GB2517988A - Compounds - Google Patents

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GB2517988A
GB2517988A GB1316014.8A GB201316014A GB2517988A GB 2517988 A GB2517988 A GB 2517988A GB 201316014 A GB201316014 A GB 201316014A GB 2517988 A GB2517988 A GB 2517988A
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United Kingdom
Prior art keywords
compound
cancer
fluoro
mmol
phenyl
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GB201316014D0 (en
Inventor
Angus Morrison
Emma Carswell
Richard Armer
Thomas Pesnot
Matilda Bingham
Inder Bhamra
James Kirkham
Paul Colbon
Craig Avery
Andrew Mccarroll
Richard Testar
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Redx Pharna PLC
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Redx Pharna PLC
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Priority to GB1316014.8A priority Critical patent/GB2517988A/en
Publication of GB201316014D0 publication Critical patent/GB201316014D0/en
Publication of GB2517988A publication Critical patent/GB2517988A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

Triazolyl compounds of formula (I) wherein A is a 5-membered heterocyclic moiety; B is C6-14aryl or C5-14heteroaryl; L is SO2NRa, where Ra is H, C1-4alkyl or C1-4haloalkyl; R1 is C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-14carbocyclyl or C3-14heterocyclyl, each optionally substituted with 1-5 substituents selected from halo, ORb, SRb, NRbRc, NO, =O, CN, C1-4acyl, C1-6alkyl, C1-6haloalkyl, C3 8cycloalkyl, C(O)Rb and C(O)ORb; R2 is H, halo, C1-4alkyl or C1-4haloalkyl; R3 is H, C1 6alkyl, C1-6haloalkyl, C3-8cycloalkyl or C3-8heterocycloalkyl; R4 is H, halo, OR5, SR5, NR5R6, NO, =O, CN, acyl, C(O)ORb, C(O)NRbRc, C1-6alkyl, C3-14carbocyclyl or C3 14heterocyclyl; R5 and R6 are H, C(O)Rb, C1-4alkyl, C1-4haloalkyl, C3-8carbocyclyl or C3 8heterocyclyl; Rb and Rc are H, C1-4alkyl, C1-4haloalkyl, C1-4acyl, C3-7cycloalkyl or C3 7halocycloalkyl; m is 0-3 and n is 0-2; may be useful as inhibitors of Raf kinases, e.g. B Raf and C-Raf. The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Raf kinases, for example cancer, including lymphoma, leukemia and melanoma, and immunological diseases.

Description

Compounds [0001] This invention relates to compounds. More specifically, the invention relates to compounds useful as kinase inhibitors, in addition to uses of the compounds as medicaments. Specifically the invention relates to inhibitors of the serine/threonine-protein kinase B-Raf, also referred to as B-Raf inhibitors.
BACKGROUND
[0002] Kinases are a class of enzyme that control the transfer of phosphate groups from phosphate donor groups, for example ATP, to specific substrates. Protein kinases are a subset of kinases and serine/threonine-protein kinase B-Raf is one such protein kinase. Serine/threonine-protein kinase B-Raf is more commonly known as B-Raf and throughout this application these two terms will be used interchangeably.
[0003] B-Raf is a member of the Raf kinase family, the other members of the family being A-Rat and C-Raf. Each member of the Raf kinases is a serine/threonine-specific protein kinase, an enzyme that phosphorylates the hydroxyl group of serine or threonine residues within a protein. The Rat kinases are involved in the mitogen-activated protein kinase (MAPK) cascade, a key pathway involved in internal cell signalling responsible for cell division, cell proliferation, programmed cell death (apoptosis), cell differentiation, and embryonic development.
[0004] Defects in the MAPK pathway can affect the signalling within a cell and can lead to uncontrolled cell growth through deviant cell division and irregular cell death. Such defects in the MAPK pathway can be caused by mutations to the Raf kinases or aberrant expression of the Raf kinases, as such abnormalities associated with the Raf kinases, such as B-Raf can give rise to uncontrolled cell growth and consequently cancer.
[0005] Thus, controlling aberrant expression of Raf kinases by small molecule inhibition presents a useful approach tor the treatment of cancers.
[0006] A number of Raf inhibitors have been identified. Two such compounds are dabrafenib and vemurafenib. Dabrafenib is a B-Raf inhibitor indicated in the treatment of malignant melanoma and marketed by GlaxoSmithKline. Dabrafenib was approved for the treatment of malignant melanoma in May 2013 by the US FDA. Similarly, in August 2011 vemurafenib was approved for the treatment of melanoma by the US FDA. As with dabrafenib, vemurafenib is a B-Raf inhibitor, specifically of the V600E B-Raf mutation.
[0007] A number of patents have published describing B-Raf inhibitors. One such publication is WO 2012/125981 which describes a compound having a structure related to dabratenib. Both compounds contain a central 5-membered heterocylce flanked by two substituted 6-membered (or higher) ring systems.
In addition to WO 2012/125981, B-raf inhibitors have also been disclosed in WO 2012/016993, WO 2011/085269, WO 2011/025927, WO 2011/092088 and WO 2011/023773, for example.
BRIEF SUMMARY OF THE DISCLOSURE
[0008] In accordance with the present invention there is provided compounds as disclosed below.
Furthermore, the invention provides compounds capable of inhibiting Raf kinases, for example B-Raf and C-Rat, and the use of these compounds in inhibiting Rat kinases, e.g. B-Rat and C-Raf. In accordance with the invention there is provided a method of treating conditions modulated by Raf kinases, e.g. B-Raf and C-Rat. The invention provides compounds for use in treating a condition which is modulated by Raf kinases, e.g. B-Raf and C-Rat.
[0009] In a tirst aspect of the invention there is provided a compound according to formula (I): N'N R1-L -(R)n (I) wherein A is a 5-membered heterocyclic moiety; B is selected from C14 aryl and C514 heteroaryl; L is _SO2NRH_, wherein Ra is selected from: H, C14 alkyl and C1.4 haloalkyl; R1 is selected from substituted or unsubstituted: C16 alkyl, C16 alkenyl, alkynyl, C314 carbocyclic and C3-14 heterocyclic; and wherein, when substituted, the substituted moiety includes Ito 5 substituents independently selected at each occurrence from the group comprising: halo, SORb, SRb, NRRc, -NO, =0, -CN, C14 acyl, C1 alkyl, C16 haloalkyl, C33 cycloalkyl, C(O)Rb and C(O)ORb R2 is independently selected at each occurrence from: H, halo, C14 alkyl and CIA haloalkyl; R3 is selected from: H, C1-6 alkyl, C13 haloalkyl, C38 cycloalkyl, C33 heterocycloalkyl; R4 is independently selected at each occurrence from: H, halo, -OR5, -SR5, -NR5R6, -NO, =0, -CN, acyl, C(O)ORb, _C(O)NRbRC, C16 alkyl, C314 carbocyclic and C314 heterocyclic; R5 and R6 are each independently selected from: H, C(O)RL, C14 alkyl, CiA haloalkyl, 038 carbocyclic and C3 heterocyclic; Rb and R' are independently selected at each occurrence from: H, 01-4 alkyl, 014 haloalkyl, Ci acyl, cycloalkyl, and 03-7 halocycloalkyl; m is selected from, 0, 1,2 and 3; and n is selected from, 0, 1 and 2.
[0010] In an embodiment the compound of formula (I) is a compound according to formula (II): Fr
N N R1_S°
R ()-(R4) (R2)m (II) [0011] In an alternative embodiment, compounds of formula (Ila) are also possible. In these compounds, the definitions of the substituents A, B, R1 to R6, R8, Rb, m and n are the same as for the compounds of formula (II), and the same embodiments described below apply equally to formula (Ila) as apply to formula (II). Fr N''N \ / -N' o B A (R2)m (Ila)
[0012] In an embodiment, the two groups other than any R2 groups that are substituted on B are substituted meta to one another, i.e. it is important that they are not sited on adjacent atoms, carbon or otherwise. In this regard, with respect to formula (I), R1-L-is substituted on B meta to the triazole within the molecule. With respect to formula (II), RlS02NRa_ is substituted on B meta to the triazole within the molecule. With respect to both formula (I) and formula (II) any R2 may be substituted on B at any position.
Meta is a term well understood by the skilled person; however, for clarification meta refers to a 1,3-relationship between two particular substituents on a cyclic compound. Therefore, an alternative way to describe the same feature would be to say that the two groups other than any R2 groups are substituted on B in a 1,3-relationship. The 1,3-relationship between the two groups on B other than P2 may be at the 1 and 3 positions of B. However, the 1,3-relationship may also be arrived at by substitution at the 2 and 4 positions or the 3 and 5 positions, etc depending on the numbering of ring B. The important feature is that there is a single atom (which may or may not be carbon) between the two atoms which bear the sulphonamide and the triazole, respectively.
[0013] In an embodiment A is a 5-membered heterocyclic moiety containing where chemically possible 1, 2 or 3 heteroatoms independently selected at each occurrence, and optionally contains 1 or 2 heteroatoms. The heteroatoms may be independently selected at each occurrence from N, 0 or S. In an embodiment A is a 5-membered heterocyclic moiety containing 1, 2 or 3 heteroatoms where chemically possible, and optionally contains 1 or 2 heteroatoms wherein at least one of the heteroatoms is N. In an embodiment A is a 5 membered heterocyclic moiety containing 1, 2 or 3 heteroatoms, optionally 1 or 2, one of which is N. [0014] In an embodiment A is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazoline and pyrazolidinyl.
[0015] In an embodiment A is selected from pyrazolyl and thiazolyl.
[0016] In an embodiment B is phenyl ora 6 membered N-containing heteroaryl.
[0017] In an embodiment B is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.
Optionally, B is phenyl or pyridyl.
[0018] In an embodiment B may be selected from: (R2)m (R2)m [0019] In a specific embodiment B may be selected from: t [0020] In an embodiment R1 is selected from substituted or unsubstituted: 01.6 alkyl, C1.6 alkenyl, C1.6 alkynyl, C3.3 cycloalkyl, C3.3 heterocycloalkyl, C6.14 aryl and 05.14 heteroaryl. Optionally, R1 is selected from substituted or unsubstituted: C1.6 alkyl, 06.14 aryl and C.14 heteroaryl. In preferred embodiments R1 may be selected from substituted or unsubstituted: phenyl, pyridyl, pyrazolyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, methyl, ethyl, propyl and butyl.
[0021] In an embodiment, R1 is unsubstituted or R1 is substituted with one or more groups, optionally one or two groups, independently seleded from: halo, SORb, NRbR0, C16 alkyl and C1. haloalkyl. In a preferred embodiment R1 is unsubstituted or substituted with one or more groups, optionally one or two groups, selected from: halo, _ORb and 01.6 alkyl. In embodiments where R1 is substituted preferred substituents are fluoro, chloro, -OMe and methyl.
[0022] In certain embodiments R1 is substituted by one substituent selected from those given above. In alternative embodiments R1 is substituted by two substituent selected from those given above. R1 may be substituted by one fluoro substituent. R1 may be substituted by two fluoro substituents. R1 may be substituted by one chloro substituent. R1 may be substituted by one methyl substituent. R1 may be substituted by two methyl substituents. R1 may be substituted by one methoxy substituent.
[0023] In an embodiment R1 may be selected from: phenyl, pyridyl, pyrazolyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl and isothiazolyl substituted with one or more, optionally one or two, fluoro, chloro, -OMe and methyl groups; or unsubstituted methyl, ethyl, propyl and butyl.
[0024] In preferred embodiments R1 may be selected from: :ø Cl-Q MeO QH [0025] In an embodiment R2 is independently selected at each occurrence from: H, halo, 01-4 alkyl and haloalkyl and m is 0, 1 or 2. Most preferably R2 is fluoro. In an embodiment m is I or 2 and R2 is independently selected at each occurrence from halo, C14 alkyl and ciA haloalkyl, optionally fluoro, chloro, methyl, ethyl, trifluoromethyl and trifluoroethyl. In a preferred embodiment m is 1 or 2 and R2 is halo, optionally fluoro or chloro. Most preferably R2 is fluoro. In an alternative embodiment m is 1 or 2 and R2 is alkyl, optionally methyl or ethyl.
[0026] In an embodiment m is 1 or 2. Preferably m is 1. In a particular embodiment m is 1 and R2 is fluoro. In an alternative embodiment m is 2 and R2 is fluoro. In an alternative embodiment m is 2 and one R2 is fluoro and the other R2 is chloro.
[0027] In certain embodiments R3 is selected from: C16 alkyl and C39 cycloalkyl. In an embodiment R3 is selected from: C14 alkyl and C cycloalkyl, optionally methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl and cyclopentyl. Preferably R3 is C14 alkyl. In an embodiment R3 is methyl, iso-propyl or tert-butyl.
[0028] In an embodiment R4 is independently selected at each occurrence from: H, halo, -OR5, -NR5R6, C(O)NRbRc, C16 alkyl, C36 carbocyclic and C3.6 heterocyclic, optionally wherein C36 carbocyclic may be C36 cycloalkyl or C3-6 aryl and C3-heterocyclic may be C3-heterocycloalkyl or C36 heterocycloaryl. In an embodiment R4 is independently selected at each occurrence front H, -OR5, -NR5R6, C(O)NRbR0, C14 S alkyl, 03.6 cycloalkyl and 03.6 heterocycloalkyl, preferably H, -OR5, -NR5R6, C1. alkyl. Preferably R4 is independently selected from C14 alkyl, or C14 alkoxy. Most preferably R4 is independently selected from methyl and methoxy. In an alternate embodiment R4 is independently selected at each occurrence from: H, -OH, -OMe, -NH2, -NHMe, -NMe2, methyl and ethyl.
[0029] In an embodiment R5 and R6 are each independently selected from: H, C-alkyl, 03-8 carbocyclic and heterocyclic, optionally wherein C-carbocyclic may be 03-6 cycloalkyl or aryl and C3-6 heterocyclic may be 03-6 heterocycloalkyl or 03-6 heterocycloaryl.
[0030] In an embodiment R5 and R6 are each independently selected from: H, C1-6 alkyl, 03-6 cycloalkyl and C36 heterocycloaryl. In an embodiment R5 and R° are each independently selected from: H and C14 alkyl; and more preferably from H, methyl and ethyl.
[0031] In an embodiment n is 1 or2. Preferably, n is 1.
[0032] In a preferred embodiment n is I and R4 is selected from: H, -OH, -OMe, -NH2, -NHMe, -NMe2, methyl and ethyl.
[0033] In an embodiment the compound of formula (I) is a compound according to formula (Ill):
F
NN
RlS0 J R (R4) (R2)m (Ill) [0034] In an embodiment the compound of formula (I) is a compound according to formula (IV): Fr
NN
O
R1_SO,__/ ")(R) Ra: (1_i N,NH (R2)m (IV) [0035] Preferred compounds of the invention include: Y Y *
_N
N N N N F N N
Nj ° F O?-HN_t:NH _fN)_HN_8NH_O_HN_8CNH
Y I Y
F N N N N N N
HNNHDHN,NH
F
Y Y Y
N''N N''N N''N )flS0 -Q-HNStTNH
Y Y Y N,
N' N F N N
N N F /
-HN
F F
N
N''N N' N F N''N
F
ftJ'; b(c
-HN
F F
Y Y Y
N N
N N N
ttcx &oSo Ld
Y I Y
N''N N &O{ &1\
H *
N'N NN NN ° F "0 flO{ Q-H2j N flOfl * Y * NN N'N N''N o F "O 0 F
N QO
F Y * I N'N
N N
° F! b O{ (1HOJm NtJ N
F
Y Y I
F N'N F
N N
ØO? ØO -d,N
F H F H F H
Y Y Y
F N'N F N'N F N'N
HN N
F, ØO ØO
F F F * Y * N"N
N N :/NN
F
H F H
Y Y Y
N''N N''N N'N N 0 F
N N HN
I I I
::o1Nc:o [0036] The following compounds show a lower degree of activity and hence are less preferred compounds of the invention. In certain embodiments, these compounds do not form part of the present invention. These compounds are: -0S Qo4t, Ph [0037] In another aspect of the invention there is provided a compound of formula (I) for use as a med icament.
[0038] In another aspect a compound of formula (I) is for use in the treatment of a condition which is modulated by Raf kinases, for example B-Raf or C-Raf. Usually conditions that are modulated by Raf kinases, optionally B-Raf or 0-Raf, are conditions that would be treated by the inhibition of Raf kinases, optionally B-Raf or C-Raf, using a compound of the present invention. A compound of formula (I) may be for use in the treatment of a condition treatable by the inhibition of Raf kinases, optionally B-Raf or C-Raf.
[0039] Raf kinase inhibition is relevant for the treatment of many different diseases associated with the abnormal activity of the MAPK pathway. In embodiments the condition treatable by the inhibition of Raf kinases, for example B-Raf or 0-Raf, may be selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia. Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphomas, carcinomas and leukemia treatable by the inhibition of Raf kinases, for example B-Raf or C-Raf, may be selected from: Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastomas, astrocytomas; gliobalstoma multiforme; ependymomas; seconday CNS tumors (metastases to the central nervous system of tumors originating outside of the central nervous system); brain tumors; brain metastases; colorectal cancer; large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck; squamous cell carcinoma of the head and neck; acute lymphoblastic leukemia; acute myelogenous leukemia (AML); myelodysplastic syndromes; chronic myelogenous leukemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; metastatic melanoma and thyroid cancers.
[0040] In an embodiment the conditions treatable by the inhibition of Rat kinases, for example B-Rat or C-Rat, may be selected from melanoma, non-small cell cancer, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer and cholangiocarcinoma.
[0041] In an aspect ot the invention, a compound ot the invention may be tor use in the treatment ot a S condition selected from those described above in relation to conditions treatable by the inhibition of Rat kinases.
[0042] In an embodiment a compound of the invention may be for use in the treatment of a condition selected from: melanoma, non-small cell cancer, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer and cholangiocarcinoma.
[0043] In an aspect of the invention there is provided a method of treatment of a condition which is modulated by Rat kinases, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.
[0044] The method of treatment may be a method of treating a condition treatable by the inhibition of Raf kinases, e.g. B-Raf or C-Rat. These conditions are described above in relation to conditions treatable by the inhibition of Rat kinases [0045] In an embodiment the method may be for treating a condition selected from: melanoma, non-small cell cancer, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer and cholangiocarcinoma, wherein the method comprises administering a therapeutic amount of a compound of the invention to a patient in need thereof.
[0046] In another aspect of the invention there is provided a pharmaceutical composition, wherein the composition comprises a compound of the invention and one or more pharmaceutically acceptable excipients.
[0047] In an embodiment the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent may be an anti-tumor agent described below.
[0048] In an aspect of the invention there is provided a use of a compound of formula (I) in the manufacture of a medicament for the treatment of a condition which is modulated by Rat kinases, e.g. B-Raf or C-Raf. The condition may be any of the conditions mentioned above.
[0049] In any of the aspects or embodiments of the invention the Raf kinases may be B-Raf or C-Raf. In any of the aspects or embodiments of the invention the B-Rat kinase may be the B-Raf V600E mutant.
Thus, the compounds of the invention may be utilised in the treatment of a condition which is modulated by B-Rat and/or C-Rat. Similarly, the compounds of the invention may be utilised in the treatment of conditions treatable by the inhibition of B-Rat and/or C-Raf. Furthermore, the compounds of the invention may be utilised in the treatment of a condition which is modulated by B-Raf V600. In addition compounds of the invention may be utilised in the treatment of conditions treatable by the inhibition of B-RafV600E. B-Raf V600E is a mutant form of wild type B-Rat which is believed to play a role in aberrant MAPK pathway signalling, giving rise to uncontrolled cell growth. 11.
DETAILED DESCRIPTION
[0050] Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term.
[0051] The term "halo" refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.
[0052] The term "alkyl" refers to a linear or branched hydrocarbon chain. "C1-6 alkyl" refers to an alkyl group containing 1,2, 3,4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Similarly, "C1 SkyE' refers to an alkyl group containing 1,2, 3 or 4 carbon atoms. Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below.
Substiuents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C1M alkoxy.
[0053] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. "C1.6 Haloalkyl" refers to an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms substituted on at least one of the carbon atoms by a halogen. Similarly, "C14 Haloalkyl" refers to an alkyl group containing 1,2, 3 or 4 carbon atoms substituted on at least one of the carbon atoms by a halogen The halogen atom may be present at any position on the hydrocarbon chain. For example, "C16 haloalkyl" may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2- trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1,2,2-trifluoroethyl and 22,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.
[0054] The term "alkenyl" refers to a branched or linear hydrocarbon chain containing at least one double bond. "C26 Alkenyl" refers to an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may be present as the For 7 isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, a "C2-5 alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
[0055] The term "alkynyl" refers to a branded or linear hydrocarbon chain containing at least one triple bond. "C2.6 Alkynyl" refers to an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be at any possible position of the hydrocarbon chain. For example, the "02.6 alkynyl" may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.
[0056] The term "carbocyclic" refers to a saturated or unsaturated carbon containing ring system. A "carbocyclic" system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic.
A "carbocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Carbocyclic" encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion.
"Carbocyclic" may be C38 cycloalkyl or C610 aryl.
[0057] The term Theterocyclic" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, 0 or S. A "heterocyclic" system may contain 1, 2, 3 or 4 heteroatoms, for example 1 012. A "heterocyclic' system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A "heterocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Heterocyclic" encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties.
"Heterocyclic" may be 038 heterocycloalkyl or 0510 heteroaryl. For example, the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine. oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.
[0058] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. "C38 Cycloalkyl" refers to a cycloalkyl group containing 3,4, 5,6,7 orB carbon atoms. For example, the "C3.8 cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "halocycloalkyl" refers to a cycloalkyl group which is substituted with at least one halo group.
[0059] The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system that is not aromatic.
"C3-8 Cycloalkenyl" refers to a cycloalkenyl group containing 3, 4, 5, 6, 7 or B carbon atoms. The ring may contain more than one double bond provided that the ring system is not aromatic. For example, the "C3-8 cycloalkenyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexad ienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.
[0060] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing at least one heteroatom within the ring selected from N, 0 and S. "C3-8 Heterocycloalkyl" refers to a heterocycloalkyl group containing 3, 4, 5, 6, 7 orB atoms including the hetero atoms. For example there may be 1 2 or 3 heteroatoms, optionally 1 or 2. The "heterocycloalkyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C heterocycloalkyl" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the C3-8 heterocycloalkyl" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.
[0061] The term "C3-3 heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system, that is not aromatic, containing at least one heteroatom within the ring selected from N, 0 and S. "C3.8 Heterocycloalkenyl" refers to a heterocycloalkenyll group containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The "03-8 heterocycloalkenyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C3-3 heterocycloalkenyl" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "C3.8 heterocycloalkyl" may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.
[0062] The term "aromatic" when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n -I-2 electrons in a conjugated r system within the ring or ring system where all atoms contributing to the conjugated ii system are in the same plane.
[0063] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system may be a single ring or a fused polycyclic system, e.g. bicyclic. "06-14 Aryl" refers to an aryl group with 6 to 14 carbon atoms within the single ring or fused polycyclic ring system. Similarly, aryl refers to an aryl group with 6 to 10 carbon atoms. For example, the "aryl" may be phenyl or napthyl. The aryl system itself may be substituted with other groups.
[0064] The term "heteroaryl" refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused polycyclic ring system (e.g. bicyclic), selected from 0, N and S. "C514 Heteroaryl" refers to a heteroaryl group with 5 to 14 atoms including the heteroatoms within the single ring or fused polycyclic ring system. Similarly, 0510 heteroaryl refers to a heteroaryl group with 5 to 10 atoms.
For example, the "heteroaryl" may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.
[0065] The term "alkaryl" refers to an aryl group, as defined above, bonded to a 01.4 alkyl, where the 01.4 alkyl group provides attachment to the remainder of the molecule.
[0066] The term "alkheteroaryl" refers to a heteroaryl group, as defined above, bonded to a 014 alkyl, where the alkyl group provides attachment to the remainder of the molecule.
[0067] The term "acyl" refers to an organic radical derived from, for example, an organic acid by the removal of the hydroxyl group, e.g. a radical having the formula R-C(0)-where R is alkyl. "014 Acyl" refers to an acyl group where R is 01.4 alkyl. In one embodiment acyl is alkyl-carbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. A particular acyl group is acetyl.
[0068] Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements. The moiety may be substituted by one or more substitutuents, e.g. 1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different. Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are chemically possible and which are not.
[0069] Throughout the description the disclosure of a compound also encompasses pharmaceutically acceptable salts, solvates and stereoisomers thereof. Where a compound has a stereocentre, both (R) and (8) stereoisomers are contemplated by the invention, equally mixtures of steroisomers or a racemic mixture are completed by the present application. Where a compound of the invention has two or more sterocentres any combination of (R) and (5) stereoisomers is contemplated. The combination of (R) and (5) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer.
[0070] The invention contemplates pharmaceutically acceptable salts of the compounds of formula (I).
These may include the acid addition and base salts of the compounds.
[0071] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, S citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 1, 5-naphthalened isulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
[0072] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[0073] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods: (i) by reacting the compound of formula (I) with the desired acid or base; (ii) by removing an acid-or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
[0074] All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
[0075] The compounds of the invention may exist in both unsolvated and solvated forms. The term solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term hydrate' is employed when said solvent is water.
[0076] Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharni Sci, 64(8), 1269-1288 by Haleblian (August 1975).
[0077] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
[0078] The compounds of the invention include compounds of a number of formula as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, S geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of the invention.
[0079] Before purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used. The enantiomers can be separated by conventional techniques known in the art. Thus the invention covers individual enantiomers as well as mixtures thereof.
[0080] For some of the steps of the process of preparation of the compounds of formula (I), it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T.W. Greene (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thienie Verlag, 1994), can be used. All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.
[0081] Also, the compounds of the present invention as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.
[0082] The method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.
Optionally, the additional active agent may be an anti-tumour agent selected from the list below.
[0083] The method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following specific anti-tumour agents listed below or anti- tumour agents from one or more of the categories of listed below:- (i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan, chlorambucil, busulphan,capecitabine temozolamide, ifosamide, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, carmustine, estramustine, fotemustine, gulfosfamide, KW-21 70, mafosfamide, mitolactol, etaplatin, lobaplatin, nedaplatin, strrplatin and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, 6-mercaptopurine riboside, leucovarin, UFT, doxifluridine, carmoflur, cytarabine, enocitabine S-i, 5-azacitidine, cepecitabine, clofarabine, decitabine, eflornithine, ethynlcytidine, TS-1, nelarabine, nolatrexed, ocosfate, pelitrexol, triapine, trimetrexate, vidarabine, and hydroxyurea); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, aclarubicin, actinomycin D, amrubicin, annamycin, elsamitrucin, galarubicin, nemorubicin, neocarzinostatin, peplomycin, piarubicin, rebeccamycin, stimalamer, streptozocin, vairubicin and zinostatin); antimitotic agents (for example ymca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol, docetaxol (Taxotere), and paclitaxel and polokinase inhibitors); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, aclarubicin, amonafide, belotecan, 1 0-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, edotecarin, exatecan, gimatecan, lurtotecan, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, anisacrine, topotecan, mitoxantrone and camptothecin) and adjuvants used in combination with these therapies, for example folinic acid; (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, lasofoxifeneand iodoxyfene), antiandrogens (for example bicalutamide, mifepristone, flutamide, nilutamide, casodex and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a -reductase such as finasteride; (iii) anti-invasion agents, for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase; (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGER antibody panitumumab, the anti-erbBl antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy) -quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); ErbB2 inhibitors (for example GW-28297, Herceptin, 2C4, pertuzumab, TAK-165, GW-572016, AR-209, and 2B-1); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMNIO7); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib, tipifarnib and lonafarnib), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, P13 kinase inhibitors, P1t3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM); COXII inhibitors (for example Arcoxia (etoricoxib), Bextra (valdecoxib), Celebrex (celecoxib), Paracoxib Vioxx (rofecoxib)); MMP inhibitors (for example MMP-2 inhibitors, MMF-9 inhibitors, AG-3340, RO 32-3555, and RS 13-0830); thalidomide; lenalidomide; and for example, a VEOF receptor (for example SU-1 1248, SU-54l6, SU-6668, and angiozyme) tyrosine kinase inhibitor (such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib); acitretin; fenretinide; zoledronic acid; angiostatin; aplidine; cilengtide; A-4; endostatin; halofuginome; rebimastat; removab; revlimid; squalamine; ukrain; and vitaxincombretastatin; (vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2; (vii) immunotherapy approaches, including for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon a; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Frovenge); interferons, such as interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-la, and interferon gamma-n; FF3512676; Filgrastim (Neupogen); lentinan; sizofilan; TheraCys; ubenimex; WF-10; BAM-002; dacarbazine; daclizumab; denileukin; gemtuzumab; ozogamicin; imiquimod; lenograstim; melanoma vaccine (Corixa); molgramostim; OncoVAX-CL; sargramostim; tasonermin; tecleukin; thymalasin; tositumomab; Virulizin; Z-100; epratuzumab; mitumomab; oregovomab; pemtumomab; and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and (vUi) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (NipentTM), edotecarin, SU-11248, paclitaxel, Erbitux, and irinotecan; (ix) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betaniethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fiuprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph; (x) targeted therapies, for example PI3Kd inhibitors, for example idelalisib and perifosine; (xi) and additional active agents such as estramustine phosphate, fludarabine phosphate, farnesyl transferase inhibitors, PDGFr, streptozocin, strontium-89, suramin, hormonal therapies (for example Lupron, doxercalciferol, fadrozole, formestane and treistar), supportive care products (for example, Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi and Emend), biological response modifiers (e.g. Krestin, lentinan, sizofiran, picibanil and ubenimex), alitretinoin, ampligen, atrasenten, bexarotene, bosentan, calcitriol, exisulind, fotemustine, ibandronic acid, miltefosine, 1-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, tazarotne, TLK-286, Velcade, Tarceva, tretinoin.
[0084] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
[0085] According to a further aspect of the invention there is provided a pharmaceutical product comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore and an additional active agent for the combination treatment of a condition modulated by Raf kinases, e.g. B-Raf or C-Raf. The additional active agent may be an anti-tumour agent as defined hereinbefore for the combination treatment of a condition modulated by Raf kinases, e.g. B-Raf or C-Raf.
[0086] According to a further aspect of the invention there is provided a method of treating a condition modulated by Raf kinases, e.g. B-Raf or C-Raf comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-tumour agent, as defined hereinbefore, to a patient in need thereof.
[0087] According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-tumour agent as defined hereinbefore, in the treatment of a condition modulated by Raf kinases, e.g. B-Raf or C-Raf.
[0088] According to another aspect of the invention there is provided a use of the compound of formula (I) in combination with an anti-tumour agent as hereinbefore described. The compound of formula (I) may be used simultaneously, sequentially or separately with the additional anti-tumour agent. The use may be in a single combination product comprising the compound of formula (I) and the anti-tumour agent.
[0089] According to a further aspect there is provided a method of providing a combination product, wherein the method comprises providing a compound of formula (I) simultaneously, sequentially or separately with an anti-tumour agent, as defined hereinbefore. The method may comprise combining the compound of formula (I) and the anti-tumour agent in a single dosage form. Alternatively the method may comprise providing the anti-tumour agent as separate dosage forms.
[0090] The condition modulated by Raf kinases, for example B-Raf or C-Raf, described above may be cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia.
More specifically the condition modulated by Raf kinases, for example B-Raf or C-Raf, may be selected from: Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastomas, astrocytomas; gliobalstoma multiforme; ependymomas; seconday ONS tumors (metastases to the central nervous system of tumors originating outside of the central nervous system); brain tumors; brain metastases; colorectal cancer; large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck; squamous cell carcinoma of the head and neck; acute lymphoblastic leukemia; acute myelogenous leukemia (AML); myelodysplastic syndromes; chronic myelogenous leukemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; metastatic melanoma and thyroid cancers.
EXAMPLES AND SYNTHESIS
[0091] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Reactions heated in a microwave used a Biotage® Initiator Sixty. Compound identity and purity confirmations were performed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCAO81).
The diode array detector wavelength was 254nM and the LCMS was in positive and negative electrospray mode (m/z: 150-800). A 2pL aliquot was injected onto a guard column (0.2pm x 2 mm filters) and UPLC column (018, 50 x 2.1 mm, <2pm) in sequence maintained at 40o0. The samples were eluted at a flow rate of 0.6mLlmin with a mobile phase system composed of A (0.1% (vlv) Formic Acid in Water) and B (0.1% (vlv) Formic Acid in Acetonitrile) according to the gradients outlined in Table I below. Retention times RT are reported in minutes.
Long _______________________ ______________ Time (mm) %A 0 95 5 1.1 95 5 6.1 5 95 7 5 95 7.5 95 5 8 95 5 Short Time (mm) %A 0 95 5 0.3 95 5 2 5 95 2.6 95 5 3 95 5
Table I
[0092] NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with 5mm BBFO probe.
[0093] Compound purification was performed by flash column chromatography on silica using a Biotage® Isolera One or by preparative LCMS. LCMS purification was performed using a Waters 3100 S Mass detector in positive and negative electrospray mode (m/z: 150-800) with a Waters 2489 UVNis detector. Samples were eluted at a flow rate of 2OmLJmin on a XBridgeTM prep Cl 8 5pM OBD 1 9x1 00mm column with a mobile phase system composed of A (0.1% (v/v) Formic Acid in Water) and B (0.1% (v/v) Formic Acid in Acetonitrile) according to the gradient outlined in Table 2 below.
Time (mm) %A %B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 90 90 90 90
Table 2
[0094] Chemical names were generated using mol2nam -Structure to Name Conversion by OpenEye Scientific Software. Starting materials were purchased from commercial sources or synthesised according to literature procedures.
[0095] As used herein the following terms have the meanings given: "Binap" refers to 2,2'-bis(diphenylphosphino)-1, 1 -binaphthyl; "Boc" refers to tert-butoxycarbonyl; "DCM" refers to dichloromethane; "DIPEA" refers to N,N-diisopropylethylamine; "DMF" refers to dimethylformamide; "LCMS" refers to liquid chromatography/mass spectrometry; "MIM" refers to monoisotopic mass; "MPM" refers to methoxyphenyl methyl; "mm" refers to minutes; "NMP" refers to N-methylpyrrolidinone; "TLC" refers to thin layer chromatography; "Rf refers to Retention factor; "RT" refers to retention time; "SCX" refers to strong cation exchange; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; and "TBME" refers to tert-Butyl methyl ether.
[0096] Preparation of intermediates useful in the synthesis of compounds of the invention.
[0097] Preparation of 4-bromo-5-iodo-2H-triazole.
H N'"N BhI
Step 1) 21.
To a solution of 4,5-dibromo-2H-triazole (8 g, 353.9 mmol) [prepared according to a method described in W02012/151512 and J. Chem. Soc. Perkin Trans. 1, 1996, pp 1341] in THF (150 mL) cooled to 0°C was added dropwise PrMgCI.LiCI solution (54.45 mL, 70.79 mmol, 1.3 M solution in THE) and the reaction mixture allowed to warm slowly to room temperature. After 4 hours the reaction mixture was re-cooled to 0°C and a further portion of PrMgCl.LiCI solution (27.22 mL, 35.39 mmol, 1.3 M solution in THF) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was then cooled to 0 °C and trimethylsilyl chloride (13.40 mL, 1061.94 mmol) added and stirred at room temperature for 14 hours. The reaction mixture was quenched with cold water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organics were washed with brine, dried over sodium sulphate, filtered and concentrated to give 5.3 g (5-bromo-2H-triazol-4-yl)-trimethylsilane which was used directly in the next step.
Step 2) Potassium carbonate (401 mg, 2.9 mmol) followed by N-iodosuccinimide (17.0 g, 75.66 mmol) were added to a solution cooled toO °C of the crude (5-bromo-2H-triazol-4-y-trimethylsilane (16.0 g) in ethyl acetate (160 mL). The mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction mixture was quenched with cold water (100 mL) and extracted with ethyl acetate (200 mL). The combined organics were washed with brine, dried over sodium sulphate and concentrated. The crude material was purified by flash column chromatography using 20 % ethyl acetate in petroleum ether to give 12 g of 4-bromo-5-iodo-2H-triazole as a pale yellow solid.
13C NMR (75 MHz, DM50): 129.7 LCMS (short): PT: 2.28 mm, ES m/z 273.8, 275.8 [M+H] [0098] Preparation of 4-bromo-5-iodo-2-isopropyltriazole.
Y N'"N BhI
To a solution of 4-bromo-5-iodo-2H-triazole (10.76 g, 39.29 mmol) in DMF (100 mL) was added potassium carbonate (7.06 g, 51.08 mmol) and the mixture was stirred for 1 hour. 2-lodopropane (4.71 mL, 47.15 mmol) was added to the solution and the reaction was stirred at room temperature overnight. The reaction mixture was filtered, washed with ethyl acetate and concentrated to dryness. The residue was taken up in ethyl acetate, washed with water, dried over sodium sulphate, filtered and concentrated. The resulting residue was purified by flash colum chromatography using 0 -20 % ethyl acetate in heptane to give 9 g of 4-bromo-5-iodo-2-isopropyltriazole as a pale yellow solid.
1H NMP (400 MHz, CDCI3): 4.83 (hep, 1H, J = 6.7), 1.58 (d, 6H, J = 6.7) LCMS (short): PT 1.86 mm Similarly prepared was: 4-Bromo-5-iodo-2-methyl-triazole
NN
1F-I NMR (400 MHz, ODd3): 4.24 (s, 3H) [0099] Preparation of 4-bromo-2-tert-butyl-5-iodo-triazole. *
To a solution of 4-bromo-5-iodo-2H-triazole (3 g, 10.96 mmol) in 1 4-dioxane (20 mL) at 100 °C was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (14 mL, 58.53 mmol)dropwise. The reaction was healed at °C for 19 hours. The reaction was cooled, diluled with ethyl acetate (150 mL), water (100 mL) and saturated sodium bicarbonate solution (50 mL) and separated. The organic extracts were washed with brine (100 niL). The combined aqueous extracts were back extracted with ethyl acetate (150 mL) and the organics combined, dried over sodium sulphate, filtered and concentraled lo dryness. The resulting residues were purified by flash column chromatography, using 0-15% ethyl acetate in heplane to give 2.05 g of 4-bromo-2-tert-butyl-5-iodo-triazole as a pale yellow solid.
1H NMR (400 MHz, ODd3): 1.57(s, 9H) [00100] Preparation of 2,5-difluoro-N-[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]benzenesulfonamide and related compounds. o o F NtST
F
Step 1) To a stirring suspension of 1-bromo-2-fluoro-3-nitro-benzene (9.84 g, 44.73 mmol) and iron (9.99 g, 178.91 mmol) in ethanol (60 mL) was added glacial acetic acid (30.7 mL, 178.91 mmol). The resulting reaction mixture was healed lo 100 °C for 30 minutes and then cooled lo room temperature. The reaction mixture was filtered and washed with ethyl acelate and then concentrated to dryness. The resulting residue was taken up in ethyl acetale, and sodium bicarbonate solulion added to pH 7-8. The biphasic system was then separaled and the aqueous layer exlracted with ethyl acetate (4 x 200 mL). The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated lo give 7.18 g of 3-bromo-2-fluoro-aniline.
1H NMR (400 MHz, ODd3): 6.91 -6.88(m, 1H), 6.83-6.79 (m, 1H), 6.74-6.68 (m, 1H), 3.82 (br s, 2H).
Step 2) To a solution of 3-bromo-2-fluoro-aniline (10.4 g, 54.73 mmol) in DOM (200 mL) was added pyridine (6.4 mL, 79.13 mmol). The resulting solution was cooled in an ice water bath and 2,5-difluorobenzenesulfonyl chloride (10.75 mL, 79.89 mmol) dissolved in DCM (20 mL) was added drop-wise over 5 minutes. The resulting solution was allowed to stir for 24 hours. The reaction mixture was poured into a separating funnel, washed with 1 M HCI (2 x 100 mL), brine (100 mL), dried over sodium sulphate, filtered and concentrated to dryness. The resulting solid was purified by flash column chromatography using 20-100 % DGM in heptane to give 18.49 g of N-(3-bromo-2-fluoro-pheny-2,5-difluoro-benzenesulfonamide as a light white solid.
1H NMR (400 MHz, DMSO-d6): 10.88 (s, 1H), 7.88-7.50 (m, 4H), 7.31 -7.25(m, 1H), 7.13(1H, dt, J = 8.4, 1.4).
LCMS (short): RT: 1.74 mi ES m/z 365.9, 367.9 EM-Hf Step 3) N-(3-bromo-2-fluoro-phenyl)-2,5-difluoro-benzenesulfonamide (18.0 g, 49.16 mmol) was combined with bis(pinacolato)diboron (14.98 g, 58.99 mmol), potassium acetate (7.24 g, 73.74 mmol) and tricyclohexylphenylphosphine (1.38 g, 4.92 mmol) in 1,4-dioxane (250 mL). The vessel was sealed and purged with nitrogen for 10 minutes before adding tris(dibenzylideneacetone)dipalladium (0)(2.25 g, 2.46 mmol). The reaction mixture was heated at refiux for 5 hours, cooled and concentrated to dryness. The resulting residues were purified by flash column chromatography using 20-100% DCM in heptane to give 15.65 g of 25-difluoro-N-2-fluoro-3-(44,55-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]benzenesulfonamide a light yellow solid.
1H NMR (400 MHz, DMSO-d6): 10.59 (s, 1H), 7.66-7.36 (m, 5H), 7.16(t, 1H, J = 7.7), 1.27 (s, 12H).
LCMS (short): RT: 1.91 mi ES m/z412.0 [M-H] Similarly prepared were: 2,6-difluoro-N-[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]benzenesulfonarnide F oo ifli 1H NMR (400 MHz, CDCI3): 7.8-7.7(m, 1H), 7.55-7.43(m, 2H), 7.32 (s, 1H), 7.15-6.94(m, 3H), 1.34 (s, 12H) N-[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] propane-1 -sulfonamide ,, 1H NMP (400 MHz, CDCI3): 7.75-7.70 (m, 1H), 7.78-7.52 (m, 1H), 7.2-7.14 (m, 1H), 6.47 (s, 1H), 3.10 -3.04 (m, 2H), 1.94-1.82 (m, 2H), 1.39 (s, 12H), 1.05 (t, 3H, J = 7.4) [00101] Preparation of N-[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheriyl]-2, 2-dimethyl-propanamide.
Step 1) To a solution of 3-bromo-2-fluoroaniline (0.59 mL, 5.26 mmol) and triethylamine (1.47 mL, 10.53 mmol) in DCM (30 mL) at 0°C was added dropwise 2,2-dimethylpropanoyl chloride (0.78 mL, 6.3 mmol) under nitrogen. The solution was allowed to warm to room temperature and left to stir overnight. A further portion of triethylamine (0.37 mL, 2.63 mmol) and 2,2-dimethylpropanoyl chloride (0.32 mL, 2.63 mmol) were added and the mixture stirred at room temperature for 4 hours. DCM was added and the solution was washed with water, 1M HCI, saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulphate, filtered and concentrated to dryness. The crude product was purified by flash column chromatography using 0 -100% ethyl acetate in heptane to afford 1.72 g of N-(3-bromo-2-fluoro-phenyl)-22-dimethyl-propanamide.
1H NMR (400 MHz, CDCI3): 8.36-8.31 (m, 1H), 7.64 (s, 1H), 7.28-7.24 (m, 1H), 7.06-7.01 (m, 1H), 1.35 (s, 9H) LCMS (short): PT: 1.74 mi ES m/z 274.0, 276.0 [M+H]t Step 2) A solution of N-(3-bromo-2-fluoro-phenyl)-2,2-dimethyl-propanamide (1.2 g, 4.38 mmol), bis(pinacolato)diboron (1.33 g, 5.25 mmol), [1,1 -bis(diphenylphosphino)ferrocene-palladium(ll) chloride dichloromethane complex (0.18 g, 0.22 mmol) and potassium acetate (1.29 g, 13.13 mmol) in 1 4-dioxane (50 mL) was heated at 100 °C overnight. A further portion of bis(pinacolato)diboron (0.67 g, 2.63 mmol and [1,1 -bis(diphenylphosphino)-ferrocene-palladium(ll) chloride dichloromethane complex (0.18 g, 0.22 mmol) were added and the reaction mixture stirred at 110 °C for 3 hours. The mixture was allowed to cool to room temperature, filtered through celite and eluted with heptane. The combined organics were concentrated to dryness. The resulting residues were purified by flash column chromatography using 0 - % ethyl acetate in heptane to give 1.25 g of N-[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2, 2-dimethyl-propanamide.
1H NMR (400 MHz, CDCI3): 8.52-8.48 (m, IH), 7.74 (s, IH), 7.47-7.41 (m, IH), 7.19-7.13 (m, IH), 1.39 (s, 12H), 1.33 (s, 9H) [00102] Preparation of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yI)aniline. H2N2k
Nitrogen was bubbled through 1,4-dioxane (264 mL)for 10 minutes before addition of 3-bromo-2-fluoroaniline (7.52 g, 39.58 mmol), bis(pinacolato)diboron (12.06 g, 47.49 mmol), tris(dibenzylideneacetone) dipalladium (0) (1.81 g, 1.98 mmol), tricyclohexylphosphine tetrafluoroborate (0.78 g, 2.77 mmol), and potassium acetate (5.83 g, 59.37 mmol). The flask was flushed with nitrogen and the mixture heated to 120°C for 24 hours. The reaction mixture was allowed to cool, filtered through celite and washed through with ethyl acetate. The combined filtrate was concentrated to dryness. The resulting residues were purified by flash column chromatography using 0-30 % ethyl acetate in heptane to give 6.3 g of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as a yellow solid.
1H NMR (400 MHz, CDCI3): 7.12-7.08 (m, IH), 6.98-6.94 (m, IH), 6.92-6.87 (m, IH), 3.72 (s, 2H), 1.38 (s, 1 2H) [00103] Preparation 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole and related compounds.
QN
Nitrogen was bubbled through a mixture of 5-bromo-4-methyl-1,3-thiazole (0.5 g, 2.81 mmol), bis(pinacolato)diboron (0.71 g, 2.81 mmol), potassium acetate (0.83 g, 8.42 mmol) and 1,4-dioxane (10 mL)for 10 mins before addition of[1,1'-bis(diphenylphosphino) ferrocene]palladium(ll) chloride dichloromethane complex (115 mg, 0.14 mmol). The reaction mixture was heated at 100 °C for 18 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate and filtered through celite, washing with ethyl acetate. The crude product was concentrated to give 0.87 g of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole as a brown solid contaminated with some pinacol related impurities. The product was used without further purification.
1H NMR (400 MHz, CDCI3): 8.79 (s, 1H), 2.61 (s, 3H), 1.27 (s, 12H) Similarly prepared was: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole )çB(NN 1H NMR (400 MHz, CDCI3): 9.04 (s, 1H), 8.37 (s, 1H), 1.37 (s, 12H) [00104] Preparation of 3-methoxy-1 -L(4-methoxyphenyl)methylj-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole.
Step 1) To a cold solution of methyl propiolate (5.28 mL, 59.36 mmol) in methanol (40 mL) was added dropwise hydrazine monohydrate (3.02 mL, 62.32 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. The solution was concentrated to dryness. Ethyl acetate (350 mL) was added and the organics washed with brine (30 mL). The brine solution was back extracted with EtOAc (2 x 100 mL). The combined organics were dried over sodium sulphate, filtered and concentrated to dryness to give 4.47 g of 1,2-dihydropyrazol-3-one as a pale yellow solid which was used without further purification.
1H NMR (400 MHz, DMSO-d6): 11.5 (brs, 1H), 9.57 (brs, 1H), 7.35 (1H, d, J = 2.2), 5.43(1H, d, J = 2.2) Step 2) To a solution of 1,2-dihydropyrazol-3-one (4.47g, 53.16 mmol) in pyridine (20.21 mL, 249.87 mmol) at 95 was added a solution of acetic anhydride (5.08 mL, 53.7 mmol) in pyridine (9.55 mL, 118.02 mmol) over minutes. The reaction was heated at 95°C for 1 hour, cooled and concentrated to dryness. The resulting residue was triturated in methanol (35 ml), filtered and dried to provide 3.84 g of 2-acetyl-1 H-pyrazol-5-one as a brown solid.
1H NMR (400 MHz, DMSO-d6): 10.95 (br s, IH), 8.13 (d, 1H, J = 3), 6.01 (d, IH, J = 3), 2.48(s, 3H) Step 3) To a solution of 2-acetyl-1 H-pyrazol-5-one (3.84 g, 30.45 mmol) and potassium carbonate (4.21 g, 30.45 mmol) in 2-butanone (93 mL) was added dimethyl sulphate (3.18 mL, 33.5 mmol). The reaction was heated at 90 °C until consumption of starting material. The reaction mixture was cooled, filtered and concentrated to dryness. The resulting residue was dissolved in methanol (51 rnL), tetrahydrofuran (51 mL) and 1OM sodium hydroxide (1.54 mL) was added. The reaction was stirred for 1 hour and concentrated to dryness.
The resulting residues were taken up in ethyl acetate (200 mL) and brine (100 mL). The aqueous layer was back extracted with ethyl acetate (100 mL), pH of aqueous adjusted to -7 and re-extracted with ethyl acetate (200 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated to give 2.489 of 3-methoxy-IH-pyrazole as a red oil which was used without further purification.
1H NMR (400 MHz, CDCI3): 7.39 (d, 1H, J = 2.48), 5.76 (d, WI, J = 2.48), 3.93 (s, 3H) LCMS (short): RT: 0.75 mi ES m/z 99.0 [M+H] Step 4) To a solution of 3-methoxy-1 H-pyrazole (2.48 g, 25.28 mmol) in DMF (39 mL) at -30 °C was added N-iodosuccinimide (5.699,25.28 mmol). The reaction was stirred at this temperature for 2.5 hours. Water (45 mL) and ethyl acetate (65 mL) were added and the reaction warmed to room temperature. Brine (50 mL) and ethyl acetate (100 mL) were added and separated. The aqueous was back extracted with ethyl acetate (2 x 200 mL). The combined organics were washed with water (2 x 100 mL), 1 M sodium thiosulphate solution (100 mL), brine (100 mL), dried over sodium sulphate, filtered and concentrated to dryness to provide 4.769 of a 1:1 adduct of 4-iodo-3-methoxy-1 H-pyrazole and DMF as a dark red oil.
1H NMR (400 MHz, CDCI3): 10.07 (brs, 1H), 8.03 (s, 1H), 7.43 (s, 1H), 3.98 (s, 3H), 2.98 (s, 3H), 2.90 (s, 3H) LCMS (short): RT: 1.25 mm, ES m/z 224.9 [M+Hf Step 5) To a solution of the 4-iodo-3-methoxy-1H-pyrazole:DMF adduct (4.769) in THE (30 mL) at 0 °C was added sodium hydride (595 mg, 14.88 mmol, 60% dispersion in mineral oil). The reaction was stirred for 1 hour and 1-(bromomethyl)-4-methoxy-benzene (1.84 mL, 12.75 mmol) was then added dropwise. The reaction was stirred at room temperature for 18 hours. The reaction was partitioned between ethyl acetate (200 mL) and water (100 mL), the aqueous was back extracted with ethyl acetate (200 mL) and the combined organic layers dried over sodium sulphate, filtered and concentrated to dryness. The resulting residue was purified by flash column chromatography to give 3.169 of 4-iodo-3-methoxy-1 -[(4-methoxyphenyl)methyl]pyrazole.
1H NMR (400 MHz, CDCI3): 7.23-7.17 (m, 2H), 7.12 (s, 1H), 6.93-6.87 (m, 2H), 3.97 (s, 3H), 3.83 (s, 31-1) LCMS (short): RT: 1.77 mi ES m/z 345.0 [M+Hf Step 6) To a solution of 4-iodo-3-methoxy-1-[(4-methoxyphenyl)methyl]pyrazole (3.169, 9.18 mmol) in degassed THF (100 mL) at -10 °C was added dropwise isopropylmagnesium chloride lithium chloride complex (28.25 mL, 36.73 mmol, I.3M in THF) over 5-10 minutes. The reaction was stirred at this temperature for 40 minutes. After this time 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.37 mL, 45.91 mmol) was added and the mixture warmed to 0 °C and stirred at this temperature for a further 60 minutes. The reaction was quenched with saturated aqueous ammonium chloride (100 mL), partitioned between ethyl acetate (300 mL) and water (200 mL). The aqueous was back extracted with ethyl acetate (3 x 200 mL), the combined organics were washed with brine (200 mL), dried over sodium sulphate, filtered and concentrated to dryness. The residue was purified by flash column chromatography using 0-30 % ethyl acetate in heptane to give 2.35 g of 3-niethoxy-1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl-1 3,2-dioxaborolan-2-yl)pyrazole as an off white solid.
1H NMR (400 MHz, CDCI3): 7.39 (s, 1H), 7.23-7.18(m, 2H), 6.92-6.85 (m, 2H), 3.97 (s, 3H), 3.83 (s, 3H), 1.31 (s, 12H) LCMS (short): RT: 1.76 mm, ES m/z 345.2 [M+Hf Similarly prepared was: I -Benzyl-3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yI)pyrazole B' 1H NMR (400 MHz, CDCI3): 7.45 (s, 1H), 7.39-7.31 (3H, m), 7.26-7.22 (m, 2H), 3.97 (s, 3H), 1.32 (s, 12H) LCMS (short): RT: 1.78 mm, ES m/z 315.3 [M+Hf [00105] Preparation of 3-methoxy-I -tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-I,3,2-dioxaborolan- 2-yl)pyrazole and 5-methoxy-I -tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole. B' B'
c(LrO\
N-N N-N
Step 1) To a solution of 4-iodo-3-methoxy-1 H-pyrazole (1.33 g, 4.46 mmol) and 34-dihydro-2H-pyran (0.41 mL, 4.46 mmol) in DCM (33 mL) was added pyridinium p-toluenesulfonate (124 mg, 0.49 mmol) and the reaction mixture stirred for 18 hours. A further portion of 3,4-dihydro-2H-pyran (0.41 mL, 4.46 mmol) and pyridinium p-toluenesulfonate (124 mg, 0.49 mmol) was added and stirred for a further 6 hours. The reaction was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), brine (50 mL), dried over sodium sulphate, filtered and concentrated to dryness. The residue was purified by flash column chromatography using 0-30 % ethyl acetate in heptane to give 1.3 g of a mixture of 4-iodo-3-methoxy-1 -tetrahydropyran-2-yl-pyrazole and 4-iodo-3-methoxy-1 -tetrahydropyran- 2-yl-pyrazole as an off white semi-solid.
LCMS (short): RT: 1.65 and 1.68 mm Step 2) To a solution of 4-iodo-3-methoxy-1 -tetrahyd ropyran-2-yl-pyrazole and 4-iodo-3-methoxy-1 -tetrahydropyran-2-yl-pyrazole (1.39,4.22 mmol) in THF (40 mL) at -10°C was added dropwise over 10 minutes isopropylmagnesium chloride lithium chloride complex (12.98 mL, 16.88 mmol, 1.3M in THF). The reaction was stirred for 40 minutes, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.3 mL, 21.1 mmol) was added dropwise and the reaction stirred for 1 hour. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (50 mL) at 0 °C. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous was back extracted with ethyl acetate (3 x 100 mL). The combined organics were washed with brine (100 mL), dried over sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 0 -40 % ethyl acetate in heptane to give 1.3 g of 3-methoxy-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-ypyrazole and 5-methoxy-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyrazole as a viscous yellow oil.
LCMS (short): RT:1.68 and 1.76 mm, ESt mlz 225 [M+HTHP]* [00106] Preparation of N-[2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,1 -diphenyl-methanimine an intermediate in the synthesis of compounds of the invention.
Step 1) 1,3-dibromo-2,5-difluoro-benzene (1000 mg, 3.68 mmol), sodium tert-butoxide (0.539, 5.52 nimol), rac-BINAP (0.23 g, 0.37 mmol) and benzophenone imine (0.65 mL, 3.86 mmol) were charged to a round bottom flask fitted with a reflux condenser and toluene (40 mL) added. The reaction was placed under nitrogen and heated to 100 °C for 6 hours and then left to cool and stand overnight. To the reaction mixture was added water (40 mL) and ethyl acetate (40 mL) and the organics separated. The aqueous phase was back extracted with ethyl acetate (40 mL). The organics were combined, washed with brine (40 mL), dried over magnesium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 5-50 % DOM in heptane to give 983 mg of N-(3-bromo- 25-difluoro-phenyl)-1,1-diphenyl-methanimine as a light yellow solid.
1H NMR (400 MHz, DMSO-d6): 7.74-7.66 (m, 2H), 7.65-7.57 (iii, 1H), 7.56-7.47 (m, 2H), 7.45-7.36 (m, 3H), 7.28-7.15 (m, 3H) LCMS (short): RT: 2.24 mi ES m/z 372.1, 374.1 [M+H] Step 2) N-(3-bromo-2,5-difluoro-phenyl)-1 1 -diphenyl-methanimine (815 mg, 2.19 mmol) was combined with bis(pinacolato)diboron (667 mg, 2.63 mmol), potassium acetate (336 mg, 3.42 mmol) and tricyclohexylphenylphosphine (66 mg, 0.24 mmol) in 1,4-dioxane (22 mL). The vessel was sealed and purged with nitrogen for 10 minutes before adding tris (dibenzylideneacetone) dipalladium (0) (100 mg, 0.11 mmol). The reaction mixture was heated at reflux for 5 hours. The reaction mixture was cooled and concentrated. The resulting residues were purified by flash column chromatography using 5-60 % DCM in heptane to give 561 mg of N-[25-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1 1-diphenyl-methanimine as a yellow solid.
1H NMR (400 MHz, CDC13): 7.79-7.74 (m, 2H), 7.55-7.47 (m, 1H), 7.46-7.38 (m, 2H), 7.36-7.29 (m, 3H), 7.22-7.17(m, 2H), 6.99-6.94(m, 1H), 6.57-6.51 (m, IH), 1.34 (s, 12H) LOMS (short): RT: 1.78 mm [00107] Compounds of the Invention [00108] Example 1: 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]benzenesulfonamide
Y F N'N
HN
Step 1) A solution of N-[2-fluoro-3-(4,4,5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2. 2-dimethyl-propanamide (305 mg, 0.95 mmol), 4-bromo-5-iodo-2-isopropyl-triazole (250 mg, 0.79 mmol), potassium phosphate tribasic (504 mg, 2.37 mmol) and bis(triphenylphosphine) palladium (II) dichloride (28 mg, 0.04 mmol) in THF (21 mL) and Water (3 mL). The reaction mixture was stirred at 85 °C overnight. A further portion of N-[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2, 2-dimethyl-propanamide (128 mg, 0.4 mmol) and bis(triphenylphosphine)palladium(ll) dichloride (28 mg, 0.04 mmol) were added and stirred at 85 00 overnight. The reaction mixture was cooled to room temperature and water and DOM were added and the layers separated. The organic layer was dried over magnesium sulphate, filtered and concentrated to dryness. The crude product was purified by flash column chromatography using 0-22 % ethyl acetate in heptane, followed by preparative LCMS to give 75mg of a solid. The solid was shown to be about 60% N- [3-(5-bromo-2-isopropyl-triazol-4-yl)-2-fluoro-phenyl]-2, 2-dimethyl-propanamide by LCMS contaminated with N-[2-fluoro-3-(2-isopropyltriazol-4-yl)phenyl]-2,2-dimethyl-propanamide and used without further purification.
LCMS (short): RT: 1.81 mm, ES m/z 305.3 [M+Hf and 1.91 mm Est mlz 383.5, 385.5 [M+H]t Step 2) To a solution of N-13-(5-bromo-2-isopropyl-triazol-4-yl)-2-fluoro-phenyl]-2, 2-dimethyl-propanamide (150 mg, 0.39 mmol) in ethanol (10 mL) was added concentrated hydrochloric acid (3 mL) and the resulting mixture stirred at 85 °C for 2 days. The reaction was allowed to cool to room temperature and saturated sodium bicarbonate solution was added until gas evolution ceased. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water then brine, dried over anhydrous sodium sulphate, filtered and concentrated to dryness to give 133 mg of 3-(5-bromo-2-isopropyl-triazol-4-y[)-2-fluoro-aniline which was used without further purification.
1H NMR (400 MHz, CDC13): 7.06-6.99 (m, 1H), 6.97-6.91 (m, 1H), 6.91-6.84 (m, 1H), 4.48 (sep, 1H, J = 6.7), 3.85 (br s, 2H), 1.64 (d, 6H, J = 6.7) Step 3) To a solution of 3-(5-bromo-2-isopropyl-triazol-4-y-2-fluoro-aniline (140 mg, 0.47 mmol) and pyridine (0.06 mL, 0.7 mmol) at 0 °C was added dropwise 2,5-diflurobenzene sulfonyl chloride (149.25 mg, 0.7 mmol) and the resulting mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed and the residue dissolved in ethyl acetate, washed with water, brine, saturated sodium bicarbonate and 1 M HCI. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated to dryness. The residues were purified by flash column chromatography using 0-100 % ethyl acetate in heptane to give 181 mg of N-[3-(5-bromo-2-isopropyl-triazol-4-yl)-2-fluoro-phenyl]-2, 5-difluoro-benzenesulfonamide.
1H NMR (400 MHz, CDCI3): 7.68-7.64 (m, 1H), 7.61 -7.57 (m, 1H), 7.38-7.34 (m, 1H), 7.28-7.12 (m, 3H), 4.84 (sep, 1H, J = 6.7), 1.61 (d, 6H, J = 6.7).
LCMS (short): RT: 1.87 mm, ES m/z 475.0, 477.0 Step 4) A solution of N-[3-(5-bromo-2-isopropyl-triazol-4-y-2-fluoro-phenyl]-2, 5-difluoro-benzenesulfonamide (180 mg, 0.38 mmol), 1H-pyrazol-4-ylboronic acid (127 mg, 1.14 mmol), tricyclohexylphosphine (23.4 mg, 0.08 mmol), potassium phosphate tribasic (241 mg, 1.14 mmol) and palladium (II) acetate (8.5 mg, 0.04 mmol) in DMF (2 mL) and water (2 mL) was reacted in a microwave for 30 minutes at 130 °C. A further portion of 1 H-pyrazol-4-ylboronic acid (127 mg, 1.14 mmol) was added and the mixture heated at 130 00 for 30 minutes. Water and ethyl acetate were added and the layers separated. The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by preparative LCMS to give 11 mg of 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]benzenesulfonamide.
1H NMR (400 MHz, DMSO-d6): 13.03 (br s, I H), 10.77 (br s, I H), 7.70-7.0 (m, 8H), 4.84 (sep, 1 H, J 6.3), 1.53 (d, 6H, J = 6.7) LCMS (long): RT: 3.73 mm, ES m/z 463.2 [M+H] [00109] General Method 1 shown below was used in the preparation of Examples 2 to 12.
General Method I Boranuide I Boronic ester Pd2(dba)3, P(C6H11)3 N,, Pd(PPh3)2C12, K3P04 F N N K3P04 l''Br THF,H20 Jr Jr F N" N F 0 F3BK 0 F ° F KI-J1J? H Boranuide Boronic ester [00110] Example 2: 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]benzenesulfonamide.
Y
F NN
Step 1) A de-gassed solution of 4-bromo-5-iodo-2-isopropyl-triazole (1 g, 3.17 mmol), 2,6-difluoro-N-[2-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzene-sulfonamide (1.44 g, 3.48 mmol), potassium phosphate tribasic (2.02 g, 9.5 mmol) and bis(triphenylphosphine)palladiuml) dichloride (111 mg, 0.16 mmol) in THF (35 mL) and water (10 mL) was heated to 80 °C for 3 hours. The reaction mixture was allowed to cool and diluted with ethyl acetate, washed with water. The water was back extracted with ethyl acetate. The combined organics were dried over sodium sulphate, filtered, and concentrated to dryness.
The resulting residues were purified by flash column chromatography using 0-50% ethyl acetate in heptane to give 857 mg of N-[3-(5-bronio-2-isopropyl-triazol-4-yl)-2-fluoro-phenyl]-2, 6-difluoro-benzenesulfonamide as a cream solid.
1H NMR (400 MHz, CDCI3): 7.8-7.71 (m, IH), 7.57-7.46 (m, 1H), 7.58-7.3 (m, 1H), 7.24-7.16(m, 1H), 7.05-6.97 (m, 2H), 4.84 (sep, 1 H, J = 6.7), 1.61 (d, 6H, J = 6.7) LCMS (short): RT: 1.85 mm, ES m/z 475.1, 477.1 Step 2) A solution of N-[3-(5-bromo-2-isopropyl-triazol-4-y-2-fluoro-phenyl]-2, 6-difluoro-benzenesulfonamide (100 mg, 0.21 mmol), tris-(dibenzylideneacetone) dipalladium (0) (14.8 mg, 0.02 mmol), tricyclohexylphosphine (13 mg, 0.05 mmol), potassium phosphate tribasic (134 mg, 0.63 mmol) and potassium trifluoro(1H-pyrazol-3-yl)boranuide (110 mg, 0.63 mmol) in DMF (2 mL) and water (2 mL) was reacted in the microwave at 130 °C for 30 minutes. Water and DCM were added and the layers separated. The organic layer was washed with water, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness. The crude material was then re-reacted with tris-(dibenzylideneacetone) dipalladium (0) (15 mg, 0.02 mmol), tricyclohexylphosphine (13 mg, 0.05 mmol), potassium phosphate tribasic (134 mg, 0.63 mmol) and potassium trifluoro(1 H-pyrazol-3-yl)boranuide (110 mg, 0.63 mmol) in DMF (2 mL) and water (2 mL) for 30 mins at 130 °C. Water and DOM were added and the layers separated. The organic layer was washed with water, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness. The resulting residue was purified by preparative LCMS to give 14 mg of 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-3-yl)triazol-4-yl]phenyl]benzenesulfonamide.
1H NMR(400 MHz, DMSO-d6): 12.88(brs, 1H), 10.83(brs, 1H), 7.79-7.64(m, 2H), 7.39-7.13(m, 5H), 6.25 (s, 1H), 4.87 (sep, 1H, J = 7), 1.55 (d, 6H, J = 7) LCMS (long): RT: 3.63 mm, ESt m/z 463.3 [M+H] [00111] The compounds described below were similarly prepared by varying the Boronic ester or the Boranuide shown in General Method 1: [00112] Example 3: 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-3-yl)triazol-4-yl]phenyl]-benzenesulfonamide
F NN
1H NMR (400 MHz, DMSO-d6): 12.88 (brs, 1H), 10.83 (br s, 1H), 7.77-7.65 (m, 2H), 7.39 -7.13 (m, 5F-1), 6.25 (br s, 1H), 4.87 (sep, 1H, J = 6.6), 1.55 (d, 6H, J = 6.2) LCMS (long): RT: 3.63 mm, ESt m/z 463.3 [M+H] [00113] Example 4: 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(4-methylthiazol-5-yl) triazol-4-yl]phenyl]-benzenesulfonamide
F NN Ø4o F
F HN-j SNN 1H NMR (400 MHz, CD3OD): 8.89 (br s. IH), 7.67-7.57 (rn 2H), 7.28-7.18(m, 2H), 7.12-7.06 (m, 2H), 4.92 (sep, 1H, J = 6.7), 2.15 (s, 3H) 1.64 (d, 6H, J = 6.7) LOMS (long): RT: 4.03 mm, Est m/z 494.3 [M+H]* [00114] Example 5: 2,6-difluoro-N-[2-fluoro-3-(2-isopropyl-5-thiazol-5-yl-triazol-4-yl) phenylj-benzenesulfonamide
F NN Ø4o F
-F HN-] SN 1H NMR (400 MHz, ODd3): 8.74 (d, 1H, J = 0.6), 7.82-7.76 (m, 1H), 7.67 (s, 1H), 7.57-7.48 (m, 1H), 7.27-7.19 (m, 2H), 7.07 -7.00 (m, 2H), 4.89 (sep, 1H, J = 6.7), 1.67(d, 6H, J = 6.7) LOMS (long): RT: 3.99 mm, ESt m/z 480.2 [M+H]* [00115] Example 6: 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(2-methylpyrazol-3-yl) triazol-4-yl]phenyl]benzenesulfonamide
FN
1H NMR (400 MHz, CDCl3): 7.68-7.62 (m, IH), 7.48-7.39 (rn IH), 7.28 (d, IH, J = 2), 7.24-7.19 (m, 1H), 7.15-7.05 (m, 2H), 6.96-6.88 (m, 2H), 5.85 (d, 1H, J = 2), 4.83 (sep, 1H, J = 6.7), 3.84 (s, 3H), 1.58 (d. 6H, J = 6.7) LOMS (short): RT: 1.18 mm [00116] Example 7: N-L2-fluoro-3-L2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yljphenyl]propane-1 -sulfonamide
Y N'N
F
HN-%j c_N 1H NMR (400 MHz, DMSO-d6): 13.02 (hr s, 1H), 9.74 (hr s, 1H), 7.8-7.67 (m, 1H), 7.59-7.43 (m, 2H), 7.39-7.20 (m, 2H), 4.97 -4.76(m, 1H), 3.21 -3.O(2H, m), 1.81 -1.65(m, 2H), 1.62-1.49(m, 6H), 1.05 -0.8 (m, 3H) LCMS (long): RT: 3.41 mm, ESt m/z 393.3 [M+H] [00117] Example 8: N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-5-yl)triazol-4-yl]phenyl]propane-1 -sulfonamide
Y
NN
F
HN-%j (N 1H NMR (400 MHz, CDCI3): 7.63-7.58 (m, 1H), 7.48(d, 1H, J = 2.2), 7.32-7.27 (m, 1H), 7.18-7.13 (m, 1H), 6.5 (brs, IH), 6.3(d, IH, J = 6.7), 4.85 (sep, IH, J = 6.7), 3.04-2.98(m, 2H), 1.84-1.73 (m, 2H), 1.60 (d, 6H, J = 6.7), 0.96 (t, 3H, J = 7.4) LCMS (long): RT: 3.51 mm, ES m/z 393.2 [M+F-l] [00118] Example 9: N-[3-[2-tert-butyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-phenyl]-2, 5-difluoro-benzenesulfonamide * F N'N 1H NMR (400 MHz, CD3QD): 7.62-7.49 (m, 4H), 7.42-7.19 (m, 4H), 1.72 (s, 9H) LCMS (long): RT: 3.99 mi ES m/z 477.2 [M+F-l] [00119] Example 10: 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-5-yl)triazol-4-yl]phenyl]-benzenesulfonamide
Y
1F-I NMR (400 MHz, CD3QD): 7.59-7.53 (m, 2H), 7.53-7.48 (m, iF-I), 7.44 (d, 1H, J = 2.2), 7.26-7.21 (m, 1H), 7.18-7.13(m, IH), 7.13-7.03(m, 3H), 6.09(brs, 1H), 4.81 (sep, 1H, J = 6.7), 1.57(d, 6H, J = 6.7) LCMS (long): RT: 3.82 mm, ESt m/z 463.2 [M+H]* [00120] Example 11: 2,5-difluoro-N-12-fluoro-3-[2-methyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-benzenesulfonamide F N'N 1H NMR (400 MHz, CD3QD): 7.62-7.5 (m, 4H), 7.42-7.35 (m, 1H), 7.34-7.21 (m, 3H), 4.22 (s, 3H) LCMS (long): RT: 3.33 mm, ESt m/z 435.2 [M+H]t [00121] Example 12: N-[3-[5-(3,5-dimethyl-IH-pyrazol-4-yl)-2-isopropyl-triazol-4-yl] -2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide
Y
1H NMR (400 MHz, ODd3): 7.65-7.51 (m, 2H), 7.26-7.04 (m, 4H), 4.88 (sep, 1H, J = 6.8), 1.89 (s, 6H), 1.65(d, 6H,J= 6.6) LCMS (long): RI: 3.8 mi ESt mlz 491.3 [M-FH]t [00122] General Method 2 shown below was used in the preparation of Examples 13 to 25.
General Method 2 Boronic ester N'N Pd2(dba)2, Xphos F \L.2/ Suiphonyl chloride N' N Cs2PO4 \ / " pyridine _________ Br _________ THF, H20 H2N-(\ /1 DCM I Br N' N Boronic acid N' N \\ // Pd(dba)3, P(C6H11)3 o K3P04 N-i' HN-() DMFM2O N' HN-() N F o
HO B
HN__d flf8'.cl Boronic ester Sulphonyl chloride Boronic acid [00123] Example 13: N-[2-fluoro-3-[2-methyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]pyridine-3-sulfonamide N''N Step 1) A mixture of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yaniline (352 mg, 1.48 mmol), 4-bromo- 5-iodo-2-methyl-triazole (390 mg, 1.35 mmol), caesium carbonate (1324 mg, 4.06 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (65 mg, 0.14 mmol) and tris (dibenzylideneacetone)dipalladium(0) (50 mg, 0.07 mmol) in water (lOmL) and THE (10 mL) was degassed with nitrogen for 20 minutes and heated at 60°C for 18 hours. The reaction mixture was cooled, diluted with ethyl acetate (75 mL) and separated. The aqueous was back extracted with ethyl acetate (30 mL).
The combined organics were dried over sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 0-100 % ethyl acetate in heptane to give 197 mg of 3-(5-bromo-2-methyl-triazol-4-yl)-2-fluoro-aniline as a biege solid.
1H NMR (400 MHz CIJCI3): 7.07-7.01 (m, 1H), 6.96-6.86 (m, 2H), 4.27 (s, 3H), 3.86 (br 5, 2H) LCMS (short): RT: 1.85 mi ES m/z 271.0, 273.0 Step 2) To a solution of 3-(5-bromo-2-methyl-triazol-4-y-2-fluoro-aniline (100 mg, 0.37 mmol) and pyridine (0.04 mL, 0.55 mmol) in DCM (2 mL) was added dropwise pyridine-3-sulfonyl chloride (0.04 mL, 0.37 mmol). The reaction was stirred for 24 hours, diluted with DCM (20 mL), washed with saturated aqueous sodium bicarbonate (30 mL). The aqueous was back extracted with DCM (20 mL). The combined organics were washed with brine (10 mL) dried over sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 0-80 % ethyl acetate in heptane to give 140 mg of N-[3-(5-bromo-2-methyl-triazol-4-yl)-2-fluoro-phenyl] pyridine-3-sulfonamide as an off white solid.
1H NMR (400 MHz, CD3OD): 8.9 (d, 1H, J = 1.7), 8.74(dd, 1H, J = 1.6, 4.9), 8.19-8.16(m, 1H), 7.67- 7.63 (m, 1H), 7.59-7.56 (m, 1H), 7.4-7.36 (m, 1H), 7.31 -7.27 (m, 1H), 4.19 (s, 3H) LCMS (short): RT: 1.48 mm, ES m/z 412.0, 414.0 Step 3) A mixture of N-[3-(5-bromo-2-methyl-triazol-4-yl)-2-fluoro-phenyl] pyridine-3-sulfonamide (100 mg, 0.24 mmol), 1H-pyrazole-4-boronic acid (81.5 mg, 0.73 mmol), tricyclohexylphosphine (15 mg, 0.05 mmol), potassium phosphate (127 mg, 0.73 mmol) and palladium tris (dibenzylideneacetone) dipalladium (0)(22 mg, 0.02 mmol) in DMF (2 mL) and water (1 mL) were heated in the microwave at 100 °C for 1 hour then °C for 1 hour. The reaction was taken up in ethyl acetate (100 mL) and washed with water (2 x 25 mL) and brine (20m1). The aqueous extracts were back extracted with ethyl acetate (100 mL). The combined organics were dried over sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 0-10 % methanol in DCM to give 54 mg of N-[2-fluoro-3-[2-niethyl-5-( 1 H-pyrazol-4-yl)triazol-4-yl]phenyl]pyridine-3-sulfonamide as an off white solid.
1H NMR(400 MHz, CD3QD): 8.90(d, 1H, J = 1.8Hz), 8.73(dd, 1H, J =4.9, 1.6), 8.16-8.13(m, 1H), 7.65 -7.45 (m, 4H), 7.34-7.25 (m, 2H), 4.21 (s, 3H) LOMS (long): RT: 2.80 mm, ESt m/z 400.2 [M+H]* [00124] The compounds described below were similarly prepared by varying the Boronic ester, Sulphonyl chloride or Boronic acid shown in General Method 2: [00125] Example 14: 2,5-difluoro-N-12-fluoro-3-[2-isopropyl-5-(3-methyl-1 H-pyrazol-4-yl)triazol-4-yljphenyl]benzenesulfonamide
Y
1H NMR (400 MHz, 7.56-7.44 (m, 2H), 7.2 -7.0(m, 5H), 4.78 (sep, 1H, J = 6.7), 2.11 (s, 3H), 1.56 (d.
6H, J = 6.7) LOMS (long): RT: 3.85 mi ES m/z 477.3 [M+H] [00126] Example 15: 3,5-difluoro-N-12-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yI)triazol-4-yI]phenyl]benzenesulfonamide
Y
F NN
1H NMR (400 MHz, CD3QD): 7.68-7.45 (m, 3H), 7.41 -7.35 (m, 2H), 7.35-7.21 (m, 3H), 4.85 (sep, 1H, J = 6.7), 1.61 (d, 6H, J = 6.7) LCMS (long): RT: 3.84 mm, ESt m/z 463.3 [M+H] [00127] Example 16: N-[3-[2-tert-butyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-phenyl]-3, 5-difluoro-benzenesulfonamide * F N''N 1H NMR (400 MHz, CD3OD): 7.65-7.48 (m, 3H), 7.41 -7.35 (m, 2H), 7.34-7.22 (m, 3H), 1.72 (s, 9H) LCMS (long): RT: 4.11 mm, ESt m/z477.3 [M+H] [00128] Example 17: N-[2-fluoro-3-[2-isopropyl-5-(3-methyl-1 H-pyrazol-4-yl)triazol-4-yl] phenyl] pyrid i ne-3-su Ifonam ide 1H NMR (400 MHz, CD013): 8.79 (d, 1H, J = 1.9), 8.72 (dd, 1H, J 4.9, 1.6), 7.96-7.91 (m, 1H), 7.66- 7.58(m, IH), 7.34-7.23(m, 2H), 7.16-7.1 (m, 1H), 4.78 (sep, IH, J = 6.7), 2.05 (s, 3H), 1.56(d, 6H, J = 6.7) LCMS (short): RT: 1.46 mm, ES m/z 442.2 [M+Hf [00129] Example 18: 2,6-difluoro-N-12-fluoro-3-[2-isopropyl-5-(3-methyl-1 H-pyrazol-4-yI)triazol-4-yI]phenyl]benzenesulfonamide
Y
F NN
HNN
1H NMR (400 MHz, CDCI3): 7.64-7.57 (m, 1H), 7.46-7.36 (m, 1H), 7.22 (s, 1H), 7.17-7.11 (m, 1 H), 7.09-7.02 (m, 1H), 6.95-6.87 (m, 2H), 4.79 (sep, 1H, J = 6.7), 2.11 (s, 3H), 1.56 (d, 6H, J = 6.7) LCMS (long): RT: 3.72 mm, ESt m/z 477.3 [M+H] [00130] Example 19: N-[3-[2-tert-butyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-phenyl]pyridine-3-sulfonamide *
NN
1H NMR(400 MHz, CD3OD): 8.91 (d, 1H, J = 1.7), 8.73(dd, 1H,J =4.9, 1.6), 8.17-8.13(m, 1H), 7.63- 7.58 (m, IH), 7.57-7.46 (m, 3H), 7.34-7.25 (m, 2H), 1.71 (s, 9H) LOMS (long): RT: 3.53 mm, ES m/z 442.3 [M+H] [00131] Example 20: N-[3-[2-tert-butyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-phenyl]-3-fluoro-benzenesulfonamide 1H NMR (400 MHz, CD3OD): 7.63-7.46 (m, 6H), 7.39-7.32 (m, 1H), 7.31 -7.21 (m, 1H), 7.30-7.21 (m, 1H), 1.71 (s, 9H) LOMS (long): RT: 4.02 mm, ESt m/z 459.3 [M+H]* [00132] Example 21: N-[3-[2-tert-butyl-5-(1 H-pyrazol-4-yI)triazol-4-yI]-2-fluoro-phenyl]-2, 4-difluoro-benzenesulfonamide *
F NN
FONH
1H NMR (400 MHz, CD3QD): 7.90-7.81 (m, 1H), 7.60-7.50 (rn 3H), 7.31 -7.21 (m, 2H), 7.21 -7.13 (rn, S 1H), 7.10-7.03 (m, 1H), 1.72 (s, 9H) LOMS (long): RI: 4.02 mm, ESt m/z 477.3 [M+H]* [00133] Example 22: 2,5-difluoro-N-[5-L2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-ylJ-3-pyridyl]benzenesulfonamide
Y F N'N
1H NMR (400 MHz, DMSO-d6): 13.15 (brs, 1H), 11.20 (brs, 1H), 8.47(d, 1H, J = 1.8), 8.35 (d, 1H, J = 2.5), 7.89 (br s, 1H), 7.72-7.71 (m, 1H), 7.68-7.49 (rn, 4H), 4.86 (sep, 1 H, J = 6.6), 1.54 (d, 6H, J = 6.6) LOMS (long): RT: 3.32 mm, Est m/z 446.3 [M+H]* [00134] Example 23: N-L2-fluoro-3-L2-isopropyl-5-(1 -methylpyrazol-4-yl)triazol-4-yljphenyl]pyridine- 3-sulfonamide
Y
NN
1H NMR (400 MHz, CDCI3): 9.03 (d, 1H, J = 2), 8.81 (dd, 1H, J = 4.8, 1.5), 8.09-8.05 (m, 1H), 7.72-7.66 (m, 1H), 7.48-7.41 (m, 2H), 7.37 (br s, 1H), 7.33-7.29 (m, 1H), 7.26-7.20 (m, 1H), 4.84 (sep, 1H, J = 6.7), 3.91 (s, 3H), 1.62 (d, 6H, J = 6.7) LCMS (long): RT: 3.43 mm, ESt m/z 442.2 [M+H]t [00135] Example 24: 2,5-difluoro-N-12-fluoro-3-[2-isopropyl-5-(1 -methylpyrazol-4-yI)triazol-4-yI]phenyl]benzenesulfonamide
F »=QJF
-F HN-(j 1F-I NMR (400 MHz, CDCI3): 7.54-7.49 (m, 2H), 7.39 (s, 1H), 7.28 (s, 1H), 7.18-7.06 (m, 4H), 7.04 (br s, 1H), 4.75 (sep, 1H, sept, J = 6.7), 3.83 (s, 3H), 1.54 (d, 6H, J = 6.7) LCMS (long): RT: 3.98 mm, ESt m/z 477.2 [M+H] [00136] Example 25: 2,6-difluoro-N-12-fluoro-3-[2-isopropyl-5-(1 -methylpyrazol-4-yl)triazol-4-yl]phenyl]benzenesulfonamide
Y
F
-F HN-<j 1F-l NMR (400 MHz, CDCI3): 7.64-7.58 (m, 1H), 7.48-7.39 (m, 2H), 7.31 (br s, 1H), 7.26-7.21 (m, 1H), 7.19-7.14(m, 1H), 7.15-7.06(m, 1H), 6.97-6.90(m, 2H), 4.76 (sep, 1H, J = 6.7), 3.82(s, 3H), 1.54(d, 6H, J = 6.7) LCMS (long): RT: 3.85 mm, ES m/z 477.2 [M+H] [00137] General Method 3 shown below was used in the preparation of Examples 26 to 35.
General Method 3 Boronic ester I N N Boronic ester 2 Pd2(dba)2, Xphos F Pd2(dba)3, P(C6H11)3 N' N Cs2CO3 \ / " K3F04 _________ Br _________ THF, H20 H2N / 1,4-dioxane, H20 I Br microwave 1. Sulphonyl chloride N' N pyridine, DMAP N F DCM N''N H2N-Q (\ 2. TFA DCM F B-° -1⁄2--°. /N "P HN -4?$ fB-% soc <T_stI Boronic ester I Boronic ester 2 Sulphonyl chloride [00138] Example 26: N-[2-fluoro-3-[2-isopropyl-5-(I H-pyrazol-4-yl)triazol-4-yl]phenyl]thiophene-3-sulfonamide Step 1) 4-bromo-5-iodo-2-isopropyl-triazole (5.13 g, 16.25 mmol), 2-fluoro-3-(4,4,5,5-tetramethyl-1 3,2- dioxaborolan-2-yl)anhline (3.83 g, 16.17 mmol), caesium carbonate (15.81 g, 48.52 mmol) and 2-dicyclohexylphosphino-2',4',6'-trUsopropylbiphenyl (0.77 g, 1.62 mmol) were dissolved in THF (100 mL) and water (100 niL) under nitrogen. The mixture was degassed with nitrogen for 15 minutes, then tris- (dibenzylideneacetone)dipalladium (0) (0.74 g, 0.81 mmol) was added. The reaction mixture was then heated to 60 °C and stirred for 2.5 hours. The reaction was cooled and diluted with ethyl acetate. The organics were collected and the aqueous layer extracted with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate solution, brine, dried with sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 0- % ethyl acetate in heptane to give 3.1 g of 3-(5-bromo-2-isopropyl-triazol-4-yl)-2-fluoro-aniline as a yellow oil.
LCMS (short): RT: 1.73 mm, ES m/z 299.1, 301.1 Step 2) To a microwave vial were added 3-(5-bromo-2-isopropyl-triazol-4-yl)-2-fluoro-aniline (2.46 g, 8.21 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (2.42 g, 8.21 mmol), tricyclohexylphosphine (324 mg, 1.16 mmol) and potassium phosphate tribasic (5228 mg, 24.63 mmol), water (2 mL) and 1,4-dioxane (8 mL). The vial was sealed and degassed with nitrogen for 10 minutes.
Tris(dibenzylideneacetone)dipalladium(O) (526 mg, 0.57 mmol) was added and the vial was degassed for a furtherS minutes. The reaction mixture was heated at 130 °C for 1 hour in a microwave. The reaction mixture was diluted with ethyl acetate and washed with water (50 mL). The aqueous layer was back extracted with ethyl acetate. The combined organics were washed with brine (50 mL) dried over sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 0-100% ethyl acetate in heptane to give 1.31 g of 2-fluoro-3-[2-isopropyl-5-(IH- pyrazol-4-yl)triazol-4-yl]aniline as a cream solid and 0.84 g of tert-butyl 4-[5-(3-amino-2-fluoro-phenyl)-2-isopropyl-triazol-4-yl]pyrazole-1 -carboxylate as a yellow oil.
2-Fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]aniline 1H NMR (400 MHz, CDCI3): 7.65 (s, 2H), 6.95-6.88(m, 1H), 6.79-6.71 (m, 2H), 4.80 (sep, 1H, J = 6.7) tert-Butyl 4-[5-(3-amino-2-fluoro-phenyl)-2-isopropyl-triazol-4-yl] pyrazole-1-carboxylate 1H NMR (400 MHz, CD013): 8.12 (s, IH), 7.76 (s, IH), 6.97-6.90 (m, 1H), 6.82-6.70 (m, 2H), 4.81 (sep, 1H, J = 6.7), 3.73 (s, 2H), 1.59-.65(ni, 15H) Step 3) Tert-butyl 4-[5-(3-amino-2-fluoro-pheny-2-isopropyl-triazol-4-yl]pyrazole-1 -carboxylate (100 mg, 0.26 mmol) was dissolved in DCM (3 mL). To this was added 3(chlorosulphonyl)-thiophene (57 mg, 0.31 mmol), pyridine (35.58 pL 0.44 mmol) and 4-dimethylamino pyridine (6 mg, 0.05 mmol). The reaction mixture was left to stir for 2 hours after this time a further portion of 3-(chlorosulphonythiophene (24 mg, 0.13 mmol) and stirred for a further 22 hours. The reaction was diluted with saturated sodium bicarbonate solution (3 mL) and the organic phase isolated using a hydrophobic tnt and concentrated to dryness. The resulting residues were purified by flash column chromatography using 20 -100 % ethyl acetate in heptane to give 87 mg of tert-butyl 4-[5-[2-fluoro-3-(3-thienylsu lfonylamino)phenyl]-2-isopropyl-triazol-4-yl]pyrazole-1 -carboxylate.
1H NMR (400 MHz, DMSO-d6): 10.28 (br s, 1H), 8.13-8.10 (m, 1H), 8.02 (s, 1H), 7.79 (s, 1 H), 7.72-7.69 (m, WI), 7.41 -7.24 (m, 4H), 4.89 (sep, 1H, J = 6.7), 1.58-1.53 (m, 15H) LCMS (short): RT: 1.92 mi ES m/z 531.2 [M-H] Step 4) Tert-butyl 4-[5-[2-fluoro-3-(3-thienylsulfonylamino)phenyl]-2-isopropyl-triazol-4-yl] pyrazole-1 -carboxylate (87 mg, 0.16 mmol) was dissolved in DCM (2 mL) to this was added trifluoroacetic acid (0.38 mL, 4.9 mmol) and stired for 1 hour. To the reaction mixture was added saturated sodium bicarbonate solution (3 mL). The organics were separated on a hydrophobic frit and concentrated to dryness. The resulting residues were purified by preparative LCMS to give 28 mg of N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]thiophene-3-sulfonamide as a white solid.
1H NMR (400 MHz, DMSO-d6): 13.00 (br s, 1H), 10.26 (br s, 1H), 8.15-8.11 (m, 1H), 7.73 (dd, 1H, J = 5.0, 3.0), 7.57 (brs, 1H), 7.45 (brs, 1H), 7.42-7.36(m, 1H), 7.30-7.20 (m, 3H), 4.84 (sep, 1H, J = 6.6), 1.54(d, 6H,J= 6.6) LCMS (long): RT: 3.54 mm, ES m/z 433.2 [M+H] [00139] The compounds described below were similarly prepared by varying the Boronic ester 1, Boronic ester 2 or Sulphonyl chloride shown in General Method 3: [00140] Example 27: N-[2-Fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]thiophene-2-sulfonamide 1H NMR (400 MHz, DMSO-d): 13.00 (brs, 1H), 10.47 (br s, 1H), 7.96-7.85 (m, 1H), 7.61 -7.37 (m, 4H), 7.30-7.19(m, 2H), 7.15-7.10(m, 1H), 4.84 (sep, 1H, J = 6.7), 1.54(d, 6H, J = 6.6) LCMS (long): RT: 3.58 mi ES m/z 433.2 [M+H]4 [00141] Example 28: N-[2-Fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-3,5-dimethyl-isoxazole-4-sulfonamide
Y
N N 4HNNH
1H NMR (400 MHz, DMSOd6): 13.04 (br s, 1H), 10.52 (br s, 1H), 7.69-7.58 (m, 1H), 7.50 -7.22 (m, 4H), 4.85 (sep, 1H, J = 6.5), 2.37 (s, 3H), 2.21 (s, 3H), 1.54 (d, 6H, J = 6.6) LCMS (long): RT: 3.58 mm, ESt m/z 446.3 [M+H]* [00142] Example 29: N-[2-Fluoro-3-L2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yljphenyljpyridine-3-sulfonamide
NN
Q-HN11N 1H NMR (400 MHz, DMSO-d6): 13.02 (br s, IH), 10.59 (br s, IH), 8.88(d, IH, J = 2.3), 8.82-8.78(m, 1H), 8.14-8.08(m, iF-I), 7.64 -7.56(m, 2H), 7.42-7.20 (m, 4F-l), 4.83 (sep, iF-I, J = 6.7), 1.53 (d, 6H, J = 6.6) LCMS (long): RT: 3.24 mm, ESt m/z 428.3 [M+H]* [00143] Example 30: N-[2-Fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-1 -methyl-pyrazole-4-sulfonamide
Y N'N
N)HN_tTTNH 1H NMR(400 MHz, DMSO-d6): 13.02 (brs, 1H), 10.11 (brs, 1H), 8.20 (s, 1H), 7.71-7.66(m, 2H), 7.45- 7.37 (m, 2H), 7.30-7.20 (m, 2H), 4.85 (sep, 1H, J = 6.6), 3.84 (s, 3H), 1.54 (d, 6H, J = 6.6) LCMS (long): RT: 3.17 mm, ESt m/z431.3 [M+H]t [00144] Example 31: 6-Chloro-N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl] phenyl] pyrid i ne-3-su Ifonam ide
Y
NN
cH_?)_o)(\ 1H NMR (400 MHz, DMSO-d6): 13.04 (brs, 1H), 10.68 (br s, 1H), 8.73-8.69 (m, 1H), 8.14 -8.10 (m, 1H), 7.75-7.65 (m, 2H), 7.43-7.22 (m, 4H), 4.84 (sep, IH, J = 6.9), 1.53 (d, 6H, J = 6.6) LCMS (long): RT: 1.58 ml ES m/z 462.2, 464.2 [M+Hf [00145] Example 31: N-[2-Fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-2,3-dimethyl-imidazole-4-sulfonamide
Y N'N
__o F-N HN-<\] N' 1H NMR (400 MHz, DMSO-d6): 7.76-7.35(m, 3H), 7.30-7.15(m, 3H), 4.84 (sep, IH, J = 6.6), 3.65 (s, 31-1), 2.31 (s, 31-]), 1.53 (d, 61-1, J = 6.7) LCMS (long): RT: 1.24 mm, ESt m/z 445.3 [M+H]* [00146] Example 32: N-[2-Fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-6-methoxy-pyridine-3-sulfonamide KD HN_d<tTN H 1H NMR (400 MHz, DMSO-d6): 13.03 (br s, 1H), 10.39 (br s, 1H), 8.48 (d, 1H, J = 2.5), 7.97 (dd, 1H, J = 8.8, 2.6), 7.67 (br s, 1H), 7.42-7.33 (m, 2H), 7.30-7.18 (m, 2H), 6.96(d, 1H, J = 6.6), 3.90 (s, 3H), 1.53 (d, 6H, J = 6.7) LCMS (long): RT: 3.61 mm, ESt m/z 458.3 [M+H]* [00147] Example 33: N-[2-Fluoro-3-L2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yljphenylj-2-methyl-pyrazole-3-sulfonamide
Y
N_N N
N F-
N HN-%j N H NMR (400 MHz, DMScJ-d6): 13.02 (br s, I H), 10.85 (br s, I H), 7.58 (br s, 1 H), 7.51 -7.42 (m, 2H), 7.41 -7.36 (m, 1H), 7.35-7.21 (m, 2H), 6.65 (d, 1H, J = 1.8), 4.85 (sep, 1H, J = 6.6), 3.99 (s, 3H), 1.54 (d, 6H, J = 6.7) LCMS (long): RT: 3.39 mm, ESt m/z 431.3 [M+H]* [00148] Example 34: N-[2-Fluoro-3-L2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yljphenylj-1 -methyl-imidazole-2-sulfonamide
Y N'N
CN F7-N HN-(xj N 1H NMR (400 MHz, DMSO-d6): 13.02 (br s, IH), 10.77 (br s, IH), 7.57 (br s, 2H), 7.51 -7.40 (m, 2H), 7.34 -7.20 (m, 2H), 7.05 (s, 1 H), 4.85 (hep, 1H, J = 6.7), 3.82 (s, 3H), 1.54 (d, 6H, J = 6.6) LCMS (long): RT: 3.06 mm, ESt m/z 431.3 [M+H]* [00149] Example 35: N-[2-Fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-2,4-dimethyl-thiazole-5-sulfonamide
Y N'N *o F
S HN-(\] LN 1H NMR (400 MHz, DMSO-d6): 13.03 (br s, 1H), 10.62 (br s, 1H), 7.68 (br s, 1H), 7.47-7.21 (m, 4H), 4.85 (sop, 1H, J = 6.7), 2.57 (s, 3H), 2.35 (s, 3H), 1.54 (d, 6H, J = 6.6) LCMS (long): RT: 3.48 mm, ESt m/z 462.3 [M+H]t [00150] Example 36: N-[2,5-difluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-2,5-difluoro-benzenesulfonamide.
F
Step 1) To a solution of 4-bromo-5-iodo-2-isopropyl-triazole (250 mg, 0.79 mmol), N-[2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1 1-diphenyl-methanimine (400 mg, 0.95 mmol), tris(dibenzylideneacetone) dipalladium (0) (36 mg, 0.04 mmol) and 2-dicyclohexylphosphino-2',4'6'-triisopropylbiphenyl (38 mg, 0.08 mmol) in dioxane (5 mL) was added caesium carbonate (773 mg, 2.37 mmol) in water (5 mL). The mixture was degassed under vacuum and placed under nitrogen and heated to 60 °C for 12 hours. The reaction mixture was allowed to cool to room temperature and tetrakis(triphenylphosphine)-palladium(0) (91 mg, 0.08 mmol) added and heated for a further 1 hour at 80 °0. The reaction mixture was concentrated to dryness and the aqueous suspension diluted with DOM. The mixture was passed through a hydrophobic frit and the organic phase concentrated to dryness. The resulting residues were purified by flash column chromatography to give 150 mg of a mixture of N-[25- difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1, 1-diphenyl-methanimine and N-[3-(5-bromo-2-isopropyl-triazol-4-yl)-2,5-difluoro-phenyl]-1 1-diphenyl-methanimine which was used without further purification.
LCMS (short): RT: 2.33 mm, ES m/z 481.3, 483.2 [M+H] Step 2) To a solution of N-[2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1, 1-diphenyl-methanimine and N-[3-(5-bromo-2-isopropyl-triazol-4-yl)-2,5-difluoro-phenyl]-1, 1-diphenyl-methanimine (150 mg) in THF (2 mL) and water (2 mL) was added 1 M HCl (2 mL) and the reaction mixture left to stir for 48 hours. The organics were removed and the resulting aqueous residues diluted with DCM (10 mL). The biphasic system was passed through a hydrophobic frit and the organics concentrated to dryness to give 138mg of an oil which was used without further purification.
Step 3) To a solution of the oil obtained above in DCM (1 mL) was added 2,5-diflurobenzene sulfonyl chloride (0.06 mL, 0.44 mmol), 4-dimethylamino pyridine (5 mg, 0.04 mmol) and pyridine (0.05 mL, 0.65 mniol) and left to stir at room temperature for 12 hours. The reaction mixture was diluted with DOM (5 mL) and shaken with saturated aqueous ammonium chloride solution (5 mL). The biphasic mixture was passed through a hydrophobic frit and the organic layer concentrated to dryness. The resulting residues were purified by flash column chromatography to give 108 mg of N-[3-(5-bromo-2-isopropyl-triazol-4-yl)-2,5-difluoro-phenyl]- 2,5-difluoro-benzenesulfonamide as a gum.
LCMS (short): RT: 2.13 mi ES m/z491.0, 493.0 [MH]* Step 4) To a solution of N-[3-(5-bromo-2-isopropyl-triazol-4-yl)-2,5-difluoro-phenyl]-2, 5-difluoro-benzenesulfonamide (108 mg, 0.21 mmol), 1H-pyrazole-4-boronic acid (37 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) and dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol) in dioxane (2 mL) was added caesium carbonate (143 mg, 0.44 mmol) in water (1 mL). The resulting reaction mixture was degassed under vacuum and placed under nitrogen and heated in a microwave at 140 00 for 1 hour. The reaction mixture was concentrated to dryness and DCM and water were added. The biphasic mixture was passed through a hydrophobic frit and the organics concentrated to dryness. The resulting residues were purified by flash column chromatography to give 10 mg of N-[2,5-difluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-2,5-difluoro-benzenesulfonamide as a colourless solid.
1H NMR (400 MHz, DMSO-d6): 13.07 (br s, 1H), 11.08 (br s, 1H), 7.78-7.35 (m, 5H), 7.34-7.17 (m, 2H), 4.85 (sep, IH, J = 6.7), 1.53 (d, 6H, J = 6.6) LOMS (long): RT: 3.96 mi ES m/z 481.3 [M+H] [00151] Example 37: 2,5-difluoro-N-12-fluoro-3-[2-isopropyl-5-(3-methoxy-1 H-pyrazol-4-yI)triazol-4-yI]phenyl]benzenesulfonamide.
Y
F NN
Step 1) N-[3-(5-brorno-2-isopropyl-triazol-4-yl)-2-fluoro-phenyl] -25-difluoro-benzenesulfonamide (123 mg, 0.26 mmol) was added to a solution of 1-benzyl-3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (140 mg, 0.45 mmol), tricyclohexylphosphine (14.52 mg, 0.05 mmol), potassium phosphate tribasic (165 mg, 0.78 mmol) and, tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.03 mmol) in DMF (2 mL) and water (1 mL). The solution was degassed with nitrogen for 5 minutes and then heated in a microwave at 130 °C for 1.5 hours. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The organics were washed with brine (3 x 30 mL) and concentrated to dryness. The resulting residues were purified by flash column chromatography to give 111 mg of N-[3-[5-(1-benzyl-3-methoxy-pyrazol-4-yl)-2-isopropyl-triazol-4-yl] -2-fluoro-phenyl]-2, 5-difluoro-benzenesulfonamide as a colourless solid.
LCMS (short): RT: 1.92 mi ES m/z 583.2 [M-H] Step 2) N-[3-[5-(1 -benzyl-3-methoxy-pyrazol-4-yl)-2-isopropyl-triazol-4-yl]-2-fluoro-phenyl] -2,5-difluoro-benzenesulfonamide (105 mg, 0.18 mmol) was dissolved in methanol (20 mL) and hydrogenated using a H-cube using a 10% Pd/C cartridge at 40°C and 20 bar pressure overnight under recycling conditions. The solvent was evaporated and the resulting residues purified by flash column chromatography using 40 -100 % ethyl acetate in heptane to give 58mg of 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(3-methoxy-1H-pyrazol-4-yl) triazol-4-yl]phenyl]benzenesulfonamide as a colourless solid.
1H NMR (400 MHz, DMSO-d6): 12.10 (br s, 1 H), 10.70 (br s, 1 H), 7.64-7.56 (m, 1H), 7.55-7.46 (m, 3H), 7.33-7.27 (m, 1H), 7.27 -7.20 (m, 1H), 7.20-7.13 (m, 1H), 4.83 (sep, 1H, J = 6.7), 3.52 (s, 3H), 1.52 (d, 6H, J = 6.6) LCMS (long): RT: 3.76 mm, ESt m/z 493.3 [M+H]* [00152] General Method 4 shown below was used in the preparation of Examples 38 to 42.
General Method 4 Boronic ester 1 N'N I Pd2(dba)2, Xphos F Sulphonyl chloride N'N 062003 \ / \ pyridine l''Br THF, H20 H2N__Q Br DCM 1.Boronicester2 N N Pd(dba) KPO N N 2. __ F B-° HN scl \oN_MPM Boronic ester I Sulphonyl chloride Boronic ester 2 [00153] Example 38: N-[2-fluoro-3-[5-(3-methoxy-1 H-pyrazol-4-yl)-2-methyl-triazol-4-yl]phenyl]pyridine-3-sulfonamide N'N Step 1) A mixture of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yaniline (352 mg, 1.48 mmol), 4-bromo- 5-iodo-2-methyl-triazole (390 mg, 1.35 mmol), caesium carbonate (1324 mg, 4.06 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (65 mg, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.07 mmol) in water (10 mL) and THF (10 mL) was degassed with nitrogen for 20 minutes and heated at 60 °C for 18 hours. The reaction mixture was cooled diluted with ethyl acetate (75 mL) and the organics separated. The aqueous layer was back extracted with ethyl acetate (30 mL). The combined organics dried over sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 0-100% ethyl acetate in heptane to give 197 mg of 3-(5-bromo-2-methyl-triazol-4-yl)-2-fluoro-aniline as a beige solid.
1H NMR (400 MHz, CtJCl3): 7.07 -7.01 (m, 1 H), 6.96-6.85 (m, 2H), 4.26 (s, 3H), 3.86 (br s, 2H) LOMS (short): RT: 1.46 mm, ES m/z 271.0, 273.0 [M+H]t Step 2) To a solution of 3-(5-bromo-2-methyl-triazol-4-y-2-fluoro-aniline (97 mg, 0.36 mmol) and pyridine (0.04 mL, 0.54 mmol) in DCM (2.5 mL) was added dropwise pyridine-3-sulfonyl chloride (0.04 mL, 0.34 mmol).
The reaction was stirred for 24 hours, diluted with DCM (20 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL). The organics were separated and the aqueous back extracted with DCM (20 mL). The combined organics were dried over sodium sulphate, filtered and concentrated to dryness. The resulting residue was purified by flash column chromatography using 0-100 % ethyl acetate to give 138 mg of N-[3-(5-bromo-2-methyl-triazol-4-yl)-2-fluoro-phenyl] pyridine-3-sulfonamide as an off white solid.
1H NMR (400 MHz, CD3QD): 8.9 (dd, 1H, J = 2.3, 0.7), 8.74 (dd, 1H, J = 4.9, 1.6), 8.20-8.16(m, IH), 7.68 -7.62 (m, iF-I), 7.6-7.55 (m, 1H), 7.40-7.35(m, 1H), 7.31 -7.26 (m, iF-I), 4.20 (s, 3F-I) LCMS (short): RT: 1.48 mi ES m/z 412.0, 414.0 [M+H]t Step 3) A mixture of N-[3-(5-bromo-2-methyl-triazol-4-yl)-2-fluoro-phenyl] pyridine-3-sulfonamide (70 mg, 0.17 mmol), 3-methoxy-1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyrazole (88 mg, 0.25 mmol) and potassium phosphate tribasic (72 mg, 0.34 mmol) in DMF (4 mL) and water (0.75 mL) was degassed with nitrogen for 10 minutes. Bis(triphenylphosphine)palladium(ll) dichloride (11 mg, 0.02 mmol) was added and the reaction mixture heated at 100 °C for 18 hours. The reaction mixture was cooled transferred to a microwave vial and 3-methoxy-1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazole (88 mg, 0.2SOOmmol), water (0.5 mL), Tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.02 mmol), tricyclohexylphosphine (10 mg, 0.03 mmol) were added, degassed with nitrogen and heated in a microwave at 130 °Cfor 1 hour. The reaction mixture was partitioned between ethyl acetate (l2OmL) and water (20 mL). The organics were washed with water (30 mL), brine (30 mL), dried over sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 0-100 % ethyl acetate in heptane to give 81 mg of N-[2-fluoro-3-[5-[3-methoxy-1 -[(4-methoxyphenyl)methyl]pyrazol-4-yl]-2-methyl-triazol-4-yl]phenyl] pyridine-3-sulfonamide as a pale yellow gummy solid.
1H NMR (400 MHz, CD3QD): 8.88 (d, 1H, J = 1.8), 8.70 (dd, 1H, J = 4.9, 1.5), 8.13-8.08 (m, 1H), 7.70- 7.63 (m, 2H), 7.61 -7.55 (m, 1H), 7.40 (s, iF-I), 7.26-7.14 (m, 4H), 6.95-6.89 (m, iF-I), 5.07 (s, 2H), 4.18 (s, 3H), 3.81 (s, 3H), 3.62 (a, 3H) LCMS (short): RT: 1.61 mm, ES m/z 550.2 [M+Hf Step 4) A solution of N-[2-fluoro-3-[5-[3-methoxy-1 -[(4-methoxyphenyl)methyl]pyrazol-4-yl]-2-methyl-triazol-4-yl]phenyl] pyridine-3-sulfonamide (80 mg, 0.15 mmol) in trifluoroacetic acid (3.5 mL was heated at 100 °C in a microwave for 1 hour. The reaction mixture transferred to a round bottom flask and heated at 100 00 for 42 hours. The reaction mixture was cooled, concentrated to dryness and partitioned between ethyl acetate (75 mL) and saturated sodium bicarbonate solution (30 mL). The organic was washed with brine (30 mL), dried over sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using U -10 % methanol in DCM to give 39 mg N-[2-fluoro-3-[5-(3-methoxy- 1 H-pyrazol-4-yl)-2-methyl-triazol-4-yl]phenyl]pyridine-3-sulfonamide as an off white solid.
1H NMR (400 MHz, CD3QD): 8.78(d, 1H, J = 2.3), 8.61 (dd, IH, J = 4.9, 1.6), 8.06-8.01 (m, IH), 7.48- 7.40 (m, 2H), 7.3 (s, 1H), 7.18 -7.07 (m, 2H), 4.08 (s, 3H), 3.51 (s, 3H) LCMS (long): RT: 2.84 mm, ESt mlz 430.2 [M+H]* [00154] The compounds described below were similarly prepared by varying the Boronic ester 1, Sulphonyl chloride or Boronic ester 2 shown in General Method 4: (00155] Example 39: 2,5-difluoro-N-12-fluoro-3-[5-(3-methoxy-IH-pyrazol-4-yl) -2-methyl-triazol-4-yljphenyl]benzenesulfonamide
F NN
1H NMR (400 MHz, CD3QD): 7.43-7.34 (m, 2H), 7.32 (s, IH), 7.30-7.22 (m, 1H), 7.21 -7.09 (m, 2H), 7.08-7.01 (m, 1H), 4.08 (s, 3H), 3.51 (s, 3H) LOMS (long): RT: 3.37 mm, ESt m/z 465.2 [M+H]* [00156] Example 40: 3,5-difluoro-N-[2-fluoro-3-L2-isopropyl-5-[3-methoxy-1 H-pyrazol-4-yl]triazol-4-yl]phenyl]benzenesulfonamide
Y
F NN
1H NMR (400 MHz, CD3OD): 7.55-7.49 (m, 2H), 7.42-7.35 (m, 2H), 7.29-7.16 (m, 3H), 4.86 (sep, 1H, J = 6.7), 3.6 (s, 3H), 1.6 (d, 6H, J = 6.7) LOMS (long): RT: 3.88 mm, Est mu 493.3 [M+H]* [00157] Example 41: N-[3-[2-tert-butyl-5-(3-methoxy-1 H-pyrazol-4-yl)triazol -4-ylJ-2-fluoro-phenyljpyridmne-3-sulfonamide *
NN Q2Jd
1H NMR (400 MHz, CD3OD): 8.90 (d, 1H, J = 1.8), 8.72 (dd, 1H, J = 4.9, 1.5), 8.17-8.12 (m, 1H), 7.58- 7.51 (m, 2H), 7.50 (a, 1H), 7.29-7.24 (m,1H), 7.22-7.16 (m, 1H), 3.57 (a, 3H), 1.70 (s, 9H) LCMS (long): RT: 3.57 mm, ESt m/z 472.3 [M+H] [00158] Example 42: N-[2-fluoro-3-[2-isopropyl-5-(3-methoxy-1 H-pyrazol-4-yl)triazol-4-yl]phenyl]pyridine-3-sulfonamide
Y
NN
1F-l NMR (400 MHz, CD3QD): 8.9 (d, 1H, J = 1.9), 8.72 (dd, 1H, J = 4.9, 1.5), 8.18-8.12 (m, iF-I), 7.59- 7.50 (m, 2H), 7.47 (a, 1H), 7.29-7.23 (m, 1H), 7.22-7.16 (m, 1H), 4.84 (sep, 1H, J = 6.7), 3.55 (a, 3H), 1.58(d, 6H,J= 6.7) LCMS (long): RT: 3.28 mm, ESt m/z 458.3 [M+H] [00159] Example 43: N-[3-[2-tert-butyl-5-(3-rnethoxy-1 H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-phenyl]- 2,5-difluoro-benzenesulfonamide
F
Step 1) To a microwave vial was added N-[3-(5-bromo-2-tert-butyl-triazol-4-yl)-2-fluoro-phenyl]-2,5-difluoro- benzenesulfonamide (80 mg, 0.16 mmol), 3-methoxy-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1 3,2- dioxaborolan-2-yI)pyrazole and 5-methoxy-1 -tetrahydropyran-2-yl-4-(4,4 5, 5-tetramethyl-1 3,2-dioxaborolan-2-yI)pyrazole (as a mixture) (100 mg, 0.33 mmol), potassium phosphate tribasic (110 mg, 0.52 mmol), tricyclohexylphosphine (10 mg, 0.04 mmol) and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.02 mniol) in DMF (3.5 mL) and water (0.5 mL) and heated in a microwave at 130 °C for 3 hours. The mixture was cooled, partitioned between ethyl acetate (100 mL) and water (30 mL). The organic was washed with water (2 x 30 mL), brine (30 mL), dried over sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 0-100% ethyl S acetate in heptane to give 22 mg of N-[3-[2-tert-butyl-5-(3-methoxy-1 -tetrahydropyran-2-yl-pyrazol-4- yl)triazol-4-yl]-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide and N-[3-[2-tert-butyl-5-(5-methoxy-1-tetrahyd ropyran-2-yl-pyrazol-4-yl)triazol-4-yl]-2-fluoro-phenyl]-2,5-d ifluoro-benzenesu Ifonamide as an inseparable mixture.
LCMS (short): RT: 1.97 mm, ES m/z 591.3 [M+H] Step 2) To a solution of N-[3-[2-tert-butyl-5-(3-niethoxy-1-tetrahydropyran-2-yl-pyrazol-4-yl) triazol-4-yl]-2-fluoro- phenyl]-2,5-difluoro-benzenesulfonamide and N-[3-[2-tert-butyl-5-(5-methoxy-1 -tetrahyd ropyran-2-yl-pyrazol-4-yl)triazol-4-yl]-2-fluoro-phenyl]-2, 5-difluoro-benzenesulfonamide (22 mg, 0.04 mmol) in methanol (4 mL) was added p-toluenesulfonic acid monohydrate (1.3 mg, 0.01 mmol) and the mixture stirred for 24 hrs. To the reaction mixture was added further p-toluenesulfonic acid monohydrate (30 mg) stirred for 24 hours followed by a further portion p-toluenesulfonic acid monohydrate (30 mg) and stirred for 24 hours.
The reaction was concentrated to dryness and partitioned between ethyl acetate (80 mL) and saturated aqueous sodium bicarbonate solution (50 mL), dried over sodium sulphate, filtered and concentrated to dryness. The resulting residues were purified by flash column chromatography using 0 -10 % methanol in DCM to give 17.6mg of N-[3-[2-tert-butyl-5-(3-methoxy-1H-pyrazol-4-yl)triazol-4-yl] -2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide as an off white solid.
1H NMR (400 MHz, CD3QD): 7.55-7.48 (m, 2H), 7.48-7.43 (m, 1H), 7.42-7.35 (m, 1H), 7.33-7.22 (m, 2H), 7.18-7.12 (m, 1H), 3.58 (s, 3H), 1.7 (s, 9H) LCMS (long): RT: 4.04 mm, ESt m/z 507.3 [M+H]* [00160] In vitro biological evaluation of compounds of the invention was carried out following the procedure detailed below. The procedure provides activity data for the compounds of the invention against B-Raf (V600E) and C-Raf. The activity is shown in Table 3 below.
[00161] LanthaScreenTM Eu kinase binding assay [00162] To determine whether compounds bind to Raf kinases, they are tested in a competition binding assay. The Invitrogen LanthaScreenTM Eu binding assay involves the binding of an Alexa-Fluor® 647-labelled, ATP-competitive kinase tracer to the kinase of interest. A Europium-labelled anti-tag antibody also binds to the kinase of interest. Simultaneous binding of the tracer and the antibody brings them into close proximity and upon excitation at 340nm, triggers fluorescence resonance energy transfer (FRET) between the Europium donor fluorophore on the antibody and the Alexa Fluor® 647 acceptor on the tracer. The dual emission signal produced can be measured at 665 and 615nm.
[00163] Compounds at a concentration of 3mM are serially diluted (e.g. lOpI into 90pl of 100% dimethyl sulfoxide (DMSO)) seven times in 96-well plates for a total of 8 dilution points. Each DM50 dilution is further diluted 1:100 in kinase buffer (e.g. SpI into 495pl kinase buffer) containing 50mM HEPES pH 7.5, 10mM MgCI,, 1mM EGTA, 0.01% Brij-35.
[00164] Each well in a 96-well OptiplateTM (Perkin Elmer 6005569) contains 30pl of final volume per sample, including lOpI compound at 3X the desired concentration, providing 10pM at the final maximum concentration, lOpI of kinase/antibody mixture at 3X the desired concentration of Raf recombinant kinases and antibody providing SnM final concentration of BRaf\E kinase (Invitrogen PV3849) and 3nM final concentration of C-Raf Y340D/Y341D kinase (Invitrogen PV3805) and 2nM final concentration of Eu-anti-GST antibody (PV5594), and 1 OpI of 3X the desired concentration of kinase tracer 178 (Invitrogen F'V5593) providing final concentrations of 2OnM tracer for kinase and 6nM tracer for C-Raf kinase. The plates are incubated for S hours at room temperature and read on an EnVision plate reader (Perkin Elmer).
[00165] All data are analysed using the GraphPad Prism software package. Inhibition of tracer binding to the kinase of interest is assessed by determination of 1C50 value, which is defined as the concentration of compound which decreased the level of FRET signal measured at 665nm by 50%.
[00166] The results of the in vitro biological activity study of the compounds of the invention are given in Table 3 below. The compounds all show activity against B-Raf V600E mutant and 0-Raf. The table shows the B-Raf and C-Raf inhibition activity of compounds of the invention categorised based on the ICSO values, the categories being "+", "-1-+" and "+++". The category "+" refers to compounds with an 1050 value of greater than 300 nM. The category "++" refers to compounds with an ICSO value of 15 nM to 300 nM.
The category "+++" refers to compounds with an 1050 value of less than 15 nM. Compounds having a designation of "+++" are thus more active against B-Raf and/or C-Raf than compounds having a designation of "++". Similarly, compounds having a designation of "++" are more active against B-Raf and/or 0-Raf than compounds having a designation of "+".
Table 3
ID B-Raf C-Raf Name No. Category Category 1 N-[3-[2-tert-butyl-5-(3-methoxy-1 H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-phenyl]-2, 5-difluoro-benzenesulfonamide 2 N-[2-fluoro-3-[2-isopropyl-5-( I H-pyrazol-4-yl)triazol-4-yl]phenyl]thiophene-3-sulfonamide 3 N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-+ + 3,5-dimethyl-isoxazole-4-sulfonamide 4 N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol-4-yl]phenyl]thiophene-2-sulfonamide 6-chloro-N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol-4-+ yl]phenyl]pyridine-3-sulfonamide 6 N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-+ 2,3-dimethyl-imidazole-4-sulfonamide 7 N-[2-fluoro-3-[2-isopropyl-5-( I H-pyrazol-4-yl)triazol-4-yl]phenyl]-+ 6-methoxy-pyridine-3-sulfonamide N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)Iriazol-4-yI]phenyl]-+ + 2-rn ethyl-pyrazole-3-sulfonamide N-[2-fluoro-3-[2-isopropyl-5-( 1 F-l-pyrazol-4-yl)triazol-4-++ ++ yI]phenyl]pyridine-3-sulfonamide N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)Iriazol-4-yI]phenyl]-+ + 1-rn ethyl-pyrazole-4-sulfonamide 11 N-[3-[2-tert-butyl-5-(1 F-l-pyrazol-4-yl)triazol-4-yI]-2-fluoro-phenyl]-+ + 2,4-difluoro-benzenesulfonamide 12 N-[2-fluoro-3-[2-isopropyl-5-(3-methoxy-1 H-pyrazol-4-yl)triazol- 4-yI]phenyl]pyridine-3-sulfonarn ide 13 N-[3-[2-tert-butyl-5-(1 H-pyrazol-4-yl)triazol-4-yI]-2-fluoro-phenyl]-++ 3-fluoro-benzenesulfonamide 14 N-[3-[2-tert-butyl-5-(3-methoxy-1 H-pyrazol-4-yI)triazol-4-yI]-2-fluoro-phenyl]pyridine-3-sulfonamide N-[3-[5-(3,5-dimethyl-1 H-pyrazoI-4-y-2-isopropyI-triazoI-4-yI]-2-+ + fluoro-phenyl]-2,5-d ifluoro-benzenesu Ifonamide N-[3-[2-tert-butyl-5-( 1 F-1-pyrazol-4-yI)triazol-4-yI]-2-fluoro-++ +++ 16 phenyl]pyridine-3-sulfonamide 17 N-[2-fluoro-3-[2-isopropyl-5-(3-methyl-1 H-pyrazol-4-yl)triazol-4-++ ++ yI]phenyl]pyridine-3-sulfonamide 18 2,5-difluoro-N-[2-fluoro-3-[5-(3-methoxy-1 H-pyrazol-4-yl)-2-++ ++ rnethyl-triazol-4-yI]phenyl]benzenesulfonarnide 19 N-[2-fluoro-3-[5-(3-methoxy-1 H-pyrazol-4-yl)-2-methyl-triazol-4-++ ++ yI]phenyl]pyridine-3-sulfonamide 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(3-methyl-1 H-pyrazol-4-++ ++ yl)triazol-4-yI]phenyl]benzenesulfonarn ide 21 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(3-methyl-1 H-pyrazol-4-++ yl)triazol-4-yI]phenyl]benzenesulfonarn ide 22 N-[2-fluoro-3-[2-isopropyl-5-( 1 -methylpyrazol-4-yl)triazol-4-+ + yI]phenyl]pyridine-3-sulfonamide 23 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-( 1 -methylpyrazol-4-+ + yl)triazol-4-yI]phenyl]benzenesulfonarn ide 24 2 6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-( 1 -methylpyrazol-4-+ + yl)triazol-4-yI]phenyl]benzenesulfonarn ide 2,5-difluoro-N-[2-fluoro-3-[2-methyl-5-( 1 H-pyrazoI-4-ytriazoI-4-++ ++ yl] phenyl] benzenes u Ifona m ide N-[2-fluoro-3-[2-rnethyl-5-( 1 H-pyrazol-4-yl)triazol-4-+ + 26 yI]phenyl]pyridine-3-sulfonamide N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-5-yl)triazol-4-+ + yI]phenyl]propane-1 -sulfonamide 28 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-5-yI)triazol-+ + 4-yI]phenyl]benzenesulfonamide N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol-4- 29 yI]phenyl]propane-1 -sulfonamide + + 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol- 4-yI]phenyl]benzenesulfonamide 31 N-[3-[2-tert-butyl-5-(1 H-pyrazol-4-yl)triazol-4-yI]-2-fluoro-phenyl]-++ 2,5-difluoro-benzenesulfonamide 32 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(3-methoxy-1 H-pyrazol- 4-yI)triazol-4-yI]phenyl]benzenesulfonamide 33 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-3-yl)triazol-+ + 4-yI]phenyl]benzenesulfonamide 34 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol-++ ++ 4-yI]phenyl]benzenesulfonamide 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(4-methylthiazol-5-+ ++ yl)triazol-4-yl]phenyl]benzenesulfonam ide 36 2,6-difluoro-N-[2-fluoro-3-(2-isopropyl-5-thiazol-5-yl-triazol-4-+ ++ yl)phenyl] be nzenesu Ifonamide 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(2-methylpyrazol-3-++ yl)triazol-4-yl]phenyl]benzenesulfonam ide 38 N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol-4-yI]phenyl]-+ + 2,4-dimethyl-thiazole-5-sulfonamide 39 N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)Iriazol-4-yI]phenyl]-+ + 1 -methyl-imidazole-2-sulfonamide 2 5-difluoro-N-[5-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]-3-+ + pyridyl]benzenesulfonamide 41 N-[2,5-difluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]-2,5-difluoro-benzenesulfonamide 42 3,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-[3-methoxy-1 H-pyrazol- 4-yl]triazol-4-yI]phenyl]benzenesulfonamide 43 N-[3-[2-tert-butyl-5-(1 H-pyrazol-4-yl)triazol-4-yI]-2-fluoro-phenyl]-++ ++ 3,5-difluoro-benzenesulfonamide 44 3,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol-++ ++ 4-yI]phenyl]benzenesulfonamide N-[2-fluoro-3-[2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol-4-yI]phenyl]-+ + 1 2-dimethyl-imidazole-4-sulfonamide 46 N-[3-[5-( 1 -benzyl-3-methoxy-pyrazol-4-yl)-2-isopropyl-triazol-4-+ + yl]-2-fluoro-phenyl]propane-1-sulfonamide N-[3-[5-( 1 -benzyl-3-methoxy-pyrazol-4-yl)-2-isopropyl-triazol-4-+ + yl]-2-fluoro-phenyl]pyrid ine-3-sulfonam ide [00167] Examples of compounds of the invention with 1C50 values in nM are given in Table 4 below.
Table 4
ID B-Rat (V600E) C-Raf 1C50 No. Name 1C50 (nM) (nM) 2 N-[2-fluoro-3-[2-isopropyl-5-(1 F-1-pyrazol-4-yl)triazol-4-3 94 3 74 yl]phenyl]thiophene-3-sulfonamide 12 N-[2-fluoro-3-[2-isopropyl-5-(3-methoxy-1 H-pyrazol-4-7 53 7 50 yl)triazol-4-yl]phenyl] pyridine-3-sulfonamide 32 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(3-methoxy-1H-3 70 3 08 pyrazol-4-yl)triazol-4-yl]phenyl]benzenesulfonamide 41 N-[2,5-difluoro-3-L2-isopropyl-5-( 1 H-pyrazol-4-yl)triazol-4-3 80 1 60 yl]phenyl]-2,5-difluoro-benzenesulfonamide [00168] Compounds of the invention were selected to be run in an AlphaScreen SureFire pERK1/2 cellular assay to assess the compounds activity within a cell.
[00169] AlphaScreen SureFire pERK1/2 cellular assay [00170] The human A375 malignant melanoma cell line endogenously expresses the B-Raf V600E mutation, which leads to constitutive activation of the MAP kinase pathway and phosphorylation of ERK in the absence of ligands. To determine whether compounds inhibit constitutive ERK phosphorylation in A375 cells, they are tested using AlphaScreen® SureFire® technology (Perkin Elmer ERK1I2 p-T202/Y204 assay kit TGRES1OK). On day 1, A375 cells (ATCC CRL-1619) are counted, centrifuged and resuspended in growth media (Dulbecco's modified Eagle's medium containing 4.5gfL D-glucose (Gibco 41965), 10% fetal bovine serum (VWR 5061) and 4mM L-glutamine (Sigma 07513)). The cells are plated, 200pl in each well of 96-well culture dish (Corning 3585) to a final cell density of 60,000 cells per well and incubated at 37°C in 5% CO2 overnight.
[00171] On day 2, compounds at a concentration of 6mM are serially diluted 1 0p1 into 90p1 of 100% dimethyl sulfoxide (DMSO) six times in 96-well plates for a total of 7 dilution points. Each dilution and a DMSO control are further diluted 1:200 (e.g. 5p1 into 995p1 serum-free growth media). The media is removed and 50pl compound dilution or control in serum-free media is added to triplicate wells containing cells, providing 3OpM compound at the maximum concentration. The cells are treated for 30 minutes at room temperature. The treatment is then removed and the cells are incubated with lysis buffer containing protease and phosphatase inhibitors for 10 minutes at room temperature. Cell lysates are transferred to a 96-well OptiplateTM (Perkin Elmer 6005569) and incubated with anti-mouse lgG acceptor beads, a biotinylated anti-ERK1/2 rabbit antibody recognising both phosphorylated and non-phosphorylated ERK1I2, a mouse antibody targeted to the Thr2O2ITyr2O4 epitope and recognising phosphorylated ERK proteins only, and streptavidin-coated donor beads. The biotinylated antibody binds to the streptavidin-coated donor beads and the phopsho-ERKI/2 antibody binds to the acceptor beads. Plates are read on an EnVision reader (Perkin Elmer) and excitation of the beads at 680nm with a laser induces the release of singlet oxygen molecules from the donor beads that trigger energy transfer to the acceptor beads in close proximity, producing a signal that can be measured at S7Onm. Both antibodies bind to phosphorylated ERK proteins, bringing the donor and acceptor beads into close proximity.
[00172] All data are analysed using the GraphPad Prism software package. Inhibition of ERK phosphorylation is assessed by determination of 1C50 value, which is defined as the concentration of compound which decreased the level of phosphorylated ERK proteins by 50%.
[00173] The results of AlphaScreen SureFire pERK1/2 cellular assay are given in Table 5 below. The compounds tested all showed activity within a cell. The activity of the compounds of the invention has been categorised based on the 1C50 values, the categories being "+", "++" and "+++". The category "+" refers to compounds with an 1C50 value of greater than 300 nM. The category "++" refers to compounds with an 1C50 value of 70 nM to 300 nM. The category "+++" refers to compounds with an 1C50 value of 10 nM to 70 nM.
Table 5
ID A375 pERK Name.
No. inhibition category 1 N-[3-[2-tert-butyl-5-(3-methoxy-1 H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-phenyl]-2, 5-difluoro-benzenesulfonamide 2 N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]thiophene-3-sulfonamide 4 N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-yl]phenyl]thiophene-2-sulfonamide N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yl)triazol-4-+ yl]phenyl]pyridine-3-sulfonamide 12 N-[2-fluoro-3-[2-isopropyl-5-(3-methoxy-1 H-pyrazol-4-yl)triazol-4-yl]phenyl]pyridine-3-sulfonamide 13 N-[3-[2-tert-butyl-5-( 1 H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-++ phenyl]-3-fluoro-benzenesulfonamide 14 N-[3-[2-tert-butyl-5-(3-methoxy-1 H-pyrazol-4-yl)triazol-4-+ yl]-2-fluoro-phenyl]pyridine-3-sulfonamide 16 N-[3-[2-tert-butyl-5-( 1 H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-+ phenyl]pyridine-3-sulfonamide 17 N-[2-fluoro-3-[2-isopropyl-5-(3-m ethyl-I H-pyrazol-4-+ yl)triazol-4-yl]phenyl]pyridine-3-sulfonamide 18 2, 5-difluoro-N-[2-fluoro-3-[5-(3-methoxy-1 H-pyrazol-4-yl)-2-methyl-triazol-4-yl]phenyl]benzenesulfonamide 19 N-[2-fluoro-3-[5-(3-methoxy-1 H-pyrazol-4-yl)-2-methyl-+ triazol-4-yl]phenyl]pyridine-3-sulfonamide 21 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(3-methyl-1 H-++ pyrazol-4-yl)triazol-4-yl]phenyl]benzenesulfonamide 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yI)triazol-4-yl]phenyl]benzenesulfonamide 31 N-[3-[2-tert-butyl-5-( I H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-phenyl]-2, 5-difluoro-benzenesulfonamide 32 2,5-d ifluoro-N-[2-fluoro-3-[2-isopropyl-5-(3-methoxy-1 H-pyrazol-4-yl)triazol-4-yl]phenyl]benzenesulfonamide 34 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-yI)triazol-4-yl]phenyl]benzenesulfonamide 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(4-methylthiazol-5-+ yl)triazol-4-yl]phenyl]benzenesulfonamide 36 2,6-difluoro-N-[2-fluoro-3-(2-isopropyl-5-thiazol-5-yl-triazol-+ 1-yl)phenyl] be nzenesu Ifona mid e 37 2,6-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(2-methylpyrazol-+ 3-yl)triazol-4-yl]phenyl]benzenesu Ifonamide [00174] Examples of compounds of the invention with A375 pERK inhibition 1C50 values in nM are given
in Table 6 below.
Table 6
ID A375 pERK inhibition No. Name ICSO (nM) 2,5-difluoro-N-[2-fluoro-3-[2-isopropyl-5-(1 H-pyrazol-4-17 91 yl)triazol-4-yl]phenyl]benzenesulfonamide 31 N-[3-[2-tert-butyl-5-( 1 H-pyrazol-4-yl)triazol-4-yl]-2-fluoro-38 28 phenyl]-2,5-difluoro-benzenesulfonamide [00175] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
[00176] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.
All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.
[00177] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

Claims (35)

  1. CLAIMSA compound according to formula (I): N'N R1-L cii:; 3_-_'R4)n (I) wherein A is a 5-membered heterocyclic moiety; B is selected from 0614 aryl and C14 heteroaryl; L is _S02NRa_, wherein Ra is selected from: H, C alkyl and 01-4 haloalkyl; R1 is selected from substituted or unsubstituted: Ci alkyl, C alkenyl, 016 alkynyl, 0314 carbocyclic and 0314 heterocyclic; and wherein, when substituted, the substituted moiety includes 1 to S substituents independently selected at each occurrence from the group comprising: halo, SORb, SRb, NRbR0, -NO, =0,-ON, 01-4 acyl, 016 alkyl, C16 haloalkyl, C36 cycloalkyl, C(0)Rb and C(0)ORb R2 is independently selected at each occurrence from: H, halo, C14 alkyl and 014 haloalkyl; R3 is selected from: H, 016 alkyl, haloalkyl, 0 cycloalkyl, heterocycloalkyl; R4 is independently selected at each occurrence from: H, halo, -OR5, -SR5, -NR5R6, -NO, =0, -ON, acyl. C(O)ORb, C(0)NRbR0, alkyl, 03.11 carbocyclic and C heterocyclic; R5 and R6 are each independently selected from: H, _C(O)Rb, 01.4 alkyl, 01.4 haloalkyl, 0 carbocyclic and 038 heterocyclic; Rb and Rc are independently selected at each occurrence from: H, C alkyl, 014 haloalkyl, C14 acyl, C37 cycloalkyl, and C37 halocycloalkyl; m is selected from, 0, 1, 2 and 3; and n is selected from, 0, 1 and 2.
  2. 2. The compound of claim 1 wherein the compound of formula (I) is a compound according to formula (II):N N
    R1_S° _-L'\----R ()-(R4) (R2)m (II)
  3. 3. The compound of claim 1 or claim 2 wherein the two groups on B other than any groups are substituted on B in a 1,3-relationship.
  4. 4. The compound of any preceding claim, wherein A is a 5 membered heterocyclic moiety containing 1, 2 or 3 heteroatoms independently selected at each occurrence from N, 0 and S.
  5. 5. The compound of claim 4, wherein at least one of the heteroatoms is N.
  6. 6. The compound of claim 4, wherein A is selected from: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazoline and pyrazolidinyl.
  7. 7. The compound of any preceding claim, wherein B is phenyl or a 6-membered N-containing heteroaryl.
  8. 8. The compound of any preceding claim, wherein R1 is selected from substituted or unsubstituted: C16 alkyl, C16 alkenyl, C16 alkynyl, C3s cycloalkyl, C38 heterocycloalkyl, C614 aryl and C514 heteroaryl.
  9. 9. The compound of claim 8, wherein R1 may be selected from substituted or unsubstituted: phenyl, pyridyl, pyrazolyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, methyl, ethyl, propyl and butyl.
  10. 10. The compound of any preceding claim, wherein R1 is unsubstituted or R1 is substituted with one or two groups, independently selected from: halo, SORb, _NRbRG, 01.6 alkyl and haloalkyl.
  11. 11. The compound of any preceding claim, wherein R2 is halo.
  12. 12. The compound of any preceding claim, wherein m is I or 2.
  13. 13. The compound of any preceding claim, wherein R3 is selected from: 01A alkyl and 03.6 cycloalkyl.
  14. 14. The compound of claim 13, wherein R3 is methyl, iso-propyl or tert-butyl.
  15. 15. The compound of any preceding claim, wherein R4 is independently selected at each occurrence from: H, -OR5, -NR5R6, C(O)NRbR, alkyl, 03.6 cycloalkyl and C heterocycloalkyl.
  16. 16. The compound of any preceding claim, wherein R5 and R6 are each independently selected from: H, C15 alkyl, C36 cycloalkyl and C36 heterocycloaryl.
  17. 17. The compound of any preceding claim, wherein n is 1 or 2.
  18. 18. The compound of claim 1, wherein the compound of formula (I) is a compound selected from: Y Y *_NN N N N F N N N' F\ HN_dt,NHY IF N'N NN N'N HNNHDHN,NHFY Y YNN W'N -jt?NH Nm HNNH / N HNY Y YN'N N'N F NN -dc sohI I IN No:g'cN j,.,N FY Y YN NN N N N FF F 0°b N JINN HNY I YN NN N N'N N'N o F 0 O( QHN-j$ N * NN N''N N'NOF -dH C O/\N° Ot, NNeNH * Y *NN N'N 0 F "0NF * IN'N NN FN No F 0 o( (1Hi1Jm ttj /FFY Y IF N'N F N''NN NØO? Øo -d,NFFF H H HY Y YF N'N F N'N F N'N Øo)3/ ØoF F F * *N NHNJNFY Y YF N''N N''N N'N OtJ<\N ENHN_d<cNH Lt
  19. 19. The compound of any preceding claim for use as a medicament.
  20. 20. The compound of any or claims 1 to 18 for use in the treatment of a condition which is modulated S by Raf kinases.
  21. 21. The compound of claim 20 wherein the condition modulated by Raf kinases is a condition treatable by the inhibition of Raf kinases.
  22. 22. The compound of claim 21, wherein the condition treatable by the inhibition of Raf kinases is selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia.
  23. 23. The compound of any of claims 20-22, wherein the condition treatable by the inhibition of Raf kinases is selected from: Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastomas, astrocytomas; gliobalstoma multiforme; ependymomas; seconday CNS tumors (metastases to the central nervous system of tumors originating outside of the central nervous system); brain tumors; brain metastases; colorectal cancer; large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck; squamous cell carcinoma of the head and neck; acute lymphoblastic leukemia; acute myelogenous leukemia (AML); myelodysplastic syndromes; chronic myelogenous leukemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; metastatic melanoma and thyroid cancers.
  24. 24. The compound of any of claims I to 18 for use simultaneously, sequentially or separately with an additional anti-tumour agent, in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma or leukemia.
  25. 25. A pharmaceutical composition, wherein the composition comprises the compound of any of claims 1 to 18 and one or more pharmaceutically acceptable excipients.
  26. 26. The pharmaceutical composition of claim 25, wherein the composition is a combination product and comprises an additional pharmaceutically active agent in addition to the compound according to any of claims ito 18.
  27. 27. A method of treating a condition which is modulated by Raf kinases, wherein the method comprises administering a therapeutic amount of a compound of any of claims 1 to 18, to a patient in need thereof.
  28. 28. The method of claim 27 wherein the condition modulated by Raf kinases is selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia.
  29. 29. A method of claims 27 or claim 28, wherein the condition modulated by Raf kinases is selected from: Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastomas, astrocytomas; gliobalstoma multiforme; ependymomas; seconday CNS tumors (metastases to the central nervous system of tumors originating outside of the central nervous system); brain tumors; brain metastases; colorectal cancer; large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck; squamous cell carcinoma of the head and neck; acute lymphoblastic leukemia; acute myelogenous leukemia (AML); myelodysplastic syndromes; chronic myelogenous leukemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; metastatic melanoma and thyroid cancers.
  30. 30. A method of treatment of a condition selected from cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma and leukemia, comprising administering a therapeutically effective amount of a compound any of claims 1 to 18, simultaneously, sequentially or separately with an additional anti-tumour agent to a patient in need thereof.
  31. 31. A method of providing a combination product, wherein the method comprises providing a compound of any of claims I to iS simultaneously, sequentially or separately with an anti-tumour agent.
  32. 32. Use of a compound of any of claims i to i8 in the manufacture of a medicament for the treatment of a condition which is modulated by Raf kinases.
  33. 33. The compound, method or use of any of claims 20 to 32 wherein the Raf kinases are B-Raf or C-Raf.
  34. 34. The compound, method or use of claim 33, wherein B-Raf is B-RafV600E mutant.
  35. 35. Use of a compound of any of claims i to i 8 in combination with an anti-tumour agent.
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WO2011023773A1 (en) * 2009-08-28 2011-03-03 Novartis Ag Compounds and compositions as protein kinase inhibitors
WO2011038261A1 (en) * 2009-09-24 2011-03-31 Selexagen Therapeutics, Inc. Heterocyclic kinase inhibitors
WO2012125981A2 (en) * 2011-03-17 2012-09-20 Selexagen Therapeutics, Inc. Raf kinase inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011023773A1 (en) * 2009-08-28 2011-03-03 Novartis Ag Compounds and compositions as protein kinase inhibitors
WO2011038261A1 (en) * 2009-09-24 2011-03-31 Selexagen Therapeutics, Inc. Heterocyclic kinase inhibitors
WO2012125981A2 (en) * 2011-03-17 2012-09-20 Selexagen Therapeutics, Inc. Raf kinase inhibitors

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