NZ723051B2 - Pharmaceutical compounds - Google Patents

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NZ723051B2
NZ723051B2 NZ723051A NZ72305115A NZ723051B2 NZ 723051 B2 NZ723051 B2 NZ 723051B2 NZ 723051 A NZ723051 A NZ 723051A NZ 72305115 A NZ72305115 A NZ 72305115A NZ 723051 B2 NZ723051 B2 NZ 723051B2
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New Zealand
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amino
phenyl
methoxy
pyrazinecarbonitrile
pyrazol
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NZ723051A
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NZ723051A (en
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Richard Justin Boyce
Robert George Boyle
Francine Farouz
Scott Peterson
Cong Hung Vo
David Winter Walker
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Sentinel Oncology Limited
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Priority claimed from GBGB1402277.6A external-priority patent/GB201402277D0/en
Application filed by Sentinel Oncology Limited filed Critical Sentinel Oncology Limited
Publication of NZ723051A publication Critical patent/NZ723051A/en
Publication of NZ723051B2 publication Critical patent/NZ723051B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • 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
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Abstract

This invention relates to compounds of formula (0) that inhibit or modulate the activity of Chk-1 kinase. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds.

Description

PHARMACEUTICAL COMPOUNDS This ion relates to compounds that inhibit or modulate the activity of Chk—1 kinase.
Also provided are pharmaceutical compositions ning the compounds and the therapeutic uses of the compounds.
Background of the Invention Chk-1 is a serine/threonine kinase involved in the induction of cell cycle oints in response to DNA damage and replicative stress [Clin. Can. Res. 2007;13(7)]. Cell cycle oints are regulatory pathways that control the order and timing of cell cycle transitions. Most cancer cells have impaired G1 checkpoint activation due to a defective p53 tumor suppressor protein. Hahn et al.,”RuIes for making human tumor cells” N. Engl.
J. Med. 2002; 347: 1593—603 and Hollstein et al., “p53 mutations in human cancers” Science 1991; 253: 49—53) have reported that tumours are ated with mutations in the p53 gene, a tumour suppressor gene found in about 50% of all human cancers.
Chk-1 inhibition abrogates the intra S and G2/M checkpoints and has been shown to selectively sensitise tumour cells to well known DNA damaging agents. Examples of DNA damaging agents where this sensitising effect has been demonstrated include Gemcitabine, Pemetrexed, bine, lrinotecan, Camptothecin, Cisplatin, Carboplatin [Clin. Cancer Res. 2010, 16, 376], Temozolomide [Journal of Neurosurgery 2004, 100, 1060], Doxorubicin [Bioorg. Med. Chem. Lett. 2006;16:421- 6], Paclitaxel [WO2010149394], y urea [Nat Cell. Biol. 2005 Feb;7(2):195-20], the nitroimidazole hypoxia-targetted drug TH-302 (Meng et al., AACR, 2013 Abstract No. 2389) and ionising radiation [Clin. Cancer Res. 2010, 16, 2076]. See also the review article by McNeely, 8., et al., “CHEK again: Revisiting the development of CHK1 inhibitors for cancer therapy, Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/ j.pharmthera.2013.10.005.
Recently published data have also shown that Chk—1 inhibitors may act synergistically with PARP inhibitors [Cancer Res.; 66: (16)], Mek tors [Blood. 2008 September 15; : 2439—2449], Farnesyltransferase inhibitors [Blood. 2005 Feb 15;105(4):1706-16], Rapamycin [Mol. Cancer Ther. 2005 3):457-70], Src inhibitors [Blood. 2011 Feb 10;117(6):1947-57] and WEE1 tors (Chaudhuri et al., Haematologica, 2013.093187). ance to chemotherapy and radiotherapy, a clinical problem for conventional therapy, has been associated with activation of the DNA damage response in which Chk-1 has been implicated (Chk—1 activation is associated with radioresistence in glioblastoma [Nature; 2006; 444(7):756-760] and the inhibition of Chk-1 sensitises lung cancer brain metastases to radiotherapy [Biochem. Biophys. Res. Commun. 2011 March 4;406(1):53-8]).
It is also envisaged that Chk-1 inhibitors, either as single agents or in combination, may be useful in treating tumour cells in which constitutive activation of DNA damage and checkpoint pathways drive genomic ility. This phenotype is associated with x karyotypes in samples from patients with acute myeloid leukemia (AML) [Cancer Research 2009, 89, 8652]. In vitro antagonisation of the Chk-1 kinase with a small molecule inhibitor or by RNA interference strongly reduces the enic ties of high-DNA damage level AML samples. In contrast Chk-1 inhibition has no effect on normal hematopoietic progenitors. rmore, recent studies have shown that the tumour microenvironment drives genetic instability [Nature; 2008;(8):180-192] and loss of Chk-1 sensitises cells to hypoxia/reoxygenation [Cell Cycle; 2010; 9(13):2502]. In neuroblastoma, a kinome RNA interference screen trated that loss of Chk-1 inhibited the growth of eight neuroblastoma cell lines. Tumour cells deficient in Fanconi anemia DNA repair have shown sensitivity to Chk-1 inhibition [Molecular Cancer 2009, 8:24]. It has been shown that the Chk-1 ic inhibitor PF-00477736 ts the growth of thirty ovarian cancer cell lines [Bukczynska et al, 23rd Lorne Cancer Conference] and triple negative ve breast cancer cells [Cancer Science 2011, 102, 882]. Also, PF-00477736 has displayed selective single agent activity in a MYC oncogene driven murine spontaneous cancer model [Ferrao et al, Oncogene (15 August 2011)]. Chk-1 inhibition, by either RNA interference or selective small molecule inhibitors, results in apoptosis of MYC-overexpressing cells both in vitro and in an in vivo mouse model of B-cell lymphoma nd et al., Clinical Cancer Research, Online First ber 20, 2011]. The latter data suggest that Chk-1 inhibitors would have utility for the treatment of MYC-driven malignancies such as B-cell lymphoma/leukemia, neuroblastoma and some breast and lung cancers. Ewing sarcoma cell lines have also been reported to be sensitive to Chk kinase inhibitors la et al., Kinase Targets in Ewing’s Sarcoma Cell Lines using RNAi-based & lnvestigational Agents Screening Approaches, Molecular Targets 2013, Boston, USA).
It has also been reported that mutations that reduce the activity of DNA repair pathways can result in synthetically lethal interactions with Chk1 inhibition. For example, mutations that disrupt the RAD50 complex and ATM ing increase responsiveness to Chk1 inhibition madie et al., Synthetic lethality in ATM-deficient RAD50-mutant tumors underlie r response to cancer therapy]. Likewise, deficiencies in the Fanconi anemia homologous DNA repair pathway lead to sensitivity to Chk1 inhibition [Chen et a|., Chk1 inhibition asd a strategy for targeting fanconi anemia (FA) DNA repair pathway deficient tumors. Mol. Cancer 2009 8:24, Duan et al., Fanconi anemia repair pathway dysfunction, a potential eutic target in lung cancer. Frontiers in Oncology 2014 4:1].
Also, human cells that have loss of function in the Rad17 gene product are ive to Chk1 suppression [Shen et al., Synthetic lethal interaction n tumor ssor RAD17 and Chk1 kinase in human cancer cells. 2014 SACNAS National Conference Abstract].
Various attempts have been made to develop inhibitors of Chk-1 . For example, WO 03/10444 and (both in the name of Millennium) disclose aryl/heteroaryl urea compounds as Chk—1 kinase tors. U82005/215556 (Abbott) discloses macrocyclic ureas as kinase inhibitors. WO 02/070494, W02006014359 and W02006021002 (all in the name of lcos) disclose aryl and heteroaryl ureas as Chk—1 inhibitors. Our earlier applications WO/2011/141716 and WO/2013/072502 both disclose substituted pyrazinyl-phenyl ureas as Chk-1 kinase inhibitors. W02005/009435 r) and W02010/077758 (Eli Lilly) disclose aminopyrazoles as Chk—1 kinase inhibitors.
The Invention The present ion provides nds having activity as Chk-1 kinase inhibitors.
Accordingly, in a first embodiment (Embodiment 1.0), the invention provides a compound of the formula (0): N / 1 T M R6 N (0) or a salt, N-oxide or tautomer thereof, wherein: T1 is ed from N and CH; T2 is selected from N, CH and CF; R1 is selected from hydrogen, fluorine, CM hydrocarbyl and CM hydrocarbyloxy; R2 is selected from hydrogen, fluorine, CM hydrocarbyl and CM hydrocarbyloxy; R3 is selected from hydrogen, methyl, fluorine, chlorine and bromine; one of M1 and M2 is a group R4 selected from hydrogen, methyl, fluorine, chlorine and bromine; and the other of M1 and M2 is a moiety —A-R7; R5 is selected from hydrogen, cyano, C13 alkyl, cyclopropyl, chlorine, carboxy, and C1_3- -carbonyl; R6 is selected from hydrogen, fluorine, CM alkyl; and CM alkoxy optionally substituted with NRdRe where Rd and Re are the same or different and each is selected from hydrogen and C1_4 alkyl, or NRdRe forms a 4 to 7 membered saturated heterocyclic ring optionally containing a second heteroatom ring member selected from N, O and S and oxidized forms of S, the saturated heterocyclic ring being optionally substituted with one or more substituents selected from oxo, methyl, hydroxy and fluorine; A is selected from: (i) a bond; (ii) (CRqu)X where RD and Rq are each independently hydrogen or methyl and x is 1 to 4; (iii) an oxygen atom; (iv) a group NRr n Rr is hydrogen or methyl; and (v) a ted chain of 2 to 10 chain members in length containing at least one carbon atom chain member, at least one heteroatom chain member selected from nitrogen and oxygen, and optionally one or more further carbon atom chain members and/or heteroatom chain members selected from nitrogen, , sulphur, sulphinyl and sulphonyl; the saturated chain being optionally substituted with one or more substituents selected from =O, CM hydrocarbyl, fluoro-C1_4 hydrocarbyl, hydroxy-CM hydrocarbyl, C1_2-alkoxy-C1_4 hydrocarbyl, and fluorine wherein two arbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring s; R7 is selected from hydrogen; R11SOZ-; amino; NH-Hyd‘; )2; and a group Cyc1 wherein Cyc1 is a carbocyclic or heterocyclic aromatic or non-aromatic group of 3 to 10 ring members of which 0 to 3 are selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic ic or non-aromatic group being optionally tuted with one or more substituents R8; provided that when A is a bond, (CRqu)X, an oxygen atom or NRr, then R7 is other than en; and provided also that when R7 is hydrogen, then A has a chain length of at least four chain members and contains at least two heteroatom chain members; R8 is selected from: . halogen; . oxo; . cyano; 2015/015030 . nitro; . a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; and . a group Ra-Rb; R81 is a bond, 0, co, X1C(X2), C(X2)X1, x1C(x2)x1, s, so, 802, NRC, SOzNRc or NRCSOZ; Rb is: . hydrogen; . a carbocyclic and heterocyclic group having from 3 to 12 ring s, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; . an acyclic C142 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1_8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring s, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; wherein one or more but not all of the carbon atoms of the acyclic C142 hydrocarbyl group may optionally be replaced by O, 8, 80, 802, NRC, x1C(x2), C(x2)x1 or x1C(x2)x1; Rc is: . en; . a carbocyclic and heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being ally substituted with one or more substituents R9; . an acyclic C142 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; n; cyano; nitro; carboxy; amino; mono- or di-C1_8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring s, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or cyclic group being optionally substituted with one or more substituents R9; wherein one or more but not all of the carbon atoms of the acyclic C142 hydrocarbyl group may ally be replaced by O, 8, 80, 802, NH, N-C1_4 alkyl, C(O)O, OC(O), NH(CO), C(O)NH, NH(CO)NH, N(C1_4 alkyl)C(O), C(O)N(C1_4 alkyl) X1 is o, s or NRC; and X2 is =0, :8 or =NRC; n R9 is selected from R8 provided that when the substituents R9 contain a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group is unsubstituted or tuted with one or more substituents R10; R10 is selected from halogen, oxo, cyano, and an acyclic CH; hydrocarbyl group optionally tuted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or 2 alkylamino; wherein one but not all of the carbon atoms of the acyclic CH; hydrocarbyl group may optionally be replaced by O, 8, 80, 802, NH or NMe; R11 is selected from amino, Hyd1, NH-Hyd1, N(Hyd1)2; and Cyc1; Hyd1 is a omatic CH; hydrocarbyl group ally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino and Cycl, wherein one or two of the carbon atoms of the non-aromatic CH; hydrocarbyl group may optionally be replaced by O, NH, N-Hyd2, C(=O), 8, 80 or 802, provided that at least one carbon atom of the hydrocarbyl group remains; Hyd2 is a CM hydrocarbyl group; and wherein in any group consisting of or containing a hydrocarbyl moiety, the hydrocarbyl moiety is a hydrocarbon group optionally containing one or more , double or triple carbon-carbon bonds or combinations thereof.
Particular embodiments of the invention are as set out below in Embodiments 1.01 to 1.107. 1.01 A compound according to Embodiment 1.0 wherein T2 is N. 1.02 A compound ing to Embodiment 1.01 wherein both T1 and T2 are N. 1.03 A nd according to any one of Embodiments 1.0 to 1.02 wherein M2 is a moiety —A-R7. 1.04 A compound according to any one of ments 1.0 to 1.03 wherein R5 is selected from hydrogen, cyano, C13 alkyl, cyclopropyl and chlorine. 1.05 A compound according to Embodiment 1.04 wherein R5 is selected from hydrogen, cyano, C13 alkyl and cyclopropyl. 1.06 A compound according to Embodiment 1.05 wherein R5 is selected from hydrogen, cyano and methyl. 1.07 A compound ing to any one of Embodiments 1.0 to 1.06 wherein R6 is selected from hydrogen, CM alkyl; and CM alkoxy optionally substituted with NRdRe where Rd and Re are the same or different and each is ed from hydrogen and CM alkyl, or NRdRe forms a 4 to 7 membered saturated heterocyclic ring optionally containing a second heteroatom ring member selected from N, O and S and oxidized forms of S, the saturated heterocyclic ring being optionally substituted with one or more substituents selected from oxo, methyl, y and fluorine. 1.08 A compound according to any one of Embodiments 1.0 to 1.07 wherein A is selected from: (i) a bond; (ii) (CR"R“)X where RD and Rq are each ndently hydrogen or methyl and x is 1 to 4; (iii) an oxygen atom; (iv) a group NRr wherein Rr is hydrogen or methyl; and (v) a ted chain of 2 to 10 chain members in length ning at least one carbon atom chain member, at least one heteroatom chain member selected from nitrogen and oxygen, and optionally one or more further carbon atom chain members and/or atom chain members selected from nitrogen, oxygen, sulphur, sulphinyl and sulphonyl; the saturated chain being optionally substituted with one or more substituents selected from =O, CM hydrocarbyl and fluorine wherein two hydrocarbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members. 1.09 A compound according to any one of Embodiments 1.0 to 1.08 wherein A is ed from: (i) a bond; (ii) CH2; (iii) an oxygen atom; and (iv) a saturated chain of 2 to 10 chain members in length containing at least one carbon atom chain member, at least one atom chain member selected from nitrogen and oxygen, and optionally one or more further carbon atom chain members and/or heteroatom chain members selected from nitrogen, oxygen, sulphur, sulphinyl and sulphonyl; the ted chain being optionally substituted with one or more substituents selected from =O, CM hydrocarbyl and fluorine wherein two hydrocarbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members. 1.1 A compound according to Embodiment 1.0 wherein the compound is of the formula (1): R \ / or a salt, N-oxide or tautomer thereof, wherein: A is selected from: (i) a bond; and (ii) a saturated chain of 2 to 10 chain members in length containing at least one carbon atom chain member, at least one heteroatom chain member selected from nitrogen and oxygen, and optionally one or more further carbon atom chain members and/or heteroatom chain members selected from en, oxygen, sulphur, sulphinyl and sulphonyl; the saturated chain being optionally substituted with one or more substituents ed from =O, CM hydrocarbyl and fluorine wherein two hydrocarbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members; R1 is selected from hydrogen, fluorine, CM hydrocarbyl and CM hydrocarbyloxy; R2 is selected from hydrogen, fluorine, CM hydrocarbyl and CM hydrocarbyloxy; R3 is selected from hydrogen, , chlorine and bromine; R4 is selected from hydrogen, methyl, chlorine and bromine; R5 is ed from hydrogen, cyano and methyl; R6 is selected from hydrogen, CM alkyl; and CM alkoxy optionally substituted with NRdRe where Rd and Re are the same or different and each is selected from hydrogen and CM alkyl, or NRdRe forms a 4 to 7 ed saturated cyclic ring optionally ning a second heteroatom ring member selected from N, O and S and oxidized forms of S, the saturated heterocyclic ring being optionally substituted with one or more substituents selected from oxo, , hydroxy and fluorine; R7 is selected from hydrogen; R11SOZ-; amino, NH-Hyd‘, N(Hyd1)2; and a group Cyc1 wherein Cyc1 is a carbocyclic or heterocyclic aromatic or omatic group of 3 to 10 ring members of which 0 to 3 are selected from O, N and S and oxidised forms thereof, the carbocyclic or cyclic aromatic or non-aromatic group being optionally S substituted with one or more substituents R8; provided that when A is a bond, then R7 is Cyc‘; and provided also that when R7 is hydrogen, then A has a chain length of at least four chain s and ns at least two heteroatom chain s; R8 is selected from: . halogen; . oxo; . cyano; . nitro; . a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; and . a group Ra-Rb; R81 is a bond, 0, CO, X1C(X2), C(X2)X1, )X1, 8, 80, 802, NRC, 802NRc or NRcsoz; Rb is: . hydrogen; . a carbocyclic and heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the yclic or heterocyclic group being optionally substituted with one or more substituents R9; . an acyclic C142 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1.8 non-aromatic hydrocarbylamino; and carbocyclic and cyclic groups having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being ally substituted with one or more substituents R9; wherein one or more but not all of the carbon atoms of the acyclic C142 hydrocarbyl group may optionally be replaced by O, 8, 80, 802, NRC, x‘C(x2), C(x2)x1 or x‘C(x2)x‘; Rc is: . hydrogen; . a carbocyclic and heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; . an acyclic C142 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or 8 non-aromatic arbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; wherein one or more but not all of the carbon atoms of the acyclic C142 arbyl group may optionally be ed by O, 8, 80, 802, NH, N-C1_4 alkyl, C(O)O, OC(O), NH(CO), C(O)NH, NH(CO)NH, N(C1_4 alkyl)C(O), C(O)N(CM alkyl) X1 is o, s or NRC; and X2 is =0, :8 or =NRC; wherein R9 is selected from R8 ed that when the tuents R9 contain a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group is unsubstituted or substituted with one or more substituents R10; R10 is selected from halogen, oxo, cyano, and an acyclic CH; hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano;carboxy; amino; mono- or di-C1.2 alkylamino; wherein one but not all of the carbon atoms of the acyclic CH; hydrocarbyl group may optionally be replaced by O, 8, 80, 802, NH or NMe; R11 is ed from amino, Hyd1, 1, N(Hyd1)2; and Cyc1; Hyd1 is a omatic CH; arbyl group optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino and Cycl, wherein one or two of the carbon atoms of the non-aromatic CH; hydrocarbyl group may optionally be replaced by O, NH, N-Hyd2, C(=O), 8, 80 or 802, provided that at least one carbon atom of the hydrocarbyl group remains; Hyd2 is a CM hydrocarbyl group; and wherein in any group ting of or containing a hydrocarbyl moiety, the hydrocarbyl moiety is a arbon group optionally containing one or more single, double or triple carbon-carbon bonds or combinations thereof. 1.2 A compound according to any one of Embodiments 1.0 to 1.1 wherein R1 is selected from hydrogen, fluorine, C13 hydrocarbyl and C13 hydrocarbyloxy. 2015/015030 1.3 A compound ing to Embodiment 1.2 wherein R1 is selected from hydrogen, ne, C12 hydrocarbyl and C12 hydrocarbyloxy. 1.4 A compound according to Embodiment 1.3 wherein R1 is selected from hydrogen, fluorine, methyl and methoxy. 1.5 A compound according to Embodiment 1.1 wherein R1 is selected from hydrogen and CM hydrocarbyloxy. 1.6 A compound according to Embodiment 1.5 wherein R1 is selected from hydrogen and methoxy. 1.7 A compound according to Embodiment 1.6 wherein R1 is hydrogen. 1.8 A compound according to Embodiment 1.6 n R1 is methoxy. 1.9 A compound according to any one of Embodiments 1.0 to 1.8 wherein R2 is selected from hydrogen, fluorine, C13 hydrocarbyl and C13 hydrocarbyloxy. 1.9A A compound according to Embodiment 1.9 wherein R2 is selected from hydrogen, fluorine and C1_3 hydrocarbyloxy. 1.10 A compound ing to Embodiment 1.9 wherein R2 is selected from hydrogen, fluorine, C12 hydrocarbyl and C12 hydrocarbyloxy. 1.11 A compound ing to ment 1.10 n R2 is selected from hydrogen, fluorine, methyl and methoxy. 1.12 A compound according to any one of Embodiments 1.0 to 1.8 wherein R2 is selected from hydrogen and CM hydrocarbyloxy. 1.13 A compound according to Embodiment 1.12 wherein R2 is selected from hydrogen and methoxy. 1.14 A compound according to Embodiment 1.13 n R2 is hydrogen. 1.15 A compound according to Embodiment 1.13 wherein R2 is methoxy. 1.16 A nd according to any one of Embodiments 1.0 to 1.1 wherein one of R1 and R2 is hydrogen and the other is methoxy. 1.17 A compound according to Embodiment 1.1 wherein both of R1 and R2 are methoxy. 1.18 A compound according to any one of Embodiments 1.0 to 1.1 wherein both of R1 and R2 are hydrogen. 1.19 A nd according to any one of ments 1.0 to 1.18 wherein R3 is selected from hydrogen and chlorine. 1.20 A compound according to any one of Embodiments 1.0 to 1.19 wherein R4 is selected from hydrogen, methyl and chlorine. 1.21 A compound according to ment 1.19 or Embodiment 1.20 wherein one of R3 and R4 is hydrogen and the other is ne. 1.22 A compound according to Embodiment 1.19 or ment 1.20 wherein both of R3 and R4 are hydrogen. 1.23 A compound ing to any one of Embodiments 1.0 to 1.1 wherein R1 is methoxy and R2, R3 and R4 are all hydrogen. 1.24 A compound according to any one of Embodiments 1.0 to 1.1 wherein R1 and R2 are both methoxy and R3 and R4 are both hydrogen. 1.25 A compound according to any one of Embodiments 1.0 to 1.1 wherein R1, R2, R3 and R4 are all hydrogen. 1.26 A compound according to any one of Embodiments 1.0 to 1.1 wherein R1 is methoxy, R2 is hydrogen, R3 is chlorine and R4 is hydrogen. 1.27 A compound according to any one of ments 1.0 to 1.26 n R5 is selected from hydrogen and cyano. 1.28 A compound according to Embodiment 1.27 wherein R5 is cyano. 1.29 A compound according to Embodiment 1.27 wherein R5 is en. 1.30 A compound according to any one of Embodiments 1.0 to 1.29 wherein R6 is selected from hydrogen, methyl and methoxy. 1.30A A compound according to Embodiment 1.30 wherein R6 is hydrogen. 1.308 A compound according to any one of Embodiments 1.1 to 1.30A wherein A is selected from: (i) a bond; (ii) (CRqu)X where RD and Rq are each independently hydrogen or methyl and x is 1 to 3; (iii) an oxygen atom; (iv) a group NRr wherein Rr is en or methyl; and (v) a saturated chain of 2 to 8 chain members in length containing at least one carbon atom chain , at least one heteroatom chain member ed from nitrogen and oxygen, and optionally one or more further carbon atom chain members and/or heteroatom chain members selected from nitrogen, oxygen, sulphur, sulphinyl and sulphonyl; the saturated chain being optionally substituted with one or more substituents selected from =O, CM hydrocarbyl, hydroxy-C1_4 hydrocarbyl, C1_2-alkoxy-C1_4 hydrocarbyl, and fluorine wherein two hydrocarbyl tuents on the same carbon atom may ally link to form a ring of three to five ring members; provided that when A is a bond, CR"Rq or an oxygen atom, then R7 is other than hydrogen; and provided also that when R7 is hydrogen, then A has a chain length of at least four chain members and contains at least two heteroatom chain members. 1.30C A compound according to Embodiment 1.308 wherein A is selected from: (i) a bond; (ii) (CRqu)X where RD and Rq are each independently hydrogen or methyl and x is 1 to 3; (iii) an oxygen atom; (iv) a group NRr wherein Rr is hydrogen or methyl; and (v) a saturated chain of 2 to 6 chain members in length containing at least one carbon atom chain member, at least one heteroatom chain member selected from nitrogen and oxygen, and ally one or more further carbon atom chain members and/or heteroatom chain members selected from nitrogen, oxygen, r, sulphinyl and sulphonyl; the saturated chain being optionally substituted with one or more substituents selected from =O, CM hydrocarbyl, y-C1_4 hydrocarbyl, C1_2-alkoxy-C1_4 hydrocarbyl, and fluorine wherein two arbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members; provided that when A is a bond, CR"Rq or an oxygen atom, then R7 is other than hydrogen; and provided also that when R7 is hydrogen, then A has a chain length of at least four chain members and contains at least two heteroatom chain members. 1.30D A compound according to Embodiment 1.30C wherein A is selected from: (i) a bond; (ii) X where RD and Rq are each independently hydrogen or methyl and x is 1; (iii) an oxygen atom; (iv) a group NRr wherein Rr is hydrogen or methyl; and (v) a saturated chain of 2 to 6 chain s in length containing at least one carbon atom chain member, at least one heteroatom chain member selected from en and oxygen, and ally one or more further carbon atom chain members and/or heteroatom chain members selected from nitrogen, oxygen, sulphur, sulphinyl and sulphonyl; the saturated chain being optionally substituted with one or more substituents selected from =O, CM hydrocarbyl, and fluorine wherein two hydrocarbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members; provided that when A is a bond, CR"Rq or an oxygen atom, then R7 is other than hydrogen; and provided also that when R7 is hydrogen, then A has a chain length of at least four chain s and contains at least two heteroatom chain members 1.30E A compound according to ment 1.30D wherein A is selected from: (i) a bond; (ii) CR"Rq where RD and Rq are each ndently hydrogen or methyl; (iii) an oxygen atom; and (v) a saturated chain of 2 to 6 chain members in length containing at least one carbon atom chain member, at least one heteroatom chain member selected from nitrogen and oxygen, and optionally one or more further carbon atom chain members and/or heteroatom chain members selected from nitrogen, oxygen, sulphur, sulphinyl and sulphonyl; the ted chain being ally substituted with one or more substituents selected from =O, CM hydrocarbyl and fluorine wherein two hydrocarbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members; provided that when A is a bond, CR"Rq or an oxygen atom, then R7 is other than hydrogen; and ed also that when R7 is hydrogen, then A has a chain length of at least four chain members and contains at least two heteroatom chain members. 1.30F A compound according to ment 1.30E wherein A is selected from: (i) a bond; (ii) CR"Rq where RD and Rq are each independently hydrogen or methyl; (iii) an oxygen atom; and (v) a ted chain of 2 to 5 chain members in length ning at least one carbon atom chain member, at least one heteroatom chain member selected from nitrogen and oxygen, and optionally one or more further carbon atom chain members and/or heteroatom chain members ed from nitrogen, oxygen, sulphur, sulphinyl and sulphonyl; the saturated chain being optionally tuted with one or more substituents selected from =O, CM arbyl and fluorine wherein two hydrocarbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members; provided that when A is a bond, CR"Rq or an oxygen atom, then R7 is other than hydrogen; and provided also that when R7 is hydrogen, then A has a chain length of at least four chain members and contains at least two heteroatom chain members. 1.30G A compound according to Embodiment 1.30F wherein A is selected from: (i) a bond; (ii) CH2; (iii) an oxygen atom; and (v) a saturated chain of 2 to 5 chain members in length containing a single heteroatom chain member which is nitrogen or oxygen; the saturated chain being optionally substituted with one or more substituents selected from =O, CM arbyl and fluorine; provided that when A is a bond, CH2 or an oxygen atom, then R7 is other than hydrogen; and provided also that when R7 is hydrogen, then A has a chain length of at least four chain members and contains at least two heteroatom chain members. 1.30H A compound according to Embodiment 1.30G wherein A is selected from: (i) a bond; (ii) CH2; (iii) an oxygen atom; and (v) a saturated chain of 2 to 5 chain members in length having the formula -(CRVRW)m-J-(CRXRy)n-; wherein J is NRZ, O or NHC(=O); R“, R‘”, R",Ry and RZ are each hydrogen or methyl; m is 0, 1, 2 or 3 and n is 0, 1, 2 or 3 wherein the sum of m and n is no greater than 4 or, when J is NH(=O), the sum of m and n is no greater than 3; provided that R7 is other than hydrogen. 1.30J A compound according to Embodiment 1.30H wherein A is selected from: (i) a bond; (ii) CH2; (iii) an oxygen atom; and (v) a saturated chain of 2 to 4 chain members in length having the formula -(CRVRW)m-J-(CRXRy)n-; wherein J is NRZ, O or NHC(=O); R“, R‘”, R",Ry and RZ are each hydrogen or methyl; m is 0, 1 or 2 and n is 0, 1 or 2 wherein the sum of m and n is no r than 3 or, when J is NH(=O), the sum of m and n is no greater than 2; provided that R7 is other than hydrogen. 1.30K A compound ing to any one of Embodiments 1.0 to 1.30C wherein, when A is (CRqu)x, then x is 1, 2 or 3. 1.30L A compound according to any one of Embodiments 1.0 to 1.30C wherein, when A is (CRqu)x, then x is 1 or 2. 1.30M A compound according to any one of Embodiments 1.0 to 1.30C n, when A is (CRqu)x, then x is 1. 1.31 A compound according to ment 1308 n A is selected from: (i) a bond; and (ii) a saturated chain of 2 to 8 chain members in length containing at least one carbon atom chain member, at least one heteroatom chain member selected from nitrogen and oxygen, and optionally one or more further carbon atom chain members and/or heteroatom chain members selected from nitrogen, oxygen, sulphur, nyl and sulphonyl; the saturated chain being optionally tuted with one or more substituents selected from =O, CM hydrocarbyl and fluorine wherein two hydrocarbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members; 2015/015030 provided that when A is a bond, then R7 is Cyc1; and provided also that when R7 is hydrogen, then A has a chain length of at least four chain members and contains at least two heteroatom chain members. 1.32 A compound according to Embodiment 1.31 wherein A is is ed from: (i) a bond; and (ii) a saturated chain of 2 to 6 chain members in length containing at least one carbon atom chain , at least one heteroatom chain member selected from nitrogen and oxygen, and optionally one or more r carbon atom chain members and/or heteroatom chain members selected from nitrogen, oxygen, sulphur, sulphinyl and sulphonyl; the saturated chain being optionally substituted with one or more substituents selected from =O, CM hydrocarbyl and fluorine wherein two hydrocarbyl substituents on the same carbon atom may ally link to form a ring of three to five ring members; provided that when A is a bond, then R7 is Cyc1; and ed also that when R7 is hydrogen, then A has a chain length of at least four chain members and contains at least two atom chain s. 1.33 A nd according to Embodiment 1.32 wherein A is is selected from: (i) a bond; and (ii) a saturated chain of 2 to 5 chain members in length containing at least one carbon atom chain member, at least one heteroatom chain member selected from nitrogen and oxygen, and optionally one or more further carbon atom chain members and/or heteroatom chain members selected from nitrogen, oxygen, sulphur, sulphinyl and sulphonyl; the ted chain being optionally substituted with one or more substituents selected from =O, CM hydrocarbyl and fluorine wherein two hydrocarbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members; provided that when A is a bond, then R7 is Cyc1; and provided also that when R7 is hydrogen, then A has a chain length of at least four chain members and contains at least two heteroatom chain members. 1.34 A compound according to Embodiment 1.33 n A is is selected from: (i) a bond; and (ii) a saturated chain of 2 to 5 chain members in length containing a single heteroatom chain member which is nitrogen or oxygen; the saturated chain being optionally substituted with one or more substituents selected from =O, CM hydrocarbyl and fluorine; provided that when A is a bond, then R7 is Cyc‘; and provided also that R7 is other than hydrogen. 1.35 A compound according to Embodiment 1.34 wherein A is is ed from: (i) a bond; and (ii) a saturated chain of 2 to 5 chain members in length containing a single atom chain member which is en; the saturated chain being optionally substituted with one or more substituents ed from =O, CM hydrocarbyl and fluorine; provided that when A is a bond, then R7 is Cyc‘; and provided also that R7 is other than hydrogen. 1.36 A compound according to Embodiment 1.35 wherein A is is selected from: (i) a bond; and (ii) a saturated chain of 2 to 5 chain members in length containing a single heteroatom chain member which is nitrogen; the saturated chain being ally substituted with one or more substituents selected from methyl and fluorine; provided that when A is a bond, then R7 is Cyc1; and provided also that R7 is other than hydrogen. 1.37 A compound according to Embodiment 1.36 wherein A is is selected from: (i) a bond; and (ii) a saturated chain of 2 to 5 chain members in length containing a single heteroatom chain member which is nitrogen; the saturated chain being optionally substituted with one or more methyl groups; provided that when A is a bond, then R7 is Cyc‘; and provided also that R7 is other than hydrogen. 1.38 A nd ing to Embodiment 1.37 wherein A is is selected from: (i) a bond; and (ii) a saturated chain of 2 to 5 chain members in length having the formula -(CRVRW)m-NH-(CRXRy)n-; wherein R“, R‘”, RX and Ry are each hydrogen or methyl; m is 0, 1, 2 or 3 and n is 0, 1, 2 or 3 wherein the sum of m and n is no greater than 4; provided that when A is a bond, then R7 is Cyc‘; and provided also that R7 is other than hydrogen. 1.39 A compound according to Embodiment 1.38 n A is is selected from: (i) a bond; and (ii) a saturated chain of 2 to 4 chain s in length having the formula -(CRVRW)m-NH-(CRXRy)n-; wherein R“, R‘”, RX and Ry are each hydrogen or methyl; m is 0, 1 or 2 and n is 0, 1 or 2 wherein the sum of m and n is no greater than 3; ed that when A is a bond, then R7 is Cyc‘; and provided also that R7 is other than hydrogen. 1.40 A compound according to any one of Embodiments 1.30H, 1.30J, 1.38 and 1.39 wherein no more than two R“, R‘”, RX or Ry groups are methyl. 1.41 A compound according to any one of Embodiments 1.3OB, 1.30C, 1.30K, 1.30L, 1.38 and 1.39 wherein all of RV, RW, RX and Ry are hydrogen. 1.42 A compound according to Embodiment 1.41 wherein one R“, R‘”, RX or Ry group is methyl and the others are all hydrogen. 1.43 A nd according to any one of Embodiments 1.0 to 1.42 n A is a saturated chain. 1.43A A compound according to any one of Embodiments 1.0 to 1.30A wherein A is selected from a bond; -CH2-NH-C(=O)-, -NH-CH2- ; '(CH2)'NH'(CH2)'§ '(CH2)'N(Me)'(CH2)'(CH2)' ; -(CH2)-NH-(CH2)-(CH2)-; -(CH2)-(CH2)-NH-(CH2)-; -(CH2)-NH-(CHMe)-; -(CH2)-NH-(CHM eHCHz)‘; 'NH-CHz-CH2'§ '(CH2)'NH'(CM92)'(CH2)'§ '0'; 'O'(CH2)'§ '(CH2)'NH' ; -(CH2)-NMe-; and -CH2-. 1.44 A compound according to any one of Embodiments 1.0 to 1.30A wherein A is selected from a bond; -NH-CH2-; -(CH2)-NH-(CH2)-; -(CH2)-N(Me)-(CH2)- ; -NH-(CH2)-(CH2)-; -(CH2)-(CH2)-NH-(CH2)-; and -(CH2)-NH-(CHMe)-. 1.45 A compound according to Embodiment 1.44 wherein A is a bond. 1.46 A nd according to ment 1.44 wherein A is ed from -NH-CH2- ; -(CH2)-NH-(CH2)-; -(CH2)-NH-(CH2)-(CH2)-; -(CH2)-(CH2)-NH-(CH2)-; and -NH-(CHMe)-. 1.47 A compound according to Embodiment 1.46 wherein A is selected from -(CH2)-NH-(CH2)-; -(CH2)-NH-(CH2)-(CH2)-; -(CH2)-(CH2)-NH-(CH2)-; and -(CH2)-NH-(CHMe)-. 1.48 A compound according to Embodiment 1.47 wherein A is -NH-(CH2)-. 1.49 A compound according to Embodiment 1.47 wherein A is -(CH2)-NH-(CH2)-(CH2)-. 2015/015030 1.50 A compound according to Embodiment 1.47 wherein A is -(CH2)-(CH2)-NH-(CH2)-. 1.51 A compound according to Embodiment 1.47 n A is -(CH2)-NH-(CHMe)-. 1.51A A compound according to Embodiment 1.43A wherein A is H-C(=O)-. 1.51 B A nd ing to Embodiment 1.43A wherein A is -NH-CH2-. 1.51C A compound according to Embodiment 1.43A wherein A is -(CH2)-N(Me)—(CH2)-(CH2)-. 1.51D A nd according to Embodiment 1.43A wherein A is -(CH2)-NH-(CHMe)-(CH2)-. 1.51 E A compound according to Embodiment 1.43A wherein A is -NH-CH2-CH2-. 1.51 F A compound according to Embodiment 1.43A wherein A is -(CH2)-NH-(CMe2)-(CH2)-. 1.51G A compound according to Embodiment 1.43A wherein A is -O-. 1.51 H A compound according to Embodiment 1.43A wherein A is -O-(CH2)-. 1.51J A compound according to Embodiment 1.43A wherein A is -(CH2)-NH-. 1.51 K A compound according to Embodiment 1.43A wherein A is -(CH2)—NMe-. 1.51 L A compound according to Embodiment 1.43A wherein A is -CH2-. 1.51M A compound according to to any one of Embodiments 1.0 to 1.30A wherein A is a group NRr wherein Rr is hydrogen or methyl. 1.51N A compound according to Embodiment 1.51M wherein Rr is hydrogen. 151P A compound according to any one of Embodiments 1.0 to 1.51N wherein R7 is ed from hydrogen; R11SOZ-; amino; NH-Hyd1; N(Hyd1)2; and a group Cyc1 wherein Cyc1 is a carbocyclic or heterocyclic aromatic or non-aromatic group of 3 to 9 ring members of which 0 to 3 are selected from O, N and S and ed forms thereof, the carbocyclic or heterocyclic aromatic or omatic group being optionally substituted with one or more substituents R8; provided that when A is a bond, (CRqu)X, an oxygen atom or NRr, then R7 is other than hydrogen; and provided also that when R7 is hydrogen, then A has a chain length of at least four chain members and contains at least two heteroatom chain members; 1.52 A compound ing to Embodiment 1.51P wherein R7 is ed from hydrogen; R11SOZ-; amino, NH-Hyd‘, )2; and a group Cyc1 which is a carbocyclic or heterocyclic aromatic or omatic group of 3 to 9 ring members of which 0 to 3 are selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic aromatic or non-aromatic group being optionally tuted with one or more substituents 1.53 A nd according to Embodiment 1.52 wherein R7 is selected from hydrogen; R11SOZ-; amino, NH-Hyd‘, N(Hyd1)2; and a group Cyc1 which is a carbocyclic or heterocyclic aromatic or non-aromatic group of 3 to 8 ring members of which 0 to 3 are selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic aromatic or non-aromatic group being optionally substituted with one or more substituents 1.54 A compound according to Embodiment 1.53 wherein R7 is selected from hydrogen; R11SOZ-; amino, NH-Hyd‘, N(Hyd1)2; and a group Cyc1 which is a carbocyclic or heterocyclic aromatic or non-aromatic group of 3 to 7 ring members of which 0 to 3 are selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic aromatic or non-aromatic group being ally substituted with one or more substituents R8. 1.55 A compound according to Embodiment 1.54 wherein R7 is selected from hydrogen; -; amino, NH-Hyd‘, N(Hyd1)2; and a group Cyc1 which is a carbocyclic or heterocyclic aromatic or non-aromatic group of 5 or 6 ring members of which 0 to 2 are ed from O, N and S and oxidised forms thereof, the yclic or heterocyclic aromatic or non-aromatic group being optionally substituted with one or more substituents 1.56 A compound ing to Embodiment 1.54 wherein R7 is selected from R11SOZ-; amino, NH-Hyd1, N(Hyd1)2; and a group Cyc1 which is a carbocyclic or heterocyclic aromatic or non-aromatic group of 5, 6 or 7 ring members of which 0 to 2 are selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic aromatic or omatic group being optionally substituted with one or more substituents R8. 1.57 A compound according to any one of Embodiments 1.0 to 1.56 wherein R7 is a group Cyc‘. 1.57A A compound according to Embodiment 1.57 wherein Cyc1 is is a carbocyclic or heterocyclic aromatic or non-aromatic group of 3 to 9 ring members of which 0 to 3 are selected from O, N and S and oxidised forms thereof, the yclic or heterocyclic aromatic or non-aromatic group being optionally substituted with one or more substituents 1.578 A compound according to Embodiment 1.57A wherein Cyc1 is is a carbocyclic or heterocyclic aromatic or non-aromatic group of 3 to 8 ring members of which 0 to 3 are ed from O, N and S and oxidised forms thereof, the yclic or heterocyclic ic or non-aromatic group being optionally substituted with one or more substituents R8. 1.57C A compound according to Embodiment 1578 n Cyc1 is is a carbocyclic or heterocyclic aromatic or non-aromatic group of 3 to 7 ring members of which 0 to 3 are selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic aromatic or non-aromatic group being optionally substituted with one or more substituents R8. 1.57D A compound according to Embodiment 1.57C wherein Cyc1 is is a carbocyclic or heterocyclic aromatic or non-aromatic group of 3 to 7 ring members of which 0 to 2 are selected from O and N, the carbocyclic or heterocyclic ic or non-aromatic group being optionally substituted with one or more substituents R8. 1.57E A compound according to Embodiment 1.57D wherein Cyc1 is a carbocyclic or heterocyclic aromatic or non-aromatic group ed from cyclopropane, , tetrahydrofuran, ydropyran, azetidine, pyrrolidine, dine, piperazine, morpholine and 1,4-diazepane, the carbocyclic or heterocyclic aromatic or omatic group being optionally substituted with one or more substituents R8. 1.58 A compound according to Embodiment 1.56 wherein R7 is selected from R11802-; amino, 1 and N(Hyd1)2. 1.59 A compound according to Embodiment 1.56 wherein R7 is R11802-. 1.60 A compound according to Embodiment 1.56 wherein R7 is selected from amino, NH-Hyd1 and N(Hyd1)2. 1.61 A compound according to any one of Embodiments 1.0 to 1.57 wherein the moiety A-R7 is other than an optionally substituted biphenyl group. 1.61A A compound according to any one of Embodiments 1.0 to 1.57 wherein, when A is a bond and R7 is Cyc‘, Cyc1 is a non-aromatic carbocyclic or heterocyclic group. 1618 A compound according to any one of Embodiments 1.0 to 1.57, 1.61 and 1.61A wherein Cyc1 is a carbocyclic or heterocyclic aromatic group of 5 to 9 ring members of which 0 to 3 are ed from O, N and S and ed forms thereof, the carbocyclic or heterocyclic aromatic group being optionally substituted with one or more substituents R8. 1.62 A compound ing to any one of Embodiments 1.57, 1.61, 1.61A and 1618 wherein Cyc1 is a benzene ring which is optionally substituted with one or more substituents R8. 1.63 A compound according to any one of Embodiments 1.57, 1.61, 1.61A and 1618 wherein Cyc1 is a heterocyclic aromatic group of 5 to 9 ring members of which 0 to 3 are selected from O, N and S and oxidised forms thereof, the heterocyclic aromatic group being optionally substituted with one or more substituents R8. 1.64 A compound according to any one of Embodiments 1.57, 1.61, 1.61A and 1618 wherein Cyc1 is a heterocyclic non-aromatic group of 4 to 7 ring members of which 1 or 2 are selected from O, N and S and ed forms thereof, the heterocyclic non-aromatic group being optionally substituted with one or more substituents R8. 1.65 A compound according to Embodiment 1.64 wherein Cyc1 is a heterocyclic non- aromatic group of 5, 6 or 7 ring s of which 1 or 2 are selected from O, N and S and oxidised forms thereof, the heterocyclic non-aromatic group being optionally substituted with one or more substituents R8. 1.66 A compound according to Embodiment 1.64 wherein Cyc1 is a cyclic non- ic group selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, rpholine-S-S-dioxide, azepane, diazepane, tetrahydrofuran and tetrahydropyran the heterocyclic non-aromatic group being ally substituted with one or more substituents R8. 1.67 A compound according to Embodiment 1.66 wherein Cyc1 is selected from pyrrolidine, dine, piperazine, morpholine, azepane and diazepane, the heterocyclic non-aromatic group being optionally tuted with one or more substituents R8. 1.68 A compound according to Embodiment 1.67 wherein Cyc1 is selected from pyrrolidine, piperidine, piperazine and morpholine, the heterocyclic non-aromatic group being optionally substituted with one or more substituents R8. 1.69 A compound according to Embodiment 1.68 wherein Cyc1 is selected from piperidine and morpholine, the heterocyclic non-aromatic group being ally substituted with one or more substituents R8. 1.70 A nd according to Embodiment 1.69 wherein Cyc1 is dine which is optionally substituted with one or more tuents R8. 1.71 A compound according to Embodiment 1.69 wherein Cyc1 is morpholine which is optionally tuted with one or more substituents R8. 1.71A A compound according to Embodiment 1.68 wherein Cyc1 is piperazine optionally substituted with one or more substituents R8. 1.72 A compound according to to any one of Embodiments 1.57, 1.61, 1.61A and 1618 wherein Cyc1 is selected from a benzene ring, piperidine and morpholine, each being optionally substituted with one or more substituents R8. 1.73 A compound according to any one of Embodiments 1.1 to 1.57 and 1.61 to 1.72 wherein R8 is selected from: o fluorine; o chlorine; . bromine; . oxo; o cyano; o a carbocyclic or heterocyclic group having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or cyclic group being optionally substituted with one or more substituents R9; and . a group Ra-Rb. 1.74 A compound according to Embodiment 1.73 wherein R8 is selected from: o fluorine; o chlorine; . e; . oxo; . cyano; . a carbocyclic group having from 3 to 6 ring members, the carbocyclic group being ally substituted with one or more substituents R9; o a heterocyclic group having from 4 to 7 ring members, of which 1, 2 or 3 are atom ring members selected from O, N and S and oxidised forms thereof, the heterocyclic group being optionally substituted with one or more tuents R9; and . a group Ra-Rb. 1.75 A compound ing to any one of Embodiments 1.1 to 1.57 and 1.61 to 1.74 wherein R8 is selected from: o fluorine; o chlorine; . bromine; . oxo; . cyano; . a carbocyclic or heterocyclic group having from 3 to 7 ring members, of which 0, 1 or 2 are heteroatom ring s selected from O, N and S and oxidised forms f, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; and . a group Ra-Rb; R81 is a bond, 0, CO, X1C(X2), C(X2)X1, )X1, 8, 80, 802, NRC, 802NRc or NRCSO2; Rb is: . hydrogen; . a carbocyclic and heterocyclic group having from 3 to 7 ring members, of which 0, 1 or 2 are atom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; . an acyclic CH; hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; fluorine; cyano; carboxy; amino; mono- or di-C1_2 hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 7 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or cyclic group being optionally substituted with one or more substituents R9; wherein one or two but not all of the carbon atoms of the acyclic CH; hydrocarbyl group may optionally be replaced by O, 8, 80, 802, NH, NMe, C02, OC(=O), CONH, NHCO; CON(Me) and N(Me)CO; Rc is hydrogen or CM hydrocarbyl; X1 is 0,8 or NRC; and x2 is =0, :8 or =NRC; 2015/015030 wherein R9 is selected from R8 provided that the tuents R9 do not contain a carbocyclic or cyclic group. 1.76 A compound according to Embodiment 1.75 wherein R8 is selected from: o fluorine; . chlorine; . bromine; . oxo; o cyano; . a carbocyclic group having 3 to 6 ring members, the carbocylic group being optionally substituted with one or more substituents R9; . a cyclic group having from 4 to 7 ring members, of which 1 or 2 are heteroatom ring members ed from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; and . a group Ra-Rb; R81 is a bond, 0, CO, OC(O), C(O)O, NRCC(O), C(O)NRC, NRCC(O)NRC, 8, 80, 802, NRC, SOZNRc or NRCSOZ; Rb is: . hydrogen; . a carbocyclic group having 3 to 6 ring members, the carbocylic group being optionally substituted with one or more substituents R9; . a heterocyclic group having from 4 to 7 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or cyclic group being optionally substituted with one or more substituents R9; . an acyclic CM hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; fluorine; cyano; carboxy; amino; mono- or 2 hydrocarbylamino; and carbocyclic groups having from 3 to 6 ring members and heterocyclic groups having from 4 to 7 ring members, of which 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic groups being optionally substituted with one or more substituents R9; wherein one but not all of the carbon atoms of the acyclic CH; hydrocarbyl group may optionally be replaced by O, 8, 80, 802, NH, NMe, C02, OC(=O), CONH, NHCO; CON(Me) and N(Me)CO; Rc is hydrogen or CH alkyl; x1 is o, s or NRC; and x2 is =0, :8 or =NRC; wherein R9 is selected from fluorine, chlorine, bromine, oxo, cyano, C1_4 alkyl, C3_4 cyc|oa|kyl, cyclopropylmethyl, C1_4 alkoxy, hydroxy, amino, mon- or 4 alkylamino, carbamoyl, mono- or diC1_4alkylcarbamoyI, aminosulphonyl, mono-ordi- C1_4alkylaminosu|phonyl, kylsu|phonamido, and when R9 consists of or contains a C1_4 alkyl group, the C1_4 alkyl group is optionally substituted with one or more fluorine atoms or by C12 alkoxy. 1.77 A nd according to ment 1.76 wherein R8 is selected from: o fluorine; o chlorine; . bromine; . oxo; o cyano; . a carbocyclic group having 3 to 6 ring members, the carbocylic group being optionally substituted with one or more substituents R9; . a heterocyclic group having from 4 to 7 ring members, of which 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the yclic or heterocyclic group being optionally substituted with one or more substituents R9; and . a group Ra-Rb; R81 is a bond, 0, CO, OC(O), C(O)O, ), C(O)NRC, NRCC(O)NRC, 8, 80, 802, NRC, SOZNRc or NRCSOZ; Rb is: . hydrogen; . a carbocyclic group having 3 to 6 ring members, the carbocylic group being optionally substituted with one or more substituents R9; . a heterocyclic group having from 4 to 7 ring members, of which 0, 1 or 2 are heteroatom ring members ed from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; . an acyclic CM hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; fluorine; cyano; carboxy; amino; mono- or di-C1_2 hydrocarbylamino; and carbocyclic groups having from 3 to 6 ring members and heterocyclic groups having from 4 to 7 ring members, of which 1 or 2 are heteroatom ring members ed from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic groups being ally substituted with WO 20390 one or more substituents R9; wherein one but not all of the carbon atoms of the acyclic CH; hydrocarbyl group may optionally be replaced by O, 8, 80, 802, NH, NMe, C02, , CONH, NHCO; CON(Me) and N(Me)CO; Rc is hydrogen or C1_4 alkyl; X1 is 0,8 or NRC; and X2 is =0, :8 or =NRC; wherein R9 is selected from fluorine, chlorine, bromine, oxo, cyano, C1_4 alkyl, C3_4 cycloalkyl, cyclopropylmethyl, C1_4 alkoxy, hydroxy, amino, mon- or di-C1_4 alkylamino, carbamoyl, mono- or diC1_4alkylcarbamoyl, aminosulphonyl, mono-ordi- C1_4alkylaminosulphonyl, C1_4alkylsulphonamido, and when R9 consists of or contains a C1_4 alkyl group, the C1_4 alkyl group is optionally substituted with one or more ne atoms or by C12 alkoxy. 1.78 A compound according to ment 1.77 wherein R8 is selected from: o fluorine; o chlorine; . bromine; . oxo; o cyano; . a carbocyclic group having 3 to 5 ring members; . a heterocyclic group having from 5 to 6 ring members, of which 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; and . a group Ra-Rb; R2:1 is a bond, 0, CO, OC(O), C(O)O, NRCC(O), C(O)NRC, NRCC(O)NRC, 8, 80, 802, NRC, SOZNRc or NRCSOZ; Rb is: . hydrogen; . a carbocyclic group having 3 to 5 ring members; o a heterocyclic group having from 5 to 6 ring members, of which 1 or 2 are atom ring s selected from O, N and S and oxidised forms thereof, the carbocyclic or cyclic group being optionally substituted with one or more substituents R9; . a CM alkyl group optionally substituted with one or more substituents selected from hydroxy; oxo; fluorine; cyano; amino; mono- or di-methylamino; yclic groups having from 3 to 5 ring members and heterocyclic groups having from 5 to 2015/015030 6 ring members, of which 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic groups being optionally substituted with one or more substituents R9; Rc is hydrogen or methyl; wherein, (i) when the carbocyclic or heterocylic groups are non-aromatic, R9 is ed from fluorine, oxo, cyano, C1_4 alkyl, C3_4 cycloalkyl, cyclopropylmethyl, C1_4 alkoxy, hydroxy, amino, mon- or di-C1_4 alkylamino, carbamoyl, mono- or diC1_4alkylcarbamoyl, aminosulphonyl, mono-or di-C1_4alkylaminosulphonyl, C1_4alkylsulphonamido, and when R9 consists of or contains a CM alkyl group, the CM alkyl group is optionally tuted with C12 alkoxy; and (ii) when the carbocyclic or heterocylic groups are ic, R9 is selected from fluorine, chlorine, bromine, cyano, C1_4 alkyl, C3_4 cycloalkyl, cyclopropylmethyl, C1_4 alkoxy, hydroxy, amino, mon- or di-C1_4 alkylamino, carbamoyl, mono- or diC1_4alkylcarbamoyl, aminosulphonyl, mono-or di-C1.4alkylaminosulphonyl, C1_4alkylsu|phonamido, and when R9 consists of or contains a CM alkyl group, the CM alkyl group is optionally substituted with one or more fluorine atoms or by C12 alkoxy. 1.79 A compound according to Embodiment 1.78 wherein R8 is selected from: o ne; o chlorine; . bromine; . oxo; o cyano; . a heterocyclic group having from 5 to 6 ring members, of which 1 or 2 are atom ring members selected from O, N and S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; and . a group Ra-Rb; R2:1 is a bond, 0, CO or 802; Rb is: . ropyl; . a heterocyclic group having from 5 to 6 ring members, of which 1 or 2 are heteroatom ring members selected from O, N and S, the yclic or heterocyclic group being optionally substituted with one or more methyl substituents R9; . a CM alkyl group optionally substituted with one or more substituents selected from oxo; fluorine; cyano; amino; mono- or di-methylamino; cyclopropyl; heterocyclic groups having from 5 to 6 ring members, of which 1 or 2 are atom ring members selected from O, N and S, the carbocyclic or heterocyclic groups being optionally substituted with one or more methyl substituents R9; 1.79A A compound ing to Embodiment 1.76 wherein R8 is selected from: o fluorine; o chlorine; . oxo; o cyano; . a group Ra-Rb; R2:1 is a bond, 0, CO or 802; Rb is selected from: . cyclopropyl; and . a CM alkyl group optionally substituted with one or more substituents selected from hydroxy; methoxy; oxo; fluorine; cyano; amino; mono- or di-methylamino; cyclopropyl. 1.798 A compound ing to Embodiment 1.79 wherein R8 is selected from fluorine, C1_3 alkyl, cyclopropylcarbonyl, dimethylaminoacetyl, aminocarbonylmethyl and yethyl. 1.79C A compound according to Embodiment 1.79 wherein R8 is selected from CM alkyl. 1.79D A compound according to Embodiment 1.79C wherein R8 is selected from C1_3 alkyl. 1.79E A compound according to Embodiment 1.79D wherein R8 is selected from methyl, ethyl and isopropyl. 1.79F A compound according to Embodiment 1.79E wherein R8 is methyl. 1.79G A compound according to Embodiment 1.79E wherein R8 is ethyl. 1.79H A nd according to Embodiment 1.79E wherein R8 is isopropyl. 1.80 A compound according to Embodiment 1.77 wherein: (i) Cyc1 is a non-aromatic group and R8 is absent or is selected from CM arbyl, drocarbylsulfonyl, oxo, di-C1.4hydrocarbylamino-C1_4alkanoyl; and CM hydrocarbylcarbonyl; or (ii) Cyc1 is an aromatic group and R8 is absent or is selected from CM hydrocarbyl; halogen; CM hydrocarbyloxy; cyano; methylenedioxy; carbamoyl; mono- or di-C1_4 alkylcarbamoyl; a 5- or ered saturated heterocyclic ring containing 1 or 2 heteroatoms ed from O, N and S, the heterocyclic ring being optionally substituted with one or more C1_4 alkyl group substituents; wherein the hydrocarbyl moieties in each of the CM hydrocarbyl and CM hydrocarbyloxy groups are optionally substituted with one or more tuents ed from fluorine, hydroxy, amino, r di-C1_4 alkylamino, oxo and C12 alkyl. 1.81 A compound according to Embodiment 1.80 wherein: (i) Cyc1 is a non-aromatic group and R8 is absent or is selected from CM hydrocarbyl, C1_4hydrocarbylsulfonyl, oxo, di-C1.4hydrocarbylaminoacetyl and CM hydrocarbylcarbonyl; or (ii) Cyc1 is an aromatic group and R8 is absent or is selected from C1.4 arbyl, halogen, C1_4 hydrocarbyloxy, cyano, morpholinyl, piperazinyl, N-methylpiperazinyl and methylenedioxy, wherein the hydrocarbyl moieties in each of the CM hydrocarbyl and CM hydrocarbyloxy groups are optionally substituted with one or more substituents ed from fluorine, hydroxy, amino, mono-or di-C1_4 alkylamino, oxo and C12 alkyl. 1.82 A compound according to Embodiment 1.81 wherein: (i) Cyc1 is a non-aromatic group and R8 is absent or is selected from CM alkyl, C1_4alkylsulfonyl, oxo, di-C1_4alkylaminoacetyl and cyclopropylcarbonyl; or (ii) Cyc1 is an aromatic group and R8 is absent or is selected from C1.4 alkyl, halogen, C1_4 , trifluoromethyl, trifluoromethoxy, morpholinyl, piperazinyl, N-methylpiperazinyl and enedioxy. 1.83 A nd according to Embodiment 1.82 wherein: (i) Cyc1 is a non-aromatic group and R8 is absent or is selected from methyl, methylsulfonyl, oxo, N,N-dimethylaminoacetyl and cyclopropylcarbonyl; or (ii) Cyc1 is an aromatic group and R8 is absent or is ed from fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, morpholinyl, piperazinyl, N-methylpiperazinyl and methylenedioxy. 1.84 A compound according to Embodiment 1.83 wherein: (i) Cyc1 is a non-aromatic heterocyclic group and R8 is absent or is selected from methyl and ropylcarbonyl; or (ii) Cyc1 is a benzene ring and R8 is absent or is selected from fluorine. 1.85 A compound according to any one of Embodiments 1.0 to 1.57E and 1.61 to 1.84 wherein 0, 1, 2, 3 or 4 substituents R8 are present in R7. 1.86 A nd ing to Embodiment 1.85 wherein 0, 1, 2 or 3 substituents R8 are present in R7. 1.87 A compound according to Embodiment 1.86 wherein 0, 1 or 2 substituents R8 are present in R7. 1.88 A compound ing to Embodiment 1.87 wherein 0 substituents R8 are present in R7. 1.89 A compound according to Embodiment 1.87 wherein 1 substituent R8 is t in 1.90 A compound according to Embodiment 1.87 wherein 2 substituents R8 are present in R7. 1.91 A compound according to Embodiment 1.86 wherein 3 substituents R8 are present in R7. 1.92 A compound according to any one of ments 1.0 to 1.57 wherein R7 is selected from: (i) phenyl optionally substituted with one or more substituents selected from methyl, fluorine, chlorine, y, cyano, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, methylenedioxy, morpholinyl, zinyl, N- methylpiperazinyl, acetyl, carbamoyl, methylcarbamoyl and dimethylcarbamoyl; (ii) cyclohexyl, morpholinyl, morpholinyl, 4- cyclopropylcarbonylmorpholinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N- isopropylpiperazinyl, piperidinyl, piperidinyl, piperidinyl, 1-methylsulfonylpiperidinyl , 1-cyclopropylcarbonylpiperidiny|, 1,4—diazepanyl, 4-methyl-diazepan yl, and , fluoropiperidinyl, pyrrolidinyl, 3,3-difluoropyrrolidinyl, pyrrolidonyl tetrahydropyranyl. 1.92A A compound according to any one of Embodiments 1.0 to 1.57 wherein R7 is selected from: (phenyl optionally substituted with one or more substituents selected from methyl, fluorine, chlorine, methoxy, cyano, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, methylenedioxy, morpholinyl, piperazinyl, N-methylpiperazinyl, , carbamoyl, methylcarbamoyl and dimethylcarbamoyl; (ii) cyclopropyl, cyclohexyl, pyridyl, methylazetidinyl, fluoro-methyl-azetidinyl, linyl, cyclopropylcarbonylmorpholinyl, piperazinyl, methylpiperazinyl, ylpiperazinyl, ethyl-methyl-piperazinyl, ethylpiperazinyl, isopropylpiperazinyl, piperidinyl, methylpiperidinyl, fluoropiperidinyl, difluoropiperidinyl, fluoro-ethyl-piperidin, -methyl-piperidinyl, difluoro-methyl-piperidinyl, difluoro-ethyl-piperidinyl, fluoro- isopropyl-piperidinyl, dimethyl-piperidinyl, ethyl-piperidinyl, yethyl-piperidinyl, hydroxyethyl-piperidinyl, pyl-piperidinyl, aminocarbonylmethyl-piperidinyl, sulfonyl-piperidinyl, cyclopropylcarbonylpiperidinyl, diazepanyl, methyl-diazepanyl, ethyl-diazepanyl, isopropyl-diazepanyl, pyrrolidinyl, methyl-pyrrolidinyl, isopropylpyrrolidinyl , difluoropyrrolidinyl, pyrrolidonyl, tetrahydrofuranyl, tetrahydropyranyl, ethylamino, N-isopropyl-N-methylamino 1.928 A compound according to Embodiment 1.92A wherein R7 is selected from phenyl; cyclopropyl, 2—pyridyl, 1-methyl-azetidinyl, 3-fluoromethyl-azetidinyl, morpholin yl, morpholinyl, 4-cyclopropylcarbonylmorpholinyl, piperazinyl, 2—methyl-piperazin yl, 1,2—dimethyl-piperazinyl, 1-ethylmethyl-piperazinyl, N-methylpiperazinyl, N- ethylpiperazinyl, N-isopropylpiperazinyl, piperidinyl, piperidinyl, piperidinyl, 1- methyl-piperidinyl, piperidinyl, 1-methyl-piperidinyl, piperidinyl, 4-fluoropiperidinyl , 1-methyl-piperidinyl, 4-fluoroethyl-piperidinyl, 3-fluoroethyl- dinyl, 3-fluoromethyl-piperidinyl, 3,3-difluoromethyl-piperidinyl, 3,3- difluoroethyl-piperidinyl, 4-fluoroisopropyl-piperidinyl, 3-fluoro—1-isopropyl- dinyl, 2,6-dimethyl-piperidinyl, 1-ethyl-piperidinyl, 1-(2—methoxyethyl)— piperidinyl, 1-(2—hydroxyethyl)-piperidinyl, 1-isopropyl-piperidinyl, 1- aminocarbonylmethyl-piperidinyl, 1-methylsulfonyl-piperidinyl, 1- cyclopropylcarbonylpiperidiny|, 1,4-diazepanyl, yl-diazepanyl, 4-ethyldiazepanyl , 4-isopropyl-diazepany|, 4,4-difluoropiperidinyl, pyrrolidinyl, yl- pyrrolidinyl, 1-isopropyl-pyrrolidinyl, 3,3-difluoropyrrolidinyl, pyrrolidonyl, tetrahydrofuranyl, ydropyrany, ethylamino and N-isopropyl-N-methylamino. 1.93 A nd according to Embodiment 1.92 n R7 is selected from , fluorophenyl, 4-morpholinyl, 1-methylpiperidinyl and 1-cyc|opropylcarbonyl-piperidin 1.94 A compound according to Embodiment 1.1 wherein: R1 is hydrogen or methoxy; R2 is en or methoxy; R3 is hydrogen; R4 is hydrogen; R5 is hydrogen or cyano; R6 is hydrogen; A is selected from a bond, -NH-CH2— ; '(CH2)'NH'(CH2)'§ '(CH2)'NH'(CH2)'(CH2)'§ '(CH2)'(CH2)'NH'(CH2)'; and -(CH2)-NH-(CHMe)-; and R7 is selected from phenyl, 4-fluorophenyl, 4-morpholinyl, 1-methylpiperidinyl and 1- cyclopropylcarbonyl-piperidinyl. 1.95 A compound according to ment 1.1 wherein: R1 is methoxy; R2 is hydrogen or methoxy; R3 is hydrogen; R4 is hydrogen; R5 is cyano; R6 is hydrogen; A is selected from a bond, 2- ; -(CH2)-NH-(CH2)-; -(CH2)-NH-(CH2)-(CH2)-; -(CH2)-(CH2)-NH-(CH2)-; and -(CH2)-NH-(CHMe)-; and R7 is selected from phenyl, 4-fluorophenyl, 4-morpholinyl, 1-methylpiperidinyl and 1- cyclopropylcarbonyl-piperidinyl. 1.96 A compound according to Embodiment 1.95 wherein: R1 is methoxy; R2 is hydrogen or methoxy; R3 is hydrogen; R4 is hydrogen; R5 is cyano; R6 is hydrogen; A is selected from a bond, -(CH2)-NH-(CH2)-; -(CH2)-NH-(CH2)-(CH2)-; -(CH2)-(CH2)-NH-(CH2)-; and '(CH2)-NH'(CHMe)-; and R7 is selected from phenyl, 4-fluorophenyl, 4-morpholinyl, ylpiperidinyl and 1- cyclopropylcarbonyl-piperidinyl. 1.97 A compound according to Embodiment 1.96 n: R1 is methoxy; R2 is hydrogen or methoxy; R3 is hydrogen; R4 is hydrogen; R5 is cyano; R6 is hydrogen; and (i) when A is a bond, R7 is 1-methylpiperidinyl; or (ii) when A is -(CH2)-NH-(CH2)-, R7 is selected from phenyl, rophenyl and 1- cyclopropylcarbonyl-piperidinyl; or (iii) when A is (CH2)-NH-(CH2)-(CH2)-, R7 is 4-morpholinyl; or (iv) when A is -(CH2)-(CH2)-NH-(CH2)-, R7 is phenyl; or (v) when A is -(CH2)-NH-(CHMe)-, R7 is rophenyl. 1.97A A compound according to Embodiment 1.0 n: R1 is methoxy; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is cyano; R6 is hydrogen; A is a bond; and R7 is piperazinyl optionally substituted with one or two C1_4 alkyl substituents. 1.978 A compound according to Embodiment 1.97A wherein R7 is piperazinyl optionally substituted with one or two CM alkyl substituents provided that the aggregate number of carbon atoms present in the tuents does not exceed four. 1.97C A compound ing to Embodiment 1.97A or 1.978 wherein R7 is piperazinyl which is (i) unsubstituted; or (ii) monosubstituted with a substituent selected from methyl, ethyl and isopropyl; or (iii) is disubstituted with two methyl substituents. 1.97D A compound according to Embodiment 1.97A or 1.978 wherein R7 is piperazinyl which is (ii) bstituted with a substituent selected from methyl, ethyl and isopropyl; or (iii) is disubstituted with two methyl tuents. 1.97E A compound according to Embodiment 1.97D wherein R7 is piperazinyl which is monosubstituted on a nitrogen atom thereof with a substituent selected from methyl, ethyl and isopropyl. 1.97F A compound according to Embodiment 1.97D wherein R7 is piperazinyl which is monosubstituted on a carbon atom thereof with a substituent ed from methyl, ethyl and isopropyl. 1.97G A compound according to ment 1.97C which is disubstituted on a single carbon atom thereof with two methyl substituents. 1.98 A compound according to Embodiment 1.0 or Embodiment 1.1 which is selected from: -[5-(4-benzylamino-2,6-dimethoxy-phenyl)-1H-pyrazolylamino]-pyrazine carbonitrile; -[5-(4-benzylaminomethoxy-phenyl)-1H-pyrazolylamino]-pyrazinecarbonitrile; -{5-[4-(benzylamino-methyl)methoxy-phenyl]-1H-pyrazolylamino}-pyrazine itrile (e.g. the hydrochloride salt); -{5-[4-(2—benzylamino-ethyl)methoxy-phenyl]-1H-pyrazolylamino}-pyrazine carbonitrile (e.g. the hydrochloride salt); -{5-[4-(benzylamino-methyl)-phenyl]-1H-pyrazolylamino}-pyrazinecarbonitrile (e.g. the hydrochloride salt); -[5-(4-{[(S)—1-(4-fluoro-phenyl)-ethylamino]-methyl}methoxy-pheny|)-1H-pyrazol ylamino]-pyrazinecarbonitrile (e.g. the hloride salt); 5-[5-(4-{[(R)—1-(4-fluoro-phenyl)-ethylamino]-methyl}methoxy-phenyl)-1H-pyrazol ylamino]-pyrazinecarbonitrile (e.g. the hydrochloride salt); -(5-{4-[(4-fluoro-benzylamino)-methyl]methoxy—phenyl}-1H-pyrazolylamino)— pyrazinecarbonitrile (e.g. the hydrochloride salt); 2—methoxy[(2-morpholinyl-ethylamino)-methyl]-phenyl}-1H-pyrazolylamino)— pyrazinecarbonitrile (e.g. the hydrochloride salt); (5-{2—methoxy—4-[(2—morpholinyl-ethylamino)-methyl]-phenyl}-1H-pyrazolyl)—pyrazin- 2-yl-amine (e.g. the hydrochloride salt); -{5-[2-methoxy(1-methyl-piperidinyl)—phenyl]-1H-pyrazolylamino}-pyrazine-2— carbonitrile (e.g. the hydrochloride salt); -[5-(4-{[(1-cyc|opropane-carbonyI-piperidinylmethyl)-amino]-methy|}methoxyphenyl )—1H-pyrazolylamino]-pyrazinecarbonitrile (e.g. the hydrochloride salt); N-[[4-[3-[(5-cyanopyrazin-2—yl)amino]-1H-pyrazolyl]methoxy-phenyl]methyl] cyclopropanecarboxamide; -[[5-[2-methoxy[(tetrahydropyranylamino)methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; -[[5-[2-methoxy[[methyl(2—morpholinoethyl)amino]methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; -[[5-[2-methoxy(2—morpholinoethylamino)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[4—[1-[2-(dimethylamino)acetyl]piperidyl]methoxy-phenyl]-1H-pyrazol no]pyrazinecarbonitrile; -[[5-[2-methoxy—4-[[[(1R)—1-methylmorpholino-ethyl]amino]methyl]phenyl]-1H-pyrazol- 3-yl]amino]pyrazine—2—carbonitrile; -[[5-[4-[[(1,1-dimethylmorpholino-ethyl)amino]methyl]methoxy—phenyl]-1H-pyrazol- 3-yl]amino]pyrazine—2—carbonitrile; [2-methoxy(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazine-2—carbonitrile; -[[5-[2—fluoro(1-methylpiperidyl)phenyl]-1H-pyrazolyl]amino]pyrazine—2— carbonitrile; -[[5-[2-methoxy(4-methylpiperazinyl)phenyl]-1H-pyrazolyl]amino]pyrazine-2— carbonitrile; -[[5-[2-methoxy(4-methyl-1,4-diazepanyl)phenyl]-1H-pyrazolyl]amino]pyrazine-2— carbonitrile; -[[5-[2-methoxy—4-(1-methylpiperidyl)phenyl]-1H-pyrazolyl]amino]pyridine-2— carbonitrile; 6-[[5-[2—methoxy—4-(1-methylpiperidyl)phenyl]-1H-pyrazolyl]amino]pyridine carbonitrile; N-[5-[2-methoxy(1-methy|—4-piperidyl)phenyI]-1H-pyrazo|y|]methyl-pyrazin-Z- amine; [4—(1-methylpiperidyl)phenyl]-1H-pyrazoIy|]amino]pyrazine-Z-carbonitrile; -[[5-[2—methoxy—4-[(1-methy|—4-piperidyl)oxy]phenyl]-1H-pyrazoIy|]amino]pyrazine-2— carbonitrile; -[[5-[2-methoxy[(1-methyIpiperidyl)methoxy]pheny|]-1H-pyrazoI no]pyrazine-2—carbonitrile; 2-fluoro[[5-[2—methoxy(1-methyIpiperidyl)phenyl]-1H-pyrazoI y|]amino]benzonitri|e; 5-[[5-[2-methoxy[(2—pyridylamino)methyl]phenyl]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[5-fluoromethoxy(1-methy|—4-piperidyl)phenyl]-1H-pyrazoIyl]amino]pyrazine- 2-carbonitrile; -[[5-[2-methoxy-4—[(38)-pyrro|idinyl]oxy-phenyl]-1H-pyrazoIyl]amino]pyrazine—2— carbonitrile; -[[5-[2-methoxy(pyrrolidinylmethoxy)phenyl]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[2-methoxy[(1-methy|pyrro|idinyl)methoxy]phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; 5-[[5-[2-methoxy(4-piperidylmethoxy)phenyl]-1H-pyrazoIyl]amino]pyrazine—2— carbonitrile; -[[5-[2-methoxy[[(1-methyIpiperidyl)amino]methyl]phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2—isopropoxy—4—(1-methy|—4-piperidyl)phenyI]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[2-methoxy—4-(3-piperidyl)phenyl]-1H-pyrazoIyl]amino]pyrazine-2—carbonitrile; -[[5-[2-methoxy(1-methy|—3-piperidyl)phenyl]-1H-pyrazoIy|]amino]pyrazine-2— carbonitrile; [2-methoxy(1-methy|—2—piperidyl)phenyl]-1H-pyrazoIy|]amino]pyrazine-2— carbonitrile; -[[5-[2-methoxy[(3S)—1-methy|pyrro|idinyl]oxy-phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -chIoro-N-[5-[2-methoxy—4-(4-piperidyl)phenyI]-1H-pyrazoIyl]pyrazin-2—amine; -ch|oro-N-[5-[2—methoxy(1-methy|—4-piperidyl)phenyl]-1H-pyrazoIyl]pyrazin-2— amine; -[[5-[2—methoxy—4-(4-piperidyl)phenyl]-1H-pyrazoIy|]amino]pyrazine-2—carboxylic acid; -[[5-(2—methoxypiperaziny|-pheny|)—1H-pyrazoIyl]amino]pyrazine—2—carbonitrile; -[[5-[4—[(28,6S)-2,6-dimethylpiperidy|]methoxy—pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-(2—methoxy-4—tetrahydropyranyI-pheny|)-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; 2-fluoro[[5-[2—methoxy—4-(4-piperidyl)phenyI]-1H-pyrazoIyl]amino]benzonitrile; 6-[[5-[2-methoxy(4-piperidyl)phenyl]-1H-pyrazoIyl]amino]pyridinecarbonitrile; -[[5-[2—f|uoro(4-piperidyl)phenyl]-1H-pyrazoIy|]amino]pyrazine-2—carbonitrile; -[[5-[2-methoxy(4-piperidyl)phenyl]-1H-pyrazoIyl]amino]pyridinecarbonitrile; -[[5-[2-isopropoxy—4-(4-piperidyl)phenyI]-1H-pyrazoIyl]amino]pyrazine-2—carbonitrile; 5-[[5-[4—(1,4-diazepany|)methoxy—phenyI]-1H-pyrazoIyl]amino]pyrazine-2— itrile; N-[5-[2-methoxy(4-piperidyl)phenyl]-1H-pyrazo|y|]methy|—pyrazinamine; -[[5-[4-(4-piperidy|)pheny|]-1H-pyrazoIyl]amino]pyrazine—2—carbonitrile; -[[5-[2-methoxy-4—(4-piperidyloxy)phenyl]-1H-pyrazoIyl]amino]pyrazine-2—carbonitrile; [5-f|uoro-2—methoxy—4-(4-piperidyl)phenyl]-1H-pyrazoIy|]amino]pyrazine—2— carbonitrile; -[[5-[4—[(isopropylamino)methy|]-2—methoxy-pheny|]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[4—(1-ethyIpiperidyl)methoxy-pheny|]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[4—(1-isopropyIpiperidyl)methoxy-phenyl]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; 4-[3-[(5-cyanopyraziny|)amino]-1 H-pyrazo|y|]methoxy-phenyl] piperidyl]acetamide; -[[5-[2-methoxy[[methyl(tetrahydropyranyl)amino]methyl]phenyl]-1H-pyrazoI no]pyrazine-2—carbonitrile; -[[5-[4—(4-f|uoromethy|—4-piperidyl)methoxy-phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2—methoxy(1-methylazetidinyl)phenyI]-1H-pyrazoIy|]amino]pyrazine—2— carbonitrile; -[[5-[4—(3-fluoromethy|—azetidinyl)methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[5-ch|oromethoxy(1-methy|—4-piperidyl)phenyl]-1H-pyrazoIyl]amino]pyrazine- 2-carbonitrile; -[[5-[5-chIoromethoxy(4-piperidyl)phenyI]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[3-ch|oromethoxy(1-methy|—4-piperidyl)phenyl]-1H-pyrazoIyl]amino]pyrazine- 2-carbonitrile; 5-[[5-[3-chIoromethoxy(4-piperidyl)phenyI]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; methyl 5-[[5-[2-methoxy(4-piperidyl)phenyl]-1H-pyrazoIy|]amino]pyrazine-2— carboxylate; -[[5-[2-methoxy[(tetrahydrofuranylamino)methyl]phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2-methoxy[[methyl(tetrahydrofuranyl)amino]methyl]phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2-methoxy(tetrahydropyranylmethylamino)phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; 5-[[5-[2-methoxy(tetrahydropyranylmethoxy)phenyI]-1H-pyrazoIy|]amino]pyrazine- onitrile; -[[5-[4—(4-f|uoropiperidyl)methoxy-pheny|]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[4—(3-fluoroazetidinyl)methoxy-pheny|]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[2-methoxy[(3R)—1-methy|pyrrolidinyl]oxy—phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-(2—methoxymorpholino-phenyl)—1H-pyrazoIy|]amino]pyrazine—2—carbonitrile; -[[5-[4—(4-ethy|piperaziny|)methoxy-phenyI]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile;; -[[5-[4-(4-isopropy|piperaziny|)methoxy-phenyI]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[2-methoxy—4-[(3R)—3-methylpiperaziny|]pheny|]-1H-pyrazoIy|]amino]pyrazine— 2-carbonitrile; -[[5-[4—(4-ethy|—1,4-diazepany|)methoxy-phenyI]-1H-pyrazoIy|]amino]pyrazine—2— carbonitrile; 5-[[5-[4—(4-isopropyI-1,4-diazepany|)methoxy—phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—(1-ethy|—4-f|uoropiperidyl)methoxy-pheny|]-1H-pyrazoIyl]amino]pyrazine— 2-carbonitrile; -[[5-[4—(4-fluoroisopropyIpiperidyl)methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—(1-ethy|—3-f|uoropiperidyl)methoxy-pheny|]-1H-pyrazoIyl]amino]pyrazine— 2-carbonitrile; -[[5-[4—(3-fluoroisopropyIpiperidyl)methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; 5-[[5-[2—methoxy[1-(2—methoxyethy|)piperidy|]phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—(ethylaminomethyl)methoxy-pheny|]-1H-pyrazoIyl]amino]pyrazine-2— itrile; -[[5-[4—[(cyc|opropylamino)methyI]methoxy-pheny|]-1H-pyrazoIyl]amino]pyrazine carbonitrile; -[[5-[4—[(3R)—3,4-dimethylpiperaziny|]methoxy-phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; [4-[(3R)—4-ethy|—3-methyI-piperaziny|]methoxy-phenyI]-1H-pyrazoI no]pyrazine-2—carbonitrile; 5-[[5-[4—[(38)—1-isopropy|pyrrolidiny|]oxymethoxy-phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4-[(3R)—1-isopropy|pyrro|idinyl]oxy-2—methoxy—pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[(3(R,S),4(R,S))—3-fluoromethyIpiperidy|]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—(3,3-difluoromethyIpiperidyl)methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—(1-ethy|—3,3-difluoropiperidyl)methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[1-(2—hydroxyethy|)piperidy|]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[isopropy|(methyl)amino] ]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2-methoxy(pyrrolidiny|methyl)phenyI]-1H-pyrazoIy|]amino]pyrazine—2— carbonitrile; [2-methoxy(morpholinomethyl)phenyl]-1H-pyrazoIy|]amino]pyrazine—2— carbonitrile; [2—methoxy[[(2R)—1-methy|pyrrolidinyl]methoxy]phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile hydrochloride; -[[5-[2—methoxy—4-[[(28)methy|pyrro|idin-2—y|]methoxy]pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile hydrochloride; -[[5-[2-methoxy(oxazoIylmethoxy)phenyI]-1H-pyrazoIy|]amino]pyrazine—2— carbonitrile; -[[5-[4—[1-(2—f|uoroethyl)piperidy|]methoxy-pheny|]-1H-pyrazoIy|]amino]pyrazine- 2-carbonitrile; 5-[[5-[2—methoxy[(1-methyIpiperidyl)methylamino]phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[(1-ethyIpiperidyl)methylamino]methoxy—phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[(1-isopropyIpiperidyl)methylamino]methoxy-phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2-methoxy[(1-methy|—4-piperidyl)amino]phenyI]-1H-pyrazoIyl]amino]pyrazine- 2-carbonitrile; -[[5-[4—[(1-ethy|—4-piperidyl)amino]methoxy-phenyI]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[4—[(1-isopropyIpiperidy|)amino]methoxy—pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2-methoxy[(1-methyIpiperidyl)oxymethyl]phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[(1-ethy|—4-piperidy|)oxymethy|]methoxy—phenyl]-1H-pyrazoI no]pyrazine-2—carbonitrile; -[[5-[4-[(1-isopropy|—4-piperidyl)oxymethy|]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-(2—f|uoromethoxypiperaziny|-pheny|)-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[2—methoxy—4-[(2R)—4—methylmorpholiny|]phenyI]-1H-pyrazo|y|]amino]pyrazine— 2-carbonitrile; 5-[[5-[2—methoxy—4-[(2R)—4-ethylmorpholiny|]pheny|]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[2-methoxy[(28)methy|morpholin-2—yl]phenyI]-1H-pyrazoIyl]amino]pyrazine- 2-carbonitrile; -[[5-[2—methoxy[(28)ethy|morpholin-2—y|]phenyl]-1H-pyrazo|y|]amino]pyrazine-2— carbonitrile; -[[5-(2,6-dimethoxypiperaziny|-pheny|)-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[2,6-dimethoxy(4-methylpiperaziny|)pheny|]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; 5-[[5-[4—[[(3R)—3-f|uoropyrrolidiny|]methyI]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2—methoxy—4-[[(38)methoxypyrro|idiny|]methy|]phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; [2-methoxy[[(3R)—3-methoxypyrro|idiny|]methy|]phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; [4—[[(2R)—1-ethy|pyrro|idin-2—yl]methoxy]-2—methoxy—phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[(2R)—1-isopropylpyrrolidinyl]methoxy]-2—methoxy-phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; [4—[[(28)—1-ethy|pyrro|idinyl]methoxy]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[(28)—1-isopropy|pyrro|idinyl]methoxy]-2—methoxy—phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4-[(cyc|opropy|methylamino) methy|]methoxy-phenyl]—1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2—methoxy—4-[[[(3R)—tetrahydrofuranyl]amino]methyl]phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2-methoxy[[[(38)-tetrahydrofurany|]amino]methyl]phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4-[(3R)—4-isopropyImethyI-piperaziny|]methoxy-phenyI]-1H-pyrazoI no]pyrazine-2—carbonitrile; 5-[[5-[4—[(1-ethyIpiperidyl)oxy]methoxy-pheny|]-1H-pyrazoIy|]amino]pyrazine-2— carbonitrile; -[[5-[4—[(1-isopropyIpiperidyl)oxy]methoxy—phenyl]-1H-pyrazoIyl]amino]pyrazine- 2-carbonitrile; [4—(4-ethy|piperaziny|)f|uoromethoxy-phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4-(4-isopropy|piperaziny|)f|uoromethoxy—phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[(3S)—1-ethy|pyrro|idiny|]oxymethy|]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; 5-[[5-[4—[[(38)—1-isopropy|pyrro|idinyl]oxymethy|]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[(3R)—1-ethy|pyrrolidinyl]oxymethy|]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[(3R)—1-isopropy|pyrro|idiny|]oxymethy|]methoxy—pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4-(4-isobutylpiperaziny|)methoxy—phenyI]-1H-pyrazoIyl]amino]pyrazine—2— carbonitrile; -[[5-[4—[(1-ethyIpiperidyl)methy|]methoxy—phenyl]-1H-pyrazoIyl]amino]pyrazine itrile; -[[5-[4—[(1-isopropyIpiperidyl)methy|]methoxy—phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[(1-ethyIpiperidyl)methyI-methyI-amino]methoxy—pheny|]-1H-pyrazoI no]pyrazine-2—carbonitrile; -[[5-[4-[(isobutylamino)methy|]methoxy-pheny|]-1H-pyrazoIyl]amino]pyrazine-2— carbonitrile; -[[5-[4-[(2R)—4-isopropy|morpho|iny|]methoxy-phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[(1-isopropyIpiperidyl)methy|—methy|—amino]methoxy-phenyI]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[(2R)—1-ethy|pyrrolidinyl]methy|]methoxy-phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; 5-[[5-[4—[(28)isopropy|morpho|iny|]methoxy—phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[(2R)—1-isopropylpyrrolidin-2—yl]methyI]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[(28)—1-ethy|pyrro|idinyl]methy|]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-(2—methoxypiperaziny|-pheny|)—1H-pyrazoIyl]amino]pyrazine—2—carbonitrile; -[[5-[4—[[(28)—1-isopropy|pyrro|idinyl]methy|]methoxy—phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[(38)—1-isopropy|pyrrolidinyl]amino]methoxy-phenyl]-1H-pyrazoI no]pyrazine-2—carbonitrile; -[[5-[4—[[(3R)—1-isopropylpyrrolidiny|]amino]methoxy—phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[4—[[(3R)—1-ethy|pyrrolidinyl]amino]methoxy-phenyl]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; 5-[[5-[4—[[(38)—1-ethy|pyrro|idinyl]amino]methoxy-pheny|]-1H-pyrazoI y|]amino]pyrazine-2—carbonitrile; -[[5-[2-methoxy[(38)—3-methylpiperazinyl]phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; -[[5-[4—[(3R)—3-ethylpiperazinyl]methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; -[[5-[4—[(38)isopropylpiperazinyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; -[[5-[4-[(3R)—3-isopropylpiperazinyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; -[[5-[4—(3,3-dimethylpiperazinyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine-2— carbonitrile; and salts and tautomers thereof. 1.99 A compound according to any one of Embodiments 1.1 to 1.98 having a molecular weight of up to 1000, for example less than 750. 1.100 A compound according to Embodiment 1.99 having a molecular weight of less than 700. 1.101 A compound according to Embodiment 1.100 having a molecular weight of less than 650. 1.102 A compound according to Embodiment 1.101 having a molecular weight of less than 600 or less than 550. 1.103 A compound ing to Embodiment 1.102 having a molecular weight of less than 530, for example up to 525. 1.104 A compound according to Embodiment 1.1 which is the title compound of any one of es 1 to 12 below. 1.105 A compound according to any one of Embodiments 1.1 to 1.104 which is in the form of a salt. 1.106 A compound according to ment 1.105 wherein the salt is an acid on salt. 1.107 A compound according to Embodiment 1.105 or Embodiment 1.106 wherein the salt is a ceutically acceptable salt. tions In this application, the following definitions apply, unless indicated othenNise.
The term “non-aromatic carbocylic or heterocyclic group” es unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms urated” and “partially saturated” refer to rings wherein the ring structure(s) contains atoms sharing more than one valence bond i.e. the ring contains at least one multiple bond e.g. a C=C, CzC or N=C bond. The term “fully saturated” refers to rings where there are no multiple bonds between ring atoms.
Saturated carbocyclic groups include lkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, eptenyl and cyclooctenyl.
Examples of non-aromatic heterocyclic groups include morpholine, thiomorpholine and its S-oxide and oxide, piperidine, l piperidines, piperidone, pyrrolidine, pyrrolidone, ine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, opyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran, imidazoline, imidazolidinone, oxazoline, thiazoline, 2—pyrazoline, pyrazolidine, piperazone, piperazine, and N-alkyl zines.
Examples of non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl, cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, and cycloheptenyl.
The term “hydrocarbyl” as used herein is used in its standard IUPAC sense to refer to moieties consisting of carbon and hydrogen atoms, i.e. hydrocarbon moieties.
In on to carbon-hydrogen bonds, the hydrocarbyl groups can contain one or more , double or triple -carbon bonds. The hydrocarbyl groups can be aromatic or non-aromatic. Examples of omatic hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloakenylalkyl, cycloalkylalkenyl and cycloalkylalkynyl groups.
The term “alkyl” covers both straight chain and branched chain alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, yl, 3-pentyl, 2—methyl butyl, 3-methyl butyl, and n-hexyl and its isomers.
Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2- propenyl (allyl), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl, and hexenyl.
Examples of alkynyl groups e, but are not limited to, ethynyl and 2—propynyl (propargyl) groups. es of cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.
Examples of lkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl.
Examples of aromatic hydrocarbyl groups are phenyl and naphthyl.
Examples of halogen substituents include fluorine, chlorine, bromine and iodine. Fluorine and chlorine are particularly preferred. When attached to a non-aromatic moiety, ne is preferred.
Salts The compounds of the invention may be presented in the form of salts.
The salts (as defined in Embodiments 1.105 to 1.107) are typically acid addition salts.
The salts can be synthesized from the parent compound by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, ion, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639—026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by ng the free base form of the compound with the acid in water or in an organic solvent, or in a e of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
Acid addition salts (as defined in Embodiment 1.106) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2—dichloroacetic, adipic, c, ic (e.g. rbic), L-aspartic, benzenesulphonic, benzoic, 4- acetamidobenzoic, butanoic, (+) camphoric, camphor-sulphonic, (+)-(1S)-camphor sulphonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric, ethane- 1,2—disu|phonic, ethanesulphonic, 2—hydroxyethanesulphonic, formic, fumaric, galactaric, ic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L- glutamic), o-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, (+)-L-lactic, (i)-DL-lactic, lactobionic, maleic, malic, (-)-L-ma|ic, malonic, (i)- DL-mandelic, methanesulphonic, naphthalenesulphonic, naphthalene-1,5-disulphonic, 1-hydroxynaphthoic, nic, nitric, oleic, , oxalic, palmitic, , phosphoric, propionic, L-pyroglutamic, lic, 4-amino-salicylic, sebacic, stearic, succinic, sulphuric, , (+)-L-tartaric, thiocyanic, p-toluenesulphonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.
The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable " J. Pharm. Sci., Vol. 66, pp. 1-19.
However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts.
Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the ion, also form part of the invenfion.
Geometric isomers and tautomers The compounds of the invention may exist in a number of different geometric ic, and eric forms and references to the compounds of formula (0) or formula (1) as defined in Embodiments 1.0 to 1.107 include all such forms. Forthe avoidance of doubt, where a compound can exist in one of several ric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula (0) or formula (1) or subgroups, subsets, ences and examples thereof.
For example, the compounds of formula (0) may exist in either or both of tautomeric forms A and B below. “‘1' Rf4<\5 t [1 4 ~3- , J” . r \ M R“ “RN “N Although only tautomeric form A is shown in the formula drawings in this application, it should be understood that a (0) and the otherformulae in this application are intended to cover both tautomeric forms. l Isomers Where compounds of the formula contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to the compounds include all optical isomeric forms thereof (e.g. enantiomers, epimers and reoisomers), either as individual l isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.
The optical isomers may be characterised and identified by their optical activity (i.e. as + and — isomers, or d and I isomers) or they may be characterised in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, lngold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, lngold & Prelog, Angew. Chem. Int.
Ed. Eng/., 1966, 5, 385-415.
Optical isomers can be ted by a number of techniques including chiral chromatography (chromatography on a chiral t) and such techniques are well known to the person skilled in the art.
As an alternative to chiral chromatography, optical s can be ted by g diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyrog|utamic acid, (-)-di-to|uoyl-L-tartaric acid, (+)-mandelic acid, |ic acid, and (-)-camphorsu|phonic, separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.
Where compounds of the invention exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain stances, it may be desirable to use as a therapeutic agent only one of a pair of omers, or only one of a plurality of diastereoisomers. Accordingly, the invention provides compositions containing a compound having one or more chiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (0) orformula (1) is present as a single optical isomer (e.g. enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (0) or formula (1) may be t as a single optical isomer (e.g. enantiomer or diastereoisomer).
Isotopes The compounds of the invention as defined in any one of Embodiments 1.0 to 1.107 may n one or more isotopic substitutions, and a reference to a particular element includes within its scope all es of the element. For example, a reference to hydrogen includes within its scope 1H, 2H (D), and 3H (T). Similarly, references to carbon and oxygen include within their scope respectively 12C, 13C and 14C and 16O and 18O.
The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds n no radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. nds containing such radioisotopes may be useful in a diagnostic context.
WO 20390 Solvates Compounds of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 may form solvates.
Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a xic pharmaceutically acceptable solvent (referred to below as the solvating solvent).
Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulphoxide. Solvates can be prepared by tallising the nds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by ting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.
The solvates can be stoichiometric or non-stoichiometric solvates.
Particularly preferred solvates are hydrates, and examples of es include hemihydrates, monohydrates and dihydrates.
For a more detailed discussion of es and the s used to make and characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 006710-3.
Prodrugs The compounds of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 may be presented in the form of a pro-drug.
By “prodrugs” is meant for example any compound that is converted in vivo into a biologically active compound of the formula (0) or formula (1 ), as defined in any one of Embodiments 1.0 to 1.107.
For example, some gs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any hydroxyl groups t in the parent compound with, where appropriate, prior tion of any other reactive groups present in the parent compound, followed by deprotection if required.
Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical on, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the g may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Complexes and clathrates Also encompassed by formula (0) or formula (1) or subgroups, subsets, preferences and examples thereof are complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds.
Biological Activity The compounds of the formulae (1) and oups thereof are potent inhibitors of Chk-1 and consequently are expected to be beneficial alone or in combination with various chemotherapeutic agents or radiation for treating a wide spectrum of proliferative disorders. red nds of the a (0) or a (1) are those nds that have IC50 values of less than 0.1 uM against Chk-1 kinase. Particularly preferred compounds are those that have |C50 values of less than 0.01 uM against Chk-1 kinase. Still more preferred compounds are those that have |C50 values of less than 0.001 uM against Chk- 1 kinase.
Accordingly, in further embodiments (Embodiments 2.1 to 2.14), the invention provides: 2.1 A compound of the formula (0) or formula (1) as d in any one of Embodiments 1.0 to 1.107 for use in medicine or therapy. 2.2 A compound of the formula (0) or a (1) as defined in any one of Embodiments 1.0 to 1.107 for for use as a Chk-1 kinase inhibitor. 2.3 A compound of the formula (0) or formula (1 ) for use as defined in Embodiment 2.2 wherein the compound has an |C50 values of less than than 1 uM t Chk—1 kinase (e.g. when determined according the assays described herein). 2.4 A nd of the formula (0) or formula (1 ) for use as defined in Embodiment 2.3 wherein the compound has an |C50 value of less than 0.1 uM against Chk-1 kinase. 2.5 A compound of the formula (0) or formula (1)for use as d in Embodiment 2.3 wherein the compound has an |C50 value of less than 0.01 uM against Chk-1 kinase. 2.6 A compound of the formula (0) or formula (1 ) for use as defined in Embodiment 2.3 wherein the compound has an |C50 value of less than 0.001 uM against Chk-1 kinase. 2.7 A compound of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6 for use in enhancing a therapeutic effect of radiation therapy or chemotherapy in the treatment of a proliferative disease such as cancer. 2.8 A compound of the formula (0) or formula (1) as d in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6 for use in the treatment of a proliferative disease such as cancer. 2.9 The use of a compound of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6 for the manufacture of a ment for enhancing a therapeutic effect of ion therapy or herapy in the treatment of a proliferative disease such as cancer. 2.10 The use of a compound of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6 for the cture of a medicament for the treatment of a proliferative disease such as cancer. 2.11 A method for the prophylaxis or treatment of a erative disease such as cancer, which method comprises administering to a patient in combination with herapy or chemotherapy a compound of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6. 2.12 A method for the prophylaxis or treatment of a erative disease such as , which method comprises administering to a patient a compound of the formula (0) or a (1) as defined in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6. 2.13 A compound for use, use or method as defined in any one of Embodiments 2.7 to 2.12 wherein the cancer is selected from omas, for example carcinomas of the bladder, breast, colon, kidney, epidermis, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin, poieitic tumours such as leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, hairy cell ma, or Burkett's lymphoma; hematopoieitic tumours of myeloid lineage, for example acute and chronic myelogenous leukaemias, myelodysplastic syndrome, or promyelocytic leukaemia; thyroid follicular cancer; tumours of mesenchymal origin, for example arcoma or habdomyosarcoma; tumours of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma tosum; keratoctanthoma; thyroid follicular cancer; Ewing’s sarcoma or Kaposi's sarcoma. 2.14 A compound for use, use or method according to Embodiment 2.13 wherein the cancer is selected from breast , colon cancer, lung , ovarian cancer, pancreatic cancer, prostate , glioma, Ewing’s sarcoma and leukemia.
It is also envisaged that the Chk-1 inhibitors of the invention may be useful in ng tumours in which there is a defective DNA repair mechanism or a defective cell cycle, for example a cancer in which mutations (e.g. in p53) have led to the G1/S DNA damage checkpoint being lost (see the uctory section of this application). The Chk—1 inhibitors of the invention may also be useful in treating RAD17 mutant tumours, ATM- deficient RAD50-mutant tumours and fanconi anaemia. Accordingly in further embodiments (Embodiments 2.15 to 2.24), the invention provides: 2.15 A compound for use, use or method as d in any one of Embodiments 2.7 to 2.14 wherein the cancer is one which is characterized by a defective DNA repair mechanism or defective cell cycle. 2.16 A compound for use, use or method according to Embodiment 2.15 wherein the cancer is a p53 negative or mutated tumour. 2.17 A compound for use, use or method as defined in any one of Embodiments 2.7 to 2.14 wherein the cancer is an MYC oncogene-driven cancer. 2.18 A nd for use, use or method according to Embodiment 2.16 wherein the MYC oncogene-driven cancer is a B-cell lymphoma, leukemia, neuroblastoma, breast cancer or lung cancer. 2.19 A compound of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 for use in the treatment of a patient suffering from a p53 negative or mutated tumour (e.g. a cancer selected from breast cancer, colon cancer, lung , ovarian cancer, pancreatic cancer, te , glioma, and leukemia) in combination with radiotherapy or chemotherapy. 2.20 A compound for use according to any one of Embodiments 2.7 to 2.19 wherein, in addition to administration of a compound of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107, the treatment comprises administration to a t of a chemotherapeutic agent selected from cytarabine, etoposide, gemcitabine and SN- 38. 2.21 The use of a compound of the a (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6 for the manufacture of a medicament for the treatment of a patient suffering from a cancer which is terised by a defective DNA repair mechanism or defective cell cycle.
WO 20390 2.22 The use according to Embodiment 2.21 wherein the cancer is a p53 negative or 2.23 A method for the treatment of a patient (e.g. a human patient) suffering from a cancer which is characterised by a defective DNA repair mechanism or defective cell cycle, which method comprises administering to the patient a therapeutically effective amount of a compound of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6. 2.24 A method according to Embodiment 2.23 wherein the cancer is a p53 negative or mutated tumour. 2.2 5 A compound for use, use or method as defined in any one of Embodiments 2.7 to 2.14 wherein the cancer is a RAD17-mutant tumour or an ATM-deficient RAD50-mutant tumour. 2.26 A compound of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6 for use in the treatment of Fanconi anaemia. 2.27 The use of a nd of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6 for the manufacture of a medicament for the treatment of i anaemia. 2.28 A method of treating Fanconi anaemia in a subject (e.g. a human subject) in need thereof, which method comprises administering to the subject a therapeutically effective amount of a compound of the a (0) or a (1) as defined in any one of Embodiments 1.0 to 1.107 or 2.3 to 2.6.
The Chk-1 tor compounds of the ion may be used alone or they may be used in combination with DNA-damaging anti-cancer drugs and/or radiation therapy to treat subjects with multi-drug resistant cancers. A cancer is considered to be resistant to a drug when it resumes a normal rate of tumour growth while undergoing treatment with the drug after the tumour had initially responded to the drug. A tumour is considered to "respond to a drug" when it exhibits a decrease in tumor mass or a decrease in the rate of tumour growth.
Methods for the Preparation of Compounds of the ae (0) and (1) Compounds of the formulae (0) and (1) can be prepared in accordance with synthetic methods well known to the skilled person and as described herein.
Accordingly, in r ment (Embodiment 3.1), the invention provides a process for the preparation of a nd as defined in any one of Embodiments 1.0 to 1.107, which process comprises: (A) the reaction of a compound of formula (11): (11) or a protected form thereof, wherein R1 to R6, T1 and T2 are as hereinbefore defined; with hydrazine, followed by removal of any protecting groups present, where required; or (B) the reaction of a compound of the formula (12): (12) (or its pyrazole-ring tautomer) wherein R1 to R3, M1 and M2 are as hereinbefore defined, and Q is hydrogen or a ting group PG; with a compound of the formula (13): LG R Ti\ ’1 (13) where R5 and R6 are as hereinbefore defined and LG is a leaving group or atom such as bromine, in the presence of a base such as a metal hydride base (e.g. sodium hydride), followed by removal of any protecting group PG where necessary; and thereafter: (C) optionally ting one compound of the formula (0) or (1 ), into another compound of the formula (0) or (1). ln formula (11), a nitrogen atom g part of the moiety A in M1 or M2 may be ted by an amino group protecting group. The protecting group, when present, is a group capable of protecting the amino function against unwanted side ons and examples of such protecting groups are well known to the skilled person, see the reference book (Protective Groups in c Synthesis (Greene and Wuts) referred to below.
A particularly preferred protecting group is the tert-butoxycarbonyl (Boc) group. The Boc group may readily be d when required by treatment with an acid such as hydrochloric acid or trifluoroacetic acid.
In process variant (A), the reaction of the compound of formula (11) with hydrazine is typically carried out in a polar solvent such as ethanol or aqueous ethanol in the presence of acetic acid, with moderate heating, for example to a temperature of about 60 °C. nds of the formula (11)wherein R1 to R4, A and R7 are as defined in formula (1), can be prepared by the sequence of reactions shown in Scheme 1.
Scheme 1 Compounds of the formula (14) can be prepared by the methods described below in the Examples section below or by methods analogous thereto. The compound of a (14) is reacted with carbon disulfide and iodomethane in the presence of a metal hydride base such as sodium hydride in a polar solvent such as yl sulfoxide, THF or DMF to give the intermediate (15). The intermediate (15) is then reacted with the aminopyrazine (16) in the presence of a metal hydride base (such as sodium e) in a polar solvent such as THF to give the compound (11).
In s variant (B), the compound of formula ((12) is typically reacted with the pyrazine compound (13) in the presence of a metal hydride base such as sodium hydride in a non-protic polar solvent such as THF. The reaction is typically d out at low temperature, for example around 0 °C. The leaving group LG is lly a halogen such as bromine. When a metal hydride base is used, the moiety Q is preferably a protecting group PG such as a Boc group. As an alternative to using a metal hydride base, a non- nucleophilic (or poorly nucleophilic) base such as N,N-diisopropylethylamine (DIPEA) can be used, in which case a protecting group can be omitted from the pyrazole ring (i.e. Q = hydrogen).
Compounds of the formula (12) wherein R1 to R4, A and R7 are as defined in formula (1) and PG is a protecting group can be prepared by the sequence of reactions shown in Scheme 2.
Hvfim 4 O\ R4 {37) Scheme 2 Compounds of the formula (17) can be prepared by the methods described below in the es section or by methods analogous thereto. The compound of formula (17) is reacted with itrile in the ce of an alkyl lithium base such as butyl lithium to give the cyano compound of formula (18). The reaction is lly d out in an inert non-polar aprotic solvent such as toluene at a low temperature, for example about -78 °C.
The cyano compound of formula (18) is then reacted with hydrazine in a polar solvent such as ethanol in the presence of acetic acid to give the pyrazole (19). The nitrogen atom at the 1-position of the pyrazole ring is then protected with a tert—butyloxycarbonyl (Boc) protecting group by reaction with Boc—anhydride in THF in the presence of a metal e base such as sodium hydride to give the pyrazole intermediate (12) where PG is Boc. The reaction is typically carried out at a low temperature, for example a temperature of about 0 °C.
Once formed, one compound of the formula (0) or (1 ), or a protected derivative thereof, can be converted into r compound of the formula (0) or (1) by methods well known to the skilled person. Examples of synthetic procedures for converting one functional group into another functional group are set out in standard texts such as Advanced c Chemistry and Organic Syntheses (see references above) or Fiesers’ Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0 58283-2) .
In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the le.
Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
Compounds made by the foregoing s may be isolated and purified by any of a variety of methods well known to those skilled in the art and examples of such methods include recrystallisation and chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC.
Many of the synthetic intermediates of the formulae (11) to (19) described above and in the reaction schemes and examples below are novel and, as such, represent a r aspect of the invention.
Pharmaceutical Formulations While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation). ingly, in another embodiment (Embodiment 4.1) of the ion, there is provided a pharmaceutical composition comprising at least one nd of the formula (0) or formula (1) as defined in any one of ments 1.0 to 1.107 together with a ceutically able ent.
The ceutically acceptable excipient can be, for example, a carrier (e.g. a solid, liquid or semi-solid carrier), a diluent or bulking agent, a granulating agent, coating agent, binding agent, disintegrant, lubricating agent, preservative, antioxidant, buffering agent, suspending agent, thickening agent, flavouring agent, sweetener, taste masking agent or any other excipient conventionally used in ceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below.
The pharmaceutical compositions can be in any form suitable for oral, parenteral, l, intranasal, ophthalmic, otic, , intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery. The delivery can be by bolus injection, short term infusion or longer term infusion and can be via passive delivery or through the ation of a suitable on pump.
Pharmaceutical formulations adapted for parenteral stration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, iostats, co-solvents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing on formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a e form and rendering the formulation isotonic with the blood of the intended ent. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2) 2004, p 201-230).
A drug molecule that is ionizable can be solubilized to the desired concentration by pH adjustment if the drug's pKa is sufficiently away from the formulation pH value. The acceptable range is pH 2—12 for intravenous and uscular administration, but subcutaneously the range is pH 2.7-9.0. The solution pH is controlled by either the salt form of the drug, strong acids/bases such as hloric acid or sodium hydroxide, or by solutions of buffers which include but are not limited to ing solutions formed from glycine, citrate, acetate, maleate, ate, histidine, phosphate, tris(hydroxymethyl)-aminomethane (TRIS), or carbonate.
The combination of an aqueous solution and a water-soluble organic solvent/surfactant (Le, a cosolvent) is often used in injectable ations. The water-soluble organic solvents and surfactants used in injectable formulations include but are not limited to propylene glycol, ethanol, polyethylene glycol 300, hylene glycol 400, glycerin, dimethylacetamide (DMA), N- methylpyrrolidone (NMP; Pharmasolve), dimethylsulphoxide (DMSO), Solutol HS 15, Cremophor EL, hor RH 60, and polysorbate 80. Such ations can usually be, but are not always, diluted prior to injection.
Propylene glycol, PEG 300, ethanol, Cremophor EL, Cremophor RH 60, and polysorbate 80 are the entirely organic miscible solvents and surfactants used in commercially available able formulations and can be used in combinations with each other. The resulting organic formulations are usually diluted at least 2-fold prior to IV bolus or IV infusion.
Alternatively increased water solubility can be achieved through molecular complexation with cyclodextrins.
The ations may be presented in unit-dose or dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid r, for example water for injections, immediately prior to use.
The pharmaceutical formulation can be prepared by lyophilising a compound of formula (0) or formula (1) or acid addition salt thereof. Lyophilisation refers to the procedure of freeze-drying a composition. -drying and lyophilisation are therefore used herein as synonyms. A typical process is to solubilise the compound and the resulting formulation is clarified, sterile filtered and aseptically transferred to containers appropriate for lyophilisation (e.g. vials). In the case of vials, they are partially stoppered with lyo- stoppers. The formulation can be cooled to freezing and subjected to lyophilisation under standard conditions and then hermetically capped forming a stable, dry le formulation. The composition will typically have a low residual water t, e.g. less than 5% e.g. less than 1% by weight based on weight of the lyophile.
The lyophilisation formulation may contain other ents for example, thickening agents, dispersing agents, buffers, antioxidants, preservatives, and tonicity adjusters.
Typical buffers include ate, acetate, e and glycine. Examples of antioxidants include ascorbic acid, sodium bisulphite, sodium metabisulphite, monothioglycerol, thiourea, butylated ytoluene, butylated hydroxyl anisole, and ethylenediaminetetraacetic acid salts. Preservatives may include benzoic acid and its salts, sorbic acid and its salts, alkyl esters of para-hydroxybenzoic acid, phenol, chlorobutanol, benzyl alcohol, osal, benzalkonium de and cetylpyridinium chloride. The buffers mentioned previously, as well as dextrose and sodium chloride, can be used for tonicity adjustment if necessary.
Bulking agents are generally used in lyophilisation technology for facilitating the process and/or providing bulk and/or mechanical integrity to the lyophilized cake. Bulking agent means a freely water soluble, solid particulate diluent that when co-lyophilised with the compound or salt f, provides a physically stable lyophilized cake, a more optimal -drying process and rapid and complete reconstitution. The g agent may also be utilised to make the solution isotonic.
The water-soluble g agent can be any of the pharmaceutically acceptable inert solid materials typically used for lyophilisation. Such bulking agents include, for e, sugars such as glucose, e, sucrose, and e; polyalcohols such as sorbitol or ol; amino acids such as glycine; polymers such as polyvinylpyrrolidine; and polysaccharides such as dextran.
The ratio of the weight of the bulking agent to the weight of active compound is typically within the range from about 1 to about 5, for example of about 1 to about 3, e.g. in the range of about 1 to 2.
Alternatively they can be provided in a solution form which may be concentrated and sealed in a suitable vial. Sterilisation of dosage forms may be via filtration or by autoclaving of the vials and their contents at appropriate stages of the formulation process. The supplied formulation may require further on or preparation before ry for e dilution into suitable sterile infusion packs.
Extemporaneous ion solutions and suspensions may be ed from e s, granules and tablets.
In one preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion.
In another preferred embodiment, the pharmaceutical composition is in a form suitable for sub-cutaneous (s.c.) administration.
Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, , solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.
Pharmaceutical compositions containing compounds of the formula (I) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or r such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, m carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.
Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
The solid dosage forms (eg; tablets, capsules etc.) can be coated or un-coated, but typically have a coating, for e a protective film coating (e.g. a wax or varnish) or a release controlling coating. The coating (e.g. a Eudragit T'V' type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under n pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum.
Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be d to selectively e the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic ide polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic l of the release of the compound.
Osmotic release and other d release or ned release formulations may be prepared in accordance with methods well known to those skilled in the art.
The compound of formula (0) orformula (1), as defined in any one of Embodiments 1.0 to 1.107, or a prodrug thereof, may be formulated with a carrier and administered in the form of nanoparticles. Nanoparticles offer the possibility of direct penetration into the cell.
Nanoparticle drug delivery systems are described in “Nanoparticle Technology for Drug Delivery”, edited by Ram B Gupta and Uday B. Kompella, a Healthcare, ISBN 9781574448573, published 13th March 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172, and in Sinha eta/., Mol.
Cancer Ther. August 1, (2006) 5, 1909.
The ceutical ations may be presented to a t in “patient packs” containing an entire course of treatment in a single e, usually a blister pack.
Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient’s supply of a pharmaceutical from a bulk supply, in that the t always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient ance with the physician’s instructions.
Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
Compositions for eral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.
Examples of formulations for rectal or intra-vaginal administration e pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound.
Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by tion, the powdered formulations typically comprise the active compound er with an inert solid powdered diluent such as lactose.
The compounds of the formula (0) or formula (1)wi|| generally be presented in unit dosage form and, as such, will typically contain sufficient compound to e a d level of biological activity. For example, a ation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient.
Within this range, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more y from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 rams), or 1 microgram to 20 rams (for example 1 microgram to 10 rams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).
For oral compositions, a unit dosage form may n from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 miligrams to 1 gram, of active compound.
The active compound will be administered to a patient in need thereof (for example a human or animal t) in an amount sufficient to achieve the desired therapeutic effect.
Methods of Treatment It is envisaged that the compounds of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 as defined herein will be useful either alone or in combination therapy with chemotherapeutic agents (particularly DNA-damaging agents) WO 20390 or radiation therapy in the prophylaxis or treatment of a range of proliferative disease states or conditions. Examples of such disease states and conditions are set out above.
The compounds of formula (0) or formula (1 ), whether administered alone, or in combination with DNA damaging agents and other anti-cancer agents and therapies, are lly administered to a subject in need of such administration, for e a human or animal patient, preferably a human.
According to another embodiment of the invention, Embodiment 5.1, there is provided a combination of a compound of formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 together with another chemotherapeutic agent, for example an anticancer drug.
Examples of chemotherapeutic agents that may be co-administered with the compounds of formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 include: . Topoisomerase | inhibitors . Antimetabolites o Tubulin targeting agents 0 DNA binder and topoisomerase II tors 0 Alkylating Agents 0 Monoclonal dies.
. Anti-Hormones 0 Signal Transduction Inhibitors o Proteasome Inhibitors . DNA methyl transferases . Cytokines and retinoids o a triggered DNA damaging agents (e.g. Tirapazamine, TH-302) ular examples of herapeutic agents that may be administered in combination with the compounds of of a (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107 include: nitrogen mustards such as mechlorethamine, cyclophosphamide, ifosfamide, melphalan and chlorambucil; nitrosoureas such as carmustine, Iomustine and semustine; ethyleneimine/methylmelamine compounds such as triethylenemelamine, triethylene thiophosphoramide and hexamethylmelamine; alkyl sulphonates such as busulfan; nes such as dacarbazine Antimetabolites such as folates, methotrexate, trimetrexate, rouracil, deoxyuridine, gemcitabine, cytosine arabinoside, 5-azacytidine, 2, 2'- difluorodeoxycytidine, 6-mercaptopurine, 6-thioguanine, azathioprine, 2'- deoxycoformycin, erythrohydroxynonyl-adenine, fludarabine phosphate and 2- chlorodeoxyadenosine; type | topoisomerase inhibitors such as camptothecin, topotecan and ecan; type II topoisomerase tors such as the epipodophylotoxins (e.g. etoposide and teniposide); antimitotic drugs such as axel, Taxotere, Vinca alkaloids (e.g. vinblastine, vincristine, vinorelbine) and estramustine (e.g. estramustine phosphate); antibiotics such as actimomycin D, daunomycin (rubidomycin), doxorubicin (adriamycin), mitoxantrone, idarubicine, bleomycin, mithramycin, mitomycin C and dactinomycin enzymes such as L-asparaginase; cytokines and ical response modifiers such as interferon (or, By), interleukin-2G- CSF and GM-CSF: retinoids such as retinoic acid derivatives (e.g. bexarotene); radiosensitisers such as metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, azole, nimorazole, nicotinamide, 5-bromodeoxyuridine, 5- iododeoxyuridine and bromodeoxycytidine; platinum nds such as cisplatin, carboplatin, spiroplatin, iproplatin, atin, tetraplatin and oxaliplatin; anthracenediones such as mitoxantrone; ureas such as hydroxyurea; hydrazine derivatives such as N-methylhydrazine and procarbazine; adrenocortical suppressants such as mitotane and aminoglutethimide; adrenocorticosteroids and nists such as prednisone, dexamethasone and aminoglutethimide; progestins such as hydroxyprogesterone (e.g. hydroxyprogesterone te), medroxyprogesterone (e.g. medroxyprogesterone acetate) and megestrol (e.g. megestrol acetate); gens such as diethylstilbestrol and ethynyl estradiol; anti-oestrogens such as tamoxifen; androgens such as testosterone (e.g. testosterone propionate) and fluoxymesterone; anti-androgens such as flutamide and |eupro|ide; nonsteroidal anti-androgens such as flutamide; and signal transduction inhibitors such as PARP tors [e.g. as disclosed in Cancer Res; 66: (16)], Mek inhibitors [e.g as disclosed in Blood. 2008 September 15; 112(6): 2439— 2449], farnesyltransferase inhibitors [e.g. as disclosed in Blood. 2005 Feb ;105(4):1706-16], wee1 inhibitors [e.g.as sed in Haematologica 2013.093187 (epub ahead of print)], rapamycin and Src inhibitors [e.g as disclosed in Blood. 2011 Feb ;117(6):1947-57].
Examples of the chemotherapeutic agents than may be used in combination with the Chk-1 inhibitor compounds of Embodiments 1.0 to 1.107 as defined herein include the chemotherapeutic agents bed in Blasina et al., Mol. Cancer Ther., 2008, 7(8), 2394- 2404, Ashwell et al., Clin. Cancer Res., 2008, 14(13), 037, Ashwell et al., Expert Opin. lnvestig. Drugs, 2008, 17(9), 1331-1340, Trends in Molecular Medicine February 2011, Vol. 17, No.2 and Clin Cancer Res; 16(2) January 15, 2010.
Particular examples of chemotherapeutic agents that may be used in combination with the Chk—1 inhibitor compounds of Embodiments 1.0 to 1.107 as defined herein include antimetabolites (such as capecitabine, cytarabine, fludarabine, abine and pemetrexed), Topoisomerase-l inhibitors (such as SN38, topotecan, irinotecan), platinum compounds (such as carboplatin, oxaloplatin and cisplatin), Topoisomerase-ll inhibitors (such as daunorubicin, doxorubicin and etoposide), thymidylate synthase tors (such as 5-fluoruracil), mitotic tors (such as docetaxel, axel, vincristine and vinorelbine, ) and alkylating agents (such as mitomycin C).
A further set of chemotherapeutic agents that may be used in ation with the Chk—1 inhibitor compounds of Embodiments 1.0 to 1.107 as d herein includes agents that induce stalled replication forks (see l et al., Clin. Cancer Res., above), and examples of such compounds include gemcitabine, 5-fluorouracil and hydroxyurea.
The nds of the invention and combinations with chemotherapeutic agents or radiation therapies as described above may be administered over a ged term to maintain beneficial therapeutic s or may be administered for a short period only.
Alternatively they may be administered in a pulsatile or continuous manner.
The nds of the invention will be administered in an effective amount, i.e. an amount which is effective to bring about the desired therapeutic effect either alone (in erapy) or in combination with one or more chemotherapeutic agents or radiation therapy. For example, the "effective amount" can be a quantity of compound which, when administered alone or together with a DNA-damaging drug or other anti-cancer drug to a subject suffering from cancer, slows tumour growth, ameliorates the symptoms of the disease and/or increases ity. More particularly, when used in combination with radiation therapy, with a DNA-damaging drug or other anti-cancer drug, an effective amount of the Chk-1 tor of the invention is the quantity in which a greater response is achieved when the Chk-1 inhibitor is co-administered with the DNA damaging anti- cancer drug and/or radiation therapy compared with when the DNA damaging anti-cancer drug and/or radiation therapy is administered alone. When used as a combination therapy, an tive amount" of the DNA damaging drug and/or an "effective" ion dose are administered to the subject, which is a quantity in which ancer effects are normally achieved. The Chk-1 inhibitors of the invention and the DNA damaging anti- cancer drug can be co-administered to the subject as part of the same ceutical composition or, alternatively, as separate pharmaceutical compositions.
When administered as separate pharmaceutical compositions, the Chk—1 inhibitor of the invention and the DNA-damaging anti-cancer drug (and/or radiation therapy) can be administered simultaneously or at different times, provided that the enhancing effect of the Chk—1 inhibitor is retained.
In one embodiment, a nd of any one of ments 1.0 to 1.107 as defined herein is administered before (e.g by up to 8 hours or up to 12 hours or up to one day before) administration of the DNA-damaging anticancer drug.
In r embodiment, a compound of any one of Embodiments 1.0 to 1.107 as defined herein is administered after (e.g by up to 8 hours or up to 12 hours or up to 24 hours or up to 30 hours or up to 48 hours after) stration of the DNA-damaging anticancer drug. In another embodiment, a first dose of a compound of any one of Embodiments 1.0 to 1.107 as defined herein is administered one day after administration of the DNA- damaging anticancer drug and a second dose of the said compound is administered two days after administration of the DNA-damaging anticancer drug.
In a further embodiment, a first dose of a compound of any one of Embodiments 1.0 to 1.107 as d herein is administered one day after stration of the DNA- damaging anticancer drug, a second dose of the said compound is administered two days after administration of the DNA-damaging anticancer drug, and third dose of the said nd is administered three days after administration of the DNA-damaging anticancer drug.
Particular dosage regimes comprising the stration of a compound of any one of Embodiments 1.0 to 1.107 as defined herein and a DNA-damaging anticancer drug may be as set out in WO2010/118390 (Array Biopharma), the contents of which are orated herein by reference.
The amount of Chk—1 inhibitor compound of the invention and (in the case of combination therapy) the DNA damaging anti-cancer drug and radiation dose administered to the subject will depend on the nature and potency of the DNA damaging anti-cancer drug, the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled person will be able to determine appropriate dosages depending on these and other factors.
Effective dosages for commonly used anti-cancer drugs and radiation therapy are well known to the skilled person.
A typical daily dose of the compound of formula (0) or formula (1 ), whether administered on its own in erapy or administered in combination with a DNA damaging anticancer drug, can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more lly 5 nanograms to 25 milligrams per kilogram of bodyweight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 rams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for e 1 microgram to 10 milligrams per kilogram) per kilogram of bodyweight although higher or lower doses may be administered where required. The compound can be stered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or or 14, or 21, or 28 days for example.
Ultimately, however, the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.
Methods of Diagnosis Prior to administration of a compound of the formula (0) or formula (1) as defined in any one of Embodiments 1.0 to 1.107, a t may be screened to determine whether a cancer from which the patient is or may be suffering is one which would be susceptible to treatment with either a Chk-1 kinase inhibitor compound or a ation of a chemotherapeutic agent (such as a DNA-damaging agent) and a Chk-1 kinase inhibitor compound.
More particularly, a patient may be screened to determine r a cancer from which the patient is or may be suffering is one which is characterised by a defective DNA repair mechanism or a defective cell cycle, for example a defective cell cycle due to a p53 mutation or is a p53 negative cancer.
Cancers which are characterised by p53 mutations or the absence of p53 can be identified, for example, by the methods bed in Allred et al., J. Nat. Cancer Institute, Vol. 85, No. 3, 200-206 (1993) and the methods described in the articles listed in the introductory part of this application. For e, p53 protein may be detected by immuno-histochemical methods such as immuno-staining.
The diagnostic tests are typically conducted on a biological sample selected from tumour biopsy samples, blood samples tion and enrichment of shed tumour cells), stool biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, or urine.
In on to p53, mutations to other DNA repair factors such as RAD17, RAD50, and members of the Fanconi’s anaemia complementation group may be predictive of response to Chk1 inhibitors alone, or in combination with chemotherapy. Cancers which contain mutations in these DNA repair pathways may be identified by DNA ce analysis of tumor biopsy tissue or circulating tumor DNA (ctDNA) or, in the case of Fanconi’s anaemia, by evaluating DNA foci formation in tumor biopsy specimens using an antibody to FANCD2, as described in Duan et al.,Frontiers in Oncology vol.4, 1-8 (2014).
Thus, the compounds of any one of Embodiments 1.0 to 1.107 may be used to treat members of a sub-population of patients who have been screened (for example by g one or more biological samples taken from the said patients) and have been found to be suffering from a cancer characterised by p53 mutation or a p53 negative cancer, or a cancer containing a RAD17 or RAD50 mutation, or a mutation in a member of the Fanconi’s anaemia complementation group.
EXAMPLES The invention will now be illustrated, but not limited, by nce to the ic embodiments described in the following es.
In the examples, the ing abbreviations are used.
ACN acetonitrile Ac20 acetic anhydride AcOH acetic acid AIBN azobisisobutyronitrile AICI3 aluminium chloride aq aqueous Boc20 di-tert-butyl dicarbonate BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl DAST Diethylaminosulfur trifluoride DCM dichloromethane DEAD diethyl azodicarboxylate DIPEA ropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EDCI 1-ethyl(3-dimethylaminopropyl)carbodiimide Et3N triethylamine Et20 diethyl ether EtOAc ethyl acetate EtOH ethanol HCI en chloride HPLC high mance liquid chromatography LCMS liquid chromatography-mass spectrometry LiHMDS lithium imethylsilyl)amide MeCN acetonitrile MeOH methanol Mesyl methanesulfonyl NaBH4 sodium borohydride NaBH(AcO)3 sodium toxyborohydride NaH sodium hydride NaHCO3 sodium hydrogen carbonate NaOH sodium hydroxide Na2804 sodium sulfate NBS N-bromosuccinimide NH3 ammonia NH4CI ammonium chloride NMR nuclear magnetic resonance WO 20390 PdC|2(dppf).DCM [1 ,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with romethane TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl THF tetrahydrofuran TMOA trimethylorthoacetate TMS trimethylsilyl Proton magnetic resonance (1H NMR) spectra were recorded on a Bruker 400 instrument operating at 400 MHz, in DMSO-d6 or MeOH-d4 (as indicated) at 27°C, unless otherwise stated and are reported as follows: chemical shift 6/ppm (multiplicity where s=sing|et, d=doub|et, dd, double doublet, |et, q=quartet, m=mu|tip|et, br=broad, number of protons). The residual protic solvent was used as the al reference.
Liquid chromatography and mass spectroscopy analyses were carried out using the system and operating conditions set out below. Where atoms with different isotopes are present and a single mass , the mass quoted for the compound is the monoisotopic mass (i.e. 35Cl; 79Br etc.) LCMS CONDITIONS The LCMS data given in the following examples were obtained using Method A or Method B as set out below.
LCMS Method A Samples were analysed by reverse phase HPLC-MS using a Waters 2795 Alliance HT HPLC, a ass ZQ mass spectrometer and a Waters 996 photodiode array UV detector. The LCMS used electrospray ionisation and the chromatography system as follows: Mass Spectrometer: Ionization mode: Positive Negative Capillary e: 3.20kV -3.00kV Cone Voltage: 30V -30V Source Temperature: 110 °C 110 °C Desolvation Temperature: 350°C 350°C Cone Gas Flow: 30 L/Hr 30 L/Hr Desolvation Gas Flow: 400 L/Hr 400 L/Hr Scan duration: 0.50 seconds 0.50 seconds lnterscan delay: 0.20 seconds 0.20 seconds Mass range: 80 to 1000 AMU 80 to 1000 AMU LCMS was carried using a BEH C18 X 2.1mm, 1.7 micron column. Column flow was 0.55 m|/min and the mobile phase used were 0.1 % formic acid in water and 5 mM ammonium acetate (A) and 0.1 % formic acid in acetonitrile (B), with an injection volume of 10 uL.
The gradient was as described below.
LCMS Method B Samples were analysed by reverse phase HPLC-MS using a Waters 2795 Alliance HPLC, an Acquity QDA mass spectrometer and a Waters 996 photodiode array UV detector. The LCMS used ospray ionisation and the chromatography system as follows: Mass Spectrometer: Ionization mode: Positive Negative Capillary Voltage: 1.50kV -0.80kV Cone Voltage: 10V -30V Source ature: 120 °C 120 °C ation Temperature: 600°C 600°C Scan on: 0.50 seconds 0.50 seconds lnterscan delay: 0.10 seconds 0.10 seconds Mass range: 100 to 700 AMU 100 to 700 AMU LCMS was carried using a X-BRIDGE C18 100 x 4.6mm, 5 micron . Column flow was 1.0 ml/min and the mobile phase used were 0.1 % formic acid in water (A) and methanol (B), with an injection volume of 10 uL.
The gradient was as described below.
Time min %A %B 3.00 10 90 .00 90 10 EXAMPLES 1 TO 163 The compounds of es 1 to 163 shown in Table 1 below have been prepared. Their NMR and LCMS properties are set out in Table 2.
Table 1 NC NC ) I H I H / \ O N >/ \ O N N N N N N \ N \ H o\ H Example 1 Example 2 NC)_\ I NC N/ \NmN/Q N>/—\\N I O N\/©H — H N \ N \ H \N,N H H ‘N-N H Example 3 Example 4 NC NC Nb | in Q O — N \ N \ 1%)F H N-NH H \N,NH Example 5 Example 6 Example 7 Example 8 § l «“0 N’ 0 ifNWNJ l / \ O “N N N \r—m—< \: \=< N \\ N H \ N,NH H N,NH Example 9 e 10 Example 18 \\ \ N-NH N'NH Example 19 Example 20 2015/015030 NC NC N/ I ‘ l (\N/ F O N \J N\ N \ N\ /N /{ \ \/ N \\~ N \‘\ H H N-NH N-NH Example 21 Example 22 NC / )=\ | J NC | N/ \_{ \ / N \ N \ H \ \ N-NH H N-NH Example 23 Example 24 ‘ N/ x | N’ ‘N/ N N \ N \ H \ H \ N-NH N-NH Example 25 Example 26 NC N/ NC \\ /{N L/( U N N \ \ \ \ H H N ’ N H N’N H 0\ Example 27 Example 28 NC N/ H‘ O N \/O/ F \ (NW N \ \ H \ \ N-N H o\ H N'N H Example 29 Example 30 NC \ N>l I I \\N O M N’ H FN‘N H Example 31 Example 32 NC NC H N >= ‘ o >—\_ N 0,, 0V0 N N N \\ N H /{ \\ 1/ \ \ N N H \N, N H H N - N H 0\ Example 33 Example 34 ”CH \“ NCH NCN OVQ NW 0fl“ \ ( \ /( N \ \ H \ H \ N- N H O\ N-N H 0\ Example 35 Example 36 NC / NC N/ Y N N>=\N I § O O N N N \\ (1NWH L/< H H N.N H N'N H Example 37 Example 38 H I N N NC NC > I F | — O 0 N N N N \\ (z \\ /\/ N \‘\ N \“ H N-NH H N-NH Example 39 Example 40 NC NC N¥=\ I I O N>=fi o On MW C,N C- N \ H \ H \ N-NH e 41 Example 42 Cl Cl / N N>=fi o L? \\_/<N N \ \ H \ N-NH H L-NH Example 43 Example 44 HO_§~\ NC l N H I __ 0 ).N ~ 0 N \J N N N N V f \ / N-NH H N.NH Example 45 Example 46 NC NC I N H I O N—“ O ‘ N N O \\ (IN \\ /\/ \ N \ H \ H \ N-NH N-NH Example 47 e 48 NC NC ‘ NH | NH O ‘ O \ /N N \‘\ N \‘\ H N-NH H N-NH Example 49 Example 50 NC NC NH ‘ NH —— F -— o N3?1» NQ H N.NH H N-NH Example 51 Example 52 PCT/U82015/015030 NC NC ( H Y N H ‘ ‘ O H‘ O N N N N N \\ /r \\ /{ \ \ N N H \ N-NH H N-NH Example 53 Example 54 I N H N H \\ {IN \\ /\/ N ‘\ N ‘\ \ H \ H N-NH N-NH e 55 Example 56 X=n NH ) l O “ N O N N V N N H \\ \ /( N \ F H \ \ N-NH o\ H N.NH Example 57 Example 58 NC NJ ) | * O N N \\ /( u \ N-NH Example 60 NC) N H 2 I N/\n’ ~ 0 O \\ er H \N-N H Example 61 Example 62 1‘\ 0| N N0 \\ (IN I N \ N H \N-N H H \ N-N H Example 63 e 64 )5. g N/ \\ /rN N \ H \N-N H Example 65 Example 66 NC C, N/ No) CI N H \\ /{ L/< \ \ \ u \ H N.N H o\ N-N H 0\ Example 67 Example 68 NC N/ NC: N H N N N N \\ x: \\ (x H H N-N H o\ N-N H 0\ Example 69 Example 70 0 O / fig: _ ('3 >=\ ('3 N NL) N N \\ (,N L/< H \ \ \ fl \ H N.N H N-N H Example 71 Example 72 0 1 l O )=\ 6 H § O N N L) N N N N \ \ '</ , I Hm m \ \ N \ N’N H N’N H Example 73 Example 74 NC NC NH )‘\ ' | O )~\ O 0 N J33 N w”W \\ /./N F N N H \ \‘\ N-NH H N-NH e 75 Example 76 NC NC }_\ l NH | “ o ‘ O O N\/N NCi F n— M \ \ u 9 N - N H N,NH Example 77 Example 78 NC r’\o NC )_\ I I («N/\ § 0 N NJ N>=RN O N"J \ / H C(Nfi/(jrH \ N,NH N.NH Example 79 Example 80 NC ax NC *NH N>=\N I o Np )‘\ O N N \2 \ \\ /( H\ fl \\ N.NH N,NH Example 81 Example 82 NC N )‘\ .
O N NL/(N Q“ E 5 N Q \\ (NW N \ N \ N-NH H N-NH Example 83 Example 84 )‘\ O \\ /\/N H \N-N H Example 85 Example 86 NC F NC F N/k ) I N/\ E I § O N N\ N \\ (/N M \ N \ H ‘ H \ N’N H N’ N H Example 87 Example 88 N /\/O\ | > | >~fi O § O N N N\ N ”A \\ /r \‘/< \ \ N N H \N-N H H N H e 89 Example 90 I (L /N > I 9 >= \\ 1/ H H/ M \ \ H \ N‘N H N—N H Example 91 Example 92 I 2\N/\ NC § O I N \J ‘ O N NH3 0,, v m N \ \ N H \ N—l‘I H H N-N H Example 93 Example 94 u \ N-NH Example 96 F N/\\ )‘\ | NL/(N u \ N—N H Example 98 NC N/\/OH >_ I > | ~ 0 N ~—N N\ N N \\ / lr I N ‘\ N \\‘ H N-NH H N—NH Example 99 Example 100 NC H I >=\ ('3 N‘ 0 MW”\ HRINK/O\ N-NH N-NH e 101 Example 102 NC \N NC \N H— I I o 0 “Q E o OVQ N\\ \\ (/N N\\ (/N N \“ N \‘* H N—NH H N-NH Example 103 Example 104 NC NC N$\ N/\/ N>=\ | l O ng/O N>=\N O \\ (/N \\ /{ H N-NH H N-NH Example 105 Example 106 PCT/U82015/015030 NC N/ H I w NC w . H O N N N N N)=\ O L/< \\ \ (/N N \ \ N H N-NH H N-NH Example 107 Example 108 NC N’L\ NC 37, I H i7, I H O N o N N _-NNW N ‘-Nhim 13 H L-NH '4 N-NH Example 109 Example 110 M3 NC | H | H ~ O N N N NwN N>=\N O V ,f V N\/ 4? \[::j H HNW N-NH N-NH N\|/ Example 111 Example 112 NC N/ h 0 Op “CH . -— o o N fl“ \_<N\/ WU\ u”$90 H \ N.NH H N-NH Example 113 e 114 Nk | (\NH heI as N)=\N o Nd Lfilm\/ \ H\ H \ N-NH N-NH F Example 115 Example 116 $ N NC NC N3=\N “‘on | O O “‘on / N3=/\N \ \ H H N-NH N-NH Example 117 Example 118 VV()2015/120390 N ( NC NC >= I j | 0 J NL/<N o m \‘ L(N\ N‘NH N-NH Example 119 Example 120 NC NH NC N/ N3=xN | K‘ Nd 6 O RN”o/ m/ H \ N-NH 0\ H N-NH 0\ e 121 Example 122 M3.W NC N§:%N O T::>”F Nf=jN O W::>—c/ H\\ L<N \ H \ N—NH N-NH Example 123 Example 124 NC (N N3=i>u NC NE=RN I O W:::>IIO/ o o\de:> \_<N / H N-NH H N.NH Example 125 Example 126 NC A >—\ 5 o N \\\‘“Q \\ /er H N-NH N-NH Example 127*** Example 128 NC 4N N)=\N . OVO N3=/\N I \-_fi;—«(a§7:]:::]/fl\H O fimO\/ H N-NH \ N-NH Example 129 Example 130 o o NET/(N I I 0 Ni) NCH N\\:/<N 0 ”“0 N \\ N \\ H H N-NH N-NH Example 131 Example 132 I (LNJ\ NJ NCH I N)=\N 0 N\:N O O Vw H ”V N N \ \ H H N-NH N-NH Example 133 Example 134 NC NC NAN a o N>=\N a ON/\ H \N-NH H \N-NH F Example 135 Example 136 NC J\ NC N/— | {\N H I 0 V O 0‘0 HNW/ H» L<N \\ H N-NH F H N—NH Example 137 Example 138 “N ,— . ML <5 CFC) £5 N3=/\NWmO NMN 0 N \\ H H N’NH N-NH Example 139 Example 140 §— NC N | (\N’Y N3=/\N I - 0 0 CL) N\\):\/<N NJ HN \\ \ H H N.NH N-NH Example 141 Example 142 H I NCH I N\‘/N O N\~ N O H Nv \~’( N M \ \ \ \I/ N—N H H N‘N H e 143 Example 144 NC N/\ NC N)=\N | N\/Cl| I O o \\ (z N>=\N \\ /{NWHY HN” N-NH H N-NH Example 145 Example 146 \N/ NC NC NJ\ I I N>=\N (I) “£01 N>=\N O N L<N\ / \\ /( \ \ \ \ H H N-NH N-NH Example 147 Example 148 NC N > I I/ H I — o 1,, N — o j N N N N o \\ /( D \\ (1 N \ H \N-NH H ‘N-NH Example 149 Example 150 NC NC H I ‘7’ )=\ I 1’ ‘ O 1,, N O N N N N N l ,1 D l ’r N \\ N \\ H N—NH H N-NH Example 151 Example 152 NC F3C {\NH NC N27“! . I y _ N 0 d N37!“_ 0 N N \\ N \\ H NJ“H H N_NH Example 153 Example 154 NC I >=x (I) H ‘ H ‘\ N-NH M \\NHN‘ Example 155 e 156 § HI MN O'J H \ N—NH Example 157 Example 158 | {NH - Nd MN MN \\ H \\ NaNH N—NH Example159 Example 160 N NQ \ \ H \N—NH H \ N‘ NH Example 161 Example 162 N—NH e 163 SYNTHETIC METHODS Synthetic methods A to T were used to prepare the compounds of Examples 1 to 163.
The reaction schemes for synthetic methods A to T are shown below.
Synthetic Method A WO 20390 N u. a xA.» Mn N. xii». \ H .. ~ ~mKa“ .T. ~ .1~. \\\\\\\\;\\\\\\<‘\\\\\\’ \‘1 ‘2 N“ 2.. I... \ 0-:: ,5 . “KNN“aIn 2.1%3..“c Synthetic Method B ‘0 0 0 KCO3, Mel Fe NHCl Mum nitrite BnNH3,NaBH(OAc)3 OZN OZN HZN Br DMF MeOH g0 CuBr, MeCN ACOH, DCM OH O\ O\ 0\ B/Q/wA©—>/\O/\/SnBU3 \(Q/‘NA0—>Boc3O, Et3N \(Q/Em—>NaH, cs3, Mel Pd(PPh3) DMSO 1 ,4-dioxane N NH2 NAG I I NC ‘N H N3H.H30 S N N / / , I j’ / HA0 _> NaH THF cOH /S O O\ ’ O NC \N /S O\ “‘0 HCIin EtOAc THF/MeCN NAG N—NH 0\ N-NH 0\ Synthetic Method C I?“ :‘fl'fii {if l\\vNO 3 (33135303, M130!»,w‘ a N' A ‘- ”18": .3 E Hth._ Me PhCHQJ au>1{0,0333r-- . .x \\ .u ‘« ,éN‘x 1. ,1 3 N W 5:: 3my W ACOH 0 .5 23 NH CE. HEOH ACDH DOM ' r) \ N ' \ 3: EJ-j 33 {iv/«‘3 3333‘ as E 1 z‘”\¢»hv’\\f: “AQ,A§;~HQE<R, 'ANf’E, quuwr \f . , 3 1".in 803 ‘0. ELK 34$"? NaH 933.“?h: a,- FdszPhé3 13/ “3/ am \3/‘3/ OMS“ \ Let—dic-Kaae U '33 a -3\ 3 -"- r"‘« M \: 53 3 {Sn-s ’:§ 3’: EE 3 r” 1’ x; E 3 {vi-7‘ r’\/ \W‘é :\ E 3;?" (”K-31" «V/ \;/ 3 s a 333,333. ,3? 33 £ ,. ; iHi) W?\, W «‘1»\ \3345. /‘\ 7/ M MH, 'fl-EF L is 3 3? BOHtAcOH 3 2 \ .2 1 u 1 1’ \ N;3 3, N I“ \ “'4 ’i‘m. mi“ \,\ 332—33 ‘ i H (\l 333 «V x3, 33,; 0333 E109»: M 333 33,3 /~\_,,E~3\V.’&rf’ Me' ......................... : 3' m ‘—<“““ 3,1\ ‘ Stiff?. x f THFWESC1 :3, N “fir .~ “31:34 xx“ -‘= N’ EH (3‘ WO 20390 Synthetic Method D Synthetic Method F Na(OAc)BH, I O Boc2,o H —> O\ /0 RT , I O | MeCN/THF o N2H4.HZO, EtOH o O UCN N N —> I —> I —> 3°C 3°C 4800 to RT NC Reflux \ DIPEA, EtOH, 800C H 2 N 0 \N—N H I 4N HCI in dioxane N),—\N C') >—\/\ O NO NO MeCN THF RT N N ;> H \=< ['30c N \ —<: N-\N H S nthetic Method G N Br NBoc NBoc NBoc I j, LHMDS MeCN N2—>H4H20 NC N EtOH NC \ DIPEA Dioxane NC NBoc NC NH I NC NJk/N\ >/_\‘ HCI in Dioxang H ”O N‘ h N\=<N MSCN/THF N\=<N EDC.HC|,HOBt N\=<N \ \ \ \ N N H H DMF \ N_NH o\ N-NH o\ H N_NH 0\ Synthetic Method H NC NH NC N/\ N), \\N CH3CHO, DIPEA —> N), \\N \=( Na(OAc) BH \=( N \\ MeOH/MZCN N \ H N-NH o\ H N-NH 0\ Synthetic Method | NBoc F NBoc F F K2003, Mel H NJ NJ M60Q Acetone K2003, DMF MeO o OH O\ O O\ N Br LHMDS MeCN QNBOC N2H4.H20 QNBOC \—>NNCI 1r EtOH DIPEA Dioxane HZN N-NH 0\ NC (\NBoc NC (\NH NC (\N/ N),—\\N Nd HCI in Dioxane \ Nd (HCHO)n,D|PEA NN),—\\ NJ \=( MeCN/THF \ N\=(; Na(OAc)3BH,AcOH N N\=(: H \N—NH O\ N-NH MeOH/MeCN O\ H N—NH O\ Snthetic MethodJ NBoc /|B NBoc NCUN NN3_?N HCI in Dioxane CS23,CO BINAP \ HF HZN ‘ N-NH O\ Pd2(dba): Dioxane N-NH O\ NNQN NH (HCHO), DIPEA Na((OAc)BH, AcOH N—\NH O\ eCN NNQN N—\NH 0\ Synthetic Method K NBOC HNaCIo,ZNaHPO OH I) o HO H2480HmeOYECErOH DMSO/Ho DIAD, PPh3 meow/Q 03°C O O 0 \ THF O\ N Br LHMDS MeCN Uses —»H0HI I‘ _. flUses HZHAHZO NC \ EtOH H2N \ DIPEA Dioxane N_NH O\ HCIin e H(CHO)nDIPEA MeCN/THF NH Na(OAc)BH AcOH N_NH O -NH 0\ MeOH/MeCN \N-NH O\ S nthetic Method L Br QBOC NBoc NBoc HO F 1__>2ethanediol {NO/g;0 BrACN DAST, DCM OHC p__>TS/-\PhMe —> —> n-BULi, THF 0 OHC Zn, THF N Br NBoc NBoc NBoc F F L B// N2H4'H20 NC N Dess-Martin NC EtOH \ DIPEA, Dioxane H2N \ OH 0\ N_N H 0\ NC NBoc NC ’ NH NC N 1’ F F F “ >_\ >—\ N N HCI in dioxane N’ \N (HCHO),]I DIPEA N/ \N \_<— —> —> _ _ \ MeCN/THF N \ Na(OAc)BBH, AcOH \ \ N \ \—(N H \ N—NH 0\ H N-NH o\ MeOH/MeCN H N—NH 0\ Synthetic Method M 2015/015030 NBoc NBoc F NBoc “EmsDMS THF DAST LHMDs,MeCN 2) NaOH H220 Meo DCM MeO THF WEEN24H.H20 0 O\ NBoc NCJ:NleBr NC NBOC NBoc N N DIPEA Donane H2N N \\ N-NH o N-NH o\ F F NC NH NC N/\ HCIin Dioxane N:’ \‘N CHSCHO,DIPEA N)—\/\N MeCN/THF \=<N \ Na(OAc)sBH \=( ‘N_NH o\ MeOH/MeCN N N_NH O Snthetic Method N NB“ ”3°C F NBoc Dess-Martin AST LHMDS, MeCN CM MeO THF 0 o\ :)N2H.H20NB“ NC NBoc NOINNj’B F NBoc )/_\\ N N DIPEA Donane H2 N N \\ N-NH o\ H N-NH o\ F F NC F NH NC F N/ HCI in Dioxane Nj’ \N (HCHO)n,DIPEA N)/ \\N —> —> MeCN/THF \ Na(OAc)2BH,AcOH N \=(N \ H N‘NH o\ MeOH/MeCN H \N—NH 0\ Synthetic Method 0 “ROE/q:N—>\/OBOCXantphos Cs2003 N Boc2O,DMAP N LHMDS,MeCN —> ——-> Pd2((dba)3 M90 DCM MeO THF Dioxane o o O O N Br m Elm NBOC J: j, NC N2H4.H20 N N NC N N>l \\N Elsie/0mm —> _ NC EtOH \ DIPEA Dioxane \ O HZN 0\ \N_NH \ o\ N-NH 0 NC NC NI \N N HCI in Dioxane p H w/ (HCHO)n,DIPEA I \ N MeCN/THF \ N Na(OAc)SBH, AcOH H ‘N_NH MeOH/MeCN NW; o\ \N_NH O Synthetic Method P Br 0 meofit/Q/ WBFSK \ . OH AD-MIx—fi,Na2803 1)TMSCI,TMOA DCM _ > M80 __> M80 ——> M Oe PdC|2(dppf), EtaN t—BuOH O O O 2) K2003, MeOH \ n-PrOH O\ o o\ O 0\ OH OH I H |?oc \/\OH BocZO,Et3N “‘on PPha,DEAD M O I DCM MeO Ph—Me> O O\ O O\ BOG BOG Nj/B LHMDS MeCN N“H-H0 _NE:0] NNN),—\\ [N] .—F>TH EtOH WNW DIPEA,_>Dioxane N\_ f; \‘ 0 N_NH o\ N_NH o\ H I NC NC HCI in Dioxane N),—\N [O] mom)", DIPEA —> —> N),—\N \ [O]‘ MeCN/THF N\=(; Na(OAc)3BH,AcOH N\__I:( MeOH/MeCN N—NH 0\ H N_NH 0\ Synthetic Method Q OH OTBDMS OTBDMS TBDMSCI, Im M LHMDS, MeCN N2H4.H20 eO _—> MeO —> —> DMF THF EtOH 0\ O O\ 0 O N Br Nc Nc WOTBDMS I If \ Nc )— )_‘ N N/ \N OTBDMS TBAF N/ \N OH _> ———> _ _ H2N \\ ioxane \ THF \ N_NH o\ N N \ \ H N_NH o\ H N_NH o\ Bess-Martin NHN ”F —> _> DCM \=( Na(OAc)aBH, DIPEA 0'”: N \\ MeOH/MeCN H N—NH 0\ N-NH o S nthetic Method R IBOC [Boo [Boo N N e0 (E) LHMDS, MeCN 0 L) NaH, DMF MeO THF 0 o\ NC 0 o\ o 0\ [Eco [N Br [Boc N I I No N N2H4.H20 CL) NC N )1 0L) E‘OH DIPEA Dioxane \ \_< HZN \ \ N—NH 0\ N-NH o H /— NC N NC N HCI in Dioxane )/ \\ (E) CH3CHO, DIPEA >,—\\ o L) N o _> N N N MeCN/THF \=( \ Na(OAc)aBH, ACOH \—<— \N—N H MeOH/MeCN N O\ H \N—N H O\ S nthetic Method 8 PO(OEt)2 0080c PO OEt)3( \ Pd-C H MeO ’ 2 , MeomBoc NaH THF MeO NBDC MeOH O O \ O O O O\ \ NIj/Br NC LHMDS MeCN Nc/W/Q/UBoc—,N24”.HO WBWL NH;\N EtOH _ H N NBoc O \N_NH ioxane O\ N \\ H N-NH 0\ NC NC HCIin Dioxane N, \‘N CH3CHO,D|PEA N), \\N ’ —> _ NH _ MeCN/THF \ N\/ N Na(OAc)aBH \—<N \ H \N_NH MeOH/MeCN O\ H \N_NH 0\ Synthetic Method T O"‘\OH \\ o , (HO)2B Bess-Martin NO 4-MePhsozN2H4 N O"\N‘N‘.s' N N‘ O. ’ MeO D 'BOC DOM .Boc EtOH BOO K23,CO Dioxane Boo Fm MID/B NQTN Boo I N L——"HMDSWON D N—>“HHO 0—» EtOH D H2N \\ DIPEA Dioxane N_NH o ‘N_NH o\ HCI in e N/\N "-D CHscHOI DIPEA —> 1,9 MeCN/THF Na(OAc)sBH \N_NH O MeOH/MeCN \N-NH O 320.. .8522 < < < < < < $5.33). wmv mom 8v 83. «3 3% Emum :3 0,: mm: 0,: 3.8 .3 N3 .3 5w .3 wow mm...” .3 35 mm: .3 Foam 8.0, .AIF mo...” 5w .AIF AIF mg .AIF .AIF .AIF OS IN .AIF 5w .AIN .AIN .3 .w .3 .3 35 .AIN .AIF .AIF .AIF .33 .3 35 .3 .AIN .3 .AIF .3 mm: 5.5: .Imd mm: IN .w .3 .3 z: .AIN 0,3 .23 8.3 .3 mmg IN a3 v3 mm: .3 m3 53 .AIF .AIF 8+ $8 8.8 .3 .3 8.8 .AIF 3:0, .AIF 8.8 .AIN .AIF Ed, .3 .AIm 8.8 .w .AIN .AIF 8.3-8.3 .AIF .AIF .AIF .3 .AIm 53 .3 .AIF .3 8....” Em .3 .AIF .3 .3 .w .3 8.3 .3 .AIF .AIm .AIF NM: .83 .AIF mg m2 .3 I8 .3 88 .AIN 53 No .3 E: wow mm...” .3 mop .3 .3 .AIF .AIF .8 8.: 8.8 .AIIw3 .3 .AIm .AIF . .AIF N IN .3 .AIF 8.8 .AIF 0:3: 8.8 .AIm .w Foam 8.8 .23 Iv 5.8 .3 .3 8.33.3“ 2an .3 n .3 3m n n n .3 m: e3 n n com 3 IV 53 .AIN com .AIN .c 3E mm 3303203 5w .AIF amp .AIN :5 5w .3 mm.w .3 . 5.38.8 53 «we .AIm .3 .AIF . 3303203 .AIN .AIF IF 3303203 IN .AIF .3 IQ .AI8.3 .AIN .3 8+ 3303203 .AIF mtg: 8+ .c 3303203 .3 m: 35 3303203 .3 e3 on: Imw, 25556 .8522 -©.N-8_Em_>Nc83-m -m-_0Nm§-Iwcémfigxofiméc 3::coemo-m-mc_Nm§-_8_Em; ->xo£me-m-8_$3283-35 -_0c_em_>-m-_0Nm§-I79.25% -m-_ONm§-I#:32938ng 3Ecoemo-m-mcneéégem; Egficmémviéé -m-_ONm§-I m__:_coemo-m-mc_Nm§ -0583283in $95286? 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N-(4-AcetyI-3,5-dimethoxy-phenyl)—acetamide AICI3 (36.0 g, 27.5 mmol) was added in portions to a stirred solution of 3,5-dimethoxy- phenylamine (12.0 g, 78.4 mmol) and Ac20 (20.0 g, 19.6 mmol) in DCM (120 mL) at 0°C. The mixture was stirred for 15 minutes then allowed to warm to room temperature and stirring continued for a further one hour. The reaction mixture was poured onto ice and the resulting precipitate collected by filtration. The ted solid was dried under reduced pressure to give the title compound (5.0 g, 27%) as a white solid. 1B. 1-(4-Amino-2,6-dimethoxy—phenyl)—ethanone A mixture of N-(4-acetyl-3,5-dimethoxy—phenyl)—acetamide (5.0 g, 21.1 mmol) in MeOH (50 mL) and 5N aq. NaOH (50 mL) was heated to reflux for 4 hours. The e was allowed to cool to room temperature and concentrated under reduced pressure. The residue was partitioned between water (100 mL) and EtOAc (50 mL) then the separated aqueous phase was ted with EtOAc (3 x 50 mL). The combined organic extracts were dried (Na2804) and evaporated under reduced re to give the title compound (3.8 g, 92%). 1C. tyI-3,5-dimethoxy—phenyl)-carbamic acid tert—butyl ester Boc2O (6.37 g, 29.2 mmol) was added to a stirred solution of 1-(4-amino-2,6- dimethoxy-phenyl)—ethanone (6.37 g, 29.2 mmol) and guanidine hydrochloride (1.85 g, 19.5 mmol) in EtOH (38 mL). The e was heated to reflux for 12 hours and then allowed to cool to room temperature. DCM (200 mL) was added then the mixture washed with water (2 x 50 mL), dried (Na2804) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel (60-120 mesh) using 0-10% EtOAc/hexanes as the eluent to give the title compound (3.5 g, 61%). 2015/015030 1D. 4-Acet l-3 5-dimethox - hen l-benz l-carbamic acid tert-but lester NaH (60% in mineral oil, 0.57 g, 14.2 mmol) was added in portions to a stirred solution of (4-acetyl-3,5-dimethoxy—phenyl)-carbamic acid tert-butyl ester (3.5 g, 11.9 mmol) in THF (18 mL) at 0°C and the resulting mixture stirred for 30 minutes. Benzyl bromide (3.04 g, 17.8 mmol) was added dropwise over 10 minutes then the mixture was heated to 70°C for 3 hours. The solution was allowed to cool to room temperature then water (40 mL) was carefully added and the mixture extracted with EtOAc (4 x 50 mL). The combined organic extracts were dried (Na2804) and evaporated under reduced pressure to leave a residue that was purified by column tography on neutral silica gel (60-120 mesh size) using 0-5% EtOAc/hexanes as the eluent to give the title compound (3.0 g, 66%). 1E. Benz l- 4- 3 3-bis—meth lsulfan l-ac lo l-3 5-dimethox - hen l-carbamic acid tert-butyl ester A solution of (4-acetyl-3,5-dimethoxy-phenyl)-benzyl-carbamic acid tert-butyl ester (3.0 g, 7.8 mmol) in DMSO (15 mL) was added slowly to a stirred slurry of NaH (0.78 g, 19.5 mmol) in DMSO (15 mL) ining the internal temperature at 10-15°C. After stirring at 10°C for 10 minutes, carbon disulfide (1.18 g, 15.6 mmol) was added and stirring continued for a further 10 minutes. Methyl iodide (2.19 g, 15.6 mmol) was added at 10°C then the mixture was d to warm to room ature and ng continued for 10 minutes. The reaction mixture was carefully poured onto ice then extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2804) and evaporated under reduced re to leave a residue that was purified by column chromatography on neutral silica gel (60-120 mesh size) using 0-17% EtOAc/hexanes as the eluent to give the title compound (1.7 g, 45%). 1F. Benz l- 4- Z 5-c ano- razin lamino meth n l-acr lo l-3 5- dimethoxy-phenyl{-carbamic acid utyl ester A solution of 2-aminocyanopyrazine (1.25 g, 5.2 mmol) in THF (10 mL) was added slowly to a stirred slurry of NaH (60% in mineral oil) (0.21 g, 5.2 mmol) in THF (17 mL) at 0°C. The mixture was stirred for 30 minutes at 0°C then a solution of benzyl-[4-(3,3- thylsulfanyl-acryloyl)—3,5-dimethoxy-phenyl]-carbamic acid tert-butyl ester (1.7 g, 3.48 mmol) in THF (7 mL) was added dropwise and the reaction mixture was heated to 80°C for 12 hours. The solution was allowed to cool to room temperature then water (40 mL) was carefully added and the mixture extracted with EtOAc (3 x 25 mL).
The combined organic extracts were dried (Na2804) and evaporated under reduced pressure to leave a residue that was purified by column chromatography on neutral silica gel 0 mesh size) using 0-70% hexanes as the eluent to give the title compound (0.9 g, 46%). 1G. Benz l- 4- 5- 5-c ano- razin lamino -2H- razol l-3 5-dimethox - hen l- carbamic acid tert-butyl ester A stirred on of hydrazine monohydrate (0.077 g, 2.40 mmol), benzyl-{4-[(Z)—3-(5- cyano-pyrazinylamino)—3-methylsulfanyl-acryloyl]-3,5-dimethoxy-pheny|}-carbamic acid tert-butyl ester (0.90 g, 1.6 mmol) and acetic acid (2 drops) in EtOH (0.7 mL) was heated to 60°C for 15 minutes. The e was allowed to cool to room temperature and the precipitated solid collected by filtration. The solid was washed with EtZO (2 x 5 mL) and dried under reduced pressure to give the title compound (0.10 g, 12%). 1H. 5- 5- 4-Benz lamino-2 6-dimethox - hen | -1H- razol lamino - razine carbonitrile oroacetic acid (1 mL) was added dropwise to a stirred solution of benzyl-{4-[5-(5- cyano-pyrazinylamino)-2H-pyrazolyl]-3,5-dimethoxy-pheny|}-carbamic acid tert- butyl ester (0.10 g, 0.19 mmol) in DCM (2 mL) at room temperature. The mixture was stirred at room temperature for 3 hours then heated to 40°C for a r 2 hours. The solvents were evaporated under reduced pressure to leave a residue which was purified by preparative HPLC to give the title compound (0.025 g, 34%) as an off-white solid.
Synthetic Route B (Illustrated with reference to Example 3: e 3 - 5- 4- Benz lamino-meth thox - hen l-1H- razol lamino - razine carbonitrile hydrochloride) 3A. 3-Methoxy—4-nitro-benzaldehyde A mixture of 2-hydroxynitro-benzaldehyde (8.0 g, 47.9 mmol), methyl iodide (10.2 g, 71.9 mmol) and potassium carbonate (6.61 g, 47.9 mmol) in DMF (80 mL) was stirred at 60°C for 3 hours. The cooled reaction mixture was diluted with EtOAc (100 mL), washed with water (200 mL), dried (Na2804) and evaporated under reduced pressure to give the title compound (6.5 g, 75%) which was used without further cation. 3B. 4-Aminomethoxy—benzaldehyde A stirred mixture of 3-methoxynitro-benzaldehyde (6.5 g, 35.9 mmol), iron powder (4.51 g, 80.8 mmol) and NH4C| (3.87 g, 71.8 mmol) in MeOH (50 mL) and water (50 mL) was heated to reflux for 3 hours. The cooled reaction mixture was filtered through a pad of celite and diluted with EtOAc (100 ml). The separated organic phase was washed with water (2 x 50 mL), dried (Na2804) and ated under reduced pressure to give the title compound (4.5 g, 83%) which was used without further purification. 3C. 4-Bromomethoxy-benzaldehyde A mixture of 4-aminomethoxy-benzaldehyde (4.5 g, 29.8 mmol), n-butyl nitrite (4.6 g, 35.8 mmol) and copper e (6.83 g, 47.7 mmol) in MeCN (45 mL) was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with water (200 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel (60-120 mesh) using 0-70% EtOAc/hexanes as the eluent to give the title nd (4.2 g, 66%). 3D. Benz l- 4-bromomethox -benz l -amine NaBH(OAc)3 (6.24 g, 29.4 mmol) was added in portions to a d solution of 4- bromomethoxy-benzaldehyde (4.2 g, 19.6 mmol), benzylamine (2.51 g, 23.6 mmol) and acetic acid (2.35 g, 39.3 mmol) in DCM (42 mL) at room temperature. The resulting solution was stirred for 12 hours then diluted with EtOAc (40 mL), washed with water (40 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was ed by column chromatography on l silica gel (60-120 mesh) using 0-2% MeOH/DCM as the eluent to give the title compound (3.8 g, 64%). 3E. 1-|4-(Benzylamino-methyl)methoxy-phenyl|-ethanone A stirred solution of benzyl-(4-bromomethoxy-benzyl)-amine (3.8 g, 12.5 mmol) and tributyl(1-ethoxyvinyl)tin (5.39 g, 15.0 mmol) in 1,4-dioxane (40 mL) was degassed with nitrogen for 15 minutes. Tetrakis(tripheny|phosphine)palladium(0) (0.72 g, 0.62 mmol) was added to the mixture and the resulting solution heated to 130°C for 16 hours. The mixture was allowed to cool to room temperature then diluted with EtOAc (60 mL), washed with water (40 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column tography on neutral silica gel (60-120 mesh) using 0-2% MeOH/DCM as the eluent to give the title compound (1.5 g, 45%). 3F. (4-Acetylmethoxy—benzyl)—benzyl-carbamic acid tert-butyl ester Boc20 (1.45 g, 6.69 mmol) was added to a stirred solution of 1-[4-(benzylamino- methyl)methoxy-phenyl]-ethanone (1.5 g, 5.57 mmol) and EN (1.69 g, 16.7 mmol) in DCM (5 mL) and the ing mixture stirred at room temperature for 3 hours. The mixture was diluted with DCM (20 mL), washed with water (2 x 20 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel (60-120 mesh) using 0-2% CM as the eluent to give the title compound (1.5 g, 73%). 3G. Benz l- 4- 3 3-bis-meth lsulfan l-ac lo lmethox -benz l-carbamic acid tert- butyl ester A solution of tylmethoxy—benzyl)-benzyl-carbamic acid tert-butyl ester (1.5 g, 4.1 mmol) in DMSO (15 mL) was added slowly to a stirred slurry of NaH (60% in mineral oil,0.41 g, 10.2 mmol) in DMSO (20 mL) maintaining the internal temperature at 10-15°C. After stirring at 10°C for 10 minutes, carbon disulfide (0.62 g, 8.1 mmol) was added and ng ued for a r 10 minutes. Methyl iodide (1.15 g, 8.1 mmol) was added at 10°C then the mixture was allowed to warm to room temperature and stirring continued for 10 minutes. The reaction mixture was carefully poured onto ice then extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue that was purified by column chromatography on neutral silica gel (60- 120 mesh) using 0-30% EtOAc/hexanes as the eluent to give the title nd (0.75 g, 39%). 3H. Benz l- 4- Z 5-c ano- razin lamino meth lsulfan l-ac lo l methoxy—benzylt-carbamic acid utyl ester A solution of 2-aminocyanopyrazine (0.29 g, 2.4 mmol) in THF (8 mL) was added slowly to a stirred slurry of NaH (60% in mineral oil, 0.095 g, 2.4 mmol) in THF (8 mL) at 0°C. The mixture was stirred for 30 minutes at 0°C then a solution of benzyl-[4-(3,3- bis-methylsulfanyl-acryloyl)methoxy-benzyl]-carbamic acid tert-butyl ester (0.75 g, 1.58 mmol) in THF (7 mL) was added dropwise and the reaction mixture was then heated to 80°C for 12 hours. The solution was allowed to cool to room temperature then water (40 mL) was carefully added and the e extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried (Na2804) and evaporated under reduced pressure to leave a residue that was ed by column chromatography on neutral silica gel (60-120 mesh) using 0-80% hexanes as the eluent to give the title nd (0.28 g, 32%). 3|. Benz l- 4- 5- 5-c ano- razin lamino -2H- razol lmethox -benz l- carbamic acid tert-butyl ester A stirred solution of hydrazine monohydrate (0.024 g, 0.77 mmol), benzyl-{4-[(Z)—3-(5- cyano-pyrazinylamino)methylsulfanyl-acryloyl]methoxy-benzyl}-carbamic acid tert-butyl ester (0.28 g, 0.51 mmol) and acetic acid (2 drops) in EtOH (0.7 mL) was heated to 60°C for 15 minutes. The solution was allowed to cool to room temperature then water (10 mL) was added and the mixture extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried (Na2804) and evaporated under reduced pressure to leave a residue that was ed by column chromatography on neutral silica gel (60-120 mesh) using 0-10% CM as the eluent to give the title compound (0.035 g, 13%). 3J. 5- 5- 4- Benz lamino-meth lmethox - hen l-1H- razol lamino - razine- onitrile hydrochloride A 4N solution of HCI in EtZO (1 mL) was added dropwise to a stirred solution of - {4-[5-(5-cyano-pyrazinylamino)-2H-pyrazolyl]methoxy-benzyl}-carbamic acid tert-butyl ester (0.035 g, 0.06 mmol) in DCM (2 mL) at room temperature. The mixture was stirred for 18 hours at room temperature and then the solvents were evaporated under reduced pressure to leave a solid which was washed with EtZO (2 x 5 mL) and dried to give the title compound (0.012 g, 43%) as a white solid.
Synthetic Route C (Illustrated with reference to Example 4: Example 4 - 5- 4- 2-Benz lamino-eth lmethox - hen l-1H- 3- lamino - razine carbonitrile hydrochloride) 4A. 1-Bromomethox E ro-vin l ne A stirred solution of 4-bromomethoxy-benzaldehyde (5.0 g, 23.3 mmol), ammonium acetate (2.4 g, 30.2 mmol) and nitromethane (6.3 mL, 116 mmol) in glacial acetic acid (20 mL) was heated to 80°C for 12 hours. The mixture was allowed to cool to room temperature then poured into water (100 mL). The resulting solid was collected by filtration and then dissolved in DCM (80 mL). The solution was washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column tography on neutral silica gel using DCM as the eluent to give the title compound (4.2 g, 40%). 4B. 2-(4-Bromomethoxy—phenyl)—ethylamine Sodium borohydride (2.9 g, 77.5 mmol) was added in portions to a stirred solution of 1- bromomethoxy((E)nitro-vinyl)-benzene (4.0 g, 15.5 mmol) in MeOH (50 mL) at 0°C. The resulting solution was allowed to warm to room temperature and ng continued for one hour. Water (2 mL) was carefully added followed by the careful on of 50% s acetic acid solution (5 mL) whilst maintaining the temperature below 30°C. Zinc powder (5.1 g, 77.5 mmol) and saturated aqueous NH4C| solution (20 mL) were added and the resulting mixture heated to 50°C for one hour. The cooled mixture was diluted with DCM (50 mL) and filtered through a cotton wool plug.
Water (40 mL) was added to the filtrate and the separated aqueous phase was extracted with DCM (2 x 50 mL). The combined organic extracts were washed with brine (20 ml), dried (Na2804) and evaporated under d pressure to leave a residue that was purified by column chromatography on neutral silica gel (60-120 mesh) using 8—10% MeOH/DCM as the eluent to give the title compound (2.0 g, 56%). 4C. Benzyl-|2-(4-bromomethoxy-phenyl)—ethyl|-amine Benzaldehyde (0.83 g, 7.9 mmol) was added dropwise to a stirred solution of 2-(4- bromomethoxy—phenyl)-ethylamine (2.0 g, 8.7 mmol) and glacial acetic acid (0.94 mL, 15.8 mmol) in EtOH (40 mL) at room temperature. The mixture was stirred for one hour then NaBH(OAc)3 (3.35 g, 15.8 mmol) was added in portions and the resulting e stirred for a further 4 hours. Saturated aq. NaHCOs (50 mL) was added and the mixture extracted with DCM (3 x 30 mL). The combined organic extracts were washed with brine (20 ml), dried (Na2804) and evaporated under reduced pressure to leave a residue that was purified by column chromatography on neutral silica gel (60- 120 mesh) using 2-3.5% MeOH/DCM as the eluent to give the title nd (1.5 g, 59%). 4D. 1-|4-(2-Benzylamino-ethyl)—2-methoxy-phenyl|-ethanone A stirred solution of benzyl-[2-(4-bromomethoxy-phenyl)-ethyl]-amine (1.5 g, 4.68 mmol) and tributyl(1-ethoxyvinyl)tin (2.1 g, 5.6 mmol) in 1,4-dioxane (20 mL) was degassed with nitrogen for 15 minutes. Tetrakis(tripheny|phosphine)palladium(0) (0.27 g, 0.23 mmol) was added to the mixture and the resulting on heated to 100°C for 12 hours. The solution was allowed to cool to room ature and 1N aq. HCI solution (6 mL) was added and the mixture stirred for a further 2 hours. Saturated aq.
NaHC03 solution was carefully added to attain pH10 and the mixture extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried (Na2804) and evaporated under reduced pressure. The e was dissolved in DCM (10 mL) and 3N HCI in dioxane (2 mL) added. The solution was stirred for 30 s then the solvents were d under reduced pressure. The resulting solid was triturated with EtZO (4 x 50 mL) and dried to give the title compound (1.4 g, 93%) as its hydrochloride salt. 4E. 2- 4-Acet lmethox - hen l-eth l-benz amic acid tert-but |ester Boc20 (1.51 g, 6.58 mmol) was added to a stirred solution of 1-[4-(2-benzylamino- ethyl)methoxy-phenyl]-ethanone (1.40 g, 4.38 mmol) and EN (1.23 mL, 8.76 mmol) in DCM (30 mL) and the resulting mixture stirred at room temperature for 6 hours. The mixture was partitioned between DCM (30 mL) and water (50 mL) then the separated aqueous phase was extracted with DCM (3 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure to leave a e that was purified by column chromatography on neutral silica gel 0 mesh) using 10-20% hexanes as the eluent to give the title compound (1.2 g, 71%). 4F. Benz l- 2- 4- 3 3-bis-meth lsulfan l-acr lo lmethox - hen l-eth l-carbamic acid tert-butyl ester A solution of [2-(4-acetylmethoxy-phenyl)-ethyl]-benzyl-carbamic acid tert-butyl ester (1.0 g, 2.60 mmol) in DMSO (3 mL) was added slowly to a stirred slurry of NaH (60% in mineral oil, 0.26 g, 6.5 mmol) in DMSO (6 mL) maintaining the internal temperature at 10-15°C. After stirring at 10°C for 30 minutes, carbon disulfide (0.32 mL, 5.20 mmol) was added and stirring continued for a further 20 minutes. Methyl iodide (0.35 mL, 5.72 mmol) was added at 10°C then the e was allowed to warm to room temperature and stirring continued for 30 minutes. Water (50 mL) was carefully added and the mixture ted with EtOAc (3 x 30 mL). The ed organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue that was purified by column chromatography on neutral silica gel (60-120 mesh size) using 0-30% EtOAc/hexanes as the eluent to give the title compound (0.60 g, 47%). 4G. Benz l- 2- 4- Z 5-c ano- razin lamino meth lsulfan l-acr lo l methoxy—phenylt-ethyl)—carbamic acid tert-butyl ester A solution of 2-aminocyanopyrazine (0.12 g, 0.92 mmol) was added in portions to a stirred slurry of NaH (60% in mineral oil) (0.040 g, 0.92 mmol) in THF (3 mL) at room ature. The mixture was stirred for 30 minutes then benzyl-{2-[4-(3,3-bis- methylsulfanyl-acryloyl)methoxy-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.30 g, 0.62 mmol) was added and the reaction mixture was then heated to 65°C for 12 hours. The solution was allowed to cool to room ature then water (10 mL) was carefully added and the mixture extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue that was purified by column chromatography on neutral silica gel (60-120 mesh) using 15-30% EtOAc/hexanes as the eluent to give the title compound (0.17 g, 49%). 4H. Benz l- 2- 4- 5- 5-c ano- razin lamino -2H- razol lmethox - hen l- ethyl)—carbamic acid utyl ester A stirred solution of ine monohydrate (0.03 mL, 0.60 mmol), benzyl-(2-{4-[(Z)—3- (5-cyano-pyrazinylamino)methylsulfanyl-acryloyl]methoxy-pheny|}-ethyl)- carbamic acid tert-butyl ester (0.17 g, 0.30 mmol) and acetic acid (0.05 mL, 0.9 mmol) in EtOH (2 mL) was heated to 65°C for 3 hours. The solution was allowed to cool to room temperature then water (20 mL) was added and the mixture extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue that was purified by column chromatography on neutral silica gel 0 mesh) using 1.5% MeOH/DCM as the eluent to give the title compound (0.095 g, 60%). 2015/015030 4|. 5- 5- 4- 2-Benz lamino-eth lmethox - hen l-1H- razol lamino - razine- 2-carbonitrile hydrochloride 3N HCI in dioxane (0.5 mL) was added dropwise to a d solution of benzyI-(2-{4-[5- (5-cyano-pyrazinylamino)-2H-pyrazolyl]methoxy-phenyl}-ethyl)-carbamic acid tert-butyl ester (0.090 g, 0.17 mmol) in MeCN (2 mL) and THF (2 mL) at room temperature. The mixture was stirred for 30 minutes at room temperature then the mixture heated to 50°C for 3 hours. The mixture was d to cool to room temperature and the precipitated solid was collected by tion. The collected solid was washed with THF/MeCN (1 :1, 1.5 mL) and EtZO (10 mL) and dried to give the title nd (0.055 g, 70%) as a white solid.
Synthetic Route D (Illustrated with reference to Example 11: Example 11 - 5- 2-Methox eth l- i eridin l- hen l-1H- razol lamino - razine 11A. 4- 3-Methox methox carbon l- hen l-3 6-dih dro-2H- ridinecarbox lic acid tert-butyl ester A solution of omethoxy-benzoic acid methyl ester (4.0 g, 16.5 mmol), 1-Boc- piperidineboronic acid pinacol ester (5.1 g, 16.5 mmol) and K2C03 (6.6 g, 49.5 mmol) in DMF (25 mL) was degassed with nitrogen for 15 minutes. PdCl2(dppf).DCM (1.0 g, 0.6 mmol) was added at room temperature then the mixture was heated to 90°C and stirring continued for 5 hours. Water (100 mL) was added and the mixture extracted with EtOAc (2 x 50 mL) then the combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 10-15% EtOAc/hexanes as the e|uent to give the title compound (5.0 g, 87%). 11B. 4- 3-Methox methox carbon l- hen l- i eridinecarbox lic acid tert-but | ester A mixture of 4-(3-methoxymethoxycarbonyl-phenyl)—3,6-dihydro-2H-pyridine carboxylic acid utyl ester (5.0 g, 14.4 mmol) and 10% Pd/C (0.5 g) was stirred under a hydrogen atmosphere at room temperature for 6 hours. The mixture was filtered through a pad of celite and the ts evaporated under d pressure to give the title compound (4.5 g, 90%) which was used without further purification. 11C. 2-Methoxy—4-piperidinyl-benzoic acid methyl ester 3N HCI in dioxane (15 mL) was added to a stirred on of 4-(3-methoxy methoxycarbonyl-phenyl)-piperidinecarboxylic acid tert-butyl ester (4.5 g, 12.8 mmol) in DCM (50 mL) at 0°C. The mixture was allowed to warm to room temperature and stirring continued for 5 hours then the solvents were removed under reduced pressure. The residue was triturated with EtZO (2 x 10 mL) then partitioned between DCM (50 mL) and saturated NaHC03 solution (50 mL). The separated aqueous phase was extracted with DCM (2 x 50 mL) then the combined organic extracts were dried 4) and ated under reduced pressure to give the title compound (2.5 g, 78%) which was used without further purification. 11D. 2-Methox 1-meth l- i eridin l-benzoic acid meth lester Formalin (37% formaldehyde in water) (5.0 mL, 50 mmol) was added to a stirred solution of 2-methoxy—4-piperidinyl-benzoic acid methyl ester (0.3 g, 1.1 mmol) in MeOH (15 mL) and the mixture stirred for 30 minutes. The solution was cooled to 0°C and NaBH(AcO)3 (3.20 g, 15 mmol) was added and the resulting on stirred for 3 hours at room temperature. Saturated NaHC03 solution (100 mL) was added and the mixture extracted with DCM (3 x 75 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2804) and ated under reduced pressure to give the title compound (2.5 g, 95%) which was used without further purification. 11E. 3- 2-Methox 1-meth l- i |- hen loxo- ro ionitrile LHMDS (1M in ) (24 mL, 24 mmol) was added dropwise to MeCN (1.78 mmol, 34.2 mmol) in dry e (50 mL) at -78°C under a nitrogen atmosphere and the resulting yellow solution stirred for 30 minutes at -78°C. A solution of 2-methoxy(1- methyl-piperidinyl)—benzoic acid methyl ester (1.8 g, 6.84 mmol) in dry toluene (50 mL) was added dropwise maintaining the temperature at -78°C, then the mixture was allowed to warm to room temperature and stirring continued for 30 minutes. The mixture was cooled to 0°C and water (150 mL) was carefully added then the separated aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (25 mL), dried (Na2804) and evaporated under d pressure to leave a residue that was purified by column chromatography on neutral WO 20390 silica gel (60-120 mesh) using 2-3% MeOH/DCM as the eluent to give the title compound (1.40 g, 75%). 11F. 5- 2-Methox 1-meth l- i l- hen l-1H- razol lamine A stirred solution of hydrazine monohydrate (0.22 g, 4.44 mmol) and 3-[2-methoxy (1-methyl-piperidinyl)-phenyl]oxo-propionitrile (1.0 g, 3.67 mmol) in EtOH (2 mL) was heated to 85°C for 10 hours. The solution was allowed to cool to room temperature and evaporated under reduced pressure to leave a residue that was purified by column chromatography on neutral silica gel (60-120 mesh size) using 10% MeOH/DCM as the eluent to give the title compound (0.60 g, 57%). 11G. 3-Amino ox 1-meth l- i eridin l- hen l- razolecarbox lic acid tert-butyl ester NaH (60% in mineral oil) (0.031 g, 0.77 mmol) was added in portions to a stirred on of 5-[2-methoxy(1-methyl-piperidiny|)-phenyl]-1H-pyrazolylamine (0.20 g, 0.69 mmol) in a mixture of THF (15 mL) and DMF (5 mL) at 0°C. The mixture was stirred for 30 minutes then Boc2O (0.17 g, 0.77 mmol) was added and then the mixture allowed to warm to room temperature and stirring continued for one hour. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (25 mL), dried (Na2804) and ated under reduced re to leave a solid that was washed with EtZO (8 mL) to give the title compound (0.23 g, 84%). 11H. 5- 5- 2-Methox 1-meth l- i eridin l- hen l-1H- razol lamino - pyrazinecarbonitrile hloride NaH (60% in mineral oil) (0.016 g, 0.38 mmol) was added in portions to a stirred solution of 3-amino[2-methoxy(1-methyl-piperidinyl)-phenyl]-pyrazole ylic acid tert-butyl ester (0.75 g, 0.19 mmol) in THF (3 mL) at 0°C. The mixture was stirred for 10 minutes then 5-bromopyrazinecarbonitrile (0.036 g, 0.19 mmol) was added and then the mixture allowed to warm to room temperature and ng continued for one hour. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (25 mL), dried (Na2804) and evaporated under reduced pressure to leave a solid that was purified by preparative HPLC to give the title compound (0.03 g, 40%) as its free base.
This material was dissolved in MeCN (1 mL) and THF (1 mL) then 3N HCl in dioxane (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes then the solvents were removed under reduced pressure to leave a solid which was washed with EtZO (5 mL) and dried to give the title compound (0.032 g, 98%) as a white solid.
Synthetic Route E (Illustrated with reference to Example 13: Example 13 N- 4- 3- 5-c ano razin lamino -1H- razol lmethox - phenyl|methyl|cyclopropanecarboxamide) 13A. Methyl 2-hydroxymethyl-benzoate trated H2804 (200 mL) was added dropwise over 30 minutes to a d solution of 2-hydroxymethyl-benzoic acid (100 g, 657 mmol) in MeOH (500 mL) at room temperature. The mixture was heated to reflux for 5 hours then allowed to cool to room temperature and carefully poured into ice cold saturated NaHC03 solution (300 mL). The mixture was extracted with DCM (4 x 500 mL) and the combined organic extracts dried (Na2804) and evaporated under reduced pressure to give the title compound (100 g, 94%) which was used t further purification. 13B. Methyl 2-methoxymethyl-benzoate A solution of methyl 2-hydroxymethyl-benzoate (100 g, 602 mmol) in DMF (170 mL) was added dropwise over 30 minutes to a stirred slurry of NaH (33.8 g, 1.41 mol) in dry DMF (330 mL) at 0°C under a nitrogen atmosphere. The resulting e was stiired at 0°C for a further 30 minutes then iodomethane (255 g, 1.81 mol) was added se over 20 minutes. The e was heated to 70°C for 3 hours then allowed to cool and carefully poured into ice-cold 1N HCl on (1500 mL). The mixture was extracted with DCM (2 x 1000 mL) and the ed organic extracts dried (Na2804) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 15%EtOAc/hexanes as the eluent to give the title compound (102 g, 94%). 13C. Methyl 4-(bromomethyl)methoxy-benzoate A stirred solution of methyl 2-methoxymethyl-benzoate (100 g, 555 mmol) and N- bromosuccinimide (108.6 g, 610 mmol) in carbon tetrachloride (1300 mL) was degassed with nitrogen for 15 minutes. d,d’-Azoisobutyronitrile (18.2 g, 111 mmol) was added in one portion and the resulting mixture heated to 70°C for 15 hours then allowed to cool to room temperature. The mixture was poured into water (600 mL) and then the separated aqueous phase extracted with DCM (2 x 800 mL). The combined organic extracts were dried 4) and evaporated under reduced pressure to give the title compound (144 g) which was used without further purification. 13D. Methyl 4-(acetoxymethyl )—2—methoxy—benzoate A stirred mixture of methyl momethyl)methoxy-benzoate (144 g, 558 mmol) and potassium acetate (285 g, 2.9 mol) in dry DMF (1440 mL) was heated to 80°C for one hour then the cooled mixture was poured into ter (5000 mL). The mixture was extracted with DCM (2 x 1000 mL) and the combined organic extracts were dried (Na2804) and evaporated under reduced pressure. The e was purified by column chromatography on neutral silica gel using 15%EtOAc/hexanes as the eluent to give the title compound (63.0 g, 48% over two steps). 13E. Methyl 4-(hydroxymethyl)—2-methoxy-benzoate A on of methyl 4-(acetoxymethyl)methoxy-benzoate (63.0 g, 265 mmol) in MeOH (500 mL) was added dropwise to a stirred solution of sodium methoxide (2.86 g, 52.9 mmol) in MeOH (280 mL) at room temperature. The mixture was stirred for two hours then poured into 2N HCI solution (1000 mL) and extracted with DCM (3 x 1000 mL). The combined organic extracts were dried (Na2804) to afford the title compound (49.0 g, 94%) which was used without further purification. 13F. Methyl 2-methoxy(methylsulfonyloxymethyl)benzoate Methanesulfonyl chloride (2.1 mL, 26.8 mmol) was added dropwise to a stirred on of methyl roxymethyl)methoxy-benzoate (5.0 g, 25.5 mmol) and triethylamine (7.1 mL, 51.0 mmol) in DCM (120 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for two hours then partitioned between DCM (100 mL) and 1N HCI (100 mL). The separated organic phase was washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to give the title compound (7.6 g, 100%) which was used without further cation. 13G. Methyl 4-(azidomethyl)—2-methoxy—benzoate A solution of sodium azide (9.0 g, 138 mmol) and methyl 2-methoxy—4- (methylsulfonyloxymethyl)benzoate (7.6 g, 27.7 mmol) in dry DMF (60 mL) was heated to 70°C for 3 hours. The cooled reaction mixture was poured into cold water (500 mL) and the resulting mixture extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried 4) and evaporated under reduced pressure to give the title compound (7.8 g, 100%) whch was used without r purification. 13H. Methyl 4-(aminomethyl)—2-methoxy—benzoate A mixture of methyl domethyl)methoxy-benzoate (7.8 g, 27.7 mmol) and 10% Pd on carbon (0.78 g) in MeOH (80 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The mixture was filtered through celite and the filtrate evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 6-7% MeOH/chloroform to give the title nd (3.1 g, 45% over two steps). 13l. Methyl 4-|(cyclopropanecarbonylamino)methyl|methoxy-benzoate 1-Ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride (1.75g, 11.3 mmol) and hydroxybenzotriazole (0.14g, 1.0 mmol) were added to a stirred solution of methyl 4- (aminomethyl)methoxy-benzoate (2.0 g, 10.3 mmol) and cyclopropane carboxylic acid (0.82 mL, 10.3 mmol) in DCM (85 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours then diluted with DCM (150 mL) and washed with saturated NaHC03 solution (3 x 75 mL), brine (50 mL), dried 4) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 55% EtOAc/hexane as the eluent to give the title compound (2.2 g, 82%). 13J. N-||4-(2-cyanoacetyl)—3-methoxy-phenyl|methyl|cyclopropanecarboxamide A solution of LiHMDS (1.0M in hexane, 29.4 mL, 29.4 mmol) was added dropwise over minutes to a d on of acetonitrile (1.72 g, 42.0 mmol) in dry THF (58 mL) at -78°C under a nitrogen atmosphere. ng was ued for 30 minutes then a solution of methyl 4-[(cyclopropanecarbonylamino)methyl]methoxy—benzoate (2.2 g, 8.4 mmol) in THF (50 mL) was added dropwise over 20 minutes maintaining the temperature at -78°C. The mixture was d to warm to room temperature and stirring continued for 2 hours. The mixture was poured into cold saturated ammonium chloride solution (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to give the title compound (2.0 g, 88%) as a white solid. 13K. N- 4- 3-amino-1H- razol lmethox - hen lmeth lc clo ro ane carboxamide A stirred mixture of N-[[4-(2-cyanoacetyl)methoxy- phenyl]methyl]cyclopropanecarboxamide (0.5 g, 1.8 mmol) and hydrazine hydrate (98% in water, 0.11 g, 2.20 mmol) in EtOH (10 mL) was heated to reflux for 18 hours.
The solvents were evaporated under reduced presuure to leave a solid which was recrystallized from EtOH to give the title nd (0.35 g, 67%) as a white solid. 13L. utyl 3-amino|4-|(cyclopropanecarbonylamino)methyl|—2-methoxy— phenyl|pyrazolecarboxylate A on of (3-amino-1H-pyrazolyl)methoxy-phenyl]methyl]cyclopropane carboxamide (0.5 g, 1.70 mmol) in a mixture of dry DMF (12 mL) and dry THF (18 mL) was added dropwise to a stirred suspension of sodium hydride (0.07 g, 1.70 mmol) in dry THF (12 mL) at 0°C under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 0°C then a solution of Boc2O (0.37 g, 1.70 mmol) in dry THF (10 mL) was added dropwise maintaining the ature at 0°C. The reaction mixture was allowed to warm to room temperature and stirring continued for 1.5 hours. The on was poured into ice-water (100 mL) and extracted with EtOAc (3 x 100 mL).
The ed organic extracts were washed with brine (50 mL), dried 4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 2% MeOH/DCM as the eluent to give the title compound (0.37 g, 55%) as an off-white solid. 13M. N- 4- 3- 5-c ano razin lamino -1H- razol lmethox - phenyl|methyl|cyclopropanecarboxamide A solution of tert-butyl 3-amino[4-[(cyclopropanecarbonylamino)methyl]methoxy— phenyl]pyrazolecarboxylate (185 mg, 4.80 mmol) in a mixture of dry THF (2 mL) and dry DMF (1 mL) was added dropwise to a stirred suspension of sodium hydride (38 mg, 9.6 mmol) in THF (2 mL) at 0°C under a nitrogen atmosphere. The mixture was stirred for 10 minutes then a solution of 5-bromopyrazinecarbonitrile (88 mg, 4.80 mmol) in dry THF (1 mL) was added dropwise maintaining the temperature at 0°C.
The mixture was allowed to slowly warm to room temperature and stirring continued for 2 hours. After pouring into ice-water (20 mL) the mixture was extracted with EtOAc (5 x 25 mL) then the combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under d pressure. The e was dissolved in 4N HCI in EtOAc (10 mL) and stirred for 30 mins then the solvents were evaporated under reduced pressure to leave a residue which was purified by ative HPLC to give the title nd (41 mg, 31%) as an off-white solid.
Synthetic Route F (Illustrated with reference to Example 14: Example14 - 5- 2-Methox tetrah dro ran lamino meth l hen l-1H- razol lamino razinecarbonitrile h drochloride 14A. Methyl 4-formylmethoxy—benzoate Dess-Martin periodinane (81.2 g, 191 mmol) was added in portions to a d solution of methyl 4-(hydroxymethyl)methoxy-benzoate (25.0 g, 128 mmol) in DCM (375 mL) under a nitrogen atmosphere. The solution was stirred for one hour then filtered through a pad of celite washing with DCM (100 mL). The filtrate was evaporated under d pressure to leave a residue which was purified by column chromatography on neutral silica gel using 10%EtOAc/hexane as the eluent to give the title compound (23.5 g, 95%). 14B. Meth l2-methox tetrah dro ran lamino meth lbenzoate Sodium methoxide (0.83 g, 15.4 mmol) was added to a stirred solution of tetrahydro- 2H-pyranamine hloride (2.12 g, 15.4 mmol) in MeOH (35 mL) at room temperature under a nitrogen atmosphere and the mixture stirred for 30 minutes. The solution was passed through a Millipore filter and the resulting clear solution added to a stirred solution of methyl 4-formylmethoxy-benzoate (3.0 g, 15.4 mmol) in MeOH (35 mL). l acetic acid (1.8 mL, 30.8 mmol) was added and the mixture d for one hour then the solution was cooled to 0°C and sodium triacetoxyborohydride (9.79 g, 4.62 mmol) was added in portions over 15 minutes. The mixture was allowed to warm to room temperature and stirring continued for 18 hours before partitioning between saturated NaHC03 solution (200 mL) and EtOAC (200 mL). The separated aqueous phase was extracted with EtOAc (2 x 200 mL) then the ed organic extracts were washed with brine (75 mL), dried (Na2804) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 2% MeOH/DCM as the eluent to give the title compound (3.1 g, 72%). 14C. Meth |4- tert-butox carbon Itetrah dro ran lamino meth lmethox - Boc2O (1.83 g, 8.40 mmol) was added to a d solution of methyl 2-methoxy [(tetrahydropyranylamino)methyl]benzoate (2.40 g, 7.60 mmol) and EN (2.15 g, 8.40 mmol) in DCM (60 mL) and the resulting mixture stirred at room temperature for 18 hours. The mixture was diluted DCM (200 mL), washed with 5% citric acid on, water (2 x 50 mL), brine (20 mL), dried (Na2804) and evaporated under reduced pressure to give the title compound (3.1 g, 95%) which was used without further purification. 14D. tert-But IN- 4- 2-c t thox - hen lmeth l-N-tetrah dro ran yl-carbamate A on of LiHMDS (1.0M in hexane, 23.1 mL, 23.1 mmol) was added se over minutes to a stirred solution of acetonitrile (1.35 g, 33.0 mmol) in dry THF (70 mL) at -78°C under a nitrogen atmosphere. Stirring was continued for 30 minutes then a solution of methyl 4-[[tert-butoxycarbonyl(tetrahydropyrany|)amino]methyl] methoxy-benzoate (2.5 g, 6.6 mmol) in THF (140 mL) was added dropwise over 20 minutes maintaining the temperature at -78°C. The mixture was stirred at -78°C for 30 minutes then allowed to warm to room temperature and stirring ued for one hour.
The mixture was poured into cold saturated ammonium chloride on (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to give the title compound (2.9 g, 100%) as a white solid. 14E. tert-But IN- 4- 3-amino-1H- razol lmethox - hen lmeth l-N- tetrahydropyranyl-carbamate A solution of tert-butyl N-[[4-(2-cyanoacetyl)methoxy-phenyl]methyl]-N- tetrahydropyranyl-carbamate (2.90 g, 7.5 mmol) and hydrazine hydrate (99% in water, 2.9 g, 9.0 mmol) in ethanol (60 mL) was heated to reflux for 18 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 2-3% MeOH/CHCI3 as the eluent to give the title nd (1.5 g, 50%). 14F. tert-But IN- 4- 3- 5-c ano razin lamino -1H- razol lmethox - hen lmeth l-N-tetrah dro ran l-carbamate WO 20390 A stirred solution of tert-butyl (3-amino-1H-pyrazolyl)methoxy- phenyl]methyl]-N-tetrahydropyranyl-carbamate (0.5g, 1.2 mmol), diisopropylethylamine (0.63 mL, 3.6 mmol) and 5-bromopyrazinecarbonitrile (0.66 g, 3.6 mmol) in dry 1,4-dioxane (12 mL) was heated to 80°C for 24 hours. After cooling to room temperature the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined c extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 1% MeOH/CHCI3 as the eluent to give the title compound (0.39 g, 64%). 14G. 5- 5- 2-Methox tetrah dro ran lamino meth l hen l-1H- razol lamino razinecarbonitrile h drochloride 4N HCI in dioxane (0.4 mL) was added to a stirred solution of utyl N-[[4-[3-[(5- cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy—phenyl]methyl]-N- tetrahydropyranyl-carbamate (0.09 g, 0.18 mmol) in dry dioxane (10 mL) and the resulting mixture stirred at room temperature for 4 hours. The solvents were evaporated under reduced pressure to leave a solid that was triturated with Et20 (3 x mL) and dried to give the title compound (52 mg, 72%) as an off-white solid.
Synthetic Route G (Illustrated with reference to Example 17: Example17 - 51 Dimeth lamino acet l i erid thox - hen l-1H- razol lamino razinecarbonitrile h drochloride 17A. tert-But l4- 4- 2-c anoacet lmethox - hen l i eridinecarbox late A solution of LiHMDS (1.0M in hexane, 90.0 mL, 90.0 mmol) was added dropwise over 20 minutes to a stirred solution of itrile (5.3 g, 129 mmol) in dry THF (250 mL) at -78°C under a en atmosphere. Stirring was continued for 30 minutes then a solution of methyl utyl 4-(3-methoxymethoxycarbonyl-phenyl)piperidine carboxylate (Example 11B) (9.0 g, 25.8 mmol) in THF (250 mL) was added dropwise over 20 s maintaining the temperature at -78°C. The mixture was stirred at - 78°C for 30 s then allowed to warm to room temperature and stirring continued for one hour. The mixture was poured into cold saturated ammonium chloride solution (300 mL) and extracted with EtOAc (5 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2804) and evaporated under reduced re to leave a residue which was purified by column chromatography on neutral silica gel using 40% hexane as the eluent to give the title compound (7.0 g, 76%) as a white solid. 17B. tert-But l4- 4- 3-amino-1H- razol lmethox - hen l i eridine carboxylate A solution of utyl 4-[4-(2-cyanoacetyl)methoxy-phenyl]piperidinecarboxylate (7.0 g, 19.5 mmol) and hydrazine hydrate (99% in water, 1.17 g, 23.4 mmol) in ethanol (150 mL) was heated to reflux for 18 hours. The mixture was d to cool to room temperature and the ts evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 2% MeOH/CHCI3 as the eluent to give the title compound (5.1 g, 70%). 17C. tert-But l4- 4- 3- 5-c ano razin lamino -1H- razol lmethox - |piperidinecarboxylate A stirred solution of tert-butyl 4-[4-(3-amino-1H-pyrazolyl)methoxy- phenyl]piperidinecarboxy|ate (0.6 g, 1.6 mmol), diisopropylethylamine (0.84 mL, 4.8 mmol) and 5-bromopyrazinecarbonitrile (0.88 g, 4.8 mmol) in dry 1,4-dioxane (12 mL) was heated to 80°C for 24 hours. After cooling to room temperature the reaction e was poured into ice-water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 3% MeOH/DCM as the eluent to give the title compound (0.56 g, 73%). 17D. 5- 5- 2-Methox 4- i erid l hen l-1H- razol lamino razine carbonitrile 4N HCI in dioxane (25 mL) was added to a stirred solution of utyl 4-[4-[3-[(5- cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl]piperidinecarboxylate (0.56 g, 0.98 mmol) in a mixture of dry dioxane (25 mL) and dry THF (25 mL) and the resulting mixture stirred at room temperature for 2 hours. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtOAc (3 x mL) and dried to give the title compound (0.54 mg, 100%) as an off-white solid. 17E. 5- 51 Dimeth lamino acet l i erid lmethox - hen l-1H- razol- 3- lamino razinecarbonitrile h oride 1-Ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20g, 1.02 mmol) and hydroxybenzotriazole (12 mg, 0.09 mmol) were added to a stirred solution of 5-[[5-[2- methoxy(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile (0.35 g, 0.93 mmol) and N,N’-dimethylglycine (96 mg, 0.93 mmol) in DMF (4 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 hours then diluted with DCM (150 mL) and washed with ted NaHC03 solution (3 x 75 mL), brine (50 mL), dried 4) and evaporated under reduced pressure. The e was purified by column chromatography on neutral silica gel using 7% MeOH/DCM as the eluent. The resulting solid was dissolved in a mixture of MeOH (4 mL) and MeCN (8 mL) and a solution of 4N HCI in dioxane (0.2 mL) was added and the ing mixture stirred for 30 minutes. The solvents were evaporated under d pressure to leave a solid that was triturated with EtOAc (3 x 10 mL) and dried to give the title compound (0.24 g, 54%) as an off-white solid.
Synthetic Route H (Illustrated with reference to Example 60: Example 60 - 51-eth l i erid lmethox - hen l-1H- 3- lamino razine-2— carbonitrile hydrochloride) Diisopropylethylamine (0.25 mL, 1.46 mmol) was added to a stirred suspension of 5- [[5-[2-methoxy(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile hydrochloride (prepared using Synthetic Route G) (0.3 g, 0.73 mmol) in a mixture of MeOH (10 mL) and MeCN (20 mL) and the mixture stirred for 20 minutes at room temperature under a nitrogen atmosphere. Acetaldehyde (0.1 g, 2.19 mmol) was added and the mixture stirred for a further 20 minutes then the mixture was cooled to 0°C and Ac)3 (0.50 g, 2.34 mmol) was added in portions over 10 minutes. The mixture was allowed to warm to room temperature and stirred for a further hour then poured into ice-water (30 mL) and solid NaHC03 was added to adjust the pH of the solution to 8. The mixture was extracted with EtOAc (4 x 50 mL) and the combined organic ts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 9% MeOH/DCM as the . The resulting solid was dissolved in a mixture of THF (4 mL) and MeCN (4 mL) and a solution of 4N HCI in dioxane (1 mL) was added and the resulting mixture stirred for one hour. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtOAc (3 x 10 mL) and dried to give the title compound (71 mg, 29%) as an off-white solid.
Synthetic Route l (Illustrated with reference to Example 22: Example 22 - 5- 2-methox 4-meth l i erazin l hen l-1H- razol lamino razine itrile hydrochloride) 22A. Methyl 4-fluoromethoxy-benzoate Potassium carbonate (15.5 g, 112 mmol) was added to a stirred solution of 4-fluoro hydroxy-benzoic acid (5.0 g, 32.1 mmol) in acetone (100 mL) and the mixture heated to 40°C under a nitrogen atmosphere for 20 minutes. Methyl iodide (15.8 g, 112 mmol) was added dropwise and then the mixture heated to reflux for 20 hours then allowed to cool to room temperature. The mixture was filtered through celite and the te concentrated under reduced re to give the title compound (5.9 g, 100%) which was used without further purification. 22B. tert-But l4- 3-methox methox carbon l- hen l i erazinecarbox late Potassium carbonate (1.49 g, 10.8 mmol) was added to a stirred on of methyl 4- fluoromethoxy-benzoate (1.0 g, 5.4 mmol) in DMSO (10 mL) and the mixture stirred at room ature under a nitrogen atmosphere for 20 minutes. N-Boc piperazine (2.01 g, 10.8 mmol) was added and then the e heated to 80°C for 18 hours. The cooled mixture was poured into ice-water (100 mL) and extracted with EtOAc (5 x 150 mL). The combined organic extracts were washed with brine (100 mL), dried 4) and evaporated under reduced pressure to leave a residue which was ed by column chromatography on neutral silica gel using 45% EtOAc/hexane as the eluent to give the title compound (4.6 g, 41%) as a white solid. 22C. tert-But l4- 4- 2-c t lmethox - hen | i erazinecarbox late A on of LiHMDS (1.0M in hexane, 46.0 mL, 46.0 mmol) was added dropwise over 40 minutes to a stirred solution of acetonitrile (2.69 g, 65.5 mmol) in dry THF (100 mL) at -78°C under a nitrogen atmosphere. Stirring was continued for 30 minutes then a solution of tert-butyl 4-(3-methoxymethoxycarbonyl-phenyl)piperazine carboxylate (4.6 g, 13.1 mmol) in THF (100 mL) was added dropwise over 20 minutes maintaining the ature at -78°C. The e was stirred at -78°C for 30 s then allowed to warm to room temperature and stirring continued for one hour. The mixture was poured into cold saturated ammonium chloride solution (150 mL) and extracted with EtOAc (5 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave the title compound (5.3 g, 100%) which was used without further purification. 22D. tert-But l4- 4- 3-amino-1H- 5- lmethox - hen | i erazine carboxylate A on of tert-butyl 4-[4-(2-cyanoacetyl)methoxy-phenyl]piperazinecarboxylate (5.3 g, 14.8 mmol) and hydrazine hydrate (99% in water, 2.96 g, 59.2 mmol) in l (120 mL) was heated to reflux for 18 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 2% MeOH/CHCI3 as the eluent to give the title compound (2.0 g, 36%). 22E. tert-But l4- 4- 3- 5-c ano razin lamino -1H- razol lmethox - phenyl|piperazinecarboxylate A stirred on of tert-butyl 4-[4-(3-amino-1H-pyrazolyl)—3-methoxy— phenyl]piperazinecarboxylate (0.5 g, 1.3 mmol), diisopropylethylamine (0.70 mL, 3.9 mmol) and 5-bromopyrazinecarbonitrile (0.71 g, 3.9 mmol) in dry 1,4-dioxane (5 mL) was heated to 80°C for 4 hours. After cooling to room temperature the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (3 x 100 mL).
The combined organic extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a e which was purified by column chromatography on neutral silica gel using 1.5% MeOH/DCM as the eluent to give the title compound (0.32 g, 50%). 22F. 5- 5- 2-Methox i erazin l- hen l-1H- 3- lamino razine carbonitrile hydrochloride 4N HCI in dioxane (4 mL) was added to a stirred solution of tert—butyl 3-[(5- cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl]piperazinecarboxylate (0.56 g, 0.98 mmol) in a mixture of dry MeCN (10 mL) and dry THF (10 mL) and the resulting mixture stirred at room temperature for 4 hours. The solvents were evaporated under reduced re to leave a solid that was triturated with n-pentane (3 x 10 mL) and EtZO (3 x 10 mL) and dried to give the title compound (0.24 mg, 100%) as an off-white solid. 22G. 5- 5- 2-Methox 4-meth l i erazin l hen l-1H- razol lamino razinecarbonitrile h drochloride Diisopropylethylamine (0.12 mL, 0.68 mmol) was added to a stirred suspension of 5- [[5-(2-methoxypiperazinyl-phenyl)-1H-pyrazolyl]amino]pyrazinecarbonitrile hydrochloride (0.14 g, 0.34 mmol) in a mixture of MeOH (2 mL) and MeCN (4 mL) and the mixture stirred for 20 minutes at room temperature under a en atmosphere.
Formalin % w/v in water; 31 mg, 0.10 mmol) was added followed by the addition of glacial acetic acid (0.04 mL, 0.68 mmol) and the mixture stirred for a further 20 minutes then the mixture was cooled to 0°C and NaBH(OAc)3 (0.22 g, 1.02 mmol) was added in portions over 10 minutes. The mixture was d to warm to room temperature and stirred for a further hour then poured into ice-water (30 mL) and solid NaHC03 was added to adjust the pH of the solution to 8. The mixture was extracted with EtOAc (4 x 30 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure. The residue was triturated with EtOAc (3 x 5 mL) and dried to leave an ite solid. The solid was dissolved in a mixture of THF (3 mL) and MeCN (3 mL) then a solution of 4N HCI in e (0.5 mL) was added and the resulting mixture stirred for one hour. The solvents were evaporated under reduced pressure to leave a solid that was triturated with n-pentane (3 x 10 mL) and dried to give the title compound (35 mg, 24%) as an off-white solid. tic Route J (Illustrated with reference to Example 24: Example 24 - 5- 2-methox eth l i erid l hen l-1H- razol lamino ridine itrile hydrochloride) 24A. tert-But l4- 4- 3- 6-c ano rid lamino -1H- razol lmethox - |piperidinecarboxylate A stirred suspension of tert-butyl 4-[4-(3-amino-1H-pyrazolyl)methoxy- phenyl]piperidinecarboxylate (Example 17B) (1.0 g, 2.7 mmol), 5-bromo cyanopyridine (0.59 g, 3.2 mmol), cesium carbonate (1.75 g, 5.4 mmol) and (i)-BINAP (0.125 g, 0.2 mmol) in dry dioxane (10 mL) was degassed with nitrogen for 30 minutes at room temperature. Tris(dibenzylideneacetone)dipalladium(0) (0.183 g, 0.2 mmol) was added and the resulting mixture heated to 100°C for 5 hours. After cooling to room temperature the reaction mixture was poured into ice-water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried 4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 3% MeOH/CHCI3 as the eluent to give the title nd (0.40 g, 31%). 24B. 5- 5- 2-Methox 4- i erid l hen l-1H- 3- lamino ridine carbonitrile hydrochloride 4N HCI in dioxane (10 mL) was added to a stirred solution of tert-butyl 4-[4-[3-[(6- cyanopyridyl)amino]-1H-pyrazolyl]methoxy—phenyl]piperidinecarboxylate (0.40 g, 0.89 mmol) in a mixture of dry MeCN (10 mL) and dry THF (10 mL) and the ing mixture stirred at room temperature for one hour. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtZO (3 x mL) and dried to give the title compound (0.38 mg, 100%) as an off-white solid. 24C. 5- 5- 2-methox 1-meth l i erid l hen l-1H- razol lamino ridine- 2-carbonitrile hydrochloride Diisopropylethylamine (0.23 mL, 1.30 mmol) was added to a stirred suspension of 5- -methoxy—4-(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyridinecarbonitrile hydrochloride (0.27 g, 0.65 mmol) in a mixture of MeOH (4 mL) and MeCN (16 mL) and the mixture stirred for 20 minutes at room temperature under a nitrogen atmosphere. Formalin (37-41% w/v in water; 0.1 mL, 1.3 mmol) was added followed by the addition of glacial acetic acid (0.08 mL, 1.30 mmol) and the mixture stirred for a further 20 minutes then the mixture was cooled to 0°C and NaBH(OAc)3 (0.44 g, 2.08 mmol) was added in portions over 10 s. The mixture was allowed to warm to room temperature and stirred for a further hour then poured into ice-water (30 mL) and solid NaHC03 was added to adjust the pH of the solution to 8. The mixture was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure. The residue was ed by column chromatography on neutral silica gel using 9% MeOH/CHCI3 as the eluent to leave an off-white solid. The solid was dissolved in a mixture of THF (10 mL) and MeCN (10 mL) then a solution of 4N HCI in dioxane (0.2 mL) was added and the resulting mixture d for one hour. The solvents were evaporated under reduced pressure to leave a solid that was ated with EtZO (3 x 10 mL) and dried to give the title compound (140 mg, 51%) as an off-white solid.
Synthetic Route K (Illustrated with reference to Example 28: Example 28 - 5- 2-methox 1-meth l i erid lox hen l-1H- razol lamino razine- 2-carbonitrile hydrochloride) 28A. 4-Hydroxymethoxy-benzoic acid Sodium ogen phosphate (63.1 g, 526 mmol) and sodium chlorite (41.6 g, 460 mmol) were added to a d solution of 4-hydroxymethoxy-benzaldehyde (20.0 g, 132 mmol) in a mixture of DMSO (400 mL) and water (300 mL) at 0°C. The mixture was d to warm to room temperature and stirring ued for 6 hours. The mixture was diluted with water (1000 mL) and solid NaHC03 was added to adjust the pH of the solution to 8. The solution was washed with EtOAc (1000 mL), the pH adjusted to 4 by the on of 1N HCI solution and extracted with EtOAc (6 x 500 mL). The combined organic extracts were washed with brine (300 mL), dried (Na2804) and evaporated under reduced pressure to give the title compound (22.0 g, 100%) which was used without further purification. 288. Methyl 4-hydroxymethoxy-benzoate Concentrated H2804 (52 mL) was added dropwise over 20 minutes to a stirred solution of 4-hydroxymethoxy-benzoic acid (22.0 g, 131 mmol) in MeOH (520 mL) at room temperature. The mixture was heated to reflux for 2 hours then d to cool to room temperature and poured into ice-water (300 mL). The mixture was extracted with EtOAc (2 x 1000 mL) and the combined organic extracts dried 4) and evaporated under d pressure. The residue was ed by column chromatography on neutral silica gel using 25% EtOAc/hexane as the eluent to give the title compound (12.0 g, 50%). 28C. tert-Butyl 4-(3-methoxymethoxycarbonyl-phenoxy)piperidinecarboxylate Diisopropyl azodicarboxylate (5.6 g, 27.5 mmol) was added to a stirred solution of methyl 4-hydroxymethoxy-benzoate (2.0 g, 11.0 mmol), tert—butyl 4- hydroxypiperidinecarboxy|ate (6.6 g, 33 mmol) and triphenylposphine (7.2 g, 27.5 mmol) in THF (100 mL) at 0-100C under a nitrogen atmosphere. The resulting mixture was sonicated at 40°C for 2 hours then poured into ice-water (100 mL). The mixture was ted with EtOAc (2 x 250 mL) and the combined organic extracts washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure. The residue was purified by column tography on neutral silica gel using 10% EtOAc/hexane as the eluent to give the title compound (4.80 g, 100%). 28D. tert-But l4- 4- 2-c anoacet thox - henox i eridinecarbox late A solution of LiHMDS (1.0 M in hexane, 92.0 mL, 92.0 mmol) was added dropwise over 40 minutes to a stirred solution of acetonitrile (5.4 g, 131 mmol) in dry THF (250 mL) at -78°C under a nitrogen atmosphere. ng was continued for 30 minutes then a solution of tert-butyl 4-(3-methoxymethoxycarbonyl-phenoxy)piperidine carboxylate (4.8 g, 13.1 mmol) in THF (250 mL) was added dropwise over 20 minutes maintaining the temperature at -78°C. The mixture was stirred at -78°C for 30 minutes then allowed to warm to room temperature and stirring continued for one hour. The mixture was poured into cold saturated ammonium chloride solution (150 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave the title nd (5.0 g, 100%) which was used without further purification. 28E. tert-But l4- 4- o-1H- 5- lmethox - henox i eridine carboxylate A solution of tert-butyl 4-[4-(2-cyanoacetyl)methoxy-phenoxy]piperidine carboxylate (1.0 g, 2.7 mmol) and hydrazine hydrate (99% in water, 0.54 g, 10.0 mmol) in ethanol (20 mL) was heated to reflux for 16 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 90% EtOAc/hexane as the eluent to give the title compound (0.2 g, 19%). 28F. tert-But l4- 4- 3- 5-c ano razin lamino -1H- razol lmethox - phenoxy|piperidinecarboxylate A stirred solution of tert-butyl 4-[4-(3-amino-1H-pyrazolyl)methoxy- phenoxy]piperidinecarboxylate (1.0 g, 2.6 mmol), diisopropylethylamine (1.4 mL, 7.8 mmol) and 5-bromopyrazinecarbonitrile (1.43 g, 7.8 mmol) in dry 1,4-dioxane (10 mL) was heated to 80°C for 24 hours. After cooling to room ature the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2804) and ated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 45% EtOAc/hexane as the eluent to give the title compound (0.21 g, 17%). 28G. 5- 5- 2-Methox 4- i erid lox hen l-1H- razol lamino razine carbonitrile hydrochloride 4N HCI in dioxane (6 mL) was added to a stirred solution of tert-butyl 4-[4-[3-[(5- yrazinyl)amino]-1 H-pyrazolyl]methoxy-phenoxy]piperidine-1 - carboxylate (0.21 g, 0.50 mmol) in a e of dry MeCN (5 mL) and dry THF (5 mL) and the resulting mixture stirred at room temperature for 2 hours. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtOAc (3 x 2 mL) and MeOH (3 x 2 mL) and dried to give the title compound (0.20 g, 100%) as an off-white solid. lamino razinecarbonitrile ropylethylamine (0.16 mL, 0.94 mmol) was added to a stirred suspension of 5- [[5-[2-methoxy(4-piperidyloxy)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile hydrochloride (0.20 g, 0.47 mmol) in a mixture of MeOH (4 mL) and MeCN (8 mL) and the mixture stirred for 20 minutes at room temperature under a en atmosphere.
Formalin (37-41% w/v in water; 0.08 mL, 0.94 mmol) was added followed by the addition of l acetic acid (0.05 mL, 1.50 mmol) and the mixture stirred for a further minutes then the mixture was cooled to 0°C and NaBH(OAc)3 (0.32 g, 1.50 mmol) was added in portions over 10 s. The e was allowed to warm to room temperature and stirred for a further hour then poured into ice-water (30 mL) and solid NaHC03 was added to adjust the pH of the solution to 8. The mixture was extracted with EtOAc (4 x 50 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced re. The residue was purified by column chromatography on neutral silica gel using 7% HCI3 as the eluent to leave an off-white solid. The solid was dissolved in a mixture of THF (5 mL) and MeCN (5 mL) then a solution of 4N HCI in dioxane (0.5 mL) was added and the resulting e stirred for one hour. The solvents were ated under d re to leave a solid that was triturated with EtZO (3 x 5 mL) and dried to give the title nd (68 mg, 69%) as an off-white solid.
Synthetic Route L (Illustrated with reference to Example 64: Example 64 - 5- 4- 4-Fluorometh l i erid lmethox - hen l-1H- razol lamino razinecarbonitrile h drochloride 64A. 2-(4-Bromomethoxy-phenyl)—1,3-dioxolane A mixture of 4-bromomethoxy-benzaldehyde (25.0 g, 117 mmol), ethanediol (9.7 mL, 175 mmol) and p-toluenesulfonic acid (67 mg, 0.35 mmol) in toluene (250 mL) was heated to reflux under tark conditions for 5 hours. The cooled solution was poured into saturated NaHC03 solution (100 mL) and the separated aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue that was purified by column chromatography on neutral silica gel using % EtOAc/hexane as the eluent to give the title compound (6.8 g, 23%). 64B. tert-But l4- 4- 1 3-dioxolan lmethox - hen lh drox - i eridine carboxylate A solution of n-BuLi (1.6 M in hexane, 21.5 mL, 34.3 mmol) was added dropwise to a stirred solution of 2-(4-bromomethoxy-phenyl)-1 xolane (6.8 g, 26.4 mmol) in dry THF (90 mL) at -78°C under a nitrogen atmosphere. The mixture was stirred for minutes then a solution of tert-butyl 4-oxopiperidinecarboxylate (5.26 g, 26.4 mmol) in THF (45 mL) was added dropwise maintaining the ature at -78°C. The reaction mixture was allowed to slowly warm to room temperature and stirring continued for 12 hours. The mixture was poured into cold saturated ammonium de solution (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic ts were washed with brine (50 mL), dried (Na2804) and evaporated under d pressure to leave a residue that was purified by column chromatography on neutral silica gel using 45% EtOAc/hexane as the eluent to give the title compound (2.9 g, 29%). 64C. tert-But l4-fluoro 4-form lmethox - hen l- i eridinecarbox late Diethylaminosulfur trifluoride (1.1 mL, 8.4 mmol) was added se to a stirred on of tert-butyl 4-[4-(1,3-dioxolanyl)methoxy-phenyl]hydroxy-piperidine ylate (2.9 g, 7.6 mmol) in DCM (10 mL) at -78°C under a nitrogen atmosphere.
The reaction mixture was d to warm to room temperature and ng continued for 5 hours. The mixture was poured into saturated sodium carbonate solution (50 mL) and the separated aqueous phase extracted with DCM (3 x 50 mL). The combined organic extracts were washed with 1N citric acid solution (30 mL), dried (Na2804) and ated under reduced pressure to leave a e that was purified by column chromatography on neutral silica gel using 10% EtOAc/hexane as the eluent to give the title compound (1.8 g, 70%). 64D. tert-But l4- 4- 2-c anoh drox -eth lmethox - hen lfluoro- i eridine carboxylate A solution of 2-bromoacetonitrile (1.1 g, 9.0 mmol) in dry THF (10 mL) was added to a stirred suspension of tert-butyl 4-fluoro(4-formylmethoxy—phenyl)-piperidine carboxylate (1.8 g, 5.3 mmol) and zinc dust (0.69 g, 10.6 mmol) in dry THF (10 mL).
The mixture was stirred for 30 minutes then poured into saturated ammonium chloride on (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue that was purified by column chromatography on neutral silica gel using 20% EtOAc/hexane as the eluent to give the title compound (1.7 g, 84%). 64E. tert-But l4- 4- 2-c anoacet lmethox - hen lfluoro- i eridine carboxylate Dess-Martin periodinane (2.29 g, 5.4 mmol) was added in portions to a stirred solution of tert-butyl 4-[4-(2-cyanohydroxy-ethyl)methoxy-phenyl]fluoro-piperidine carboxylate (1.7 g, 4.5 mmol) in DCM (50 mL) under a nitrogen atmosphere. The solution was stirred for 30 minutes then filtered through a pad of celite washing with DCM (50 mL). The filtrate was ated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using %EtOAc/hexane as the eluent to give the title compound (1.6 g, 95%). 64F. tert-But l4- 4- 3-amino-1H- razol lmethox - hen |f|uoro- i eridine carboxylate A solution of tert-butyl 4-[4-(2-cyanoacetyl)methoxy-phenyl]fluoro-piperidine carboxylate (1.6 g, 4.3 mmol) and hydrazine hydrate (99% in water, 0.33 g, 6.5 mmol) in ethanol (15 mL) was heated to reflux for 18 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under d pressure to leave a residue which was ed by column chromatography on neutral silica gel using 75% EtOAc/hexane as the eluent to give the title compound (0.73 g, 44%). 64G. ut l4- 4- 3- 5-c ano razin-2— lamino -1H- razol lmethox - phenyl|fluoro-piperidinecarboxylate A stirred on of tert-butyl 4-[4-(3-amino-1H-pyrazolyl)methoxy-phenyl] fluoro-piperidinecarboxylate (0.73 g, 1.9 mmol), diisopropylethylamine (1.0 mL, 5.7 mmol) and 5-bromopyrazinecarbonitrile (1.04 g, 5.7 mmol) in dry 1,4-dioxane (8 mL) was heated to 80°C for 24 hours. After cooling to room temperature the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 4% HCI3 as the eluent to give the title compound (0.52 g, 56%). 64H. 5- 5- 4- 4-Fluoro i erid lmethox - hen l-1H- razol lamino razine- 2—carbonitrile hydrochloride 4N HCI in dioxane (4 mL) was added to a d solution of utyl 4-[4-[3-[(5- cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl]f|uoro-piperidine ylate (0.37 g, 0.75 mmol) in a mixture of dry MeCN (6 mL) and dry THF (10 mL) and the resulting mixture stirred at room temperature for 30 minutes. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtOAc (3 x 2 mL) and dried to give the title compound (0.30 g, 92%) as an off-white solid. 64l. 5- 5- 4- 4-Fluorometh l i erid lmethox - hen l-1H- razol lamino razinecarbonitrile h drochloride Diisopropylethylamine (0.08 mL, 0.46 mmol) was added to a stirred suspension of 5- -(4-fluoropiperidyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile hydrochloride (0.10 g, 0.23 mmol) in a mixture of MeOH (2 mL) and MeCN (8 mL) and the mixture stirred for 20 s at room temperature under a en here. Formalin (37-41% w/v in water; 0.014 g, 0.46 mmol) was added and the e stirred for a further 20 minutes then the e was cooled to 0°C and Ac)3 (0.16 g, 0.74 mmol) was added in portions over 10 minutes. The mixture was allowed to warm to room temperature and stirred for a further hour then poured into ice-water (30 mL). The mixture was extracted with EtOAc (4 x 25 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 8% MeOH/CHCI3 as the e|uent to leave an off-white solid. The solid was dissolved in a mixture of THF (5 mL) and MeCN (5 mL) and a solution of 4N HCI in dioxane (0.5 mL) was added and the resulting mixture stirred for one hour. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtZO (3 x 5 mL) and dried to give the title compound (80 mg, 45%) as an off-white solid.
Synthetic Route M (Illustrated with reference to Example 87: Example 87 lamino razinecarbonitrile h drochloride 87A. tert-But |3-h drox 3-methox methox carbon l- hen l i eridine carboxylate Borane.DMS (3.3 mL, 34.5 mmol) was added to a stirred solution of tert-butyl 4-(3- methoxymethoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridinecarboxylate (Example 11A) (10 g, 28.8 mmol) in dry THF (100 mL) at 0°C under a nitrogen here. The e was allowed to warm to room temperature and stirring continued for 6 hours before adding 3N sodium hydroxide solution (10.6 mL, 3.17 mmol) and hydrogen peroxide solution (30% in water, 11.8 mL, 104 mmol) at 0°C. The mixture was stirred WO 20390 at 50°C for 15 hours then the cooled mixture poured into ice-water (100 mL). The mixture was extracted with EtOAc (3 x 150 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 20% EtOAc/hexane as the eluent to give the title compound (7.8 g, 74%). 87B. ut oro 3-methox methox carbon l- hen l i eridine carboxylate Diethylaminosulfur oride (1.8 mL, 13.6 mmol) was added dropwise over 10 minutes to a stirred solution of tert-butyl 3-hydroxy(3-methoxymethoxycarbonyl- phenyl)piperidinecarboxylate (2.5 g, 6.8 mmol) in DCM (25 mL) at -78°C under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirring continued for 2 hours. The mixture was poured into saturated sodium bicarbonate solution (100 mL) and the separated aqueous phase extracted with EtOAc (4 x 100 mL). The combined organic extracts were washed with 1N citric acid solution (30 mL), dried (Na2804) and ated under d re to leave a residue that was purified by column chromatography on neutral silica gel using 16% EtOAc/hexane as the eluent to give the title compound (1.8 g, 72%). 87C. tert-But l4- 4- 2-c anoacet lmethox - hen lfluoro- i eridine carboxylate A solution of LiHMDS (1.0 M in hexane, 18.9 mL, 18.9 mmol) was added dropwise over 30 minutes to a stirred solution of acetonitrile (1.1 g, 27.0 mmol) in dry THF (75 mL) at -78°C under a en atmosphere. Stirring was continued for 30 minutes then a solution of tert-butyl 3-fluoro(3-methoxymethoxycarbonyl-phenyl)piperidine carboxylate (2.0 g, 5.4 mmol) in THF (75 mL) was added dropwise over 20 minutes maintaining the temperature at -78°C. The mixture was stirred at -78°C for 30 minutes then allowed to warm to room temperature and stirring continued for two hours. The mixture was poured into cold ted ammonium chloride solution (100 mL) and extracted with EtOAc (5 x 200 mL). The combined c extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave the title compound (2.3 g, 100%) which was used without further cation. 87D. tert-But l4- 4- 3-amino-1H- razol lmethox - hen lfluoro- i eridine carboxylate A solution of utyl 4-[4-(2-cyanoacetyl)methoxy-phenyl]fluoro-piperidine carboxylate (0.6 g, 1.6 mmol) and hydrazine hydrate (99% in water, 0.12 g, 2.4 mmol) in ethanol (12 mL) was heated to reflux for 18 hours. The e was allowed to cool to room temperature and the solvents evaporated under reduced pressure to leave a e which was ed by column chromatography on neutral silica gel using 80% EtOAc/hexane as the eluent to give the title compound (0.34 g, 54%). 87E. ut l4- 4- 3- 5-c ano 2- lamino -1H- razol lmethox - phenyl|fluoro-piperidinecarboxylate A stirred solution of tert-butyl 4-[4-(3-amino-1H-pyrazolyl)methoxy-phenyl] fluoro-piperidinecarboxy|ate (0.8 g, 2.1 mmol), diisopropylethylamine (1.1 mL, 6.3 mmol) and 5-bromopyrazinecarbonitrile (1.2 g, 6.3 mmol) in dry oxane (11 mL) was heated to 80°C for 48 hours. After cooling to room temperature the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (4 x 60 mL). The combined organic extracts were washed with brine (30 mL), dried 4) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on l silica gel using 70% EtOAc/hexane as the eluent to give the title compound (0.70 g, 69%). 87F. 5- 5- 4- 3-fluoro i erid lmethox - hen l-1H- razol lamino razine- 2-carbonitrile hydrochloride 4N HCI in dioxane (4 mL) was added to a stirred solution of tert—butyl 4-[4-[3-[(5- cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl]fluoro-piperidine carboxylate (0.70 g, 1.4 mmol) in a mixture of dry MeCN (16 mL) and dry THF (16 mL) and the resulting mixture stirred at room temperature for 3 hours. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtOAc (3 x 2 mL) and dried to give the title compound (0.30 g, 92%) as an off-white solid. 87G. 5- 51-eth lfluoro i erid lmethox - hen l-1H- razol lamino razinecarbonitrile h drochloride Diisopropylethylamine (0.16 mL, 0.94 mmol) was added to a stirred suspension of 5- [[5-[4-(3-fluoropiperidyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile (0.20 g, 0.47 mmol) in a mixture of MeOH (2 mL) and MeCN (8 mL) and the mixture d for 20 minutes at room temperature under a nitrogen atmosphere.
Acetaldehyde (0.05 mL, 0.94 mmol) was added and the mixture stirred for a further 20 minutes then the mixture was cooled to 0°C and NaBH(OAc)3 (0.32 g, 1.5 mmol) was added in portions over 10 minutes. The mixture was allowed to warm to room temperature and stirred for a further 30 minutes then poured into ice-water (30 mL) and solid NaHC03 was added to adjust the pH of the solution to 8. The mixture was extracted with EtOAc (4 x 50 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure. The e was purified by column chromatography on neutral silica gel using 2% MeOH/CHCI3 as the e|uent. The resulting solid was dissolved in a mixture of THF (10 mL) and MeCN (10 mL) and a solution of 4N HCI in dioxane (1 mL) was added and the resulting mixture stirred for one hour. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtZO (3 x 10 mL) and dried to give the title compound (75 mg, 35%) as a pale yellow solid.
Synthetic Route N (Illustrated with nce to Example 97: Example 97 5- 5- 4- 33-Difluorometh l i erid lmethox - hen l-1H- razol lamino razinecarbonitrile h oride 97A. tert-But l4- 3-methox hox carbon l- hen loxo- i eridine carboxylate artin periodinane (29.1 g, 68.5 mmol) was added in portions to a stirred solution of tert-butyl 3-hydroxy(3-methoxy—4-methoxycarbonyl-phenyl)piperidine carboxylate (Example 87A) (5.0 g, 13.7 mmol) in DCM (100 mL) under a nitrogen atmosphere. The solution was stirred for 30 minutes then filtered through a pad of celite washing with DCM (50 mL) and then solid NaHCO3 was added to the filtrate to adjust the pH of the solution to 8. The mixture was extracted with EtOAc (3 x 100 mL) and the ed organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under d pressure to leave the title compound (4.9 g, 99%) which was used t r purification. 97B. tert-But l3 3-difluoro 3-methox methox carbon l- hen l i eridine carboxylate Diethylaminosulfur trifluoride (5.4 mL, 40.5 mmol) was added dropwise over 10 minutes to a stirred solution of tert-butyl 4-(3-methoxymethoxycarbonyl-phenyl) oxo-piperidinecarboxylate (4.9 g, 13.5 mmol) in DCM (100 mL) at -78°C under a 2015/015030 en atmosphere. The reaction mixture was allowed to warm to room temperature and stirring continued for one hour. The mixture was poured into saturated sodium bicarbonate solution (100 mL) and the separated aqueous phase extracted with EtOAc (4 x 60 mL). The combined organic extracts were washed with 1N citric acid solution (30 mL), dried (Na2804) and evaporated under d pressure to leave a residue that was purified by column chromatography on neutral silica gel using 10% EtOAc/hexane as the eluent to give the title nd (2.6 g, 50%). 97C. tert-But l4- 4- 2-c anoacet lmethox - hen l-3 3-difluoro- i e ylate A solution of LiHMDS (1.0 M in , 22.8 mL, 22.8 mmol) was added dropwise over 30 minutes to a stirred solution of acetonitrile (1.33 g, 3.25 mmol) in dry THF (25 mL) at -78°C under a nitrogen atmosphere. Stirring was continued for 30 s then a solution of tert-butyl 3,3-difluoro(3-methoxymethoxycarbonyl-phenyl)piperidine- 1-carboxylate (2.5 g, 6.5 mmol) in THF (25 mL) was added dropwise over 20 minutes maintaining the ature at -78°C. The mixture was stirred at -78°C for 30 minutes then allowed to warm to room temperature and stirring continued for one hour. The mixture was poured into cold saturated ammonium chloride solution (100 mL) and ted with EtOAc (3 x 50 mL). The ed organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave the title compound (2.5 g, 98%) which was used without further purification. 97D. tert-But l4- 4- 3-amino-1H- razol l methox - hen l-3 3-difluoro- piperidinecarboxylate A solution of tert-butyl 4-[4-(2-cyanoacetyl)methoxy-phenyl]-3,3-difluoro-piperidine- 1-carboxylate (2.5 g, 6.3 mmol) and hydrazine hydrate (99% in water, 1.58 g, 31.5 mmol) in ethanol (50 mL) was heated to reflux for 15 hours. The e was allowed to cool to room temperature and the solvents evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 50% EtOAc/hexane as the eluent to give the title compound (1.8 g, 70%). 97E. tert-But l4- 4- 3- 5-c ano razin lamino -1H- razol lmethox - phenyl|-3,3—difluoro-piperidinecarboxylate A stirred solution of tert-butyl 4-[4-(3-amino-1H-pyrazolyl)methoxy-phenyl]-3,3- difluoro-piperidinecarboxylate (0.5 g, 1.2 mmol), diisopropylethylamine (0.63 mL, 3.6 mmol) and 5-bromopyrazinecarbonitrile (0.66 g, 3.6 mmol) in dry 1,4-dioxane (10 mL) was heated to 80°C for 24 hours. After cooling to room temperature the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2804) and ated under reduced pressure to leave a e which was purified by column chromatography on neutral silica gel using 2% MeOH/DCM as the eluent to give the title compound (0.43 g, 69%). 97F. 5- 5- 4- 3 3-difluoro i erid lmethox - hen l-1H- razol lamino razinecarbonitrile h drochloride 4N HCI in dioxane (4 mL) was added to a stirred solution of utyl 4-[4-[3-[(5- cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl]-3,3-difluoro-piperidine carboxylate (0.70 g, 1.4 mmol) in a mixture of dry MeCN (16 mL) and dry THF (16 mL) and the resulting mixture d at room ature for 1 hour. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtZO (3 x 5 mL) and dried to give the title compound (0.30 g, 92%) as an off-white solid. 97G. 5- 5- 4- 33-Difluorometh l i erid lmethox - hen l-1H- razol lamino razinecarbonitrile h drochloride Diisopropylethylamine (0.12 mL, 0.66 mmol) was added to a stirred suspension of 5- [[5-[4-(3,3-difluoropiperidyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile hloride (0.15 g, 0.33 mmol) in a mixture of MeOH (1.5 mL) and MeCN (6.5 mL) and the mixture stirred for 20 minutes at room temperature under a nitrogen atmosphere. Formalin (37-41% w/v in water; 0.05 mL, 1.06 mmol) was added and the e stirred for a further 20 minutes then the mixture was cooled to 0°C and NaBH(OAc)3 (0.22 g, 1.06 mmol) was added in portions over 10 minutes. The mixture was allowed to warm to room temperature and stirred for a further 20 minutes then poured into ice-water (30 mL). The mixture was extracted with EtOAc (3 x 25 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and ated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 2% MeOH/DCM as the eluent to leave an off-white solid. The solid was dissolved in a mixture of THF (3 mL) and MeCN (3 mL) and a on of 4N HCI in dioxane (1 mL) was added and the resulting mixture stirred for one hour. The ts were evaporated under reduced pressure to leave a solid that was triturated with EtZO (3 x 5 mL) and dried to give the title compound (120 mg, 77%) as an off-white solid.
Synthetic Route 0 (Illustrated with reference to Example 107: Example 107 lamino razinecarbonitrile h drochloride 107A. tert-But l4- 3-methox methox carbon l-anilino meth l i e carboxylate Nitrogen was bubbled through a d suspension of methyl 4-bromo methoxybenzoate (4.0 g, 16.3 mmol), utyl 4-(aminomethyl)piperidine carboxylate (3.5 g, 16.3 mmol), cesium carbonate (10.6 g, 32.6 mmol) and xantphos (3.76 g, 6.5 mmol) in 1,4-dioxane (80 mL) for 20 minutes. Pd2(dba)3 (2.39 g, 2.6 mmol) was added and the resulting mixture heated to 80°C for 6 hours. The cooled reaction mixture was poured into water (100 mL) and ted with EtOAc (2 x 100 mL). The combined c extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column tography on neutral silica gel using 30% EtOAc/hexanes as the eluent to give the title nd (4.5 g, 73%). 107B. tert-Butyl 4-| ( N-tert—butoxycarbonylmethoxymethoxycarbonyl- anilino)methyl|piperidinecarboxylate A stirred solution of tert-butyl 4-[(3-methoxymethoxycarbonyl- anilino)methyl]piperidinecarboxylate (1.15 g, 3.0 mmol), Boc20 (9.8 g, 4.5 mmol), diisopropylethylamine (2.6 mL, 1.5 mmol) and 4-dimethylaminopyridine (0.04 g, 0.3 mmol) in THF (5 mL) was heated to 75°C for 18 hours. The cooled reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 20% EtOAc/hexanes as the eluent to give the title compound (2.6 g, 45%). 107C. tert-Butyl 4-||N-tert-butoxycarbonyl(2-cyanoacetyl)—3-methoxy— anilino|methyl|piperidinecarboxy|ate A solution of LiHMDS (1.0 M in , 37.8 mL, 37.8 mmol) was added dropwise over 30 minutes to a stirred solution of acetonitrile (2.2 g, 5.40 mmol) in dry THF (100 mL) at -78°C under a nitrogen atmosphere. Stirring was continued for 30 minutes then a solution of tert-butyl 4-[(N-tert-butoxycarbonylmethoxymethoxycarbonyl- anilino)methyl]piperidinecarboxy|ate (2.6 g, 5.4 mmol) in THF (100 mL) was added dropwise over 30 minutes maintaining the temperature at -78°C. The mixture was stirred at -78°C for 30 minutes then allowed to warm to room temperature and stirring continued for 2 hours. The mixture was poured into cold saturated ammonium de solution (100 mL) and extracted with EtOAc (3 x 100 mL). The combined c extracts were washed with brine (50 mL), dried 4) and evaporated under reduced pressure to leave the title compound (2.7 g, 98%) which was used without further purification. 107D. ut l4- 4- 3—amino-1H- razol l-N-tert-butox carbon lmethox - anilino|methyl|piperidinecarboxylate A on of tert-butyl 4-[[N-tert-butoxycarbonyl(2-cyanoacetyl)methoxy- anilino]methyl]piperidinecarboxy|ate (1.0 g, 2.1 mmol) and hydrazine hydrate (99% in water, 0.42 g, 8.4 mmol) in ethanol (10 mL) was heated to reflux for 18 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 1.5% MeOH/CHCI3 as the eluent to give the title compound (0.33 g, 32%). 107E. tert-But |4- N-tert-butox carbon | 3- 5-c ano razin lamino -1H- pyrazolyl|methoxy-anilino|methyl|piperidinecarboxylate A stirred solution of tert-butyl 4-[[4-(3-amino-1H-pyrazolyl)-N-tert-butoxycarbonyl y-anilino]methyl]piperidinecarboxy|ate (0.7 g, 1.4 mmol), diisopropylethylamine (0.73 mL, 4.2 mmol) and 5-bromopyrazinecarbonitrile (0.77 g, 4.2 mmol) in dry 1,4-dioxane (10 mL) was heated to 80°C for 48 hours. After cooling to room temperature the reaction mixture was poured into ice-water (50 mL) and ted with EtOAc (3 x 50 mL). The ed organic extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on l silica gel using 1% MeOH/DCM as the eluent to give the title compound (0.47 g, 57%). 107F. 5- 5- 2-Methox 4- i erid lmeth lamino hen l-1H- razol lamino razinecarbonitrile h drochloride 4N HCI in dioxane (5 mL) was added to a stirred suspension of tert-butyl 4-[[N-tert- butoxycarbonyl[3-[(5-cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy- anilino]methyl]piperidinecarboxylate (0.50 g, 0.83 mmol) in a e of dry MeCN (4 mL) and dry THF (4 mL) and the resulting mixture stirred at room temperature for 4 hours. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtZO (3 x 5 mL) and dried to give the title nd (0.44 g, 98%) as an off-white solid. 107G. 5- 5- 2-Methox 1-meth l i erid lmeth lamino hen l-1H- 3- lamino razinecarbonitrile h oride Diisopropylethylamine (0.12 mL, 0.68 mmol) was added to a stirred sion of 5- [[5-[2-methoxy(4-piperidylmethylamino)phenyl]-1H-pyrazolyl]amino]pyrazine itrile hydrochloride (0.15 g, 0.34 mmol) in a mixture of MeOH (3 mL) and MeCN (6 mL) and the mixture stirred for 20 minutes at room ature under a en atmosphere. Formalin (37-41% w/v in water; 0.06 mL, 6.8 mmol) and glacial acetic acid (0.04 mL, 6.8 mmol) were added and the mixture stirred for a further 20 minutes then the mixture was cooled to 0°C and NaBH(OAc)3 (0.23 g, 1.09 mmol) was added in portions over 10 minutes. The mixture was allowed to warm to room temperature and stirred for a further 45 minutes then poured into ice-water (30 mL). The mixture was extracted with EtOAc (4 x 25 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure.
The residue was purified by column chromatography on neutral silica gel using 16% MeOH/DCM as the eluent to leave an off-white solid. The solid was dissolved in a mixture of THF (4 mL) and MeCN (4 mL) and a solution of 4N HCI in dioxane (0.5 mL) was added and the resulting mixture stirred for one hour. The solvents were evaporated under reduced pressure to leave a solid that was triturated with a 1:1 mixture of n-pentane/EtZO (3 x 5 mL) and dried to give the title compound (60 mg, 39%) as an off-white solid.
Synthetic Route P (Illustrated with reference to Example 117: Example 117 - 5- 2-Methox 2R meth lmor holin l hen l-1H- razol lamino razinecarbonitrile h drochloride 117A. Methyl 2-methoxyvinyl-benzoate A stirred solution of methyl 4-bromomethoxybenzoate (25.0 g, 103 mmol), ium ethenyl(trifluoro)borate (17.8 g, 133 mmol), 1,1'- bis(diphenylphosphino)ferrocene dichloropalladium(|l) dichloromethane complex (2.5 g, 3.1 mmol) and trimethylamine (14.3 mL, 103 mmol) in n-proponal (250 mL) was heated to reflux for 3 hours. The cooled reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 5% EtOAc/hexanes as the eluent to give the title compound (16.4 g, 83%). 117B. Methyl 4-|(1R)—1,2-dihydroxyethyl|methoxy-benzoate Methyl 2-methoxyvinyl-benzoate (3.5 g, 18.2 mmol) was added to a stirred solution of AD-mix—B (22.0 g) in t-butanol (70 mL) and water (70 mL) at 0°C and the resulting mixture allowed to warm to room temperature. The mixture was stirred for 3 hours then sodium sulfite (6.88 g, 54.6 mmol) was added and stirring continued for one hour.
The mixture was extracted with EtOAc (3 x 100 mL) and the combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave a solid. The solid was triturated using n-pentane (3 x 40 mL) and dried to give the title compound (3.5 g, 85%) as a white solid. 117C. Methyl 2-methoxy|(2R)—oxiranyl|benzoate Chlorotrimethylsilane (15.7 mL, 124 mmol) was added dropwise to a stirred solution of methyl 4-[(1R)—1,2-dihydroxyethyl]methoxy-benzoate (7.0 g, 31 mmol) and hylorthoacetate (15.6 mL, 124 mmol) in DCM (70 mL) at room temperature under a nitrogen atmosphere. The mixture was d for 90 s then the solvents were ated under reduced pressure. The residue was dissolved in MeOH (15 mL) and ium carbonate (8.56 g, 62 mmol) was added and the resulting mixture stirred at room temperature under a nitrogen atmosphere for 3 hours. The solvents were evaporated under d re and the e partitioned between water (100 mL) and EtOAc (100 mL). The ted aqueous phase was extracted with EtOAc (2 x 100 mL) then the combined organic extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure. The residue was ed by column chromatography on neutral silica gel using 23% hexanes as the eluent to give the title compound (5.6 g, 87%). 117D. Methyl 4-|(1R)—1-hydroxy(2-hydroxyethylamino)ethyl|methoxy-benzoate A stirred mixture of methyl oxy—4-[(2R)—oxiranyl]benzoate (1.0 g, 4.8 mmol) and ethanolamine (2.6 mL, 43.2 mmoL) in THF (6 mL) was heated to 60°C for 6 hours.
The cooled reaction mixture was poured into water (20 mL) and extracted with a mixture of EtOAc and THF (1 :1, 3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure to leave the title compound (0.9 g, 62%) which was used without further cation. 117E. Methyl 4-|(1R)—2-|tert-butoxycarbonyl(2-hydroxyethyl)amino|—1-hydroxy—ethyl|—2- methoxy—benzoate Boc20 (3.64 g, 16.7 mmol) was added to a stirred solution of methyl 4-[(1R) hydroxy(2-hydroxyethylamino)ethyl]methoxy-benzoate (4.5 g, 16.7 mmol) and Et3N (3.5 mL, 25.1 mmol) in DCM (45 mL) and the resulting mixture stirred at room temperature for 3 hours. The reaction mixture was poured into water (50 mL) and the separated aqueous phase was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave a e which was purified by column tography on neutral silica gel using 85% EtOAc/hexanes as the eluent to give the title compound (3.45 g, 56%). 117F. tert-Butyl (2R)—2-(3-methoxy—4-methoxycarbonyl-phenyl)morpholine carboxylate Diethylazodicarboxylate (40% solution in toluene, 10.1 mL, 23.3 mmol) was added dropwise to a stirred on of methyl 4-[(1R)—2-[tert-butoxycarbony|(2- hydroxyethyl)amino]hydroxy-ethy|]methoxy-benzoate (3.45 g, 9.3 mmol) and triphenylphosphine (3.66 g, 14.0 mmol) in toluene (60 mL) at 0°c under a nitrogen atmosphere. The e was allowed to warm to romm temperature and stirring continued for 12 hours then poured into water (100 mL) and extracted with EtOAc (3 x mL). The combined c extracts were washed with brine (10 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on l silica gel using 32% EtOAc/hexanes as the eluent to give the title compound (1.85 g, 56%). 117G. tert-But | 2R 4- 2-c anoacet lmethox - hen lmor holinecarbox late A on of LiHMDS (1.0M in hexane, 32.4 mL, 32.4 mmol) was added dropwise over 40 minutes to a stirred solution of acetonitrile (3.13 mL, 6.0 mmol) in dry THF (150 mL) at -78°C under a nitrogen atmosphere. Stirring was continued for 30 minutes then a solution of tert-butyl (2R)—2-(3-methoxymethoxycarbonyl-phenyl)morpholine carboxylate (2.1 g, 6.0 mmol) in THF (150 mL) was added dropwise over 30 minutes maintaining the ature at -78°C. The mixture was stirred at -78°C for 30 s then allowed to warm to room temperature and stirring continued for 30 minutes. The mixture was poured into cold saturated ammonium chloride solution (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave the title nd (2.1 g, 98%) which was used without r purification. 117H. tert-But | 2R 4- 3-amino-1H- razol lmethox - hen lmor holine carboxylate A solution of tert-butyl (2R)[4-(2-cyanoacetyl)methoxy-phenyl]morpholine carboxylate (2.1 g, 5.8 mmol) and hydrazine hydrate (99% in water, 0.44 g, 8.7 mmol) in ethanol (20 mL) was heated to reflux for 12 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 1.8% MeOH/CHCI3 as the eluent to give the title compound (0.78 g, 36%). 117i. tert-But | 2R 4- 3- 5-c ano razin lamino -1H- 5- lmethox - phenyl|morpholinecarboxylate A stirred mixture of utyl (2R)—2-[4-(3-amino-1H-pyrazolyl)methoxy- phenyl]morpholinecarboxylate (0.78 g, 2.1 mmol), diisopropylethylamine (0.73 mL, 4.2 mmol), ium iodide (0.18 g, 1.1 mmol) and 5-bromopyrazinecarbonitrile (1.04 g, 5.7 mmol) in dry 1,4-dioxane (10 mL) was heated to 80°C for 18 hours. After g to room temperature the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic ts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 65% EtOAc/hexanes as the eluent to give the title compound (0.60 g, 61%). 2-carbonitrile hydrochloride 4N HCI in dioxane (5 mL) was added to a stirred suspension of tert-butyl (2R)—2-[4-[3- [(5-cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl]morpholine carboxylate (0.6 g, 1.3 mmol) in a mixture of dry MeCN (5 mL) and dry THF (5 mL) and the resulting e d at room temperature for 3 hours. The ts were ated under reduced pressure to leave a solid that was triturated with EtZO (3 x 5 mL) and dried to give the title nd (0.51 g, 98%) as an off-white solid. 117K. 5- 5- 2-methox 2R meth lmor holin l hen l-1H- razol lamino razinecarbonitrile h oride ropylethylamine (0.17 mL, 0.98 mmol) was added to a stirred suspension of 5- [[5-[2-methoxy[(2R)-morpholinyl]phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile hydrochloride (0.16 g, 0.39 mmol) in a mixture of MeOH (5 mL) and MeCN (5 mL) and the mixture stirred for 20 minutes at room temperature under a nitrogen atmosphere. Formalin (37-41% w/v in water; 0.3 mL, 3.9 mmol) was added and the mixture stirred for a further 20 minutes then the mixture was cooled to 0°C and NaBH(OAc)3 (0.26 g, 1.25 mmol) was added in portions over 10 minutes. The mixture was allowed to warm to room temperature and stirred for a further 45 minutes then poured into ice-water (30 mL). The mixture was extracted with EtOAc (4 x 25 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure. The residue was triturated with n-pentane (3 x mL) and dried. The solid was dissolved in a mixture of THF (3 mL) and MeCN (3 mL) and a solution of 4N HCI in dioxane (3 mL) was added and the resulting mixture stirred for 30 minutes. The solvents were evaporated under reduced pressure to leave a solid that was triturated with a 10% EtOAc/n-pentane/EtZO (3 x 5 mL) and dried to leave the title compound (0.12 g, 73%) as a beige solid.
Synthetic Route Q (Illustrated with reference to Example 123: e 123 - 5- 4- 3R fluoro rrolidin lmeth lmethox - hen l-1H- razol lamino razinecarbonitrile h drochloride) 123A. Methyl 4-||tert-butyl(dimethyl)silyl|oxymethyl|methoxy-benzoate A solution of utyldimethylsilyl chloride (9.99 g, 66.3 mmol) in DMF (20 mL) was added dropwise over a period of 15 minutes to a stirred solution of methyl 4- (hydroxymethyl)methoxy-benzoate (5.0 g, 25.5 mmol) and imidazole (4.17 g, 61.2 mmol) in DMF (50 mL) at 0°C. The mixture was allowed to warm to room temperature and stirring continued for one hour then the mixture was poured into water (200 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a e which was purified by column chromatography on neutral silica gel using 4% EtOAc/hexane as the eluent to give the title compound (4.1 g, 52%). 123B. 3- 4- tert-But ldimeth lsil lox meth lmethox - hen loxo- ro rile A solution of LiHMDS (1.0M in hexane, 90 mL, 90.0 mmol) was added dropwise over minutes to a stirred solution of acetonitrile (5.4 mL, 103 mmol) in dry THF (220 mL) at -78°C under a nitrogen atmosphere. Stirring was ued for 30 minutes then a on of methyl 4-[[tert-butyl(dimethyl)silyl]oxymethyl]methoxy-benzoate (4.0 g, 12.9 mmol) in THF (220 mL) was added dropwise over 30 minutes maintaining the ature at -78°C. The mixture was stirred at -78°C for 30 minutes then allowed to warm to room temperature and stirring continued for one hour. The mixture was poured into cold saturated ammonium chloride solution (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic ts were washed with brine (50 mL), dried (Na2804) and evaporated under d pressure to leave the title compound (4.8 g) which was used without further purification. 123C. 5- 4- tert-But h lsil lox meth lmethox - hen l-1H- razolamine A solution of 3-[4-[[tert-butyl(dimethy|)silyl]oxymethyl]methoxy-phenyl]oxo- propanenitrile (4.8 g, 13.3 mmol) and hydrazine hydrate (99% in water, 2.7 g, 53.2 mmol) in ethanol (180 mL) was heated to reflux for 16 hours. The mixture was d to cool to room temperature and the solvents evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 1.5% MeOH/CHCI3 as the eluent to give the title compound (2.0 g, 40%). 123D. 5- 5- 4- tert-But ldimeth lsil lox meth lmethox - hen l-1H- razol lamino razinecarbonitrile A stirred solution of 5-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]methoxy-phenyl]-1H- lamine (0.6 g, 1.8 mmol), diisopropylethylamine (0.95 mL, 5.4 mmol) and 5- bromopyrazinecarbonitrile (0.99 g, 5.4 mmol) in dry 1,4-dioxane (7.5 mL) was heated to 80°C for 20 hours. After cooling to room temperature the reaction mixture was poured into ter (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 1.5% MeOH/DCM as the eluent to give the title compound (0.60 g, 76%). 123E. 5- 5- 4- H drox meth lmethox - hen l-1H- razol lamino razine carbonitrile A on of tetrabuytlammonium e (1.0M in THF, 4.2 mL, 4.2 mmol) was added to a stirred solution of 5-[[5-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]methoxy-phenyl]- 1H-pyrazolyl]amino]pyrazinecarbonitrile (0.6 g, 1.4 mmol) in THF (12 mL) at 0°C.
The resulting solution was allowed to warm to room temperature and stirring continued for one hour then the mixture was poured into water (40 mL) and extracted with EtOAc (2 x 100 mL). The ed organic extracts were washed with brine (10 mL), dried (Na2804) and evaporated under reduced pressure to leave the title compound (0.93 g) which was used t further purification. 123F. 5- 5- 4-Form lmethox - hen l-1H- 3- lamino razinecarbonitrile Dess-Martin periodinane (3.69 g, 8.7 mmol) was added in portions to a stirred solution of 5-[[5-[4-(hydroxymethyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile (0.92 g, 2.9 mmol) in THF (50 mL) under a nitrogen atmosphere. The solution was stirred for one hour then filtered through a pad of celite washing with THF (50 mL). The filtrate was evaporated under reduced pressure to leave a residue which was ed by column chromatography on neutral silica gel using 1.8%MeOH/CHCI3 as the eluent to give the title compound (0.3 g, 33%). 123G. 5- 5- 4- 3R fluoro rrolidin lmeth lmethox - hen l-1H- 3- lamino razinecarbonitrile h oride Diisopropylethylamine (0.16 mL, 0.94 mmol) was added to a stirred sion of (3R)—3-fluoropyrrolidine hydrochloride (0.12g, 0.94 mmol) in 1,2-dichloroethane (6 mL) and the mixture stirred for 20 minutes resulting in a colourless solution. 5-[[5-(4- Formylmethoxy—phenyl)-1H-pyrazolyl]amino]pyrazinecarbonitrile (0.15 g, 0.47 mmol) and glacial acetic acid (0.056 g, 0.94 mmol) were added and the mixture stirred for 30 minutes then cooled to 0°C and NaBH(OAc)3 (0.32 g, 1.5 mmol) was added in portions over 10 minutes. The mixture was allowed to warm to room temperature and 2015/015030 stirred for a further 30 minutes then poured into ter (30 mL) and solid NaHC03 was added to adjust the pH of the solution to 8. The mixture was extracted with EtOAc (2 x 25 mL) and the combined organic ts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure to leave a solid which was triturated with EtZO (3 x 5 mL). The resulting solid was dissolved in a mixture of THF (1 mL) and MeCN (1 mL) and a on of 4N HCI in dioxane (1 mL) was added and the resulting mixture stirred for 30 minutes. The solvents were evaporated under reduced pressure to leave a solid that was ated with EtZO (3 x 5 mL) and dried to give the title compound (76 mg, 38%) as an off-white solid. tic Route R (Illustrated with nce to Example 140: Example 140 - 5- 4- 3R eth l rrolidin lox meth lmethox - hen l-1H- razol lamino razinecarbonitrile h drochloride 140A. tert-Butyl (3R)—3-|(3-methoxy—4-methoxycarbonyl-phenyl)methoxy|pyrrolidine carboxylate A solution of tert-butyl (3R)—3-hydroxypyrrolidinecarboxylate (2.9 g, 15.5 mmoL) in DMF (8 mL) was added to a stirred slurry of sodium hydride (60% in mineral oil, 1.86 g, 4.65 mmol) in DMF (10 mL) at 0°C under a nitrogen atmosphere and the resulting mixture stirred for 10 minutes. A solution of methyl 4-(bromomethyl)—2-methoxy- benzoate (4.0 g, 15.5 mmol) in DMF (7 mL) was added dropwise over 20 minutes maintaining the ature at 0°C. The resulting mixture was allowed to warm to room temperature and stirring continued for 30 minutes before cooling back to 0°C.
Methyl iodide (2.9 mL, 4.65 mmol) was added and the solution was allowed to warm to room temperature and stirring continued for one hour then the mixture was poured into ice cold water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined c extracts were washed with brine (10 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 20%EtOAc/hexane as the eluent to give the title compound (4.3 g, 76%). 140B. tert-But | BR 4- 2-c anoacet lmethox - hen lmethox rrolidine carboxylate A solution of LiHMDS (1.0M in hexane, 42 mL, 42.0 mmol) was added dropwise over minutes to a stirred solution of acetonitrile (3.2 mL, 60 mmol) in dry THF (50 mL) at -78°C under a nitrogen atmosphere. Stirring was ued for 30 minutes then a solution of tert-butyl (3R)—3-[(3-methoxymethoxycarbonyl- )methoxy]pyrrolidinecarboxylate (4.3 g, 12.0 mmol) in THF (50 mL) was added dropwise over 30 s maintaining the temperature at -78°C. The mixture was stirred at -78°C for 30 minutes then allowed to warm to room temperature and stirring continued for one hour. The mixture was poured into cold saturated ammonium chloride solution (50 mL) and extracted with EtOAc (4 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave the title compound (4.4 g) which was used without r purification. 140C. tert-But | BR 4- 3-amino—1H- razol lmethox - phenyl|methoxy|pyrrolidinecarboxylate A solution of tert-butyl (3R)—3-[[4-(2-cyanoacetyl)methoxy— phenyl]methoxy]pyrrolidinecarboxylate (4.4 g, 12.0 mmol) and hydrazine hydrate (99% in water, 1.2 g, 24.0 mmol) in ethanol (45 mL) was heated to reflux for 18 hours.
The e was allowed to cool to room temperature and the solvents evaporated under reduced pressure to leave a e which was purified by column tography on neutral silica gel using 3% MeOH/CHCI3 as the eluent to give the title compound (2.6 g, 57%). 140D. tert-But | BR 4- 3- 5-c ano razin lamino -1H- razol thox - phenyl|methoxy|pyrrolidinecarboxylate A stirred solution of tert-butyl (3R)—3-[[4—(3-amino-1H-pyrazolyl)methoxy- phenyl]methoxy]pyrrolidinecarboxylate (1.0 g, 2.6 mmol), diisopropylethylamine (1.4 mL, 7.8 mmol) and 5-bromopyrazinecarbonitrile (1.43 g, 7.8 mmol) in dry 1,4- dioxane (20 mL) was heated to 80°C for 48 hours. After cooling to room temperature the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 2% MeOH/DCM as the eluent to give the title nd (0.90 g, 71%). 140E. 5- 5- 2-Methox 3R - rrolidin lox meth l hen l-1H- razol lamino carbonitrile h drochloride 4N HCI in dioxane (3 mL) was added to a stirred solution of tert-butyl (3R)—3-[[4-[3-[(5- cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl]methoxy]pyrrolidine carboxylate (0.90 g, 1.8 mmol) in a mixture of dry MeCN (10 mL) and dry THF (10 mL) and the resulting mixture stirred at room temperature for 3 hours. The solvents were evaporated under d pressure to leave a solid that was triturated with EtZO (3 x 2 mL) ed by n-pentane (2 x 5 mL) and dried to give the title compound (0.8 g, 100%) as an off-white solid. 140F. 5- 5- 4- 3R eth l rrolidin lox meth lmethox - hen l-1H- razol lamino razinecarbonitrile Diisopropylethylamine (0.08 mL, 0.46 mmol) was added to a stirred suspension of 5- [[5-[2-methoxy[[(3R)-pyrrolidinyl]oxymethyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile hydrochloride (0.5 g, 1.2 mmol) in a mixture of MeOH (10 mL) and MeCN (15 mL) and the mixture stirred for 20 minutes at room temperature under a nitrogen atmosphere. dehyde (0.35 mL, 6.0 mmol) was added and the mixture stirred for a further 30 minutes then the e was cooled to 0°C and NaBH(OAc)3 (0.81 g, 3.8 mmol) was added in portions over 10 minutes. The mixture was d to warm to room temperature and stirred for a further 30 s then poured into ice-water (30 mL) and solid NaHC03 was added to adjust the pH to 8. The mixture was extracted with EtOAc (4 x 50 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and evaporated under reduced pressure.
The residue was purified by column chromatography on neutral silica gel using 10% MeOH/CHCI3 as the eluent to leave a solid. The solid was dissolved in a e of THF (2 mL) and MeCN (2 mL) and a solution of 4N HCI in dioxane (0.5 mL) was added and the resulting mixture stirred for one hour. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtZO (3 x 5 mL) and dried to give the title compound (66 mg, 12%) as an off-white solid.
Synthetic Route 8 (Illustrated with reference to Example 143: 2015/015030 Example 143 lamino razinecarbonitrile h oride 143A. Methyl 4-(diethoxyphosphomlmethyl)—2-methoxy—benzoate A on of methyl 4-(bromomethyl)methoxy-benzoate (6.0 g, 23.3 mmol) in triethyl phosphite (12 mL) was heated to 100°C in a sealed tube for 12 hours. The solution was allowed to cool to room temperature and evaporated under reduced pressure to leave the title compound (7.2 g, 98%) as a yellow solid which was used without further purification. 143B. tert-Butyl 4-|(3-methoxymethoxycarbonyl-phenyl)methylene|piperidine carboxylate A solution of methyl 4-(diethoxyphosphorylmethyl)methoxy-benzoate (7.0 g, 22.1 mmol) in anhydrous THF (25 mL) was added dropwise over 10 minutes to a stirred slurry of sodium hydride (60% dispersion in oil, 2.65 g, 66.3 mmol) in ous THF (50 mL) at 0°C under a nitrogen atmosphere. The resulting e was d for 30 minutes then a solution of tert-butyl 4-oxopiperidinecarboxylate (4.4 g, 22.1 mmol) in THF (25 mL) was added dropwise over 10 minutes. The mixture was allowed to warm to room temperature and stirring continued for one hour then the mixture was poured into ice-water (100 mL) and extracted with EtOAc (4 x 100 mL). The combined organic ts were washed with brine (10 mL), dried (Na2804) and evaporated under d pressure to leave the title compound (7.0 g, 91%) which was used without further purification. 143C. tert-But l4- 3-methox methox carbon l- hen lmeth l i eridine carboxylate A suspension of tert-butyl 4-[(3-methoxymethoxycarbonyl- phenyl)methylene]piperidinecarboxylate (7.0 g, 19.4 mmoL) and 10% Pd on carbon (1.6 g) in MeOH (140 mL) was stirred under a hydrogen atmosphere for 3 hours. The mixture was filtered through a pad of celite and evaporated under reduced pressure.
The residue was purified by column chromatography on neutral silica gel using 30% EtOAc/hexane as the eluent to give the title compound (6.0 g, 85%).
WO 20390 143D. tert-but l4- 4- 2-c anoacet lmethox - hen lmeth | i eridine carboxylate A solution of LiHMDS (1.0M in hexane, 29 mL, 29.0 mmol) was added dropwise over minutes to a stirred solution of acetonitrile (2.2 mL, 41.5 mmol) in dry THF (30 mL) at -78°C under a nitrogen here. Stirring was continued for 30 minutes then a solution of tert-butyl 4-[(3-methoxymethoxycarbonyl-phenyl)methyl]piperidine carboxylate (3.0 g, 8.3 mmol) in THF (30 mL) was added dropwise over 30 minutes ining the temperature at -78°C. The mixture was d at -78°C for 30 minutes then allowed to warm to room temperature and stirring continued for 30 minutes. The mixture was poured into cold saturated ammonium chloride solution (50 mL) and ted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced re to leave the title compound (3.0 g, 98%) which was used without further purification. 143E. tert-But l4- 4- 3-amino-1H- razol lmethox - hen lmeth | i eridine carboxylate A solution of tert-butyl 4-[[4-(2-cyanoacetyl)methoxy-phenyl]methyl]piperidine carboxylate (3.0 g, 8.1 mmol) and hydrazine hydrate (99% in water, 2.1 mL, 40.5 mmol) in ethanol (30 mL) was heated to reflux for 6 hours. The e was allowed to cool to room temperature and the solvents evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 2% MeOH/CHCI3 as the eluent to give the title compound (1.3 g, 42%). 143F. tert-But l4- 4- 3- 5-c ano 2- lamino -1H- razol lmethox - phenyl|methyl|piperidinecarboxylate A stirred solution of tert-butyl 4-[[4-(3-amino-1H-pyrazolyl)methoxy- phenyl]methyl]piperidinecarboxylate (1.0 g, 2.6 mmol), diisopropylethylamine (1.4 mL, 7.8 mmol) and 5-bromopyrazinecarbonitrile (1.43 g, 7.8 mmol) in dry 1,4- dioxane (10 mL) was heated to 80°C for 15 hours. After cooling to room temperature the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic ts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column tography on neutral silica gel using 1.5% CM as the eluent to give the title compound (0.70 g, 55%). 143G. 5- 5- 2-Methox 4- i erid lmeth l hen l-1H- 3- lamino razine carbonitrile hydrochloride 4N HCI in dioxane (5 mL) was added to a d solution of tert-butyl [3-[(5- cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl]methyl]piperidine carboxylate (0.70 g, 1.4 mmol) in a mixture of dry MeCN (10 mL) and dry THF (10 mL) and the resulting mixture stirred at room temperature for 2 hours. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtZO (3 x 2 mL) and dried to give the title compound (0.6 g, 99%) as an off-white solid. 143H. 5- 5- 4- 1-eth l i erid lmeth lmethox - hen l-1H- razol lamino razinecarbonitrile h drochloride ropylethylamine (0.23 mL, 1.3 mmol) was added to a stirred suspension of 5-[[5- [2-methoxy(4-piperidylmethyl)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile hydrochloride (0.28 g, 0.65 mmol) in a mixture of MeOH (10 mL) and THF (10 mL) and the mixture stirred for 20 minutes at room temperature under a nitrogen atmosphere.
Acetaldehyde (0.18 mL, 3.2 mmol) was added and the e stirred for a further 20 minutes then the mixture was cooled to 0°C and Ac)3 (0.44 g, 2.08 mmol) was added in portions over 10 minutes. The mixture was allowed to warm to room temperature and stirred for a further 30 minutes then poured into ice-water (30 mL) and solid NaHC03 was added to adjust the pH of the solution to 8. The mixture was extracted with EtOAc (3 x 50 mL) and the combined c extracts were washed with brine (20 mL), dried 4) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 9% MeOH/DCM as the eluent. The ing solid was dissolved in a mixture of THF (10 mL) and MeCN (10 mL) and a solution of 4N HCI in dioxane (0.5 mL) was added and the resulting mixture stirred for 30 minutes. The solvents were evaporated under reduced pressure to leave a solid that was triturated with Et20 (3 x 10 mL) and dried to give the title compound (0.18 g, 60%) as a pale yellow solid.
Synthetic Route T (Illustrated with reference to Example 149: Example 149 - 5- 4- 2R eth l rrolidin lmeth lmethox - hen l-1H- razol lamino razinecarbonitrile h drochloride 149A. tert-Butyl (2R)—2-formylpyrrolidinecarboxylate Dess-Martin periodinane (15.9 g, 37.4 mmol) was added in portions over 5 minutes to a stirred solution of tert—butyl (2R)—2-(hydroxymethyl)pyrrolidinecarboxylate (5.0 g, 24.9 mmol) in DCM (75 mL) under a nitrogen atmosphere. The resulting suspension was d for one hour then filtered through a pad of celite washing with DCM (100 mL). The filtrate was evaporated under reduced pressure to leave a residue which was purified by column tography on neutral silica gel using 12% EtOAc/hexanes as the eluent to give the title compound (4.4 g, 89%). 149B. tert-But l 2R E - -tol n lh drazono meth l rrolidinecarbox late 4-Methylbenzenesulfonohydrazide (3.7 g, 22.1 mmol) was added to a stirred solution of utyl -formylpyrrolidinecarboxylate (4.4 g, 22.1 mmol) in EtOH (45 mL) and the resulting solution was heated to 90°C for 2 hours. The mixture was allowed to cool to room temperature and the solvents evaporated under redcuced pressure to leave a solid that was recrystallized from EtOH to give the title compound (5.1 g, 63%). 149C. tert-Butyl (2R)—2-|(4-acetylmethoxy—phenyl)methyl|pyrrolidinecarboxylate A mixture of tert-butyl (2R)—2-[(E)-(p-tolylsulfonylhydrazono)methyl]pyrrolidine carboxylate (1.7 g, 4.6 mmol), (3-methoxymethoxycarbonyl-phenyl)boronic acid (1.16 g, 5.5 mmol) and K2C03 (0.95 g, 6.9 mmol) in 1,4-dioxane ( 45 mL) was stirred at 110°C for 3 hours. The cooled reaction mixture was evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 13% hexanes as the eluent to give the title compound (1.4 g, 87%). 149D. ut l 2R 4- 2-c anoacet lmethox - hen lmeth l rrolidine carboxylate A solution of LiHMDS (1.0M in hexane, 14 mL, 14.0 mmol) was added dropwise over minutes to a stirred solution of acetonitrile (0.8 g, 20.0 mmol) in dry THF (70 mL) at -78°C under a nitrogen atmosphere. ng was continued for 30 minutes then a solution of tert-butyl (2R)—2-[(4-acetylmethoxy-phenyl)methyl]pyrrolidine carboxylate (1.4 g, 4.0 mmol) in THF (70 mL) was added dropwise over 30 minutes maintaining the temperature at -78°C. The mixture was d at -78°C for 30 minutes then allowed to warm to room temperature and stirring ued for 30 minutes. The mixture was poured into cold saturated ammonium chloride solution (50 mL) and extracted with EtOAc (4 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2804) and evaporated under reduced pressure to leave the title nd (1.9 g, 98%) which was used without further cation. 149E. tert—But l 2R 4- 3-amino-1H- razol lmethox - phenyl|methyl|pyrrolidinecarboxylate A solution of utyl -[[4-(2-cyanoacetyl)methoxy-phenyl]methyl]pyrrolidine- 1-carboxylate (1.8 g, 5.2 mmol) and hydrazine hydrate (99% in water, 1.04 g, 20.8 mmol) in ethanol (20 mL) was heated to reflux for 16 hours. The mixture was d to cool to room temperature and the solvents evaporated under reduced pressure to leave a residue which was ed by column chromatography on neutral silica gel using 2% MeOH/CHCI3 as the eluent to give the title compound (1.0 g, 52%). 149F. tert—But l 2R 4- 3- 5-c ano razin lamino -1H- 5- lmethox - phenyl|methyl|pyrrolidinecarboxylate A stirred solution of tert-butyl (2R)—2-[[4—(3-amino-1H-pyrazolyl)methoxy- phenyl]methyl]pyrrolidinecarboxylate (1.0 g, 2.7 mmol), diisopropylethylamine (1.4 mL, 8.1 mmol) and 5-bromopyrazinecarbonitrile (1.5 g, 8.1 mmol) in dry 1,4-dioxane (11 mL) was heated to 70°C for 16 hours. After cooling to room temperature the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2804) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 45% EtOAc/hexanes as the eluent to give the title compound (0.70 g, 55%). 149G. 5- 5- 2-Methox 2R - rrolidin lmeth l hen l-1H- razol lamino razinecarbonitrile h drochloride 4N HCI in dioxane (2 mL) was added to a stirred solution of utyl (2R)—2-[[4-[3-[(5- cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl]methyl]pyrrolidine carboxylate (0.70 g, 1.4 mmol) in a mixture of dry MeCN (10 mL) and dry THF (10 mL) and the resulting mixture d at room temperature for 2 hours. The solvents were evaporated under reduced pressure to leave a solid that was triturated with EtOAc (3 x 2 mL) and dried to give the title compound (0.55 g, 91%) as an off-white solid. 149H. 5- 5- 4- 2R Eth l rrolidin lmeth lmethox - hen l-1H- razol lamino razinecarbonitrile h drochloride ropylethylamine (0.18 mL, 1.0 mmol) was added to a stirred suspension of 5-[[5- [2-methoxy[[(2R)-pyrrolidinyl]methyl]phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile hydrochloride (0.22 g, 0.53 mmol) in a mixture of MeOH (5 mL) and THF (5 mL) and the mixture stirred for 20 minutes at room temperature under a nitrogen atmosphere. Acetaldehyde (0.12 mL, 2.1 mmol) was added and the mixture stirred for a further 30 minutes then the mixture was cooled to 0°C and Ac)3 (0.36 g, 1.7 mmol) was added in portions over 10 minutes. The mixture was allowed to warm to room temperature and stirred for a r one hour then poured into ter (30 mL) and solid NaHC03 was added to adjust the pH of the on to 8. The mixture was extracted with EtOAc (5 x 50 mL) and the combined organic extracts were washed with brine (20 mL), dried (Na2804) and ated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 4% MeOH/DCM as the e|uent. The resulting solid was dissolved in a mixture of THF (5 mL) and MeCN (5 mL) and a on of 4N HCI in dioxane (0.2 mL) was added and the resulting mixture stirred for 30 minutes. The ts were evaporated under reduced re to leave a solid that was triturated with EtZO (3 x 10 mL) and dried to give the title compound (84 mg, 36%) as a light brown solid.
BIOLOGICAL ACTIVITY EXAMPLE A Chk-1 Kinase Inhibiting Activity The compounds of the invention were tested for activity against Chk—1 kinase using the materials and protocols set out below.
Reaction Buffer: Base Reaction buffer: 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO *Required cofactors are added individually to each kinase reaction Reaction Procedure: (i) Prepare indicated substrate in freshly prepared Base Reaction Buffer (ii) Deliver any required cofactors to the substrate solution above (iii) r indicated kinase into the substrate solution and gently mix (iv) Deliver compounds in DMSO into the kinase reaction mixture (v) Deliver 33P-ATP (specific activity 0.01 uCi/ul final) into the reaction mixture to te the reaction. (vi) Incubate kinase reaction for 120 minutes at room ature (vii) Reactions are spotted onto P81 ion exchange paper (Whatman # 3698-915) (viii) Wash filters extensively in 0.1% phosphoric acid. (ix) Dry s and measure counts in scintillation counter Kinase information: CHK-1 — Genbank Accession # AF016582 Recombinant full length construct, N-terminal GST tagged, purified from insect cells.
No l measures were taken to activate this kinase.
Final concentration in assay = 0.5 nM Substrate: CHKtide Peptide sequence: [KKKVSRSGLYRSPSMPENLNRPR] Final concentration in assay = 20uM No additional cofactors are added to the reaction mixture From the results obtained by following the above protocol, the |C50 values against Chk- 1 kinase of each of the compounds of es 1-153 were determined and these are shown in Table 3.
Table 3 o M 0 M 0 2 0.0027 56 0.183 110 0.0000069 0.00021 0.000071 0.0000052 0.0020 59 0.000071 113 0.00027 “ 0.000097 m. 0.00010 0.00020 0.000058 62 84 116 0.000077 .0- 0.000077 0.000052 0.000027 0.011 0.00015 118 0.000022 Table 3 Examole IC . M Examole IC . M Examole IC . M 0.000048 0.000022 ND 13 0.00059 67 0.0018 121 0.00015 0.000020 “ 0.0029 0.00014 16 0.000085 70 0.010 124 0.00025 0.00029 0.00028 19 0.00029 73 0.00028 127 44 9 000035 0000023 22 0.000026 76 0.00011 130 0.000025 0.00012 0.00014 0.00010 0.014 79 0.00040 133 0.00012 ————E_000011 28 0.00013 82 0.000016 136 0.000053 29 0.000068 83 0.00011 137 0.000048 0.017 84 0.00014 138 0.000041 31 0.00037 85 0.00025 139 0.000027 32 0.00026 86 2 140 0.000021 33 0.000074 87 0.000059 141 0.000019 34 0.00014 88 79 142 0.000082 0.00014 89 0.000051 143 0.000021 36 95 90 0.000058 144 0.000026 37 0.00011 91 0.00033 145 0.0000084 38 0.00088 92 0.000016 146 0.000012 39 0.00018 93 0.000016 147 0.00016 40 0.00014 94 0.00018 148 0.000031 41 0.00051 95 5 149 ND 42 0.00021 96 0.00040 150 ND 43 0.00073 97 0.0011 151 ND 44 9 98 0.0018 152 ND 45 >01 99 5 153 0.0038 46 0.000054 100 0.000053 47 0.00023 101 0.000055 48 0.0015 102 0.00016 49 0.036 103 0.000109 50 0.020 104 0.00012 51 0.0063 105 0.000 52 0.00046 106 0.00017 53 0.0031 107 0.000081 54 0.00012 108 0.000043 ND = Not determined 1 002 EXAMPLE B Gemcitabine Combination Cell Assay Exponentially growing MIA PaCa-2 (ATCC CRL-1420) cells are treated with trypsin to remove cells from the plate surface. Approximately 10,000 cells/well are plated in 96 well plates in RPMI containing 10% fetal bovine serum, 1% sodium pyruvate and 1% L-GlutaMax. Cells are allowed to adhere to the plate surface overnight. Serial half-log ons of Chk1 inhibitor test compounds and gemcitabine are made with a final highest concentration of 3000nM and 100nM, respectively. Chk1 inhibitors and gemcitabine are combined so that each tration of Chk1 inhibitor is added to each concentration of abine. Each drug is also tested as a single agent. Drugs are added to adherent cells (in ate) and incubated for 72h. At 72h the cells are treated with Promega Cell Titer Glo reagent for approximately 15 minutes.
Luminescence (relative light units, RLU) is recorded using a BMG Polarstar Omega plate reader. The single agent concentration that results in a 50% reduction in total signal (IC50) is calculated using PRISM software and a four-parameter non-linear regression curve fit. For combination studies the RLUs are plotted using PRISM on an XY plot with the gemcitabine concentration on the X axis and RLU on the Y axis. The RLU for each concentration of Chk1 tor is plotted as a function of gemcitabine concentration. The |C50 for gemcitabine alone and at each tration of Chk1 is determined using a four-parameter non-linear regression curve fit. The approximate concentration of Chk1 inhibitor that s in a two and ten-fold reduction in the IC50 of abine alone is calculated as an indication of synergistic potency.
From the results obtained by following the above protocol, the |C50 values against MIAPaca-2 cells of the Chk1 inhibitor alone (Chk1 IC50), the approximate concentration of Chk1 tor that results in a two-fold (2xLS) and a 10-fold (10xLS) reduction in the leo of gemcitabine alone of each of the compounds of Examples 1-154 are shown in Table 4.
Chk1 2st Chk1 2st 1411 100 1000 79 478 3 275 1 0 100 80 36 <3 ND N ND ND ND ND 82 74 <3 338 30 300 83 107 <3 Table4 Chk1 2st 10st Chk1 2st 10st e Examp'e |C5o(nM) (nM) (nM) |C50(nM) (nM) (nM) 7 208 10 ~200 84 82 <100 8 259 10 ~200 85 138 3 100 ——“__<100 >3000 1000 >3000 87 540 10 300 11 214 3 <100 88 424 10 300 ——E§-__100 13 >3000 ~20 300 90 <300 14 894 <3 ~50 91 411 <3 <100 17 1819 10 300 94 475 3 100 <100 1111 ~5 100 97 1495 10 300 ——“__<1000 22 88 <3 <30 99 30 23 288 <3 <100 100 247 3 <100 24 934 <100 >3000 300 >3000 10 300 28 5585 1000 >3000 103 184 3 300 27 5753 100 28 279 <3 <100 30 1000 29 178 3 100 108 441 3 100 31 838 3 100 77 <3 30 32 784 30 300 109 82 <3 <30 33 62 100 34 183 3 100 <3 100 217 3 100 112 253 <3 100 38 2754 100 1000 115 515 3 <300 <3 30 100 41 1114 30 300 118 1198 3 300 42 73 <300 43 1329 100 1000 3 100 44 1284 100 1000 121 177 3 <100 <100 47 235 3 100 124 322 3 <300 <300 49 3588 1000 <3000 3 <100 50 >3000 300 3000 127 189 <3 <100 <100 PCT/U82015/015030 Table4 Chk1 2st 10st Chk1 2st 10st Examp'e Examp'e |C50(nM) (nM) (nM) |C50(nM) (nM) (nM) 53 2296 100 1000 130 142 3 <100 55 >3000 1000 >3000 <300 56 >3000 1000 >3000 133 139 <3 30 56 676 30 300 <3 100 59 263 3 100 136 226 3 100 <100 62 675 10 300 139 743 10 300 <300 65 144 3 <100 142 306 3 100 <300 67 1320 100 1000 <300 66 1364 100 1000 145 267 <3 <100 70 2621 300 3000 300 71 >3000 >3000 >3000 146 254 <3 <100 72 173 30 74 262 3 100 151 101 <3 <30 77 164 <3 <100 154 395 3 100 ND = Not determined PHARMACEUTICAL FORMULATIONS (i) Tablet Formulation A tablet ition containing a compound of the formula (I) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner. 1 00 O1 (ii) Capsule Formulation A capsule formulation is prepared by mixing 100 mg of a compound of the formula (I) with 100 mg lactose and filling the resulting mixture into standard opaque hard gelatin capsules. (iii) lnjectable Formulation | A parenteral composition for administration by injection can be prepared by dissolving a compound of the formula (0) or formula (1) (e.g. in a salt form) in water containing % propylene glycol to give a concentration of active compound of 1.5 % by weight.
The solution is then sterilised by tion, filled into an ampoule and sealed. iv ln'ectable Formulation II A parenteral ition for injection is prepared by ving in water a compound of the formula (0) or formula (1) (e.g. in salt form) (2 mg/ml) and mannitol (50 mg/ml), sterile ing the solution and filling into sealable 1 ml vials or ampoules. v ln'ectable formulation ||| Aformulation for i.v. delivery by injection or infusion can be prepared by dissolving the nd of formula (0) orformula (1) (e.g. in a salt form) in water at 20 mg/ml. The vial is then sealed and sterilised by autoclaving. vi) lnjectable formulation IV Aformulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of formula (0) or formula (1) (e.g. in a salt form) in water ning a buffer (e.g. 0.2 M acetate pH 4.6) at 20mg/ml. The vial is then sealed and sterilised by autoclaving. (vii) aneous Injection Formulation A composition for sub-cutaneous administration is prepared by mixing a compound of the a (0) or formula (1 ) with ceutical grade corn oil to give a concentration of 5 mg/ml. The composition is ised and filled into a suitable container. viii) Lyophilised ation Aliquots of formulated compound of formula (0) or a (1) are put into 50 ml vials and lized. During lyophilisation, the compositions are frozen using a one-step freezing protocol at (—45 °C). The temperature is raised to —10 °C for annealing, then d to freezing at —45 °C, followed by primary drying at +25 °C for approximately 3400 minutes, followed by a secondary drying with sed steps if temperature to 50 °C. The pressure during primary and secondary drying is set at 80 millitor.
Eguivalents The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are ed to be embraced by this application.

Claims (18)

1. A compound of the formula (0): or a salt, N-oxide or tautomer thereof, n: T1 and T2 are both N; R1 is selected from hydrogen, fluorine, C1-4 hydrocarbyl and C1-4 hydrocarbyloxy; R2 is selected from hydrogen, fluorine, C1-4 arbyl and C1-4 hydrocarbyloxy; R3 is selected from hydrogen, , fluorine, chlorine and bromine; one of M1 and M2 is a group R4 selected from hydrogen, methyl, fluorine, chlorine and bromine; and the other of M1 and M2 is a moiety –A-R7; R5 is selected from hydrogen, cyano, C1-3 alkyl, cyclopropyl, chlorine, carboxy, and C1 alkoxy-carbonyl; R6 is selected from hydrogen, fluorine, C1-4 alkyl; and C1-4 alkoxy optionally tuted with NRdRe where Rd and Re are the same or different and each is selected from hydrogen and C1-4 alkyl, or NRdRe forms a 4 to 7 membered ted heterocyclic ring optionally containing a second heteroatom ring member selected from N, O and S and oxidized forms of S, the saturated heterocyclic ring being ally substituted with one or more substituents selected from oxo, methyl, hydroxy and fluorine; A is selected from: (i) a bond; (ii) (CRpRq)x where Rp and Rq are each independently hydrogen or methyl and x is 1 to 4; (iii) an oxygen atom; (iv) a group NRr wherein Rr is hydrogen or methyl; and (v) a saturated chain of 2 to 10 chain s in length containing at least one carbon atom chain member, at least one heteroatom chain member selected from nitrogen and oxygen, and optionally one or more further carbon atom chain members and/or heteroatom chain members selected from nitrogen, oxygen, sulphur, nyl and sulphonyl; the saturated chain being optionally substituted with one or more substituents selected from =O, C1-4 hydrocarbyl, fluoro-C1-4 arbyl, y- C1-4 hydrocarbyl, C1alkoxy-C1-4 hydrocarbyl, and ne wherein two hydrocarbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members; R7 is a group Cyc1 wherein Cyc1 is a carbocyclic or heterocyclic non-aromatic group of 3 to 10 ring members of which 0 to 3 are selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic ic or non-aromatic group being optionally substituted with one or more substituents R8; R8 is selected from: • halogen; • oxo; • cyano; • nitro; • a carbocyclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members ed from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; and • a group Ra-Rb; Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NRc, SO2NRc or NRcSO2; Rb is: • hydrogen; • a carbocyclic and heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members ed from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; • an acyclic C1-12 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the yclic or heterocyclic group being optionally substituted with one or more substituents R9; n one or more but not all of the carbon atoms of the acyclic C1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C(X2), C(X2)X1 or X1C(X2)X1; Rc is: • hydrogen; • a carbocyclic and heterocyclic group having from 3 to 12 ring s, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the yclic or heterocyclic group being optionally substituted with one or more substituents R9; • an acyclic C1-12 hydrocarbyl group optionally tuted with one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and ed forms thereof, the carbocyclic or heterocyclic group being optionally tuted with one or more substituents R9; wherein one or more but not all of the carbon atoms of the acyclic C1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NH, N-C1-4 alkyl, C(O)O, OC(O), NH(CO), C(O)NH, NH(CO)NH, N(C1-4 alkyl)C(O), C(O)N(C1-4 alkyl) X1 is O, S or NRc; and X2 is =O, =S or =NRc; wherein R9 is selected from R8 provided that when the substituents R9 n a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group is unsubstituted or substituted with one or more substituents R10; R10 is selected from halogen, oxo, cyano, and an acyclic C1-6 hydrocarbyl group optionally tuted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-2 alkylamino; wherein one but not all of the carbon atoms of the c C1-6 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NH or NMe; R11 is selected from amino, Hyd1, NH-Hyd1, N(Hyd1)2; and Cyc1; Hyd1 is a non-aromatic C1-6 hydrocarbyl group optionally substituted by one or more substituents ed from halogen, cyano, hydroxy, amino and Cyc1, wherein one or two of the carbon atoms of the non-aromatic C1-6 hydrocarbyl group may optionally be replaced by O, NH, N-Hyd2, C(=O), S, SO or SO2, provided that at least one carbon atom of the hydrocarbyl group remains; Hyd2 is a C1-4 hydrocarbyl group; and wherein in any group consisting of or containing a hydrocarbyl moiety, the hydrocarbyl moiety is a hydrocarbon group optionally containing one or more single, double or triple carbon-carbon bonds or combinations thereof.
2. A compound according to claim 1 having the a (1): or a salt, N-oxide or tautomer thereof, wherein: A is selected from: (i) a bond; and (ii) a saturated chain of 2 to 10 chain members in length containing at least one carbon atom chain member, at least one heteroatom chain member selected from nitrogen and , and optionally one or more further carbon atom chain members and/or heteroatom chain members selected from nitrogen, oxygen, r, sulphinyl and sulphonyl; the ted chain being optionally substituted with one or more substituents ed from =O, C1-4 hydrocarbyl and ne wherein two hydrocarbyl substituents on the same carbon atom may optionally link to form a ring of three to five ring members; R1 is selected from hydrogen, fluorine, C1-4 arbyl and C1-4 hydrocarbyloxy; R2 is selected from hydrogen, fluorine, C1-4 hydrocarbyl and C1-4 hydrocarbyloxy; R3 is selected from hydrogen, methyl, chlorine and bromine; R4 is selected from hydrogen, methyl, chlorine and bromine; R5 is selected from hydrogen, cyano and methyl; R6 is selected from hydrogen, C1-4 alkyl; and C1-4 alkoxy optionally substituted with NRdRe where Rd and Re are the same or different and each is selected from hydrogen and C1-4 alkyl, or NRdRe forms a 4 to 7 membered saturated heterocyclic ring optionally containing a second heteroatom ring member ed from N, O and S and ed forms of S, the saturated heterocyclic ring being optionally substituted with one or more substituents selected from oxo, methyl, hydroxy and fluorine; R7 is a group Cyc1 wherein Cyc1 is a carbocyclic or heterocyclic non-aromatic group of 3 to 10 ring members of which 0 to 3 are ed from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic aromatic or non-aromatic group being optionally substituted with one or more substituents R8; R8 is selected from: • halogen; • oxo; • cyano; • nitro; • a yclic or heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; and • a group Ra-Rb; Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NRc, SO2NRc or NRcSO2; Rb is: • hydrogen; • a carbocyclic and heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and ed forms thereof, the carbocyclic or cyclic group being optionally substituted with one or more substituents R9; • an acyclic C1-12 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-8 omatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; n one or more but not all of the carbon atoms of the acyclic C1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C(X2), C(X2)X1 or X1C(X2)X1; Rc is: • hydrogen; • a carbocyclic and heterocyclic group having from 3 to 12 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R9; • an acyclic C1-12 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; mono- or di-C1-8 non-aromatic hydrocarbylamino; and carbocyclic and heterocyclic groups having from 3 to 12 ring s, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S and oxidised forms thereof, the carbocyclic or heterocyclic group being ally substituted with one or more substituents R9; wherein one or more but not all of the carbon atoms of the acyclic C1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NH, N-C1-4 alkyl, C(O)O, OC(O), NH(CO), , NH(CO)NH, N(C1-4 C(O), C(O)N(C1-4 alkyl) X1 is O, S or NRc; and X2 is =O, =S or =NRc; wherein R9 is selected from R8 provided that when the substituents R9 contain a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group is unsubstituted or substituted with one or more substituents R10; R10 is selected from halogen, oxo, cyano, and an c C1-6 hydrocarbyl group optionally substituted with one or more tuents selected from hydroxy; oxo; n; cyano;carboxy; amino; mono- or di-C1-2 alkylamino; wherein one but not all of the carbon atoms of the acyclic C1-6 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NH or NMe; R11 is selected from amino, Hyd1, NH-Hyd1, N(Hyd1)2; and Cyc1; Hyd1 is a non-aromatic C1-6 hydrocarbyl group optionally substituted by one or more substituents ed from halogen, cyano, hydroxy, amino and Cyc1, wherein one or two of the carbon atoms of the non-aromatic C1-6 hydrocarbyl group may optionally be replaced by O, NH, N-Hyd2, C(=O), S, SO or SO2, provided that at least one carbon atom of the hydrocarbyl group remains; Hyd2 is a C1-4 hydrocarbyl group; and wherein in any group consisting of or containing a hydrocarbyl moiety, the hydrocarbyl moiety is a hydrocarbon group optionally containing one or more single, double or triple carbon-carbon bonds or combinations thereof.
3. A compound according to claim 1 or claim 2 wherein R1 is selected from hydrogen and methoxy.
4. A nd according to claim 1 wherein R2 is selected from hydrogen and methoxy.
5. A compound according to claim 1 wherein both of R3 and R4 are hydrogen.
6. A compound according to claim 1 wherein R5 is selected from hydrogen and cyano.
7. A compound according to claim 6 wherein R5 is cyano.
8. A compound according to claim 1 wherein R6 is hydrogen.
9. A compound according to claim 1 wherein A is selected from a bond; -NHCH2- ; -NH-(CH2)-; -NH-(CH2)-(CH2)-; -(CH2)-NH-(CH2)-; and -NH-(CHMe)- and R7 is a group Cyc1.
10. A compound according to claim 1 wherein A is a bond.
11. A nd according to claim 1 wherein R7 is piperidine optionally substituted with one or more substituents R8.
12. A compound according to claim 11 wherein R8 is selected from fluorine, C1-3 alkyl, cyclopropylcarbonyl, dimethylaminoacetyl, aminocarbonylmethyl and hydroxyethyl.
13. A compound according to claim 1 or claim 2 n: R1 is methoxy; R2 is hydrogen or methoxy; R3 is hydrogen; R4 is en; R5 is cyano; R6 is hydrogen; A is a bond; and R7 is piperidine optionally substituted with one of more substituents R8.
14. A compound according to claim 1 or claim 2 which is selected from: 2-methoxy[(2-morpholinyl-ethylamino)-methyl]-phenyl}-1H-pyrazol ylamino)-pyrazinecarbonitrile (e.g. the hydrochloride salt); (5-{2-methoxy[(2-morpholinyl-ethylamino)-methyl]-phenyl}-1H-pyrazolyl)- pyrazinyl-amine (e.g. the hydrochloride salt); 5-{5-[2-methoxy(1-methyl-piperidinyl)-phenyl]-1H-pyrazolylamino}-pyrazine carbonitrile (e.g. the hydrochloride salt); 4-{[(1-cyclopropane-carbonyl-piperidinylmethyl)-amino]-methyl}methoxyphenyl )-1H-pyrazolylamino]-pyrazinecarbonitrile (e.g. the hydrochloride salt); N-[[4-[3-[(5-cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl]methyl] ropanecarboxamide; 5-[[5-[2-methoxy[(tetrahydropyranylamino)methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[[methyl(2-morpholinoethyl)amino]methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy(2-morpholinoethylamino)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[4-[1-[2-(dimethylamino)acetyl]piperidyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[[[(1R)methylmorpholino-ethyl]amino]methyl]phenyl]-1H- pyrazolyl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(1,1-dimethylmorpholino-ethyl)amino]methyl]methoxy-phenyl]-1H-pyrazol- 3-yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile; 5-[[5-[2-fluoro(1-methylpiperidyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy(4-methylpiperazinyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy(4-methyl-1,4-diazepanyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; N-[5-[2-methoxy(1-methylpiperidyl)phenyl]-1H-pyrazolyl]methyl-pyrazin amine; [4-(1-methylpiperidyl)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[(1-methylpiperidyl)oxy]phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy[(1-methylpiperidyl)methoxy]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[5-fluoromethoxy(1-methylpiperidyl)phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[(3S)-pyrrolidinyl]oxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy(pyrrolidinylmethoxy)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy[(1-methylpyrrolidinyl)methoxy]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy(4-piperidylmethoxy)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy[[(1-methylpiperidyl)amino]methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-isopropoxy(1-methylpiperidyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy(3-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile; [2-methoxy(1-methylpiperidyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy(1-methylpiperidyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy[(3S)methylpyrrolidinyl]oxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-chloro-N-[5-[2-methoxy(4-piperidyl)phenyl]-1H-pyrazolyl]pyrazinamine; 5-chloro-N-[5-[2-methoxy(1-methylpiperidyl)phenyl]-1H-pyrazolyl]pyrazin amine; 5-[[5-(2-methoxypiperazinyl-phenyl)-1H-pyrazolyl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(2S,6S)-2,6-dimethylpiperidyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-(2-methoxytetrahydropyranyl-phenyl)-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-fluoro(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile; 5-[[5-[2-isopropoxy(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile; 5-[[5-[4-(1,4-diazepanyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; N-[5-[2-methoxy(4-piperidyl)phenyl]-1H-pyrazolyl]methyl-pyrazinamine; 5-[[5-[4-(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy(4-piperidyloxy)phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile; 5-[[5-[5-fluoromethoxy(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; [4-(1-ethylpiperidyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine itrile; 5-[[5-[4-(1-isopropylpiperidyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 2-[4-[4-[3-[(5-cyanopyrazinyl)amino]-1H-pyrazolyl]methoxy-phenyl] piperidyl]acetamide; 5-[[5-[2-methoxy[[methyl(tetrahydropyranyl)amino]methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-(4-fluoromethylpiperidyl)methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy(1-methylazetidinyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[4-(3-fluoromethyl-azetidinyl)methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[5-chloromethoxy(1-methylpiperidyl)phenyl]-1H-pyrazol no]pyrazinecarbonitrile; 5-[[5-[5-chloromethoxy(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[3-chloromethoxy(1-methylpiperidyl)phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[3-chloromethoxy(4-piperidyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy[(tetrahydrofuranylamino)methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[[methyl(tetrahydrofuranyl)amino]methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy(tetrahydropyranylmethylamino)phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy(tetrahydropyranylmethoxy)phenyl]-1H-pyrazolyl]amino]pyrazine- onitrile; 5-[[5-[4-(4-fluoropiperidyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[4-(3-fluoroazetidinyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy[(3R)methylpyrrolidinyl]oxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-(2-methoxymorpholino-phenyl)-1H-pyrazolyl]amino]pyrazinecarbonitrile; 5-[[5-[4-(4-ethylpiperazinyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[4-(4-isopropylpiperazinyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy[(3R)methylpiperazinyl]phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; 5-[[5-[4-(4-ethyl-1,4-diazepanyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[4-(4-isopropyl-1,4-diazepanyl)methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-(1-ethylfluoropiperidyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; 5-[[5-[4-(4-fluoroisopropylpiperidyl)methoxy-phenyl]-1H-pyrazol no]pyrazinecarbonitrile; 5-[[5-[4-(1-ethylfluoropiperidyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; 5-[[5-[4-(3-fluoroisopropylpiperidyl)methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; [2-methoxy[1-(2-methoxyethyl)piperidyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(cyclopropylamino)methyl]methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[4-[(3R)-3,4-dimethylpiperazinyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(3R)ethylmethyl-piperazinyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(3S)isopropylpyrrolidinyl]oxymethoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(3R)isopropylpyrrolidinyl]oxymethoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(3(R,S),4(R,S))fluoromethylpiperidyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-(3,3-difluoromethylpiperidyl)methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-(1-ethyl-3,3-difluoropiperidyl)methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[1-(2-hydroxyethyl)piperidyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy(pyrrolidinylmethyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy(morpholinomethyl)phenyl]-1H-pyrazolyl]amino]pyrazine itrile; 5-[[5-[2-methoxy[[(2R)methylpyrrolidinyl]methoxy]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile hydrochloride; 5-[[5-[2-methoxy[[(2S)methylpyrrolidinyl]methoxy]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile hydrochloride; 5-[[5-[4-[1-(2-fluoroethyl)piperidyl]methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; 5-[[5-[2-methoxy[(1-methylpiperidyl)methylamino]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(1-ethylpiperidyl)methylamino]methoxy-phenyl]-1H-pyrazol no]pyrazinecarbonitrile; 5-[[5-[4-[(1-isopropylpiperidyl)methylamino]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[(1-methylpiperidyl)amino]phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; [4-[(1-ethylpiperidyl)amino]methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; [4-[(1-isopropylpiperidyl)amino]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[(1-methylpiperidyl)oxymethyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(1-ethylpiperidyl)oxymethyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(1-isopropylpiperidyl)oxymethyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-(2-fluoromethoxypiperazinyl-phenyl)-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy[(2R)methylmorpholinyl]phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; 5-[[5-[2-methoxy[(2R)ethylmorpholinyl]phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2-methoxy[(2S)methylmorpholinyl]phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; 5-[[5-[2-methoxy[(2S)ethylmorpholinyl]phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-(2,6-dimethoxypiperazinyl-phenyl)-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[2,6-dimethoxy(4-methylpiperazinyl)phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[4-[[(3R)fluoropyrrolidinyl]methyl]methoxy-phenyl]-1H-pyrazol no]pyrazinecarbonitrile; 5-[[5-[2-methoxy[[(3S)methoxypyrrolidinyl]methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[[(3R)methoxypyrrolidinyl]methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(2R)ethylpyrrolidinyl]methoxy]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(2R)isopropylpyrrolidinyl]methoxy]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(2S)ethylpyrrolidinyl]methoxy]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(2S)isopropylpyrrolidinyl]methoxy]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(cyclopropylmethylamino) methyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[[[(3R)-tetrahydrofuranyl]amino]methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[[[(3S)-tetrahydrofuranyl]amino]methyl]phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; [4-[(3R)isopropylmethyl-piperazinyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(1-ethylpiperidyl)oxy]methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine itrile; 5-[[5-[4-[(1-isopropylpiperidyl)oxy]methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; 5-[[5-[4-(4-ethylpiperazinyl)fluoromethoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-(4-isopropylpiperazinyl)fluoromethoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(3S)ethylpyrrolidinyl]oxymethyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(3S)isopropylpyrrolidinyl]oxymethyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(3R)ethylpyrrolidinyl]oxymethyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(3R)isopropylpyrrolidinyl]oxymethyl]methoxy-phenyl]-1H-pyrazol no]pyrazinecarbonitrile; 5-[[5-[4-(4-isobutylpiperazinyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[4-[(1-ethylpiperidyl)methyl]methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; 5-[[5-[4-[(1-isopropylpiperidyl)methyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(1-ethylpiperidyl)methyl-methyl-amino]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(2R)isopropylmorpholinyl]methoxy-phenyl]-1H-pyrazol no]pyrazinecarbonitrile; 5-[[5-[4-[(1-isopropylpiperidyl)methyl-methyl-amino]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(2R)ethylpyrrolidinyl]methyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[(2S)isopropylmorpholinyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(2R)isopropylpyrrolidinyl]methyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(2S)ethylpyrrolidinyl]methyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-(2-methoxypiperazinyl-phenyl)-1H-pyrazolyl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(2S)isopropylpyrrolidinyl]methyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(3S)isopropylpyrrolidinyl]amino]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(3R)isopropylpyrrolidinyl]amino]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-[[(3R)ethylpyrrolidinyl]amino]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; [4-[[(3S)ethylpyrrolidinyl]amino]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[2-methoxy[(3S)methylpiperazinyl]phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; 5-[[5-[4-[(3R)ethylpiperazinyl]methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine carbonitrile; 5-[[5-[4-[(3S)isopropylpiperazinyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; [4-[(3R)isopropylpiperazinyl]methoxy-phenyl]-1H-pyrazol yl]amino]pyrazinecarbonitrile; 5-[[5-[4-(3,3-dimethylpiperazinyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazine- 2-carbonitrile; and salts and tautomers thereof.
15. A compound according to claim 1 or claim 2 which is 5-[[5-[4-(4-fluoromethyl piperidyl)methoxy-phenyl]-1H-pyrazolyl]amino]pyrazinecarbonitrile or a salt thereof.
16. A pharmaceutical composition comprising a nd as defined in any one of claims 1 to 15 and a pharmaceutically acceptable excipient.
17. A combination comprising a nd as defined in any one of claims 1 to 15 and another chemotherapeutic agent, for example an anticancer drug.
18. Use of a compound as defined in any one of claims 1 to 15, optionally in combination with another chemotherapeutic agent or radiotherapy, in the manufacture of a medicament for the treatment of a proliferative disease.
NZ723051A 2014-02-10 2015-02-09 Pharmaceutical compounds NZ723051B2 (en)

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PCT/US2015/015030 WO2015120390A1 (en) 2014-02-10 2015-02-09 Pharmaceutical compounds

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