h. The mixture was then c=oncentrated to dryness and the resulting residue was distributed between water and toluene=. The organic phase was washed with brine twice, dried over sodium sulfate, filtered an-d concentrated. The residue was dissolved in anhydrous ether (700 mL) and hydrogen chloride in anhydrous ether (2M, 70 mL) was added slowly to the vigorously stirred solution. T he precipitate was filtered o-ff, washed with ether and hexane and then dried in vacuum. "H-™MR (500 MHz, de-DMSO) § 10.31 (s,br, 1H), 8.86 (s, 1H), 8.37 (d, 1H), 7.88 (d, 1H), 6.08 &(s, 1H), 3.56 (s,br), 1.27 (s, 6H), 1.19 (s, 6H). MS: m/z 198,200 [MH].
[0219] The above solid was dissolved in a mixture of water @500 mL), ethanol (200 mL) and concentrated aqueous hydrochloric acid (50 mL) at 50-65 °C. The mixture was then stirred at room temperature for 16 h before being neutrafized teo pH = 8 with sodium bicarbonate. The resulting precipitate was filtered off and the aqueous phase extracted thr-ee times with ethyl acetate. The combined organic phases are wasshed with brine, dried over sodium sulfate, filtered and concentrated. The resulting residume and the precipitate obtained are crystallized from ethanol to afford 5-bromo-1H-pyrazolo[28,4-b]pyridine (6.615 g, 50%%
yield) as a crystalline beige to pale olive-green solid. "H-NMR (500 MHz, ds-DMSO) S 13.91 (s, 1H), 8.60 (d, 1H), 8.54 (d, 1H), 8.16 (s, br, 1H). MS: r=/z 198, 200 [MH].
Step 4: Synthesis of 5-bromo-3-iodo-1H-pyrazolo|3,4-b]gpyridine..
[0220] S-bromo-1H-pyrazolo[3,4-blpyridine (3.00 g, 15.2 mrmaol) and N-iodosuccinimicie (3.60 g, 16.0 mmol) were dissolved in anhydrous dichloroethane (100 mL). The resulting mixture was stirred under reflux conditions for 6 h, cooled to room temperature and diluteed with THF (300 mL). The resulting solution was washed with a. saturated aqueous solution of sodium thiosulfate (100 mL) and brine, then dried over magresium sulfate, filtered ani concentrated. The residue was titurated with a 1:1 mixture of dichloromethane and ether and then ether before being dried in vacuum to afford 5-bromo—3-iodo-1H-pyrazolo(3,4- blpyridine (3.795 g, 77% yield) as a beige-brown solid. "H-NMR (500 MHz, dg-DMSO) § 14.31 (s, 1H), 8.65 (d, 1H), 8.20 (d, 1H). MS: m/z 323, 325 MH.
Step S: Synthesis of 5-bromo-3-iodo-1-(2-trimethylsilan=yl-ethoxymethyl)-1H- pyrazolo[3,4-b]pyridine.
[0221] Under nitrogen 5 -bromo-3-iodo-1H-pyrazolo[3,4-b]p_yridine (2.68 g, 8.27 mmo-1) was dissolved in anhydrous DMF (40 mL). The solution was c=ooled to 0-5 °C and an excess of dry sodium hydride added until further addition does not result in hydrogen formation. To the resulting suspension was added 2-trimethylssilanyl-ethoxymethyichlorzde (2.5 ml, 14 mmol) drop wise at 0-5 °C. The resulting mixture wwas stirred at 0 °C for 1 h and thereafter quenched by addition of methanol and subsequently of a saturated aqueous solution of ammonium chloride. The mixture was then concen_trated to dryness at SO °C under reduced pressure. The resulting residue was distributed oetween water, brine and dichloromethane. The aqueous phase was then extracted with «dichloromethane and the combined organic phases were dried over sodium sulfate, filter—ed and concentrated. The= crude product was purified by flash silica gel chromatography —using a gradient of ethyl acetate in hexanes to afford 5-bromo-3-iodo-1-(2-trimethylsilamyl-ethoxymethyl)-14- pyrazolo[3,4-blpyridine (2.929 g, 78% yield) as a beige to brown solid. "H-NMR (500
MHz, de-DMSO) 68.85 (d, 1H), 8.40 (d, 1H), 5.85 (s, 2H), 3.69 (t, 2H), 0.92 (t, 2H), 0.1.1 (s, 9H).
Step 6: Synthesis of S-bromo— 3-(2-methoxy-phenyl)-1-(2-trim ethylsilanyl- ethoxymethyl)-1H-pyrazolo{3.4-b]pyridine.
[0222] A mixture of 5.bromo-3-io0do-1-(2-trimethylsilanyl-ethoxymmethyl)-1H-
Pyrazolo[3,4-b]pyridine (1.606 g, 3.537 mmol), 2-methoxy-phenyl-tooronic acid (575 mg, 3.78 mmol) and of 1,1*bis(diphensyiphosphino)ferrocenepalladium(r )-dichloride
Clichlormethane adduct (145 mg, O .178 mmol) in acetonitrile (8 mL) and aqueous solution of
Sodium carbonate (2M, 8 mL) was stirred in a closed vial at 85 °C for 100 min. The ®esulting mixture was then distributed between a saturated aqueous solution of sodium bicarbonate and dichloromethane znd the aqueous phase extracted three times with «dichloromethane. The combined organic phases were dried over soedium sulfate, filtered and concentrated. The crude prod uct was purified by flash silica ge 1 chromatography using a gradient of ethyl acetate in hexames to afford 5-bromo-3-(2-methoxy-phenyl)-1-(2- ~trimethylsilanyl-ethoxymethyl)-1 F1-pyrazolo[3,4-b]pyridine (1.002 g, 65 % yield) as an off- white oil. "H-NMR (500 MHz, ds -DMSO) 58.70 (d, 1H), 8.40 (d, 3H), 7.61 (d, 1H), 7.50 (ddd, 1H), 7.23 (dd, 1H), 7.10 (dd.d, 1H), 5.81 (s, 2H), 3.85 (s, 3H), 3.66 (t, 2H), 0.84 (1, 2H), —0.10 (s, 9H). MS: m/z 456, 458 [MNa'].
Step 7: Synthesis of 3-(2-metthoxy-phenyl)-5-(4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-y)-1-2-trimethylsilanyl-ethoxymethy-1)-1H-pyrazolo[3,4- b]pyridine.
[0223] Bis(pinacolato)diboron (1.20 g, 4.73 mmol), 1,1- his(diphenylphosphino)ferroceneppalladium(ir)-dichloride dichlormesthane adduct (100 mg, 0.122 mmol) and anhydrous sodiuim acetate (625 mg, 7.62 mmol) v=vere placed in a nitrogen flushed vial. To this was added a solution of 5-bromo-3-(2-methox=y-phenyl)-1-(2- trimethylsilanyl-ethoxymethyl)-1 _H-pyrazolo[3,4-b]pyridine (1.002 g, 2.307 myuol) in anhydrous DMF (15 mL). The resulting mixture was irradiated in =a Personal Chemistry
Optimizer at 130 °C for 60 min amd then concentrated at 50 °C undker reduced pressure. The resulting residue was distributed between ether and brine and the aequeous phase was extracted with ether. The organic phases were combined, dried ovesr sodium sulfate, filtered and concentrated. The crude product was then purified by flash sil=ica gel chromatography using a gradient of ethyl acetate in hexanes to afford 3-(2-methoxy—phenyl)-5-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl}-1 -(2-trimethylsilanyl-ethoxy=methyl)-1H- pyrazolo[3,4-blpyridine (1.370 g, 123 % yield) as a pale olive-greesn solid. "H-NMR (500
MHz, de-DMSO) 58.76 (d, 1H), 8.40 (d, 1H), 7.59 (dd, 1H), 7.51 «(ddd, 1H), 7.25 (m, 1H),
7.12 (ddd, 1H), 5.84 (s, 2H), 3.82 (s, 3H), 3.67 (1, 2H), 1 .33 (5, 12H), 0.84 (t, 2H), -0.10(s, 9H).
Step 8: Synthesis of {2-hydroxy-5-[3-(2-methoxy~gphenyl)-1H-pyrazolo{3,4— b]pyridin-5-yl}-pehenyl}-morpholin-4-yl-methanomne.
[0224] A mixture o f3-(2-methoxy-phenyl)-5-(4,4,5,5—tetramethyl-[ 1,3,2]dioxab-orolan-2- y1)-1-(2-trimethylsilanyl-ethoxymethyl)- 1 H-pyrazolof3, 4-b]pyridine (100 mg, 0.2 1 mmol), (5-bromo-2-hydroxy—phenyl)-morpholin-4-yl-methanon_e (66 mg (0.23 mmol) and® 1,1- bis(diphenylphosphiro)ferrocenepalladium(i)-dichlorid_e dichlormethane adduct (9 mg, 11 umol) in acetonitrile (2 mL) and aqueous solution of soedium carbonate (2M, 2 ml _) was irradiated in a Persormal Chemistry Optimizer at 135 °C —for 20 min. The crude rea-ction mixture was distribut-ed between dichloromethane and aa. saturated aqueous solutio m of sodium bicarbonate. The aqueous phase was then extra=cted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrate d. The crude product was th-en purified by flash silica gel chrormatography using a gradient of ethyl acetate in hexanes to afford {2-hydroxy-5-[3-(2-methoxxy-phenyl)-1-(2-trimethylslanyl- ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-ylj-phenyl }-morpholin-4-yl-methanone (35 mg, 30 % yield)as a colorless solid. "H-NMR (500 MFL_z, de: DMSO) 58.86 (d, 1), 8.27 (d, 1H), 7.64 (dd, 1H), 7.62 (dd, 1H), 7.54 (d, 1H), 7.49% (ddd, 1H), 7.24 (d,br, 1H), 7.11 (ddd, 1H), 7.00 (d, 13), 5.84 (s, 2H), 3.84 (5, 3H), 3.69 (t, 2H), 3.7-3.2 (m, 8H), €.86 (1, 2H), -0.08 (s, 9H). NMS: m/z 583 [MNa'*], 561 [MH], 4-43 [MH '-(Me;Si(CH2).03]
[0225] A solution eof {2-hydroxy-5-[3-(2-methoxy-ph-: enyl)-1-(2-trimethylsilany-1- ethoxymethyl)-1H-p-yrazolo[3,4-b}pyridin-5-yl}-phenyl }-morpholin-4-yl-methancne (34 mg, 61 pmol) in dichloromethane (15 mL) was cooled ®o0 0-5 °C and boron trifluceride diethyl etherate (100 pl, 0.8 mmol) was added. The mixture was then stirred at 0—5 °C for 40 min before 10 ml of a 10 % (w/v) solution of potassmum hydroxide was added. The mixture was further sstirred at room temperature for 1 h— The pH was then adjuste=d to approximately 3-4 by addition of citric acid and the aqueous phase saturated with. sodium sulfate. The resultin. g mixture was extracted dichloromethane (3x). The organic phases were combined, washed with a saturated aqueous solutmon of sodium bicarbonate, dried over sodium sulfate and evaporated to afford {2-hydroxy-5-Jf3-(2-methoxy-phenyl)-17d- : pyrazolo[3,4-blpyridlin-5-yl}-phenyl}-morpholin-4-yl-rmacthanone (11.5 mg, 44% yield) asa colorless solid. "H-NMR (500 MHz, 4s-DMSO) 613.7 6(s, 1H), 10.06 (s, 1H), 8_78 (d,
: 1H), 8.23 (d, 1H), 7.64 (dd, 1H), 7.62 (dd, 1H). 7.51 (d, 1H), 7.46 (ddd, 1 H), 7.22 (4, 1H), 7.10 (t, 1H), 6.99 (d, 1H), 3.84 (s, 3H), 3.7-3.2 (m, 8H). MS: m/z 431 [MEE].
[0226] Other compounds prepared by Method 1:
Tablel / oO
HNN a
NT
ZZ
QW
N ~
OH O
MS: m/z 375 (M+H)
Method 2:
HN-N \ Pa
HN-N \ NY NT ~ NH \ NT 1 [_ N
N = step1 UI __ Step 2 Z Step 3 = 0) ©
L = 9 {J
NA
0 0 oO
Step 1: Synthesis of morpholin-4-yl-[3-C1H-pyrazolo[3,4-b]pyrid_in-5-yl)-phenyl]- me=thanone.
[0227] A mixture of 5-bromo-1H-pyrazolo[ 3,4-b]pyridine (1.50 g, 7.57 mmol), 3- (morphholin-4-carbonyl)phenylboronic acid (2.136 g, 9.09 mmol) and tetraki s(triphenylphosphine)palladium(0) (43 5S mL, 0.376 mmol) in dim _ethoxyethane (8 mL) ard saturated aqueous solution of sodiurm bicarbonate (8 mL) was mrradiated in a
Persorxal Chemistry Optimizer at 175 °C for 60 min. The crude reactiorm mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueovas phase was then extracted with clichloromethane, and thaen ethyl acetate and the combinead organic phases were dried over sodium sulfate, filtered and concentrated to afford a pale green foam containing 80 % of morpholin-4-yl-[3-( BM H- pyrazolo[3,4-b]pyridin-=5-yl)-phenyl]-methanone (2.30 g, 80 % yield) and 20 % of triphenylphosphine oxicle. "H-NMR (500 MHz, dg-DMS©) & 13.75 (s, 1H), 8.87 (4, 1H), 8.54 (d, 1H), 8.21 (d, 1E9), 7.85 (m, 1H), 7.77 (m, 1H), 7. 58 (1, 1H), 7.41 (m, 1H».
Step 2: Synthesis ef [3-(3-iodo-1H-pyrazolo[3,4-bApyridin-5-yl)-phenyl}— morpholin-4-yl-methanone.
[0228] Morpholin-4-=yl-[3-(1H-pyrazolo[3,4-b]pyridin—5-yl)-phenyl]-methanome (230g, 80 % pure, ~6 mmol) a-nd of N-iodosuccinimide (2.50 g, 11.1 mmol) were dissoNved in dichloroethane (180 mM). The mixture was stirred undex reflux conditions for 5h, then cooled to room temper=ature and diluted with dichlorome=thane. The solution was washed with saturated aqueous solution of sodium thiosulfate (1) and then with a satur=ated aqueous solution of soadium bromide(2x), dried over sod ium sulfate, filtered ancl concentrated. The resulting residue was washed with ether (80 mL) and dried teo afford [3- (3-iodo-1H-pyrazolo[ 2 ,4-b]pyridin-5-y1)-phenyl]-morpolin-4-yl-methanone ass a beige powder (2.881 g, 88% yield over two steps). 'H-NMR (500 MHz, de-DMSO) 514.19 (5, 1H), 8.92 (d, 1H), 8.141 (d, 1H), 7.91 (m, 1H), 7.83 (m, AH), 7.59 (ddd, 1H), 7.44 (dt, 1H), 3.75-3.35 (m, 8H).
Step 3: Synthesis of morpholin-4-yl-{3-[3-(1H-pwrazol-4-yl)-1H-pyrazolo[3,4- b]pyridin-5-yl]-p henyl}-methanone.
[0229] A mixture o2f[3-(3-iodo- 1 H-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-mo~rpholin-4-yl- methanone (25 mg, 5&8 pmol), 1,1"-bis(diphenylphosphi no)ferrocenepalladium(_1)-dichloride dichlormethane adduct (5 mg, 6 pmol) and 1H-pyrazol —4-ylboronic acid (11 m_g, 98 pmol) in acetonitrile (2 mL) and 2 M solution of sodium carbonate (1 mL) was irradi=ated in a
Personal Chemistry Optimizer at 175 °C for 30 min. T he crude reaction mixture was diluted with water (1 mL) and ethyl acetate (3 mL) and the organic phase sepa-rated, filtered and concentrated. Tine resulting crude mixture was then purified by mass-triggsered reverse phase HPLC using a gradient of acetonitrile in water containing 0.1 % of formmic acid to afford morpholin-4-y~1- (3-[3-(1H-pyrazol-4-yl)-1H-py=razolo[3,4-b]pyridin-5-y1]-phenyi}- methanone (6.2 mg, 229% yield) of as a colorless powder. "H-NMR (500 MHz=, ds-DMSO) & 13.59 (s, 1H), 13.17 (5, 1H), 8.87 (4, 1H), 8.73 (d, 1K, 8.60 (s, br, 1H), 8.17 Cs, br, 1H),
7.95 (ddd, 1H), 7.89 (t, 1H), (t, 1H), 7.59 (t, 1H), 7.483 (ddd, 1H), 3.80-3.35 (m, 8H). MS: m/z 397 [MNa'], 3-75 [MH'].
[0230] Other commpounds prepared by Method 2:
Table 2 0” ¥
HN-N HN-N HN-N 0 CO <0)
NT NT NT lL l 0 0 0
LA JA LE lo} 0) lo}
MS: m/z 417 (M+H,
MS: m/z 415 (M+) E47 QBS MS: m/z 424 (M+H'
Et oo” E oo
HN-N HNN HN-N =N
JO-0O BO |B lL > al 9 0
VS NIeUS oS o) o} lo}
MS: m/z 413 (M+H" MS: m/z 433 (MHH™ MS: m/z 447 (M+H) % _- oo Et
HN—N y | HN \ a Or C § \ 7 7 = (To 0
NA
0 o 0} i.
MS: m/z 405 (M+ ( MS: m/z 42%0 (M+H")
MS: m/z 429 (M+H")
Method 3:
HNN SEM HN < \
N° " > | 1 > | Z l Step 1 Z Step 2 7 3 (J LS
NJ N Na 0) © ©
Step 1: Synthesis of {3-[3-Todo-1-(2-trimethylsilanyl-ethoxymmethyl)-1H- pyrazolo[3,4-b] pyridin-5-yl]-phenyl}-morpholin-4-yl-methamone.
[0231] To a solution of [3-(3 _iodo-1H-pyrazolo[3,4-b]pyridin-5-y=1)-phenyl}-morpholin-4- yl-methanone (2.12 g, 4.88 mmol) in anhydrous DMF (30 mL) was added sodium hydride (60% in mineral oil, 750 mg, 30 mmol) at 0-5 °C. The mixture wass stirred for a few minutes before trimethylsilylethoxymethyl chloride (2.0 ml, 11 mmol) was added drop wise at the same temperature. The mixture was stirred at 0 °C to room tesmperature for 4 hours and then cooled to 0-5 °C and quenched by an addition of methanoZl. The resulting suspension was then distributed between water, saturated aqueous ammonium chloride solution and ether. The aqueous phase was extracted three times with ether and the combined organic phases were dried over sodium sulfate, filtered amnd concentrated. The crude product was then purified by silica gel chromatography usingz a gradient of ethyl acetate in hexanes to afford {3-[3-iodo-1-(2-trimethylsilanyl-ethox_ymethyl)-1H- pyrazolo[3,4-b]pyridin-5-y1] -phenyl}-morpholin-4-yl-methanone zas a beige-brown foam (1.806 g, 66 % by "H-NMR, side product identified as morpholin-=4-yl-{3-[2-(2- trimethylsilanyl-ethoxymethy1)-2H-pyrazolo[3,4-b]pyridin-5-yl]-p=henyl} -methanone). 'H-
NMR (500 MHz, dg-DMSO) £9.08 (d, 1H), 8.29 (d, 1H), 8.01 (m-, 1H), 7.95 (t, br, 1H], 7.69 (t, 1H), 7.55 (d, br, 1H), 5.88 (s, 2H), 3.71 (t, 2H), 3.85-3.45 &(m, 8H), 0.94 (t, 2H), —0.2 (s, 9H). MS: m/z 565 [MNa'], 537 [MH'}, 447 [MH"-(Me3S=i(CH,)0)).
Step 2: Synthesis of {3-[3-(2-methoxy-pyridin-3-yl)-1 H-pymrazolo[3,4-b] pyridin-5- yl]-phenyl}-morpholin-4-yl-methanone
[0232] A mixture of {3-[3-iodo-1 -(2-trimethylsilanyl-ethoxyme~thyl)-1H-pyrazolo[3,4- blpyridin-5-yl] -phenyl}-morpholin-4-yl-methanone (33 meg, 66 Y= pure, 38 pmol), 1,1'- bis(diphenylphosphino)ferrocenepalladium(im)-dichloride dichlorrmaethane adduct (5 mg, 6
V0 2006/015124 PCT/US2005/026 7794 pol) and 3-trifluoromethylphens/lboronic acid (14 mg, 92 pmmol) in acetonitrile (2 mI) and 2 Mu solution of sodium carbonate (1 mL) was irradiated in a Personal Chemistry Optimizer at 175 °C for 20 min. The crude xeaction mixture was dilute with saturated aqueous so ution of sodium bromide (1 mL) and ethyl acetate (4 mL) =and the organic phase separated, adsorbed onto silica arad purified by flash silica gel chromatography using a gr adient of ethyl acetate in hexan es to afford {3 -[3-(2-metho=xy-pyridin-3-yl)-1-(2- tri_methylsilany!-ethoxymethyl)-1 H-pyrazolo[3,4-b]pyridin-5 -yl]-phenyl} -morpholin-4&-yl- m_ethanone (24 mg, 116 % yield) as an off-white residue. MSS: m/z 563 [MNa'], 546 [MIT], 4228 [MH'-(Me3Si(CHz)20)] [M233] This residue was dissolved in THF (2 ml) and activ—ated 4 A molecular sievess were acdded to the mixture. Tetra-n-buratylammonium fluoride in THF (1 M solution, 0.5 mi, 0.5 mmol) was added and the mixtuxre stirred at 70 °C for 26h. ‘The mixture was cooled to rc>om temperature and 1 ml of cation exchange resin (Amber-lyst, Na'-form) added aned the
Iixture was shaken for 40 min. The resin and sieves were t_hen filtered off, washing “with d_ichloromethane and methanol aand the filtrate obtained was concentrated. The residume was d_issolved in ethyl acetate and purified by flash chromatogragphy on silica gel using a gradient of ethyl acetate containing 15 % (v/v) of methanol Jn ethyl acetate. The procluct fractions was combined, concentrated and purified by mass—triggered reverse phase HPLC wmsing a gradient of acetonitrile im water containing 0.1 % of formic acid to afford {3-7Y3-(2- rnethoxy-pyridin-3-yl)-1H-pyra=zolo[3,4-blpyridin-5-yl]-phenyl} -morpholin-4-yl-met-hanone ( 32 mg, 20% yield). as a colorless solid. "H-NMR (500 MINz, d-DMSO) 614.01 (s, 1H),
S91 (d, 1H), 8.51 (d, 1H), 8.31 (dd, 1H], 8.11 (dd, 1H), 7.877 (ddd, 1H), 7.80 (t, 1H), 7.59 (1,
AH), 7.43 (dt, 1H), 7.18 (dd, 1H), 3.97 (s, 3H), 3.70-3.35 (rr, 8H). MS: m/z 416 [MIL].
[0234] Other compounds prepared by Method 3:

Claims (1)

  1. WHAT IS CLAIMED IS:
    1 1. A compound having the formula: H CY N 2 2 Li-R? 3 wherein 4 L! and 1.2 are independently a bond, -S(O)a-, -O-, -N_H-, unsubstituted C;-Cs alkylene, or unsubstituted 2 to 5 membered heteroalkylene, wherein_ n is an integer from 0 to 6 2, and 7 R! and R? are independently substituted or unsubstiti ated cycloalkyl, 8 substituted or unsubstituted heterocycloalkyl, substituted or unsubst=ituted heteroaryl, or 9 substituted or unsubstituted aryl, with the proviso that R' is not substituted or unsubstituted pyrrolyl, and that 11 1! is not unsubstituted 2 to 5 membered heteroalkylene when R! anc R? are both 12 unsubstituted phenyl, and that L! is not -S(0O),- when R? is unsubstiftuted piperazinyl, and 13 that R! is not substituted or unsubstituted isoxazolyl when R? is unsmubstituted pyridinyl.
    1 2. The compound of claim 1, wherein L! and I? are independently a 2 bond, -S(O)ys-, -O-, -NH-, or unsubstituted C;-Cs alkylene.
    1 3. The compound of claim 1, wherein L' and L? are abond. 1 4, The compound of claim 1, wherein L' or L? iss a bond.
    1 5. The compound of claim 1, wherein 2 R! is substituted or unsubstituted cycloalkyl, substitu—ted or unsubstituted 3 heterocycloalkyl, substituted or unsubstituted 5 or 6 membered hetemroaryl, or substituted or 4 unsubstituted aryl.
    1 6. The compound of claim 1, wherein 2 R! is substituted or umsubstituted 6 membered heteroaryl, or substituted or 3 unsubstituted aryl.
    1 7. The compound of claim 1, wherein R' is 2 (1) unsubstituted C3~C; cycloalkyl;
    3 (2) unsubstituted 3 to 7 membered heterocycloalkyl;
    4 (3) unsubstituted heteroaryl;
    (4) unsubstituted aryl;
    6 (5) substituted C3-C7 cycloalkyl;
    7 (6) substituted 3 to 7 membered heterocycloalkyl;
    8 (7) substituted aryl; or
    9 (8) substituted heteroaryl; wherein 11 (5) and (6) are substituted with an oxo, -OH, -CF3, -& OOH, cyano, halogen, 12 RY-substituted or unsubstituted €,~Cyo alkyl, R''-substituted or unsSubstituted 2 to 10 13 membered heteroalkyl, R!!-substituted or unsubstituted C3-C; cycloalkyl, R'-substituted or 14 unsubstituted 3 to 7 membered heterocycloalkyl, R'2-substituted or— unsubstituted aryl,
    R!%-substituted or unsubstituted heteroaryl, LCR’, -L2-ORS, -L-NR’'R”, or
    16 -L'-S(O)}R",
    17 (7) and (8) are substituted with an -OH, -CF3, -COCDH, cyano, halogen,
    18 R'_substituted or unsubstituted C;-Cyo alkyl, R''-substituted or un_substituted 2 to 10
    19 membered heteroalkyl, R''-substituted or unsubstituted C3-C7 cycl oalkyl, R''-substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R'%-substituted om unsubstituted aryl,
    21 R'Z.substituted or unsubstituted heteroaryl, -L'2-C(X")R, -L'*-OR_?, L2.NR*R%, or
    22 -L'2.8(0)nR'®, wherein
    23 (2) X" is =8, =O, or =NR'*, wherein R'® is H, -OR"**', R''-substituted or
    24 unsubstituted C,-Cyo alkyl, R!l-substituted or umnsubstituted 2 to 10 membered heteroalkyl, R''-substituted or unsubstituted C;-C; cycloalkyl, 26 R'!'_substituted or unsubstituted 3 to 7 membere=d heterocycloalkyl, R'2
    27 substituted or unsubstituted aryl, or R'>-substitwted or unsubstituted
    28 heteroaryl, wherein
    29 R'S! is hydrogen or R'-substitued or unsubstitmated C;-Cyo alkyl,
    (b) m is an integer from 0 to 2;
    31 (¢) R’ is hydrogen, R!'-substituted or unsubstituted C;-Co alkyl, R'-
    32 substituted or unsubstituted 2 to 10 membered heteroalkyl, R'-
    33 substituted or unsubstituted C;-C7 cycloalkyl, BR" -substituted or
    34 unsubstituted 3 to 7 membered heterocycloalk=yl, R'?-substituted or unsubstituted aryl, R"-substituted or unsubstit=uted heteroaryl, OR", or
    36- -NR7’R™, wherein
    37 R”', R™, and R” are independently hydrogen, R''—substituted or 38 unsubstituted C,-Cio alkyl, IR'!-substituted or umnsubstituted 2 to 10 39 membered heteroalkyl, R''- substituted or unsubstituted C;-C; 40 cycloalkyl, R'l-substituted Or unsubstituted 3 teo 7 membered 41 heterocycloalkyl, R'?-substi tuted or unsubstitumted aryl, or R'% 42 substituted or unsubstituted heteroaryl, 43 wherein R7? and R” are optionally joined with the nitrogen to which they 44 are attached to form an R'!- substituted or unsu_bstituted 3 to 7 45 membered heterocycloalkyl , or R'Z-gubstituted” or unsubstituted 46 heteroaryl; 47 (d) R% R® and R? are independent ly hydrogen, -CF3, R''-substituted or 48 unsubstituted C;-Cyp alkyl, R!!— substituted or unsubstituted 2 to 10 49 membered heteroalkyl, R'!-subsstituted or unsubstituted C;-C; cycloalkyl, 50 R!'!-substituted or unsubstituted_ 3 to 7 membered aeterocycloalkyl, R'%- 51 substituted or unsubstituted aryl, R'2-substituted omr unsubstituted 52 heteroaryl, -C(X*)R®!, or -S(0)~R¥!, wherein R®' amnd R*? are optionally 53 joined with the nitrogen to whic=h they are attached to form an RU. 54 substituted or unsubstituted 3 tow 7 membered heter—ocycloalkyl, or R'% 55 substituted or unsubstituted hetesroaryl, wherein 56 (i) X* is =S, =O, or =NR!®, wherein R'® is R'!-subsstituted or 57 unsubstituted C,-Cio alkyl, IR'!-substituted or vmnsubstituted 2 to 10 58 membered heteroalkyl, R!!- substituted or unsubstituted C3-C7 59 cycloalkyl, R'!-substituted or unsubstituted 3 teo 7 membered 60 heterocycloalkyl, R!2 substituted or unsubstituted aryl, or R'%- 61 substituted or unsubstituted heteroaryl; 62 (ii) w is an integer from 0 to 2, &and 63 (iii) R®' is hydrogen, R!!-substitzuted or unsubstitut ed C,-Cyo alkyl, R''- 64 substituted or unsubstituted 2 to 10 membered “heteroalkyl, R'L. 65 substituted or unsubstituted Cs-Cy cycloalkyl, FR" -substituted or 66 unsubstituted 3 to 7 member—ed heterocycloalky~1, R"-substituted or 67 unsubstituted aryl, R'2-substzituted or unsubstitiated heteroaryl, or 68 NREVRS, 69 wherein R®!! and R®"? are independently hydro geen, R' substituted or 70 unsubstituted C,-Cio alk], R'!-substituted aor unsubstituted 2 to
    71 10 membered heteroalkyl, R!'-substituted or —unsubstituted C3-C7
    72 cycloalkyl, R''-sub stituted or unsubstituted 3 to 7 membered
    73 heterocycloalkyl, R_!’-substituted or unsubstit-uted aryl, or R-
    74 substituted or unsubstituted heteroaryl, wherein R®!! and R®"2 are
    75 optionally joined with the nitrogen to which they are attached to
    76 form an R!!-substit-uted or unsubstituted 3 to 7 membered
    77 heterocycloalkyl, ox R'2-substituted or unsub. stituted heteroaryl;
    78 (e) R' is hydrogen, R''-substi tuted or unsubstituted C;-aC)o alkyl, R'-
    79 substituted or unsubstituted 2 to 10 membered heteroalkyl, Rl
    80 substituted or unsubstituteed C3-C5 cycloalkyl, R!'-sumbstituted or
    81 unsubstituted 3 to 7 memb ered heterocycloalkyl, R'Z-substituted or
    82 unsubstituted aryl, R'%-sub> stituted or unsubstituted heteroaryl, or
    83 -NR''R'?, wherein
    84 63) R' and R'? are independently hydrogen, R! sy stituted or
    85 unsubstituted C;-Cio alkyl, R!'-substituted or unssubstituted 2 to 10
    86 membered heteroalkyl, R!'!-substituted or unsubsstituted C3-Cy 87 cycloalkyl, R!!'-substituated or unsubstituted 3 to ~7 membered
    88 heterocycloalkyl, R'2-s ubstituted or unsubstituted aryl, or R'>-
    89 substituted or unsubsti€uted heteroaryl, wherein FR'°! and R'% are
    90 optionally joined with the nitrogen to which they= are attached to form
    91 an R''-substituted or umsubstituted 3 to 7 membe=red
    92 heterocycloalkyl, or R! 2-substituted or unsubstituted heteroaryl;
    93 (f) L? is a bond, unsubstituted.
    C,-Cy alkylene, or unsubstituted
    94 heteroalkylene;
    95 (2) R'! is oxo, -OH, -COOH, - CFs, -OCF3, -CN, amino, halogen, R'>-
    96 substituted or unsubstitutecl 2 to 10 membered alkyl, R'-substituted or
    97 unsubstituted 2 to 10 membered heteroalkyl, R'>-submstituted or
    98 unsubstituted Cs-C7 cycloalkyl, R3._substituted or urmsubstituted 3 to 7
    99 membered heterocycloalky?l, R'*-substituted or unsutostituted aryl, or R'- 100 substituted or unsubstituted heteroaryl; 101 (h) R'? is -OH, -COOH, amines, halogen, -CFs, -OCF3, CCN, R"’-substituted 102 or unsubstituted 2 to 10 membered alkyl, R'>-substitwited or unsubstituted 103 2 to 10 membered heteroalkyl, rR! substituted or unsubstituted Cs-C 104 cycloalkyl, R'%.substituted or unsubstituted 3 to 7 me=mbered
    N05 hete=rocycloalkyl, R' substituted or unsubstituted aryl, or R"-substituted 106 or vmnsubstituted heteroaryl; “107 (i) R'® fis oxo, -OH, -COOH, amino, h-alogen, -CFs, -OCF3;, -CN, 108 uns-ubstituted C1-Cio alkyl, unsubsstituted 2 to 10 membered heteroalkyl, 109 unssubstituted C3-C7 cycloalkyl, nrsubstituted 3 to 7 me=mbered 110 hetserocycloalkyl, unsubstituted aryl, unsubstituted hete—roaryl; and 111 G)R™ is -OH, -COOH, amino, halogen, -CFs, -OCFs, -CN , unsubstituted Ci- 112 Co alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C3- 113 C; cycloalkyl, unsubstituted 3 to 77 membered heterocy=cloalkyl, 114 unsubstituted aryl, unsubstituted heteroaryl.
    1 8. The compound of claim 7, wherein R! is substituteed or unsubstituted 2 6-membered heteroar yl, or substituted or unsubstituted aryl.
    1 9. The compound of claim §, wherein L' is a bond. 1 10. The compound of claim 7, wherein R! is (7) or (8), wherein (7) and 2 (8) are substituted wi—th an -OH, -CF3, halogen, unsubstituted Ci-Cio alkyl, unsubstituted 2 3 to 10 membered hetemroalkyl, unsubstituted C3-Cr cycloalkyl, unsubstitute=d 3 to 7 membered 4 heterocycloalkyl, unsubstituted aryl, unsubstituted Iaeteroaryl, or -L'2-OR_8, wherein L2isa bond. 1 11. The compound of claim 10, wwherein R® is CFs. 1 12. The compound of claim 7, wherein R! is (7) or (8) wherein (7) and 2 (8) are substituted wi th an -OCH,, -OCFs, -CH3, -C Fs, -OCH2CH3, halogzen, or 3 cyclopropyloxy. i 1 13. The compound of claim 7, wherein L' and 1? are am bond. 1 14. The compound of one of claims 1, 7, or 13, wheremn Ris 2 (1) urmsubstituted C5-Cr cycloalkyl; 3 (2) urmsubstituted 3 to 7 membered heterocycloalkyl; 4 (3) ummsubstituted heteroaryl; 5 (4) umsubstituted aryl; 6 (5) substituted C3-Cy cycloalkyl;
    7 (6) scabstituted 3 to 7 membered heter—ocycloalkyl;
    8 (7) scabstituted aryl; or
    9 (8) suabstituted heteroaryl; whereein 11 (5) ard (6) are substituted with an ox -o, -OH, -CF3, -COOH, cyaro, halogen,
    12 R*'-substituted or ursubstituted C;-Cy alkyl, R*!-sur bstituted or unsubstituted 2 to 10 13 membered heteroalk=yl, R*'-substituted or unsubstitmted Cs-C; cycloalkyl, R?!-s-ubstituted or 14 unsubstituted 3 to 7 membered heterocycloalkyl, R*=-substituted or unsubstituted aryl, or RZ substituted or ursubstituted heteroaryl, -L2-C(=*)R?, -L?2-0R", -L?-NR* RR”, or -L*- 16 S(O)R’, 17 (7) ard (8) are substituted with an -O_H, -CF3, -COOH, cyano, halogen, RL 18 substituted or unsubsstituted C;-Cg alkyl, R?!_substit-uted or unsubstituted 2 to L 0 membered 19 heteroalkyl, R*'-subsstituted or unsubstituted C3-C7 c=ycloalkyl, R*!-substituted cwr unsubstituted 3 to 7 membered heterocycloalkyl, R*-substituted or unsubstitute=d aryl, R™ 21 substituted or unsubsstituted heteroaryl, LE2.CCORE, L2-0R*, -L2-NR¥R?, or -L2- 22 S(O)R®, wherein : 23 (@) X= is =S, =0, or =NR"’, wherein FR" is H, -OR'"', R*'-substit-uted or 24 ursubstituted C,-Cyo alkyl, R* -sumbstituted or unsubstituted 2- to 10 m_embered heteroalkyl, R*!-substi tuted or unsubstituted C;-C - cycloalkyl, 26 R™'-substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R*- 27 sumbstituted or unsubstituted aryl, or R*-substituted or unsubstituted 28 hesteroaryl, wherein 29 R71" is H or R*'-substituted or unssubstituted C;-Cyq alkyl; (b) q ®s an integer from 0 to 2; 31 (©) R® is hydrogen, R*-substituted or unsubstituted C;-Cyo alkyl, R*!- 32 su_bstituted or unsubstituted 2 to 1#0 membered heteroalkyl, R='- 33 substituted or unsubstituted Cs-C; cycloalkyl, R?!-substituted. or 34 urmsubstituted 3 to 7 membered hemterocycloalkyl, R*-substitu ted or ummsubstituted aryl, R?**-substituted. or unsubstituted heteroaryl, -OR*, or 36 -NIOR**R*, wherein 37 i) R*', R*, and R* are independently hydrogen, R*!-substitu-ted or 38 unsubstituted C,-Cyo alkyl, R** -substituted or unsubstitute=d 2 to 10 39 membered heteroalkyl, R!-sulbostituted or unsubstituted C=-Cy 40 cycloalkyl, R*!-substituted or Lansubstituted 3 to 7 membexred
    41 heterocycloalkcyl, R*-substituted or unsubstituted aryl, or RZ — 42 substituted or unsubstituted heteroaryl, wherein R* and R* a-xe 43 optionally joirzed with the nitrogen to whi ch they are attached... to form 44 an R*!-substiteated or unsubstituted 3 to 7 - membered 45 heterocycloallkyl, or R?-substituted or unsubstituted heteroar—yl; 46 (d) R*, R*' and R® are independently hydrogen, —CFs, R*-substitutec or 47 unsubstituted C;-Cyg alkyl, R*-substituted or unsubstituted 2 to 11.0 48 membered heteroalkyl, R*'-substituted or unssubstituted C3-C; cyscloalkyl, 49 R?'_substituted or unsubstituted 3 to 7 membecred heterocycloalk=yl, R*- 50 substituted or unsubstituted aryl, R*-substitu_ted or unsubstituted 51 heteroaryl, -CCX*DR*, or -S(O).R*, wherein R°! and R* are opti _onally 52 joined with the nitrogen to which they are attzached to form an R* L 53 substituted or unsubstituted 3 to 7 membered heterocycloalkyl, oxxr R*- 54 substituted or uns ubstituted heteroaryl, whercin 55 (i) X*is =S, =O, or=NR'®, wherein R'® is R? substituted or 56 unsubstituted C,-Co alkyl, R?'_substitutead or unsubstituted 2 to 10 57 membered heteroalkyl, R*'-substituted or unsubstituted C;-C— 58 cycloalkyl, R* '-substituted or unsubstituted 3 to 7 membered 59 heterocycloallkyl, R?-substituted or unsubstituted aryl, or R*- 60 substituted or unsubstituted heteroaryl; 61 (ii) v is an integer from O to 2; 62 (iii) R* is hydrogen, R?'-substituted or unsubmstituted C,-Cjo alky~], R*- 63 substituted or unsubstituted 2 to 10 membered heteroalkyl, R= 64 substituted or unsubstituted C3-C; cycloal_kyl, R*!-substituted or 65 unsubstituted 3 to 7 membered heterocycli oalkyl, R*%.substitu~ted or 66 unsubstituted aryl, R*-substituted or unsiabstituted heteroaryl _, or 67 NRRH?, 68 wherein R*"! zand R*'? are independently sselected from hydrogen, R?- 69 substituted or unsubstituted C;-Co allegyl, R*'-substituted or 70 unsubstituted 2 to 10 membered heteraoalkyl, R?!-substitut=ed or 71 unsubstituted C;-C; cycloalkyl, R2L.siabstituted or unsubst=ituted 3 72 to 7 memb ered heterocycloalkyl, R*-ssubstituted or unsubstituted 73 aryl, or R*2-substituted or unsubstitute=d heteroaryl, wherein R* 74 and R*"? ar-e optionally joined with the= nitrogen to which they are
    WwWVO 2006/015124 PCT/US2005/026794
    75 attached to form an R?!-substituted or vansubstituted 3 to 7
    76 raember ed heterocycloalkyl, or R*-submstituted or unsubstituted 77 heteroaryl;
    78 (e) R® is hydrogen, R*'-substituted or unsubstitutecd C;-Cyo alkyl, R*-
    79 substituted or umsubstituted 2 to 10 membered heteroalkyl, R*-
    80 substituted or umsubstituted C3-C7 cycloalkyl, TR*'-substituted or
    81 unsubstituted 3 to 7 membered heterocycloalk—yl, R?-substituted or
    82 unsubstituted aryl, R*?-substituted or unsubstituted heteroaryl, or
    83 -NR®'R®, wher ein
    84 (i) R® and R* are hydrogen, R?!-substituted oT unsubstituted C;-Cio
    85 alkyl, R*'-suibstituted or unsubstituted 2 to 10 membered heteroalkyl,
    86 R*!-substitu ted or unsubstituted C3-C7 cycMoalkyl, R* -substituted or
    87 unsubstitutesd 3 to 7 membered heterocycloalkyl, R%-substituted or
    88 unsubstitute=d aryl, or R?2_substituted or unsubstituted heteroaryl,
    89 wherein R®! and R% are optionally joined with the nitrogen to which
    90 they are attached to form an R?!-substituteed or unsubstituted 3 to 7
    91 membered heterocycloalkyl, or R*_substit=uted or unsubstituted
    92 heteroaryl;
    93 (f) L* is a bond, unsubstituted C,-C)o alkylene or unsubstituted
    94 heteroalkylene;
    95 (2) R? is oxo, -OH, -COOH, -CF3, -OCF3, -CN, ammino, halogen, R?-
    96 substituted or umsubstituted 2 to 10 membered alkyl, R**-substituted or
    97 unsubstituted 2 to 10 membered heteroalkyl, R_*-substituted or
    98 unsubstituted C=-Cy cycloalkyl, R*_substitutec or unsubstituted 3 to 7
    99 membered heter-ocycloalkyl, R*-substituted or— unsubstituted aryl, or R?*- 100 substituted or uzxasubstituted heteroaryl; 101 (h) R* is -OH, -COPOH, amino, halogen, -CFs, OCF, -CN, R”-substituted 102 or unsubstituted. 2 to 10 membered alkyl, R**-s=ubstituted or unsubstituted 103 2 to 10 membered heteroalkyl, R*3-substituted or unsubstituted C3-C 104 cycloalkyl, R®- substituted or unsubstituted 3 teo 7 membered 105 heterocycloalky-1, R*-substituted or unsubstitunted aryl, or R**-substituted 106 or unsubstituted. heteroaryl; 107 (i) R® is oxo, -OH, -COOH, amino, halogen, -CF3_, -OCF;, -CN, 108 unsubstituted Cy -Ciq alkyl, unsubstituted 2 to 1. 0 membered heteroalkyl,
    109 unsubstituted C3-C; cycloalkyl, unsubstituted 3 to= 7 membered 110 heterocycloalkyl, unsubstituted aryl, unsubstitutec heteroaryl; and 111 (G) R* is -OH, -COOH, mmino, halogen, -CF3, -OCF3 , -CN, unsubstituted C 1- 112 Cio alkyl, unsubstitut ed 2 to 10 membered heteroalkyl, unsubstituted C3— 113 C; cycloalkyl, unsubstituted 3 to 7 membered het—-erocycloalkyl, 114 unsubstituted aryl, urasubstituted heteroaryl. 1 15. The compound o=€ claim 14, wherein 1? is a beond. 1 16. The compound o=f claim 14, wherein R? is (3) , (4), (7), or (8). 1 17. The compound of claim 15, wherein R2is (7) or (8). 1 18. The compound of claim 17, wherein (7) and (C8) are substituted with. 2 an-L2-C(X3R? -L*-O0R%, -L-NR*'R %, _L22.C(NH)-NR*R*, or —L*-S(0)R". 1 19. The compound o {claim 18, wherein 2 R® is -NR”R®; 3 X® is =0 or =NR'7; 4 R® is -NR®R%; R% is -C(O)R* or -S(O».R*". 1 20. The compound o fclaim 19, wherein R*! is -NIR*''R*2. 1 21. The compound o fclaim 15, wherein R? is (7m or (8), wherein (7) and 2 (8) are substtituted with -OH, -CF3, -CO0H, amino, halogen, unsubsstituted 2 to 10 3 membered heteroalkyl, unsubstituted C 3-C7 cycloalkyl, unsubstitute=d 3 to 7 membered 4 heterocyclo.alkyl, unsubstituted aryl, unsubstituted heteroaryl, or L2ACXA)R?, wherein 5 xX? is =O; 6 Ris unsubstituted C;-C=1o alkyl, unsubstituted 2 to 1 0 membered heteroalkyl, 7 unsubstituted C3-Cy cycloalkyl, unsubstituted 3 teo 7 membered 3 heterocycloalkyl, un substituted aryl, unsubstitute=d heteroaryl, or 9 NR*R*, wherein R* and R® are independently hydrogen, R?'-submstituted or unsubstitute=d 11 C-Cyo alkyl, R? 1 substituted or unsubstituted 2 to 10 membered 12 heteroalkyl, R2!- substituted or unsubstituted «C;-C; cycloalkyl, RZ.
    13 substituted or unsubstitLated 3 to 7 membered heteromcycloalkyl, R*- 14 substituted or unsubstitvated aryl, or R?>-substituted -or unsubstituted 15 heteroaryl, 16 wherein R*? and R® are optionally joined with the nitromgen to which they 17 are attached to form an R*!-substituted or unsubstiti ited 3 to 7 18 membered heterocycloalkyl, or R*-substituted or unsubstituted 19 heteroaryl.
    L 22. The compound of claim 15, wherein R? is (7) or (8)=, wherein (7) and
    2 (8) arc substituted with unsubstituted 2 to 10 rmembered heteroalkyl, or -L-2.C(O)R?,
    3 wherein
    4 L?? is a bond; and
    R? is -NR*’R*, wherein
    6 R* and R* are independent tly hydrogen, R?!-substitute~d or unsubstituted
    7 C:-Cio alkyl, R*!-substi_ tuted or unsubstituted 2 to 1 0 membered
    8 heteroalkyl, R*!-substitmted or unsubstituted C3-C7 «cycloalkyl, RZ.
    9 substituted or unsubstitmted 3 to 7 membered heterocycloalkyl, RZ. substituted or unsubstituted aryl, or R*-substituted or unsubstituted 11 heteroaryl, 12 wherein R*? and R*® are optionally joined with the nitrogen to which they 13 are attached to form an R?*!-substituted or unsubstitiated 3 to 7 14 membered heterocyclozaalkyl, or R??-substituted or unsubstituted heteroaryl.
    1 23. The compound of claim 1, wherein R! is a substituteed or
    2 unsubstituted fused ring aryl or substituted or unsubstituted fused ring hetesroaryl.
    1 24. The compound of claim |, wherein R? is substituted or unsubstituted
    2 indolyl, substituted or unsubstituted quinoliny, or substituted or unsubstitwted
    3 benzodioxolyl.
    1 25. The compound of clainx 1, wherein R? is a substitute=d or
    2 unsubstistuted fused ring aryl or substituted or minsubstituted fused ring heteroaryl.
    1 26. The compound of clai m 1, wherein R! is substiti sted or unsubstitute=d 2 indolyl, substituted or unsubstituted quinolirayl, or substituted or unsub~ stituted 3 benzodioxolyl. 1 27. The compound of claim 14, wherein R! and R? aare independently 2 substituted or winsubstituted hydantoinyl, substituted or unsubstituted d_ioxolanyl, substituted 3 or unsubstitutezd dioxanyl, substituted or unssubstituted trioxanyl, substmtuted or 4 unsubstituted tetrahydrothienyl, substituted «or unsubstituted tetrahydrosfuranyl, substituted or unsubstitute=d tetrahydrothiophenyl, substituted or unsubstituted tetr.ahydropyranyl, 6 substituted or minsubstituted tetrahydrothiop=yranyl, substituted or unsulbstituted pyrrolidinayl, 7 substituted or winsubstituted morpholino, substituted or unsubstituted p-iperidinyl, substitu_ted 8 or unsubstitutesd pyrazolyl, substituted or un_substituted furanyl, substituted or unsubstitut_ed 9 imidazolyl, sulbstituted or unsubstituted isox=azolyl, substituted or unsu_bstituted oxadiazoMyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyri=dyi, substituted or 11 unsubstituted goyrazyl, substituted or unsubstituted pyrimidyl, substitut=ed or unsubstituted 12 pyridazinyl, stabstituted or unsubstituted thicazolyl, substituted or unsubstituted isothioazo=lyl, 13 substituted or “unsubstituted triazolyl, substistuted or unsubstituted thierayl, substituted or 14 unsubstituted Eriazinyl, substituted or unsubsstituted thiadiazolyl, or substituted or unsubstituted ketrazolyl. 1 28. A compound having ®&he formula: NH «LIP 2” °N 2 L1-R! cm, 3 wherein 4 L! and 12 are independently =a bond, -S(O),-, -O-, -NH- , unsubstituted C,-#Cs 5 alkylene, or urasubstituted 2 to 5 membered heteroalkylene, wherein n is an integer from to 6 2,and 7 R! and R? are independently substituted or unsubstitute-d cycloalkyl, 8 substituted or unsubstituted heterocycloalky~1, substituted or unsubstituzted heteroaryl, or 9 substituted or ~unsubstituted aryl. 1 29. A compound having €he formula:
    H Na N_ R2_ ZY N 2” ON L'-R! (I, wherein L' arnd L*are independently a bond, - S(O),-, -O-, -NH-, unsubstit uted C,-C; alkylene, or unsubstit-uted 2 to 5 mernbered heteroalk xylene, wherein n is an intege=r from 0 to 2, and R' ard R”are independently substituted or unsubstituted cycloalk- yl, substituted or unsubstituted hetcroc ycloalkyl, substituted or unsubstm tuted heteroaryl, or substitu ted or unsubstituted aryl.
    30. A method of modulating the activity of a protein kinase ccomprising contacting said protemn kinase with a compound of onee of claims 1, 28, or 29.
    31. A compound of one of claim s 1, 28 or 29 for use in the ti—eatment of cancer, allergy, asthrana, inflammation, obstructive air=way disease, autoimmune diseases, metabolic disease, infection, CIS disease, brain tumor, obesity, asthma, hematological disomrder, degenerative neural disease, cardiovascular disease, or disease assomciated with angiogenesis, ne=ovascularization, or vasculogenesis.
    32. A method of modulating the activity of a protein kinase «comprising contacting said prote in kinase with a compound havirag the formula: H N 1 tN a 2 RE 27? L'-R? wherein L' and L?are independently a bond, —$(O),-, -O-, -NH-, unsubsti _ tuted C,-Cs alkylene, or unsubstituted 2 to 5 membered heteroalk ylene, wherein n is an intege=r from 0 to 2, and R' znd Rare independently substitu ted or unsubstituted cycloallMkyl, substituted or unsubstituted heteroscycloalkyl, substituted or unsubstituted heteroaryl, or 149 AMENDED SHEET AMENDED SHESEY substituted or unsubstituteed aryl with the proviso that L' is not unsubstituted 2 to S membered heteroalkylene when R' amnd R? are both unsubstituted phenyl.
    33. “The method of claim 32, wherein saidl protein kinase is an Abelson tyrosine kinase, Ron receptor tyro- sine kinase, Met receptor tyrosine kirase, Fms-like tyrosine kinasse-3, Aurora kinases, p21-actiwwated kinase-4, or 3-phosphoinositide -dependent kinase-1.
    34. “The method of claim 32, wherein said protein kinase is a Ber-AbL kinase having a mutation selectesd from the group consisting of M244-V, 1L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T3L 5, T315N, T315A, F317V, F317L, M343T, M351T, E355G_ F359A, F359V, V3791, F382L, L38 7M, H396P, H396R, S417Y ,E459K and F4868.
    3s. The method of claim 34, wherein saied protein kinase has a T3150 mutation.
    36. A compound having the formula: H D9 N 2 L'-r 1 wherein L' and Mare independently a bond, -S(Q),-, -O-, -NH-, unsubstituted C,—Cs alkylene, or unsubstitute=d 2 to 5 membered heteroalkylene, wherein n is an integer from (3 to 2, and R'and BR?are independently substituted or urasubstituted cycloalkyl, substituted or unsubstituted heterocycl oalkyl, substituted or unsubstituted h eteroaryl, or substituted or u_nsubstituted aryl with the proviso that L' is not unsubstituted 2 to 5 membeered heteroalkylene when R "and Rare both unsubstituted phenyl for use in the treatment of cancer, allergy, asthma, inflammatiomn, obstructive airway diseam se, autoimmune diseases, metabolic clisease, infection, CNS disezase, brain tumor, obesity, asthma, hematological disorder, degenerative neural disease, cardiovascuMar disease, or disease associated with angiogenesis, neovascularization, or ~wasculogenesis . 150 AMENDED SHEET A_MENDED SHEET
    Wa 2006/015124 PCT/US2005/026794~
    37. A compound of claim 36, wherein said camncer is selected from leukermia or myveloproliferative disorder.
    38. A pharmaceutical composition comprising a pharmaceutically aceceptable excipient and a compound of one of claims 1, 28, oer 29, or a compound havimng the formula: H oo N 2 R WU L'-R? wherein L'and Larc independently a bond, -S(0O},-, -C-, NH unsubstituted C,-Cs alkylene, or unsubstituted 2 to 5 membered heteroalkylene, whesrein n is an integer from (1 to 2, and R' and R? are irmdependently substituted or unsubstituted cycloalkyl, substitu-ted or unsubstituted heterocycloalkyl, substituted or unsubmstituted heteroaryl, or substituted or unsubstituted aryl with the proviso that L' is no=t unsubstituted 2 to 5 membered heteroalkylene \when R'and R*are both unsubstituted phenyl.
    39. A compound of any one of claims 1, 28 or 29, substantially as herein de=scribed and exemplified.
    40. A pharmaceutical composition of cla-im 38, substantially as ‘Therein desscribed and exemplified. 151 AMENDED SHEET AMEENDED SHEET
ZA200700314A 2004-07-27 2007-01-11 Fused ring heterocycle kinase modulators ZA200700314B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US59177804P 2004-07-27 2004-07-27

Publications (1)

Publication Number Publication Date
ZA200700314B true ZA200700314B (en) 2008-07-30

Family

ID=40478363

Family Applications (1)

Application Number Title Priority Date Filing Date
ZA200700314A ZA200700314B (en) 2004-07-27 2007-01-11 Fused ring heterocycle kinase modulators

Country Status (2)

Country Link
CN (1) CN101389626A (en)
ZA (1) ZA200700314B (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006058120A1 (en) * 2004-11-22 2006-06-01 Vertex Pharmaceuticals Incorporated Bicyclic inhibitors or rho kinase
AU2011209649A1 (en) * 2010-01-27 2012-08-09 Vertex Pharmaceuticals Incorporated Pyrazolopyrazine kinase inhibitors
CN102627646A (en) * 2012-03-19 2012-08-08 苏州四同医药科技有限公司 Preparation method of 3-iodo-5-bromo-4, 7-diazaindole
CN103980272B (en) * 2014-04-18 2016-02-17 海门瑞一医药科技有限公司 A kind of method of synthesis 5-cyano group-1H-pyrazolo [3,4-b] pyridine
WO2016026078A1 (en) * 2014-08-19 2016-02-25 Changzhou Jiekai Pharmatech Co., Ltd. Heterocyclic compounds as erk inhibitors
CN111171019A (en) * 2018-11-13 2020-05-19 上海轶诺药业有限公司 Five-membered and six-membered heterocyclic compounds and application thereof as protein receptor kinase inhibitors

Also Published As

Publication number Publication date
CN101389626A (en) 2009-03-18

Similar Documents

Publication Publication Date Title
US7906648B2 (en) Pyrrolo-pyridine kinase modulators
US7452993B2 (en) Fused ring heterocycle kinase modulators
US7601839B2 (en) Pyrrolo-pyridine kinase modulators
US7709645B2 (en) Pyrrolo-pyridine kinase modulators
US7626021B2 (en) Fused ring heterocycle kinase modulators
US9834551B2 (en) Substituted pyrrolo[2,3-b]pyrazines and substituted pyrazolo[3,4-b]pyridines as ITK and JAK kinase inhibitors
KR20100041711A (en) Substituted pyrrolopyridines and pyrazolopyridines as kinase modulators
KR20100066419A (en) Fused ring heterocycle kinase modulators
CA2667428A1 (en) Bicyclic triazoles as protein kinase modulators
ZA200700314B (en) Fused ring heterocycle kinase modulators
ZA200700315B (en) Pyrrolo-pyridine kinase modulators
Chen et al. An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies
EA019122B1 (en) Derivatives of 6-heterocyclic-imidazo[1,2-a]pyridine-2-carboxamides, preparation thereof and therapeutic application thereof