WO2011130628A1 - Traitement de cancers présentant des mutations k-ras - Google Patents

Traitement de cancers présentant des mutations k-ras Download PDF

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WO2011130628A1
WO2011130628A1 PCT/US2011/032683 US2011032683W WO2011130628A1 WO 2011130628 A1 WO2011130628 A1 WO 2011130628A1 US 2011032683 W US2011032683 W US 2011032683W WO 2011130628 A1 WO2011130628 A1 WO 2011130628A1
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compound
mmol
substituted
methyl
amino
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PCT/US2011/032683
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Rudi Bao
Chengjung Lai
Changgeng Qian
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Curis, Inc.
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Priority to CN2011800290564A priority Critical patent/CN102970868A/zh
Priority to AU2011239537A priority patent/AU2011239537A1/en
Priority to EP11769663.3A priority patent/EP2557923A4/fr
Priority to CA2795952A priority patent/CA2795952A1/fr
Priority to JP2013505177A priority patent/JP2013525308A/ja
Publication of WO2011130628A1 publication Critical patent/WO2011130628A1/fr
Priority to US13/652,152 priority patent/US20130102595A1/en

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    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the members of the ras gene family encode membrane-bound proteins of about 21 kD which are referred to as p21-ras. These proteins are believed to relay growth and differentiation signals from activated receptors to intracellular protein kinases.
  • the ras gene family includes K-ras, H-ras and N-ras.
  • the ras genes are proto-oncogenes; mutated ras genes are found in a variety of cancer types. These mutants typically exhibit a single base pair substitution, usually in codon 12, 13, 146 or 161, which leads to an expressed p21-ras product with a point mutation at the corresponding amino acid position.
  • codon 12 codes for glycine, but in the most common mutations this codon codes for aspartic acid, valine, arginine or cysteine (Mu et al., World J. Gastroenterol. 2004, 10: 471-475). While wild-type p21-ras is activated only by an activated receptor and deactivated after downstream signaling, the p21-ras mutants are constitutively active, and thus stimulate growth and differentiation continuously, in the absence of a signal (Bos, J.L., Cancer Res. 1989, 49: 4682-4689).
  • K-ras mutations occur in variety of cancers.
  • K-ras mutations are prevalent in pancreatic, colorectal, thyroid, lung, cervical and endometrial cancer.
  • K- ras mutations have also been identified in certain precancerous conditions, such as myelodysplasia syndrome and adenomas of the thyroid and the colon.
  • the present invention provides methods and compositions for treating cancers and precancerous conditions which are characterized by proliferating cells having a K-ras mutation.
  • the invention provides a method of inhibiting the proliferation of cells having a K-ras mutation, such as pre-cancerous cells or cancer cells.
  • the method comprises the steps of (1) identifying cells which have a K-ras mutation; (2) inhibiting the PI3 kinase signaling pathway in the cells; and (3) inhibiting HDAC activity in the cells.
  • the PI3 kinase signaling pathway and HDAC activity are inhibited by contacting the cells with a first compound which inhibits PI3 kinase activity and a second compound which inhibits HDAC activity.
  • the PI3 kinase signaling pathway and HDAC activity are inhibited by contacting the cells with a compound which inhibits both PI3 kinase activity and HDAC activity.
  • the invention provides a method of treating cancer or a precancerous condition associated with a K-ras mutation in a subject in need thereof.
  • the method comprises the steps of (1) identifying a subject having a cancer or a precancerous condition associated with a K-ras mutation; (2) administering to the subject (i) an amount of a PI3 kinase inhibitor and (ii) an amount of an HDAC inhibitor, where the amount of a compound which inhibits PI3 kinase and the amount of a compound which inhibits HDAC together are therapeutically effective.
  • the PI3 kinase inhibitor and the HDAC inhibitor can be administered simultaneously or sequentially and as separate compositions or combined in a single composition.
  • the invention provides a method of treating a cancer or a precancerous condition associated with mutated K-ras in a subject in need thereof.
  • the method comprises the steps of (1) identifying a subject having a cancer or precancerous condition associated with a K-ras mutation; (2) administering to the subject an effective amount of a compound is a PI3 kinase inhibitor and an HDAC inhibitor.
  • the invention additionally includes compounds and compositions for use in the disclosed methods.
  • Phosphoinositides which are phosphorylated derivatives of
  • PI3-kinases phosphorylate
  • Phosphorylated PKB inhibits apoptosis-inducing proteins such as FKHR, Bad, and caspases, and is thought to play an important role in cancer progression.
  • the PBKs are divided into classes I-III, and class I is further subclassified into classes la and lb.
  • class la enzymes are thought to play the most important role in cell proliferation in response to growth factor-tyrosine kinase pathway activation (Hayakawa et. al, Bioorganic & Medicinal Chemistry 14 6847-6858, 2006).
  • Three frequent mutations in cancer constitutively activate PBKa and, when expressed in cells, they drive the oncogenic transformation and chronic activation of downstream signalling by molecules such as PKB, S6K and 4E bpl that is commonly seen in cancer cells. (Stephens et. al., Current Opinion in Pharmacology, 5(4) 357-365, 2005). As such, PI3-kinases are attractive targets for the treatment of proliferative diseases.
  • PI3 -kinase inhibitors There are several known PI3 -kinase inhibitors including Wortmannin and
  • wortmannin is a potent PI3K inhibitor with a low nanomolar IC 50 value, it has low in vivo anti-tumor activity. (Hayakawa et al, Bioorg Med Chem 14(20), 6847-6858 (2006)). Recently, a group of morpholine substituted quinazoline,
  • pyridopyrimidine and thienopyrimidine compounds have been reported to be effective in inhibiting PBkinase pi 10a.
  • Oral dosage of a morpholine substituted thienopyrimidine compound has shown tumor suppression in glioblastoma xenografts in vivo.
  • the following publications disclose a series of thienopyrimidine,
  • pyridopyrimidine and quinazoline based PI3-Kinase inhibitors WO 2008/073785; WO 2008/070740; WO 2007/127183; U.S. Patent Publication 20080242665.
  • Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed histone deacetylases (HDACs).
  • HDAC's are represented by 18 genes in humans and are divided into four distinct classes (JMol Biol, 2004, 338: 1, 17- 31).
  • class I HDAC's HDACl-3, and HDAC8 are related to yeast RPD3 HDAC
  • class 2 HDAC4-7, HDAC9 and HDAC10 related to yeast HDA1
  • HDAC11 HDAC11
  • class 3 a distinct class encompassing the sirtuins which are related to yeast Sir2.
  • Csordas Biochem. J, 1990, 286: 23-38 teaches that histones are subject to post- translational acetylation of the, ⁇ -amino groups of N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HATl).
  • HATl histone acetyl transferase
  • Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure.
  • access of transcription factors to chromatin templates is enhanced by histone hyperacetylation, and enrichment in underacetylated histone H4 has been found in transcriptionally silent regions of the genome (Taunton et al., Science, 1996, 272:408-411).
  • transcriptional silencing due to histone modification can lead to oncogenic transformation and cancer.
  • HDAC inhibitors include hydroxamic acid derivatives, Suberoylanilide hydroxamic acid (SAHA), PXD101 and LAQ824, are currently in the clinical development.
  • SAHA Suberoylanilide hydroxamic acid
  • benzamide MS-275, MGCD0103 and CI-994 have reached clinical trials. Mourne et al. (Abstract #4725, AACR 2005), demonstrate that thiophenyl modification of benzamides significantly enhance HDAC inhibitory activity against HDAC 1.
  • the present invention provides methods for treating cancers and precancerous conditions associated with mutated K-ras.
  • the invention relates to the discovery that such cancers are particularly susceptible to the effects of concomitant inhibition of PI3 kinase and HDAC.
  • the invention provides a method of treating a cancer comprising cancer cells having a K-ras mutation comprising the step of concurrently inhibiting PI3 kinase activity and inhibiting HDAC activity within said the cancer cells.
  • a cancer cell or cells associated with a precancerous condition are said to have a mutated K-ras gene if the gene for K-ras within the cell has been mutated relative to the corresponding wild type gene in such a way as to produce a gene product having an amino acid sequence which differs from that of the wild-type K-ras protein.
  • the mutated gene has one or more nucleotide sunbstitutions in one or more codons and encodes a protein having one or more point mutations relative to the wild type protein. More preferably, the mutation is in a single codon of the K-ras gene, such as codon 12, 13 or 16. Most preferably the mutation is in codon 12 or 13.
  • a subject has a cancer or a precancerous condition is "associated with mutated K-ras" if cells obtained from the subject have a mutated K-ras gene.
  • the identification of a K-ras mutation is within the skill in the art, and in one embodiment is done using, for example, methods disclosed herein or other methods as are known in the art.
  • the subject is identified as having a cancer associated with mutated K-ras if the subject is diagnosed with a cancer type which with a high probability of mutated K-ras, including pancreatic cancer, such as pancreatic adenocarcinoma, or adenocarcinoma of the colon or lung.
  • a K-ras mutation can be identified using methods known in the art. For example, cells from a tumor biopsy, such as a surgical biopsy or a needle aspirate, can be analyzed for the presence of a mutation. The cells can also be obtained from a body fluid, such as blood or urine, or from a stool sample. Methods for detecting K-ras mutations are known in the art and include, but are not limited to, those set forth in Poehlmann, A. et al, Pathol. Res. Pract. 2007, 203: 489-497; van Heek, N.T. et al., J. Clin. Pathol. 2005, 58, 1315- 1320; Taback, B. et al., Int. J.
  • Cancers which can be associated with mutated K-ras include pancreatic cancer , such as adenocarcinoma of the pancreas, including ductal adenocarcinoma; lung cancer, such as non-small cell lung cancer and lung adenocarcinoma; colorectal cancer, such as adenocarcinoma of the colon; thyroid cancer, such as follicular carcinoma, undifferentiated carcinoma, and papillary carcinoma; testicular cancer, such as seminoma; leukemia, such as acute myologenous leukemia, chronic myologenous leukemia, multiple myeloma and acute lymphocytic leukemia; multiple myeloma, liver cancer, breast cancer, prostate cancer, ovarian cancer and endometrial cancer.
  • pancreatic cancer such as adenocarcinoma of the pancreas, including ductal adenocarcinoma
  • lung cancer such as non-small cell lung cancer and lung adenocar
  • Non-cancerous conditions which can be associated with mutated K-ras include adenomas, such as colon adenomas and thyroid adenomas, and myelodysplastic syndrome.
  • a subject is determined to have a cancer associated with a K-ras mutation if the subject is diagnosed as having a cancer in which the prevalence of K-ras mutation is greater than about 50%.
  • cancers include pancreatic cancer, such as ductal adenocarcinoma, which is the cancer type with the highest rate of K-ras mutation.
  • Such a cancer is significantly more likely than not to be associated with mutated K-ras, and a clinician may determine that treatment with an inhibitor of PI3 kinase and an inhibitor of HDAC according to the invention is warranted on the basis of the diagnosis of pancreatic cancer, such as ductal adenocarcinoma, without the need for additional testing to confirm the presence of a K-ras mutation.
  • PI3 kinase inhibitor is a compound which inhibits cellular signaling through the PI3K/AKT signaling pathway.
  • the PI3 kinase inhibitor can be, for example, an inhibitor of one or more proteins involved in this signaling pathway, including PI3 kinase, such as ⁇ , ⁇ , ⁇ , and PI3k5, PKB (AKT), mammmalian Target of Rapamycin ("mTOR”) and/or another protein in the pathway.
  • Methods for assessing the ability of a compound to inhibit such proteins include those set forth herein and others known in the art.
  • the PB kinase inhibitor is selected from LY294002 (Eli Lily), Wortmannin, Wortmannin analogues, pegylated Wortmannin, pegylated 17-hydroxy-Wortmannin, PX-866, SF1124 (Semafore Pharmaceuticals), SF1126 (Semafore Pharmaceuticals), BEZ235 (Novartis), BGT226 (Novartis), BKM120 (Novartis), XL-765 (Exelexis), XL- 147 (Exelexis), GDC-0941 (Genentech), AS-252424, ONC-201 (Oncalis), CAL-101 (Calistoga), CAL-263 (Calistoga), Atu-027, PF-4691502, PBI-05204 (Phoenix Biotechnology), GSK-2126458, PIK-90, PIK-75, PI-103, ZSTK-474, TGX115, TGX-221 and
  • the PB kinase inhibitor is selected from the compounds set forth below:
  • a]pyrimidin-4-one (TGX- 137); 7-methyl-2-(4-morpholinyl)-9-[(phenylmethyl)amino]-4H- pyrido[l ,2-a]pyrimidin-4-one (TGX-126); 9-[[(4-fluoro-2-methylphenyl)amino]-7-methyl- 2-(4-morpholinyl)-4H-pyrido[l- ,2-a]pyrimidin-4-one (TGX- 170); 7-methyl-2-(4- morpholinyl)-9-[[(lR)-l-phenylethyl] amino] -4H-pyrido[l,2-a]pyrimidin-4-one (TGX- 123); 7-methyl-2-(4-morpholinyl)-9-[(2-pyridinylmethyl)amino]-4H-pyrido[l,2-a]pyrim one (TGX-161); 9-[[[(4-chloroph
  • (+/-)-7-methyl-9- [ 1 -(3 -methylphenylamino)ethyl]-2-morpholin-4-yl-pyrido [ 1 ,2- a]pyrimidin-4-one (TGX-262); (+/-)-7-methyl-2-morpholin-4-yl-9-[l-(3- trifluoromethylphenylamino)ethyl]- -pyrido[l,2-a]pyrimidin-4-one (TGX-264); (+/-)-7- methyl-2-morpholin-4-yl-9-[l-(2-pyridinylamino)ethyl]-pyrido[l,2-a]pyrimidin-4-one (TGX-295); (+/-)-2-( ⁇ 1 7-methyl-2-(morpholin4-yl)-4-oxo-pyrido[l,2-a]pyrimidin-9-yl- ]ethyl ⁇ amino)benzoic acid (K -309);
  • (+/-) methyl 2-( ⁇ l-[7-methyl-2-(morpholin-4-yl)-4-oxo-pyrido[l,2-a]pyrimidin-9-yl]ethy- 1 ⁇ amino)benzoate K -321
  • (+/-)-2-( ⁇ 1 -[7-methyl-2-(morpholi-4-yl)-4-oxo-pyrido[l ,2- a]pyrimidin-9-yl- ]ethyl ⁇ amino)benzonitrile K -320
  • (+/-)-7-methyl-2-(morpholin-4-yl)- 9-(l - ⁇ [2-(2H-tetrazol-5-yl)phenyl]amino- ⁇ ethyl)-pyrido[ 1 ,2-a]pyrimid-4-one K -325
  • Additional PI3 kinase inhibitors of use herein include 42-(3-hydroxy-2- (hydroxymethyl)-rapamycin 2-methylpropanoate (temsirolimus, Wyeth); 42-0-(2- hydroxyethyl)-rapamycin (Novartis), and 42-(dimethylphopsinoyl)-rapamycin (Ariad).
  • Additional PI3 kinase inhibitors which can be used in the methods of the invention include those set forth in US 7,598,377; 7,662,977; 7,544,677; 7,524,850; 7,511,041; and US published applications 2009/0098135; 2009/0029997; 2009/0029998 and
  • PI3 kinase inhibitors of use in the present methods further include pharmaceutically acceptable salts, esters and prodrugs of any of the PI3 kinase inhibitors described herein.
  • HDAC inhibitor refers to a compound which inhibits the enzymatic activity of one or more isoforms of histone deacetylase.
  • the ability of a compound to inhibit HDAC activity can beassessed using methods known in the art, including, but not limited to, the method described herein.
  • Suitable HDAC inhibitors include, but are not limited to, hydroxamic acids, cyclic peptides, benzamides and aliphatic acids.
  • the HDAC inhibitor is selected from the group consisting of suberoylanilide hydroxamic acid (SAHA), butyric acid, valproic acid, and Romidepsin.
  • SAHA suberoylanilide hydroxamic acid
  • the HDAC inhibitor is belinostat, mocetinostat, LAQ824, LBH589, CI994, BML-210, M344, MS275, JNJ- 26481585 or MGCD0103.
  • the HDAC inhibitor is selected from:
  • the HDAC inhibitor is EVP-0334, MGCD-290, CHR-3996 or DAC-0060.
  • Additional HDAC inhibitors which can be used in the methods of the invention include those set forth in WO 2008/019025, WO 2006/094068, WO 2007/054719, WO 2005/007091, WO 2010/028193, WO 2008/082646, WO 2007/045962, WO 2005/087724, WO 2005/065681, WO 2004/113366, WO 2004/054999, WO 2003/011851, WO
  • HDAC inhibitors of use in the present methods further include pharmaceutically acceptable salts, esters and prodrugs of any of the HDAC inhibitors described herein.
  • the inhibitor of PI3 kinase and the HDAC inhibitor are separate compounds.
  • the inhibitor of PI3 kinase and the HDAC inhibitor are the same compound, that is, a single bifunctional compound which functions as both an inhibitor of PI3 kinase and an HDAC inhibitor.
  • the bifunctional molecule comprises a moiety which inhibits PI3 kinase and a moiety which inhibits histone deacetylase. Suitable bifunctional molecules include those having the general formula A- B-C, where A is a moiety that inhibitors PI3 kinase, C is a moiety which inhibis HDAC and B is a linker.
  • the bifunctional molecule is selected from the compounds set forth in US Patent Publication No. 2010/0222343 and US Patent
  • the bifunctional compound has the general formula (I):
  • q, r and s are independently 0 or 1 , wherein at least one of q, r and s is 1 ; preferably, one of q, r and s is 1 and the rest are 0; n is 0, 1, 2, 3 or 4;
  • p is 0, 1 or 2, preferably 0 or 1;
  • t is 0 or 1; preferably, when s is 1, t is 0;
  • X and Y are independently CRi, N(R 8 ), S or O; wherein when one of X and Y is CRi, the other is N(R 8 ), S or O; preferably X is S and Y is CRi;
  • Gi is CRi, S, O, NRio or NS(0) 2 Rio ;
  • G 2 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or, substituted or unsubstituted heterocyclic;
  • G 3 is substituted or unsubstituted Ci-Cg alkyl, substituted or unsubstituted C 2 -Cg alkenyl or substituted or unsubstituted C 2 -Cg alkynyl;
  • each R 8 is independently hydrogen, acyl, aliphatic or substituted aliphatic;
  • each Ri and R 2 is absent or is independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF 3 , CN, N0 2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
  • R a is optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl;
  • R b is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl;
  • Rio is selected from hydrogen, hydroxy, amino, alkoxy, alkylamino, dialkylamino, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; preferably Rio is hydrogen, acyl, aliphatic or substituted aliphatic;
  • C is selected from:
  • R 32 and R 34 are both present, one of R 32 or R 34 must be hydroxy and if Y 2 is absent, R 34 must be hydroxy; and R 33 is hydrogen or aliphatic group;
  • R 12 are independently selected from hydrogen or aliphatic;
  • R 2 i, R 22 and R 23 are independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF 3 , CN, N0 2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • each Ri and R 2 is independently absent, hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF 3 , CN, N0 2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl or substituted heterocyclylalkyl.
  • the bifunctional compound is represented by formula (II) or formula (III), or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, or prodrug thereof:
  • bifunctional compound in another embodiment, is represented by formula (IV) or (V) as illustrated below, or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt or prodrug thereof:
  • Gi, G 2 , Ri, R 2 , Rg, n, p, q, r, s, B and C are as defined above; and G 4 is NRg, S or O, preferably S.
  • Gi is O.
  • the bifunctional compound is represented by formula (VI) and (VII) as illustrated below, or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, or prodrug thereof:
  • Gi, G 4 , Ri, R 2 , R 3 , Rg, n, m, p, q, , s, B and C are as defined above; and o is 1, 2, 3 or 4.
  • q and r are 0 and s is 1. In another preferred embodiment q is 1 while r and s are 0. In another preferred embodiment q and s are 0 and r is 1.
  • r is 0 and q is 1.
  • B is a Ci-Cg alkyl where one or more CH 2 can be optionally replaced by O, S, S0 2 , NRg or -CONH-, C is -C(0)N(H)OH, and Gi is -O.
  • B is a Ci-Cg alkyl where one or more CH 2 can be optionally replaced by O, S, S0 2 NRg or -CONH-, C is -C(0)N(H)OH, and Gi is -NS(0) 2 CH 3 .
  • B is an aryl, heteroaryl, Ci-Cio-alkylaryl, C 1 -C 1 0- alkylheteroaryl group, Ci-Cio-alkylheterocyclylaryl, Ci-Cio-alkylheterocyclylheteroaryl, Ci-Cio-alkylheterocyclylaryl-Ci-Cio-alkyl, or Ci-Ci 0 -alkylheterocyclylheteroaryl-Ci-Ci 0 - alkyl group where one or more CH 2 can be optionally replaced by O, S, S0 2 , NRg or - CONH-, and Gi is -O or -NS(0) 2 CH 3 .
  • the bifunctional compound is represented by formula (VIII) or (IX) as illustrated below, or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt or prodrug thereof:
  • G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, imidazolyl, pyrazolyl or benzimidazolyl.
  • q is 0 and s is 1. In another preferred embodiment, q is 1 and s is 0.
  • B is a Ci-Cg alkyl where one or more CH 2 can be optionally replaced by O, S, S0 2 , NRg or - CONH-, C is -C(0)N(H)OH, and Gi is -O. In another preferred embodiment, B is a Ci-Cg alkyl where one or more CH 2 can be optionally replaced by O, S, S0 2 , NRg or -CONH-, C is -C(0)N(H)OH, and Gi is -NS(0) 2 CH 3 .
  • the bifunctional compound is represented by formula X or XI as illustrated below, or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt or prodrug thereof:
  • G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, imidazolyl, pyrazolyl or benzimidazolyl.
  • B is a Ci-Cs alkyl where one or more CH 2 can be optionally replaced by O, S, S0 2 , N(Rg), -CONH-, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic groups, C is -C(0)N(H)OH, and Gi is O.
  • B is a Ci-Cg alkyl where one or more CH 2 can be optionally replaced by O, S, S0 2 , NRg, - CONH-, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic groups, C is -C(0)N(H)OH, and Gi is -NS(0) 2 CH 3 .
  • the bifunctional compound is represented by formula XII, as illustrated below, or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt or prodrug thereof:
  • n, p, B, C, Ri, G 2 and R 2 are as defined above.
  • the bifunctional compound is represented by formula XIII as illustrated below, or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt or prodrug thereof:
  • n, p, Y 2 , W, Z, Gi, G 4 , G 2 , Ri, R 2 , R 32 , R 33 and R 34 are as defined above;
  • Mi is absent, O, S, NR 8 , Ci-C 6 alkyl, , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl,
  • M 3 is absent, O, NRg, S, SO, S0 2 , CO, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, aryl, heteroaryl, or heterocyclic;
  • M 4 is absent, O, NRg, heteroaryl, heterocyclic or aryl; and
  • M 5 is absent, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cgalkynyl, heteroaryl, heterocyclic or aryl.
  • G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, imidazolyl, pyrazolyl or benzoimidazolyl.
  • G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl or benzimidazolyl.
  • the bifunctional compound is represented by formula (XIV) as illustrated below, or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt or prodrug thereof:
  • G ls G 2 , G 4 , n, p, Ri and R 2 are as defined above; t, v and w are independently 0, 1, 2 or 3; u is 0, 1, 2, 3, 4, 5, 6, 7 or 8; G 5 is absent, Ci-Cg alkyl or a Ci-Cg alkyl interrupted by one or more O, S, S(O), S0 2 , N(R 8 ), or C(O); preferably G 5 is -N(R 8 )-Ci-C 4 -alkyl, t is 1 and u is 0;
  • G 6 is selected from CRi or NR 8 , wherein Ri and R 8 are as defined above; G 7 is selected from -CRi, -NRg, S or O wherein Ri and Rg are as defined above; or G 7 is selected from -C(Ri) 2 , and -N; R 5 and R 6 are independently selected from absent, hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF 3 , CN, N0 2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, imidazolyl, pyrazolyl or benzimidazolyl.
  • G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl or benzimidazolyl.
  • G 7 is CRi or N
  • the pyrimidine ring is directly bonded to G 7 .
  • the bifunctional compound is represented by formula
  • G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, imidazolyl, pyrazolyl or benzimidazolyl.
  • Gi is O
  • G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl or benzimidazolyl
  • G 5 is -N(Rg)-Ci-C 4 -alkyl and u is 0.
  • G 2 is optionally substituted phenyl, pyridyl, pyrimidyl or pyrrolyl selected from the group:
  • m is 1 and R 3 is hydroxyl, hydroxymethyl, amino, acylamino, such as acetylamino, or methylamino.
  • R 3 is hydroxyl, hydroxymethyl, amino, acylamino, such as acetylamino, or methylamino.
  • G 2 is an optionally substituted indazolyl or benzimidazolyl group selected from the groups shown below:
  • R 3 , Rg and m are as defined above.
  • G 2 is an optionally substituted monoaryl or monoheteroaryl group.
  • G 2 is phenyl, pyridyl, pyrimidyl or pyrrolyl with one or more substituents include but not limited to hydroxyl, hydroxymethyl, amino and substituted amino; Gi is O, G 5 is -N(Rg)-Ci-C4-alkyl and u is 0.
  • G 2 can be phenyl, pyridyl, pyrimidyl or pyrrolyl substituted by a hydroxyl, hydroxymethyl, acetylamino, amino or methylamino group.
  • Such compounds have significant inhibitory activity toward mTOR, as well as PI3 kinase and HDAC.
  • C is: ; where R 33 is selected from hydrogen and lower alkyl.
  • the bivalent B is a direct bond or straight- or branched-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkyl, alkyn
  • alkylheteroarylalkenyl alkylheteroarylalkynyl, alkenylheteroarylalkyl,
  • alkenylheteroarylalkenyl alkenylheteroarylalkynyl, alkynylheteroarylalkyl,
  • alkynylheteroarylalkenyl alkynylheteroarylalkynyl, alkylheterocyclylalkyl,
  • alkylheterocyclylalkenyl alkylhererocyclylalkynyl, alkenylheterocyclylalkyl,
  • alkenylheterocyclylalkenyl alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, or alkynylhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), S0 2 , N(R 8 ), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; such divalent B linkers include but are not limited to alkyl, alkenyl, alkynyl, alkylaryl, alkeny
  • alkylheterocyclylheteroaryl alkylheterocyclylheteroarylalkyl, alkoxyaryl, alkylaminoaryl, alkoxyalkyl, alkylaminoalkyl, alkylheterocycloalkyl, alkylheteroarylalkyl, alkylamino, N(R 8 )alkenyl, N(R 8 )alkynyl, N(R 8 )alkoxyalkyl, N(R 8 )alkylaminoalkyl,
  • N(R 8 )alkylaminocarbonyl N(R 8 )alkylaryl, N(R 8 )alkenylaryl, N(R 8 )alkynylaryl,
  • N(R 8 )C(0)alkenyl N(R 8 )C(0)- alkynyl, N(R 8 )C(0)alkylaryl, N(R 8 )C(0)alkenylaryl, N(R 8 )C(0)alkynylaryl, N(R 8 )C(0)alkoxyalkyl, N(R 8 )C(0)alkylaminoalkyl,
  • alkenylarylaminoalkylamino alkenylarylalkylaminoalkoxy
  • alkenylarylalkylaminoalkylamino alkenylarylalkylaminoalkylamino .
  • B is a straight chain alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl,
  • alkenylarylalkyl alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl,
  • alkynylarylalkenyl alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl,
  • alkenylheteroarylalkynyl alkynylheteroarylalkyl, alkynylheteroarylalkenyl,
  • alkynylheteroarylalkynyl alkylheterocyclylalkyl, alkylheterocyclylalkenyl,
  • alkylhererocyclylalkynyl alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, or alkynylhereroaryl,.
  • One or more methylenes can be interrupted or terminated by -0-, -N(R 8 )-, -C(O)-, -C(0)N(R 8 )-, or -C(0)0-.
  • the C group is attached to B via an aliphatic moiety within B.
  • the linker B is between 1-24 atoms, preferably 4-24 atoms, preferably 4-18 atoms, more preferably 4-12 atoms, and most preferably about 4-10 atoms.
  • B is selected from straight chain Ci-Ci 0 alkyl, Ci-Ci 0 alkenyl, Ci-Cio alkynyl, Ci-Cio alkoxy, alkoxyCi-Cioalkoxy, Ci-Cio alkylamino, alkoxyCi- Cioalkylamino, Ci-Cio alkylcarbonylamino, Ci-Cio alkylaminocarbonyl, aryloxyCi- Cioalkoxy, aryloxyCi-Cioalkylamino, aryloxyCi -Cioalkylamino carbonyl, Ci-Cio- alkylaminoalkylaminocarbonyl, Ci-Cio alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino, alkylcarbonylaminoalkylamino, alkyl(N-alkyl)aminoalkyl-a
  • the C group is attached to B via an aliphatic moiety carbon chain, an aryl group or a heteroaryl group within B.
  • B is an aryl, heteroaryl, Ci-Cio-alkylaryl, Ci-Cio-alkylheteroaryl group, Ci-Cio-alkylheterocyclylaryl, Ci-Cio- alkylheterocyclylheteroaryl, Ci-Ci 0 -alkylheterocyclylaryl-Ci-Ci 0 -alkyl, or Ci-Ci 0 - alkylheterocyclylheteroaryl-C i-C l o-alkyl group .
  • alkyl alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl
  • heterocyclyl and the like can be further substituted.
  • B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • d and e are independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; and R 100 is hydrogen or a group selected from Ci-Cg alkyl, C 2 -C8 alkenyl, C 2 -C8 alkynyl, and C 3 -C 8 cycloalkyl.
  • Preferred alkyl groups are -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , - CH(CH 3 )CH 3 , -C(CH 3 ) 2 CH 3 , -C(CH 3 ) 3 .
  • Ri 00 is hydrogen or methyl.
  • Representative bifunctional compounds of use herein are those selected from Table A below or the geometric isomers, enantiomers, diastereomers, racemates,
  • the PI3 kinase and inhibitor and the HDAC inhibitor, or the bifunctional compound is administered as a pharmaceutical composition comprising the active compound and a pharmaceutically acceptable carrier or excipient.
  • suitable pharmaceutical compositions comprise any solid or liquid physical form of the active compound.
  • the compounds can be in a crystalline form, in amorphous form, and have any particle size. The particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.
  • Suitable pharmaceutical compositions typically comprise a therapeutically effective amount of an active compound, and a pharmaceutically acceptable carrier.
  • Compounds of use in the methods of the invention may be administered by any suitable means, including, without limitation, parenteral, intravenous, intramuscular, subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary, transdermal, topical, vaginal, rectal, and transmucosal administrations or the like.
  • parenteral intravenous, intramuscular, subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary, transdermal, topical, vaginal, rectal, and transmucosal administrations or the like.
  • compositions include a solid, semisolid or liquid preparation (tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, liquid, emulsion, suspension, syrup, injection etc.) containing a compound of the invention as an active ingredient, which is suitable for selected mode of administration.
  • the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e., as a solid or a liquid preparation.
  • Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like.
  • Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like.
  • the composition is formulated in a capsule.
  • the compositions of the present invention comprise in addition to the active compound and the inert carrier or diluent, a hard gelatin capsule.
  • compositions of the present invention may further comprise a disintegrating agent (e.g., sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulf
  • croscarmellose sodium and a lubricant (e.g., magnesium stearate), and may additionally comprise one or more additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof.
  • compositions of the present invention may be in the form of controlled release or immediate release formulations.
  • pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions or oils.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil.
  • Solutions or suspensions can also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediammetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • compositions may further comprise binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers (e.g., tris-HCL, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat No. 4,522,811.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • compositions that contain an active compound are well understood in the art, for example, by mixing, granulating, or tablet- forming processes.
  • the active therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient.
  • the active agents are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions and the like as detailed above.
  • the amount of the compound administered to the patient is preferably less than an amount that would cause toxicity in the patient. In certain embodiments, the amount of the compound that is administered to the patient is less than the amount that causes a concentration of the compound in the patient's plasma to equal or exceed the toxic level of the compound.
  • the concentration of the compound in the patient's plasma is maintained at about 10 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 25 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 50 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 100 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 500 nM.
  • the concentration of the compound in the patient's plasma is maintained at about 1000 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 2500 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 5000 nM.
  • the optimal amount of the compound that should be administered to the patient in the practice of the present invention will depend on the particular compound used and the type of cancer being treated.
  • an "aliphatic group” or “aliphatic” is non-aromatic moiety that may be saturated (e.g. single bond) or contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen or, optionally, one or more heteroatoms and may be substituted or unsubstituted.
  • An aliphatic group, when used as a linker preferably contains between about 1 and about 24 atoms, more preferably between about 4 to about 24 atoms, more preferably between about 4-12 atoms, more typically between about 4 and about 8 atoms.
  • An aliphatic group when used as a substituent, preferably contains between about 1 and about 24 atoms, more preferably between about 1 to about 10 atoms, more preferably between about 1-8 atoms, more typically between about 1 and about 6 atoms.
  • aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl groups described herein.
  • substituted carbonyl includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof.
  • moieties that contain a substituted carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • carbonyl moiety refers to groups such as “alkylcarbonyl” groups wherein an alkyl group is covalently bound to a carbonyl group, "alkenylcarbonyl” groups wherein an alkenyl group is covalently bound to a carbonyl group, "alkynylcarbonyl” groups wherein an alkynyl group is covalently bound to a carbonyl group, “arylcarbonyl” groups wherein an aryl group is covalently attached to the carbonyl group.
  • the term also refers to groups wherein one or more heteroatoms are covalently bonded to the carbonyl moiety.
  • the term includes moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound to the carbon of the carbonyl group, e.g., an amide).
  • acyl refers to hydrogen, alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups.
  • acyl includes groups such as (Ci-C 6 )alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.), (C3-Ce)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5 -carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.
  • the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any one of the groups described in the respective definitions.
  • the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted” or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be substituted as described above in the preferred and more preferred list of substituents, respectively.
  • alkyl embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about eight carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.
  • alkenyl embraces linear or branched radicals having at least one carbon- carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl” radicals having two to about ten carbon atoms and more preferably about two to about eight carbon atoms. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl and “lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • alkynyl embraces linear or branched radicals having at least one carbon- carbon triple bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl” radicals having two to about ten carbon atoms and more preferably about two to about eight carbon atoms.
  • alkynyl radicals examples include propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2- butynyl and 1-pentynyl.
  • cycloalkyl embraces saturated carbocyclic radicals having three to about twelve carbon atoms.
  • cycloalkyl embraces saturated carbocyclic radicals having three to about twelve carbon atoms.
  • More preferred cycloalkyl radicals are "lower cycloalkyl” radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkenyl embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called “cycloalkyldienyl". More preferred cycloalkenyl radicals are "lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • alkoxy embraces linear or branched oxy-containing radicals each having alkyl portions of one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to about ten carbon atoms and more preferably having one to about eight carbon atoms.
  • radicals examples include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • alkoxyalkyl embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • heterocyclyl saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, which can also be called “heterocyclyl”, “heterocycloalkenyl” and “heteroaryl”
  • heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • saturated heterocyclyl radicals include saturated 3 to 6-membered
  • heteromonocyclic group containing 1 to 4 nitrogen atoms e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.
  • saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. morpholinyl, etc.
  • saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., thiazolidinyl, etc.
  • partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
  • Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals.
  • the term "heterocycle” also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
  • heteroaryl embraces unsaturated heterocyclyl radicals.
  • heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, 1H-1,2,3- triazolyl, 2H-l,2,3-triazolyl, etc.) tetrazolyl (e.g.
  • unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[l,5-b]pyridazinyl, etc.), etc.;
  • unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom for example, pyranyl, furyl, etc.
  • unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom for example, thienyl, etc.
  • unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.
  • unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. benzoxazolyl, benzoxadiazolyl, etc.
  • unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, thiazolyl, thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl,
  • heterocycloalkyl embraces heterocyclo-substituted alkyl radicals. More preferred heterocycloalkyl radicals are "lower heterocycloalkyl” radicals having one to six carbon atoms in the heterocyclo radicals.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom.
  • Preferred alkylthio radicals have alkyl radicals of one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylthio radicals have alkyl radicals are "lower alkylthio" radicals having one to about ten carbon atoms. Most preferred are alkylthio radicals having lower alkyl radicals of one to about eight carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.
  • aralkyl or "arylalkyl” embrace aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.
  • aryloxy embraces aryl radicals attached through an oxygen atom to other radicals.
  • aralkoxy or "arylalkoxy” embrace aralkyl radicals attached through an oxygen atom to other radicals.
  • aminoalkyl embraces alkyl radicals substituted with amino radicals.
  • Preferred aminoalkyl radicals have alkyl radicals having about one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred aminoalkyl radicals are "lower aminoalkyl” that have alkyl radicals having one to about ten carbon atoms. Most preferred are aminoalkyl radicals having lower alkyl radicals having one to eight carbon atoms. Examples of such radicals include aminomethyl, aminoethyl, and the like.
  • alkylamino denotes amino groups which are substituted with one or two alkyl radicals.
  • Preferred alkylamino radicals have alkyl radicals having about one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylamino radicals are "lower alkylamino” that have alkyl radicals having one to about ten carbon atoms. Most preferred are alkylamino radicals having lower alkyl radicals having one to about eight carbon atoms.
  • Suitable lower alkylamino may be monosubstituted N- alkylamino or disubstituted ⁇ , ⁇ -alkylamino, such as N-methylamino, N-ethylamino, N,N- dimethylamino, ⁇ , ⁇ -diethylamino or the like.
  • linker means an organic moiety that connects two parts of a compound.
  • Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NRg, C(O), C(0)NH, SO, S0 2 , S0 2 NH or a chain of atoms, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,
  • heteroarylalkynyl heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkenyl, alkenylheteroarylalkenyl, alkenylhetero
  • alkenylheteroarylalkynyl alkynylheteroarylalkyl, alkynylheteroarylalkenyl,
  • alkynylheteroarylalkynyl alkylheterocyclylalkyl, alkylheterocyclylalkenyl,
  • alkylhererocyclylalkynyl alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl,
  • the linker B is between 1-24 atoms, preferably 4-24 atoms, preferably 4-18 atoms, more preferably 4-12 atoms, and most preferably about 4-10 atoms.
  • the linker is a C(0)NH(alkyl) chain or an alkoxy chain. It is to be understood that an asymmetric linker, such as alkylaryl, can connect two structurally distinct moieties in either of its two possible orientations.
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy
  • chemical moieties are defined and referred to throughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.) or multivalent moieties under the appropriate structural circumstances clear to those skilled in the art.
  • an "alkyl” moiety can be referred to a monovalent radical (e.g. CH 3 -CH 2 -), or in other instances, a bivalent linking moiety can be "alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH 2 -CH 2 -), which is equivalent to the term
  • alkylene alkylene
  • alkoxy alkoxy
  • alkylamino alkyloxy
  • alkylthio alkyl
  • alkyl alkylthio
  • alkyl alkyl
  • alkyl alkenyl
  • alkynyl alkynyl
  • aliphatic or "cycloalkyl”
  • halogen refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • the term "aberrant proliferation” refers to abnormal cell growth.
  • adjunct therapy encompasses treatment of a subject with agents that reduce or avoid side effects associated with the combination therapy of the present invention, including, but not limited to, those agents, for example, that reduce the toxic effect of anticancer drugs, e.g., bone resorption inhibitors, cardioprotective agents; prevent or reduce the incidence of nausea and vomiting associated with chemotherapy, radiotherapy or operation; or reduce the incidence of infection associated with the administration of myelosuppressive anticancer drugs.
  • apoptosis refers to programmed cell death as signaled by the nuclei in normally functioning human and animal cells when age or state of cell health and condition dictates.
  • An “apoptosis inducing agent” triggers the process of programmed cell death.
  • cancer denotes a class of diseases or disorders
  • compound is defined herein to include pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereoisomers, racemates and the like of the compounds having a formula as set forth herein.
  • device refers to any appliance, usually mechanical or electrical, designed to perform a particular function.
  • displasia refers to abnormal cell growth, and typically refers to the earliest form of pre-cancerous lesion recognizable in a biopsy by a pathologist.
  • a therapeutically effective amount of a compound or combination of compounds with respect to the subject method of treatment refers to an amount of the subject compound or the amounts of two or more compounds in
  • a neoplasia disorder including, but is not limited to: 1) reduction in the number of cancer cells; 2) reduction in tumor size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cancer cell infiltration into peripheral organs; 4) inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 5) inhibition, to some extent, of tumor growth; 6) relieving or reducing to some extent one or more of the symptoms associated with the disorder; and/or 7) relieving or reducing the side effects associated with the administration of anticancer agents.
  • hyperplasia refers to excessive cell division or growth.
  • an "immunotherapeutic agent” refers to agents used to transfer the immunity of an immune donor, e.g., another person or an animal, to a host by inoculation.
  • the term embraces the use of serum or gamma globulin containing performed antibodies produced by another individual or an animal; nonspecific systemic stimulation; adjuvants; active specific immunotherapy; and adoptive immunotherapy.
  • Adoptive immunotherapy refers to the treatment of a disease by therapy or agents that include host inoculation of sensitized lymphocytes, transfer factor, immune R A, or antibodies in serum or gamma globulin.
  • inhibitors in the context of neoplasia, tumor growth or tumor cell growth, may be assessed by delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention.
  • Metastasis refers to the migration of cancer cells from the original tumor site through the blood and lymph vessels to produce cancers in other tissues. Metastasis also is the term used for a secondary cancer growing at a distant site.
  • Neoplasm refers to an abnormal mass of tissue that results from excessive cell division. Neoplasms may be benign (not cancerous), or malignant (cancerous) and may also be called a tumor. The term “neoplasia” is the pathological process that results in tumor formation.
  • pre-cancerous refers to a condition that is not malignant, but is likely to become malignant if left untreated.
  • PI3 kinase related disease or disorder refers to a disease or disorder characterized by inappropriate phosphoinositide-3 -kinase activity or over-activity of the phosphoinositide-3 -kinase. Inappropriate activity refers to either; (i) PI3 kinase expression in cells which normally do not express PI3 kinase; (ii) increased PI3 kinase expression leading to unwanted cell proliferation, differentiation and/or growth; or, (iii) decreased PI3 kinase expression leading to unwanted reductions in cell proliferation, differentiation and/or growth.
  • Over-activity of PI3 kinase refers to either amplification of the gene encoding a particular PI3 kinase or production of a level of PI3 kinase activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PI3 kinase increases, the severity of one or more of the symptoms of the cellular disorder increases).
  • a "radio therapeutic agent” refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia.
  • recurrence refers to the return of cancer after a period of remission. This may be due to incomplete removal of cells from the initial cancer and may occur locally (the same site of initial cancer), regionally (in vicinity of initial cancer, possibly in the lymph nodes or tissue), and/or distally as a result of metastasis.
  • treatment refers to any process, action, application, therapy, or the like, wherein a mammal, including a human being, is subject to medical aid with the object of improving the mammal's condition, directly or indirectly.
  • vaccine includes agents that induce the patient's immune system to mount an immune response against the tumor by attacking cells that express tumor associated antigens (Teas).
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the
  • nontoxic acid addition salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid lactobionic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
  • Prodrug as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the invention.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard- Larsen, et al, (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8: 1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration, such as sterile pyrogen-free water. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • pre-cancerous refers to a condition that is not malignant, but is likely to become malignant if left untreated.
  • subject refers to an animal.
  • the animal is a mammal. More preferably the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid
  • transformations and protecting group methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.
  • Certain of the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • compositions of the present invention comprise a
  • pharmaceutically acceptable carrier or excipient means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose;
  • cyclodextrins such as alpha- (a), beta- ( ⁇ ) and gamma- ( ⁇ ) cyclodextrins; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lub
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, e
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system.
  • Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No. 5,767,068 to VanDevanter et al, U.S. Pat. No.
  • a therapeutically effective amount of a compound or combination of compounds is an amount which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • the compounds of the formulae described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
  • Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with pharmaceutically excipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w).
  • such preparations may contain from about 20% to about 80%) active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
  • the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • Step lb 4-Bromo-iH-indazole (Compound 0106-3)
  • chloroform (5 mL) was added potassium acetate (0.28 g, 2.82 mmol). The mixture was cooled with ice-water bath and then acetic anhydride (0.50 mL, 5.37 mmol) was added to it. Ice-water bath was then removed and the resulting mixture was stirred at room temperature for 10 minutes after which time a white gelatinous solid formed. 18-Crown-6 (0.14 g, 0.54 mmol) was then added followed by isoamyl nitrite (0.80 mL, 5.90 mmol). The mixture was then heated under reflux for 18 hours. The reaction mixture was allowed to cool, and was partitioned between chloroform (3 x 10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL).
  • Step lh 4-(2-Cloro-6-((4-(methylthioperoxy)piperazin-l-yl)methyl)thieno[3,2-d] pyrimidin-4-yl)morpholine (Compound 0113)
  • Step li 4-(2-Chloro-6-((4-(methylthioperoxy)piperazin-l-yl)methyl)thieno[3,2-d] pyrimidin-4-yl)morpholine (Compound 0114)
  • Step lj Ethyl 5-(4-(6-((4-(methylsulfonyl)piperazin-l-yl)methyl)-4- morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)pentanoate (Compound 0116-3) and ethyl 5-(4-(6-((4-(methylsulfonyl)piperazin-l-yl)methyl)-4- morpholinothieno[3,2- d]pyrimidin-2-yl)-lH-indazol-l-yl)pentanoate (Compound 0115-3)
  • Step lk N-Hydroxy-5-(4-(6-((4-(methylsulfonyl)piperazin- 1 -yl)methyl)-4- morpholinothien-[3 ,2-d]pyrimidin-2-yl)- 1 H-indazol- 1 -yl)pentanamide (Compound 3)
  • Step 2a Ethyl 6-(4-(6-((4-(methylsulfonyl)piperazin-l-yl)methyl)-4- morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)hexanoate (Compound 0116-4) and ethyl 3 -(4-(6-((4-(methylsulfonyl)piperazin- 1 -yl)methyl)-4- morpholinothieno [3 ,2- d]pyrimidin-2-yl)-l H-indazol- l-yl)propanoate (Compound 0115-4)
  • Step 2b N-hydroxy-3-(4-(6-((4-(methylsulfonyl)piperazin- 1 -yl)methyl)-4- morpholinothieno [3 ,2-d]pyrimidin-2-yl)- 1 H-indazol- 1 -yl)propanamide (Compound 4)
  • the title compound 4 was prepared as a yellow solid (45 mg, 22%>) from 0115-4
  • Step 3a Ethyl 7-(4-(6-((4-(methylsulfonyl)piperazin-l-yl)methyl)- 4- morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)heptanoate (Compound 0116-5) and ethyl 7-(4-(6-((4-(methylsulfonyl)piperazin-l-yl)methyl)-4- morpholinothieno[3,2- d]pyrimidin-2-yl)-l H-indazol- l-yl)heptanoate (Compound 0115-5)
  • the title compound 0115-5 (110 mg, 27%) and 0116-5 (60 mg, 16%) were prepared from 0114 (280 mg, 0.55 mmol) , ethyl 7-bromoheptanoate (133 mg, 0.65 mmol) and potassium carbonate (152 mg, 1.10 mmol) in
  • Step 3b N-hydroxy-7-(4-(6-((4-(methylsulfonyl)piperazin- 1 -yl)methyl)-4- morpholinothieno[3,2-d]pyrimidin-2-yl)-lH-indazol-l-yl)heptanamide (Compound 5)
  • the title compound 5 was prepared as a white solid (70 mg, 71 >) from 0115-5 (100 mg, 0.15 mmol) and freshly prepared hydroxylamine methanol solution (4.0 mL) using a procedure similar to that described for compound 3 (Example 1): mp 127-130 °C.
  • the title compound 7 was prepared as a white solid (35 mg, 47%>) from 0116-3 (60 mg, 0.12 mmol) and freshly prepared hydroxylamine methanol solution (4.0 mL) using a procedure similar to that described for compound 3 (Example 1): mp 146-169 °C.
  • the title compound 8 was prepared as a yellow solid (15 mg, 11%) from 0116-4 (140 mg, 0.21 mmol) and freshly prepared hydroxylamine methanol solution (5.0 mL) using a procedure similar to that described for compound 3 (Example 1): mp 124-125 °C.
  • the title compound 9 was prepared as a white solid (45 mg, 76%) from 0116-5 (60 mg, 0.09 mmol) and freshly prepared hydroxylamine methanol solution (4.0 mL) using a procedure similar to that described for compound 3 (Example 1): mp 123-126 °C.
  • Step 7b 4-(2-Chloro-6-(piperazin-l-ylmethyl)thieno[3,2-(i]pyrimidin-4-yl) morpholine (Compound 0202)
  • Step 7c Ethyl 5-(4-((2-chloro-4-morpholinothieno[3,2- ⁇ i]pyrimidin-6-yl)methyl) piperazin-l-yl)pentanoate (Compound 0203-11)
  • Step 7d Ethyl 5-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-(i] pyrimidin-6- yl)methyl)piperazin-l-yl)pentanoate (Compound 0204-11)
  • Step 7e 5-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-(i] pyrimidin-6- yl)methyl)piperazin-l-yl)-N-hydroxypentanamide (Compound 11)
  • the title compound 0203-12 was prepared as a gray solid (0.57 g, 82%) from 0202
  • Step 8b Ethyl 6-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-(i]pyrimidin -6- yl)methyl)piperazin-l-yl)hexanoate (Compound 0204-12)
  • the title compound 0204-12 was prepared as a white solid (56 mg, 16%>) from 0203-12 (295 mg, 0.61 mmol), 0107-3 (164 mg, 0.67 mmol), NaHC0 3 (150 mg, 1.79 mmol) and Pd(dppf) 2 Ci2 (23 mg, 0.031 mmol) in toluene (5.6 mL), ethanol (3 mL) and water (1.5 mL) using a procedure similar to that described for compound 0204-11
  • Step 8c 6-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-(i]pyrimidin- 6- yl)methyl)piperazin-l-yl)-N-hydroxyhexanamide (Compound 12)
  • the title compound 12 was prepared as a white solid (15 mg, 13 >) from 0204-12 (120 mg, 0.21 mmol) and freshly prepared hydroxylamine methanol solution (1.0 mL, 1.77 mol/L) using a procedure similar to that described for compound 3 (Example 1): m.p.
  • Example 9 Preparation of 7-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-i/] pyrimidin-6-yl)methyl)piperazin-l-yl)- V-hydroxyheptanamide (Compound 13)
  • Step 9a Ethyl 7-(4-((2-chloro-4-morpholinothieno[3,2- ⁇ i]pyrimidin-6-yl)methyl) piperazin- 1 -yl)heptanoate (Compound 0203-13)
  • Step 9b Ethyl 7-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-(i] pyrimidin-6- yl)methyl)piperazin-l-yl)heptanoate (Compound 0204-13)
  • Step 9c 7-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-(i]pyrimidin-6- yl)methyl)piperazin-l-yl)-N-hydroxyheptanamide (Compound 13)
  • the title compound 13 was prepared as a white solid (25 mg, 37%>) from 0204-13
  • Step 10a (Z)-Ethyl-2-(ethoxymethyl)-3-methoxyacrylate (Compound 0302)
  • Step 10b Ethyl 2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate (Compound 0303)
  • Step 10c Ethyl 2-oxo-l,2-dihydropyrimidine-5-carboxylate (Compound 0304)
  • Step lOf Ethyl 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)
  • Step lOg Ethyl 2-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d] pyrimidin-6- yl)methyl)piperazin- 1 -yl)pyrimidine-5 -carboxylate (Compound 0308)
  • the title compound 0308 was prepared as a yellow solid (60 mg, 23%) from 0307 (220 mg, 0.44 mmol), 0107-3 (161 mg, 0.66 mmol), NaHC0 3 (111 mg, 1.32 mmol) and Pd(dppf)2Cl2 (19 mg, 0.022 mmol) in toluene (4.7 mL), ethanol (2.8 mL) and water (1.2 mL) using a procedure similar to that described for compound 0204-11 (Example 7):
  • the title compound 14 was prepared as a yellow solid (30 mg, 52%) from 0308 (60 mg, 0.10 mmol) and freshly prepared hydroxylamine methanol solution (3.0 mL, 1.77 mol/L) using a procedure similar to that described for compound 3 (Example 1): mp 209- 221 °C.
  • Step 11a Ethyl 2-(4-(aminomethyl)piperidin-l-yl)pyrimidine-5-carboxylate
  • Step 11c Ethyl 2-(4-(((2-(lH-indazol-4-yl)-4-morpholinothieno [3,2-d]pyrimidin-6-yl)me thylamino)methyl)piperidin- 1 -yl)pyrimidine-5-carboxylate (Compound 0403-15)
  • the title compound 0403 was prepared as a white solid (120 mg, 17%) from 0402 (630 mg, 1.18 mmol), 0107-3 (580 mg, 2.37 mmol), NaHC0 3 (297 mg, 3.54 mmol) and Pd(dppf) 2 Cl 2 (25 mg, 0.036 mmol) in toluene (11 mL), ethanol (6.6 mL) and water (3.1 mL) using a procedure similar to that described for compound 0204-11 (Example 7):
  • the title compound 15 was prepared as a white solid (30 mg, 63%) from 0403 (50 mg, 0.08 mmol) and freshly prepared hydroxylamine methanol solution (3.0 mL, 1.77 mol/L) using a procedure similar to that described for compound 3 (Example 1): mp 170- 172 °C.
  • Step 12a (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol (Compound 0501) To a mixture of compound 0112 (500 mg, 1.77 mmol) in methanol (10 mL) was added sodium borohydride (200 mg, 5.3 mmol). The mixture was stirred at room temperature
  • Step 12b 4-(6-(Bromomethyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine
  • Step 12c (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N- methylmethanamine (Compound 0503-54)
  • Step 12d Ethyl 2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)
  • Step 12e Ethyl 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl) methyl)(methyl)amino)pyrimidine-5-carboxylate (Compound 0505)
  • Step 12f 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin- 6- yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 54)
  • the title compound 54 was prepared as a white solid (17 mg, 15%) from 0505-54 (120 mg, 0.22 mmol) and freshly prepared hydroxylamine methanol solution (4.0 mL, 1.77 mol/L) using a procedure similar to that described for compound 3 (Example 1):
  • Example 13 Preparation of 2-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d] pyrimidin-6-yl)methylamino)-N-hydroxypyrimidine-5-carboxamide (Compound 53)
  • Step 13a (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine (Compound 0503-53)
  • Step 13b Ethyl 2-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino) pyrimidine-5-carboxylate (Compound 0504-53)
  • Step 13c Ethyl 2-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl) methylamino)pyrimidine-5-carboxylate (Compound 0505-53)
  • Step 13d 2-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)
  • the title compound 53 was prepared as a light yellow solid (19 mg, 24%>) from 0505-53 (80 mg, 0.15 mmol) and freshly prepared hydroxylamine methanol solution (5.0 mL, 1.77 mol/L) using a procedure similar to that described for compound 3 (Example 1): m.p. 234-237 °C.
  • Step 14b Ethyl 2-(4-((((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)methyl)piperidin- 1 -yl)pyrimidine-5 -carboxylate (Compound
  • Step 14c 2-(4-((((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)methyl)piperidin- 1 -yl)-N-hydroxypyrimidine-5 -carboxamide (Compound 16)
  • hydroxylamine hydrochloride (4.67 g, 67 mmol) in methanol (24 mL) at 0 °C
  • potassium hydroxide 5.61 g, 100 mmol
  • methanol 14 mL
  • Step 15a Ethyl 4-(tert-butoxycarbonyl((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)amino)butanoate (Compound 0404-41)
  • Ethyl 4-aminobutanoate hydrochloride (1.97 g, 11.77 mmol) was solved in chloroform (30 mL) and the pH of mixture was adjusted to 8 ⁇ 9 with triethylamine, then compound 0112 (1.66 g, 5.88 mmol) and tetraisopyl titanate (2.01 g, 7.06 mmol) were added and the mixture was stirred at reflux overnight. Removed the solvent, then 1 ,2- dichloroethane (50 mL) and sodium cyanborohydride (1.48 g, 23.53 mmol) were added and then stirred at room temperature for 12 h.
  • Step 16a Methyl 5-(tert-butoxycarbonyl((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)amino)pentanoate (Compound 0404-42)
  • Step 16b Methyl 5-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(tert-butoxycarbonyl)amino)pentanoate(Compound 0405-42)
  • Step 16c 5-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)-N-hydroxypentanamide(Compound 42)
  • the title compound 42 was prepared as a white solid (23 mg, 13.9%) from 0405-42 (260 mg, 0.45 mmol) and freshly prepared hydroxylamine methanol solution (8.0 mL) followed by deprotection using a procedure similar to that described for compound 41 (Example 15): m.p 145-147 °C.
  • Step 17a Ethyl 6-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)hexanoate (Compound 0404-43)
  • Step 17b Ethyl 6-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)hexanoate (Compound 0405-43) A mixture of compound 0404-43 (343 mg, 0.80 mmol), 0107-3 (294 mg, 1.2 mmol), sodium hydrogen carbonate (294 mg, 2.4 mmol) and
  • Step 17c 6-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)-N-hydroxyhexanamide (43)
  • Step 18a Ethyl 7-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)heptanoate (Compound 0404-44)
  • Step 18b Ethyl 7-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)heptanoate (Compound 0405-44)
  • Step 18c 7-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)-N-hydroxyheptanamide (Compound 44)
  • the title compound 44 was prepared (37 mg, 24%) as a yellow solid from 0405-44 (160 mg, 0.31 mmol) and freshly prepared hydroxylamine methanol solution (3.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 188-190 °C.
  • Example 19 Preparation of 4-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxybutanamide (Compound 101)
  • Step 19a Ethyl 4-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)butanoate (Compound 0404-101)
  • Step 19b Ethyl 4-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)butanoate (Compound 111-48-3)
  • Step 19c 4-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxybutanamide (Compound 101)
  • the title compound 101 was prepared (160 mg, 88%) as a yellow solid from 0405-
  • Example 20 Preparation of 5-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypentanamide (Compound 102)
  • Step 20a Methyl 5-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pentanoate (Compound 0404-102)
  • Step 20b Methyl 5-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pentanoate (Compound 0405-102)
  • Step 20c 5-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxypentanamide (Compound 102)
  • the title compound 102 was prepared (60 mg, 25%) as a yellow solid from 0405- 102 (240 mg, 0.48 mmol) and freshly prepared hydroxylamine methanol solution (8.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 120-122 °C.
  • Example 21 Preparation of 6-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxyhexanamide (Compound 103)
  • Step 21a Ethyl 6-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)hexanoate (Compound 0404-103)
  • Step 21b Ethyl 6-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)hexanoate (Compound 0405-103)
  • Step 21c 6-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxyhexanamide (Compound 103)
  • the title compound 103 was prepared (75 mg, 41%) as a white solid from 0405-103 (190 mg, 0.22 mmol) and freshly prepared hydroxylamine methanol solution (4.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 1 15-118 °C.
  • Example 22 Preparation of 7-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2- d] pyrimidin-6-yl)methyl)(methyl)amino)-N-hydr oxyheptanamide (Compound 104)
  • Step 22a Ethyl 7-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)heptanoate (Compound 0404-104)
  • Step 22b Ethyl 7-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)heptanoate (Compound 0405-104)
  • Step 22c 7-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxyheptanamide (Compound 104)
  • the title compound 104 was prepared (65 mg, 55 >) as a white solid from 0405-104
  • Step 23a 3-Bromo-5-fluoro-2-methylbenzenamine (Compound 0104-69)
  • Step 23b 4-Bromo-6-fluoro-lH-indazole (Compound 0106-69)
  • the title compound 0107-69 (700 mg, 57%) was prepared as a yellow solid from 0106-69 (1.0 g, 4.65 mmol), bis(pinacolato)diboron (1.77 g, 6.98 mmol), PdC12(dppf)2 (380 mg, 0.47 mmol) and dried potassium acetate (1.37 g, 14.0 mmol) in dioxane (40 mL) using a procedure similar to that described for compound 0107-3 (Example 1): LCMS: 263 [M+l] + .
  • Step 23d Ethyl 2-(((2-(6-fluoro-lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5 -carboxylate (Compound 0505-69)
  • Step 23e 2-(((2-(6-Fluoro-lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5 -carboxamide (Compound 69)
  • the title compound 69 was prepared (24 mg, 25%) as a yellow solid from 0505-69 (100 mg, 0.18 mmol) and freshly prepared hydroxylamine methanol solution (10.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 215-217 °C.
  • Step 24b Ethyl 2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(neopentyl) amino)pyrimidine-5-carboxylate (Compound 0504-83)
  • Step 24c Ethyl 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl) (neopentyl)amino)pyrimidine-5-carboxylate (Compound 0505-83)
  • Step 24d 2-(((2-( 1 H-indazol-4-yl)-4-morpholinothieno [3 ,2-d]pyrimidin-6- yl)methyl)(neopentyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 83)
  • the title compound 83 was prepared (191 mg, 65%) as a yellow solid from 0505-83 (300 mg, 0.51 mmol) and freshly prepared hydroxylamine methanol solution (20.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 240-242 °C.
  • Step 25a N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)propan-l -amine (Compound 0503-84)
  • Step 25b Ethyl 2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(propyl)amino)pyrimidine-5-carboxylate (Compound 0504-84)
  • Step 25c Ethyl 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methy l)(propyl)amino)pyrimidine-5 -carboxylate (Compound 0505-84)
  • the title compound 0505-84 was prepared (240 mg, 82%) as a white solid from 0504-84 (250 mg, 0.52 mmol), 0107-3 (154 mg, 0.63 mmol), sodium hydrogen carbonate (132 mg, 1.57 mmol) and bis(triphenylphosphine)palladium(II) chloride (18.5 mg, 0.026 mmol) in toluene (8 mL), ethanol (5 mL) and water (2 mL) using a procedure similar to that described for compound 0505-83 (Example 24): LCMS: 559 [M+l] + ; 1H NMR (400 MHz, DMSO-de
  • Step 25d 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(propyl)amino)-N-hydroxypyrimidine-5 -carboxamide (Compound 84)
  • the title compound 84 was prepared (189 mg, 81%) as a white solid from 0505-84 (240 mg, 0.43 mmol) and freshly prepared hydroxylamine methanol solution (16.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 224-226 °C.
  • Step 26a N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)butan-l -amine (Compound 0503-85)
  • the title compound 0503-85 was prepared (430 mg, 88%>) as a light yellow solid from 0502 (500mg, 1.43 mmol) and butan-l-amine (5mL) in methanol (30 mL) using a procedure similar to that described for compound 0503-84 (Example 25): LCMS: 341
  • Step 26b Ethyl 2-(butyl((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)amino)pyrimidine-5-carboxylate (Compound 0504-84)
  • Step 26c Ethyl 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(butyl)amino)pyrimidine-5-carboxylate (Compound 0505-85)
  • Step 26d 2-(((2-( 1 H-indazol-4-yl)-4-morpholinothieno [3 ,2-d]pyrimidin-6- yl)methyl)(butyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 85)
  • the title compound 85 was prepared (131 mg, 53%) as an off-white solid from 0505-85 (255 mg, 0.45 mmol) and freshly prepared hydroxylamine methanol solution (16.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 234-236 °C.
  • Step 27a 2-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)ethanol (Compound 0503-86)
  • the title compound 0503-86 was prepared (230 mg, 41 >) as a light yellow solid from 0502 (600 mg, 1.72 mmol) and 2-aminoethanol (6 mL) in methanol (60 mL) using a procedure similar to that described for compound 0503-84 (Example 25): LCMS: 329
  • Step 27b Ethyl 2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2- hydroxyethyl)amino)pyrimidine-5-carboxylate (Compound 0504-86)
  • the title compound 0504-86 was prepared (170 mg, 51%) as a white solid from
  • Step 27c Ethyl 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(2-hydroxyethyl)amino)pyrimidine-5-carboxylate (0505-86)
  • the title compound 0505-86 was prepared (120 mg, 60%) as a white solid from
  • Step 27d 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2- hydroxyethyl)amino)-N-hydroxypyrimidine-5-carboxamide (86)
  • the title compound 86 was prepared (42 mg, 36%>) as an off-white solid from 0505- 86 (120 mg, 0.21 mmol) and freshly prepared hydroxylamine methanol solution (8.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 190-194 °C.
  • Step 28a N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2- methoxyethanamine (Compound 0503-90)
  • Step 28b Ethyl 2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2- methoxyethyl)amino)pyrimidine-5-carboxylate (Compound 0504-90)
  • the title compound 0504-90 was prepared (400 mg, 81%) as a yellow solid from
  • Step 28c Ethyl 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(2-methoxyethyl)amino)pyrimidine-5 -carboxylate (Compound 0505-90)
  • Step 28d 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2- methoxyethyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 90)
  • the title compound 90 was prepared (180 mg, 71%) as a white solid from 0505-90 (260 mg, 0.45 mmol) and freshly prepared hydroxylamine methanol solution (15.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 219-222 °C.
  • LCMS 482 [M+l] + .
  • 1H-NMR 400 MHz.
  • Step 29a N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-methylpropan- 1-amine (Compound 0503-93)
  • the title compound 0503-93 was prepared (0.6 g, 88%) as a yellow solid from 0502 (694 g, 2.0 mmol), 2-methylpropan-l -amine (1.5 g, 20 mmol) and DIPEA (2.6 g, 20 mmol) in MeOH (5 mL) using a procedure similar to that described for compound 0503-84 (Example 25): LCMS: 341 [M+l] + .
  • Step 29b Ethyl 2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(isobutyl) amino)pyrimidine-5-carboxylate (Compound 0504-93)
  • the title compound 0504-93 was prepared (500 mg, 57%>) as a yellow solid from
  • Step 29c Ethyl 2-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl) (isobutyl)amino)pyrimidine-5-carboxylate (Compound 0505-93)
  • the title compound 0505-93 was prepared (257 mg, 91 >) as a white solid from
  • Step 29d 2-(((2-( 1 H-indazol-4-yl)-4-morpholinothieno [3 ,2-d]pyrimidin-6- yl)methyl)(isobutyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 93)
  • the title compound 93 was prepared (90mg, 26 %) as a white solid from 0505-93 (357 mg, 0.6 mmol) and freshly prepared hydroxylamine methanol solution (20.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 196-198 °C.
  • Step 30a Isopropyl 6-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)nicotinate (Compound 0309-76)
  • Step 30b Methyl 6-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)nicotinate (Compound 0310-76)
  • Step 30c 6-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)-N-hydroxynicotinamide (Compound 76)
  • the title compound 76 was prepared (23 mg, 16%>) as a brown solid from 0310-76-2
  • Step 31a Ethyl 4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)benzoate (Compound 0309-78)
  • Step 31b Ethyl 4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)benzoate (Compound 0310-78)
  • the title compound, 0310-78 was prepared (85 mg, 33%) as a white solid from 0309-78 (216 mg, 0.5 mmol), 0107-3 (256 mg, 0.53 mmol), sodium hydrogen carbonate (126 mg, 1.5 mmol) and bis(triphenylphosphine)palladium( II ) chloride (18 mg, 0025 mmol) in toluene (4.0 mL), ethanol (2.5 mL) and water (1.5 mL) using a procedure similar to that described for compound 0310-76 (Example 30).
  • Step 31c 4-((2-( 1 H-indazol-4-yl)-4-morpholinothieno [3 ,2-d]pyrimidin-6- yl)methylamino)-N-hydroxybenzamide (Compound 78)
  • the title compound 78 was prepared (41 mg, 28%) as a yellow solid from 0310-78 (150 mg, 0.29 mmol) and freshly prepared hydroxylamine methanol solution (10.0 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. 180-183 °C.
  • Example 32 Preparation of (E)-3-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2- d] pyrimidin-6-yl)methylamino)phenyl)-N-hydroxyacrylamide (Compound 80)
  • Step 32a (E)-ethyl 3-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)phenyl)acrylate (Compound 0309-80)
  • Step 32b (E)-ethyl 3-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)phenyl)acrylae (Compound 0310-80)
  • the title compound, 0310-80 was prepared (490 mg, 69%) as a light yellow solid from 0309-80 (600 mg, 1.31 mmol), 0107-3 (383 mg, 1.57 mmol), sodium hydrogen carbonate (329 mg, 3.92 mmol) and bis(triphenylphosphine)palladium( II ) chloride (46 mg, 0.065 mmol) in toluene (16.0 mL), ethanol (10 mL) and water (4 mL) using a procedure similar to that described for compound 0310-76 (Example 30).
  • Step 32c (E)-3-(4-((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methylamino)phenyl)-N-hydroxyacrylamide (Compound 80)
  • the title compound 80 was prepared (71 mg, 15%) as a light yellow solid from 0310-80 (490 mg, 0.91 mmol) and freshly prepared hydroxylamine methanol solution (20.0 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. >300
  • Step 33a (E)-ethyl 3-(4-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl) (methyl)amino)phenyl)acrylate (Compound 0309-81)
  • Step 33b (E)-ethyl 3-(4-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl) methyl)(methyl)amino)phenyl)acrylate (Compound 0310-81)
  • 0309- 81 (240 mg, 0.5 mmol), 0107-3 (135 mg, 0.55 mmol), NaHC0 3 (126 mg, 1.5 mmol), and bis(triphenylphosphine)palladium( II ) chloride (18 mg, 0.025 mmol) in toluene (4 mL), ethanol (2 mL) and water (1 mL) using a procedure similar to that described for compound
  • Step 33c (E)-3-(4-(((2-(lH-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)phenyl)-N-hydroxyacrylamide (Compound 81)
  • the title compound 81 was prepared (24 mg, 10 %>) as a light yellow solid from
  • Step 34a N-(3-bromophenyl)acetamide (Compound 0601-107) To the solution of 3-bromoaniline (6.3 g, 63.7mmol) in CH 2 CI 2 (50 mL) was added acetyl chloride (3.75 g, 47.7 mmol) and TEA (7.4 g, 73.4 mmol) at 0 °C, stirred for 2 hours. The mixture was washed with water, brine, dried over Na 2 S0 4 , filtered, and concentrated under reduced pressure to give the title compound 0601-107 (7.8 g, 99.3%) as a brown solid. LCMS: 215 [M+l] + .
  • Step 34b N-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetamide (Compound 0602-107)
  • Step 34c Ethyl 2-(((2-(3-acetamidophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5-carboxylate (Compound 0603-107)
  • the title compound, 0603-107 was prepared (160 mg, 99%) as a gray solid from 0504-54 (130 mg, 0.30 mmol), 0602-107 (84 mg, 0.7 mmol), sodium hydrogen carbonate (74 mg, 0.88 mmol) and bis(triphenylphosphine)palladium( II ) chloride (12 mg, 0.014 mmol) in toluene (2.5 mL), ethanol (1.6 mL) and water (0.7 mL) using a procedure similar to that described for compound 0310-76 (Example 30).
  • Step 34d 2-(((2-(3-acetamidophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 107)
  • the title compound 107 was prepared (64 mg, 50%) as a white solid from 0603-107
  • Step 35a Ethyl 6-(2-chloro-4-morpholinothieno [3, 2-d] pyrimidin-6-ylamino) hexanoate (Compound 0602-108)
  • Step 35b Ethyl 2-(((2-(3-(dimethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5-carboxylate (Compound 0603-108)
  • the title compound 0603-108 was prepared (245 mg, 91%) as a white solid from 0504-54 (224 mg, 0.5 mmol), 0602-108 (490 mg, 2.0 mmol), NaHC0 3 (126 mg, 1.5 mmol) and bis(triphenylphosphine)palladium( II ) chloride (18 mg, 0.025 mmol) in toluene (4 mL), ethanol (2 mL) and water (1 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 35c 2-(((2-(3-(dimethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 108)
  • the title compound 108 was prepared (35 mg, 15 %>) as a yellow solid from 0603- 108 (130 mg, 0.23 mmol) and freshly prepared hydroxylamine methanol solution (20 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. 172-175 °C.
  • Step 36a Ethyl 2-(methyl((4-morpholino-2-(pyridin-3-yl)thieno[3,2-d]pyrimidin-6- yl)methyl)amino)pyrimidine-5-carboxylate (compound 0603-109)
  • the title compound, 0603-109 was prepared (140 mg, 94%) as a yellow solid from 0504-54 (135 mg, 0.30 mmol), 3-pyridylboronic acid (41 mg, 0.60 mmol), NaHC0 3 (76 mg, 0.90 mmol) and Pd(dppf)2Cl2 (11 mg, 0.015 mmol) in toluene (2.5 mL), ethanol (1.6 mL) and water (0.7 mL) using a procedure similar to that described for compound 0603- 107 (Example 30).
  • LCMS 492 [M+l] + .
  • Step 36b N-hydroxy-2-(methyl((4-morpholino-2-(pyridin-3-yl)thieno[3,2-d]pyrimidin-6- yl)methyl)amino)pyrimidine-5-carboxamide (Compound 109)
  • the title compound 109 was prepared (30 mg, 44%) as a yellow solid from 0603-
  • Step 37a 5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (Compound 0602-110)
  • the title compound, 0602-110 was prepared (500 mg, 23%) as an oil from 2-amino- 5-bromopyridine (1.73 g, 10 mmol), bis(pinacolato)diboron (3.81 g, 15 mmol), potassium acetate (3 g, 30 mmol), and PdC ⁇ dppfh (408 mg, 5 mmol) using a procedure similar to that described for compound 0602-107 (Example 34).
  • the title compound, 0603-110 was prepared (200 mg, 59%) as a white solid from 0602-110 (300 mg, 0.67 mmol), 0504-54 (176 mg, 0.8 mmol), NaHC0 3 (172 mg, 2mmol) and bis(triphenylphosphine)palladium( II ) chloride (23 mg, 0.0335 mmol) in toluene (8 mL), ethanol (5 mL) and water (2 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 37c 2-(((2-(6-Aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 110)
  • the title compound 110 was prepared (25 mg, 13 %) as a yellow solid from 0603- 110 (200 mg, 0.4 mmol) and freshly prepared hydroxylamine methanol solution (20 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. 175-181 °C.
  • Step 38a 5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 0602-115)
  • Step 38b Ethyl 2-(((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin- 6- yl)methyl)(methyl)amino)pyrimidine-5-carboxylate (Compound 0603-115)
  • the title compound, 0603-115 was prepared (110 mg, 51%) as a white solid from 0602-115 (120 mg, 0.54 mmol), 0504-54 (200 mg, 0.45 mmol), NaHC0 3 (114 mg, 1.35 mmol), and bis(triphenylphosphine)palladium( II ) chloride (16 mg, 0.0225 mmol) in toluene (8 mL), ethanol (5 mL) and water (2 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 38c 2-(((2-(2-Aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 115)
  • the title compound 115 was prepared (25 mg, 23 %) as a yellow solid from 0603-
  • Step 39a 5-Bromo-N-methylpyrimidin-2-amine (compound 0601-116) and 5-bromo-N,N- dimethylpyrimidin-2-amine (compound 0601-117)
  • Step 39b N-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 0602-116)
  • the title compound, 0602-116 was prepared (350 mg, 50%) as yellow solid from 5- bromo-N-methylpyrimidin-2-amine (0.56 g, 3 mmol), bis(pinacolato)diboron (1.14 g, 4.5 mmol), potassium acetate (0.88 g, 9 mmol), and Pd(dppf) 2 Ci 2 (490 mg, 0.6 mmol) using a procedure similar to that described for compound 0602-107 (Example 34).
  • Step 39c Ethyl 2-(methyl((2-(2-(methylamino)pyrimidin-5-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate (Compound 0603-116)
  • the title compound, 0603-116 was prepared (100 mg, 64%) as a yellow solid from 0504-54 (135 mg, 0.30 mmol), 0602-116 (106 mg, 0.45 mmol), NaHC0 3 (76 mg, 0.90 mmol) and Pd(dppf) 2 Ci 2 (11 mg, 0.015 mmol) in toluene (2.5 mL), ethanol (1.6 mL) and water (0.7 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 39d N-hydroxy-2-(methyl((2-(2-(methylamino)pyrimidin-5-yl)-4- morpholinothieno [3 ,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5 -carboxamide
  • the title compound 116 was prepared (50 mg, 54%>) as a yellow solid from 0603-
  • Step 40a N,N-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 0602-117)
  • Step 40b Ethyl 2-(((2-(2-(dimethylamino)pyrimidin-5-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate (0603-117)
  • Step 40c 2-(((2-(2-(Dimethylamino)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin- 6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 117)
  • the title compound 117 was prepared (60 mg, 66%) as a yellow solid from 0603- 117 (93 mg, 0.17 mmol) and freshly prepared hydroxylamine methanol solution (5 mL) using a procedure similar to that described for compound 3 (Example 1). m.p.: 200-206 °C.
  • Step 41a Ethyl 2-(methyl((4-morpholino-2-(pyrimidin-5-yl)thieno[3,2-d]pyrimidin-6- yl)methyl)amino)pyrimidine-5 -carboxylate (Compound 0603-119)
  • the title compound, 0603-119 was prepared (160 mg, 46%>) as a white solid from 0504-54 (314 mg, 0.7 mmol), pyrimidin-2-ylboronic acid (175 mg, 1.4 mmol), NaHC0 3 (176 mg, 2.1 mmol) and bis(triphenylphosphine)palladium( II ) chloride (24 mg, 0.03 mmol) in toluene (8 mL), ethanol (5 mL) and water (3 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 41b N-hydroxy-2-(methyl((4-morpholino-2-(pyrimidin-5 -yl)thieno [3 ,2-d]pyrimidin- 6-yl)methyl)amino)pyrimidine-5-carboxamide (Compound 1 19)
  • the title compound 119 was prepared (60 mg, 40%) as a white solid from 0603-1 19 (150 mg, 0.3 mmol) and freshly prepared hydroxylamine methanol solution (5 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. 159-160 °C.
  • Step 42a 5-Bromo-2-methylpyrimidine (Compound 0601-120)
  • Step 42b 2-Methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (Compound 0602-120)
  • the title compound, 0602-120 was prepared (100 mg, 52%) as a yellow oil from 0601-120 (150 mg, 0.87 mmol), bis(pinacolato)diboron (331 mg, 1.3 mmol), PdCl 2 (dppf) 2 (21 mg, 0.026 mmol) and dried potassium acetate (256 mg, 2.62 mmol)using a procedure similar to that described for compound 0602-107 (Example 34).
  • Step 42c Ethyl 2-(methyl((2-(2-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d] pyrimidin-6-yl)methyl)amino)pyrimidine-5 -carboxylate (Compound 0603-120)
  • the title compound, 0603-120 was prepared (210 mg, 74%) as a off-white solid from 0504-54 (250 mg, 0.56 mmol), 0602-120 (880 mg, 4 mmol), sodium hydrogen carbonate (168 mg, 2 mmol), and bis(triphenylphosphine)palladium( II ) chloride (23 mg, 0.03 mmol) in toluene (8 mL), ethanol (5mL) and water (2 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 42d N-hydroxy-2-(methyl((2-(2-methylpyrimidin-5-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)amino)pyrimidine-5 -carboxamide (Compound 120)
  • the title compound 120 was prepared (150 mg, 73%) as a white solid from 0603-
  • Step 43a 5-Bromo-2-ethylpyrimidine (0601-121)
  • Step 43b 2-Ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (Compound 0602-121)
  • the title compound, 0602-121 was prepared (crude 3.7 g) as a yellow oil from 0601-121 (1.7 g, 9.1 mmol), bis(pinacolato)diboron (3.5 g, 13.6 mmol), PdCl 2 (dppf) 2 (222 mg, 0.27 mmol) and potassium acetate (2.7 g, 27 mmol) using a procedure similar to that described for compound 0602-107 (Example 34).
  • the title compound, 0603-121 was prepared (120 mg, 41%>) as a yellow solid from 0504-54 (250 mg, 0.56 mmol), 0602-121 (3.7 g, crude), sodium hydrogen carbonate (168 mg, 2 mmol) and bis(triphenylphosphine)palladium( II ) chloride (23 mg, 0.03 mmol) in toluene (8 mL), ethanol (5mL) and water (2 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 43d N-Hydroxy-2-(methyl((2-(2-methylpyrimidin-5-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)amino)pyrimidine-5 -carboxamide (Compound 121)
  • the title compound 121 was prepared (66 mg, 56%) as a white solid from 0603-121
  • Step 44a 5-Bromo-4-methylpyrimidin-2-amine (Compound 0601-125)
  • Step 44b 4-Methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Compound 0602-125)
  • the title compound, 0602-125 was prepared (430 mg, 69%) as a grey solid from 0601-125 (500 mg, 2.66 mmol), bis(pinacolato)diboron (1.01 g, 4.0 mmol), PdCl 2 (dppf) 2 (217.2 mg, 0.27 mmol), potassium acetate (783 mg, 7.98 mmol) using a procedure similar to that described for compound 0602-107 (Example 34).
  • Step 44c Ethyl 2-(((2-(2-amino-4-methylpyrimidin-5-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate (Compound 0603-125)
  • the title compound, 0603-125 was prepared (160 mg, 55%) as a white solid from
  • Step 44d 2-(((2-(2-Amino-4-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin- 6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 125)
  • the title compound 125 was prepared (92 mg, 62 %) as a white solid from 0603- 125 (150 mg, 0.29 mmol) and freshly prepared hydroxylamine methanol solution (20 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. 195-198 °C.
  • Step 45a 2-(3-Methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Compound 0602-130)
  • the title compound, 0602-130 was prepared (800 mg, 68%) as an oil from 1-bromo- methoxybenzene (930 mg, 5.0 mmol), bis(pinacolato)diboron (2.54 g, 10 mmol), potassium acetate (1.47 g, 15 mmol), and PdCi 2 (dppf) 2 (204 mg, 0.25 mmol) using a procedure similar to that described for compound 0602-107 (Example 34).
  • Step 45b Ethyl 2-(((2-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5 -carboxylate (Compound 0603-130)
  • the title compound, 0603-130 was prepared (120 mg, 51%) as a white solid from 0602-130 (126 mg, 0.54 mmol), 0504-54 (200 mg, 0.45 mmol), NaHC0 3 (114 mg, 1.35 mmol), and bis(triphenylphosphine)palladium( II ) chloride (16 mg, 0.0225 mmol) in toluene (8 mL), ethanol (5 mL), and water (2 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 45c N-hydroxy-2-(((2-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5-carboxamide (Compound 130)
  • the title compound 130 was prepared (15 mg, 15 %) as a yellow solid from 0603- 130 (110 mg, 0.2 mmol) and freshly prepared hydroxylamine methanol solution (20 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. 179-181 °C.
  • Step 46a 3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Compound 0602-132)
  • the title compound, 0602-132 was prepared (600 mg, 68%) as an oil from 3- bromophenol (700 mg, 4.0 mmol), bis(pinacolato)diboron (1.5 g, 6 mmol), potassium acetate (1.2 g, 12 mmol), and PdC12(dppf)2 (163 mg, 0.2 mmol) using a procedure similar to that described for compound 0602-107 (Example 34).
  • LCMS 221 [M+l] + .
  • Step 46b Ethyl 2-(((2-(3-hydroxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5-carboxylate (Compound 0603-132)
  • the title compound, 0603-132 was prepared (160 mg, 47%) as a white solid from 0602-132 (300 mg, 0.67 mmol), 0504-54 (176 mg, 0.8 mmol), NaHC0 3 (172 mg, 2mmol), and bis(triphenylphosphine)palladium( II ) chloride (23 mg, 0.0335 mmol) in toluene (8 mL), ethanol (5 mL) and water (2 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 46c N-hydroxy-2-(((2-(3-hydroxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5-carboxamide (Compound 132)
  • the title compound 132 was prepared (53 mg, 34 %) as a yellow solid from 0603- 132 (160 mg, 0.32 mmol) and freshly prepared hydroxylamine methanol solution (20 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. 175-181 °C.
  • Step 47a Ethyl-2-(((2-(3-aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5-carboxylate (compound 0603-134)
  • Step 47b 2-(((2-(3-Aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 134)
  • the title compound 134 was prepared (35 mg, 28%) as a white solid from 0603-134 (130 mg, 0.25 mmol) and freshly prepared hydroxylamine methanol solution (4 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. 179-182 °C.
  • Step 48a N-(4-bromobenzyl)acetamide (Compound 0601-135)
  • Step 48b N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)acetamide
  • Step 48c Methyl 2-(((2-(4-(aminomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl) (methyl)amino)pyrimidine-5-carboxylate (Compound 0603-135)
  • Step 49a N-(3-bromobenzyl)acetamide (Compound 0601-137)
  • Step 49b N-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)acetamide
  • the title compound, 0602-137 was prepared (1.0 g, 72%) as a yellow solid from 0601-137 (1.2 g, 5 mmol), bis(pinacolato)diboron (1.9 g, 7.5 mmol), potassium acetate (1.47 g, 15 mmol), and Pd(dppf) 2 Cl 2 (410 mg, 0.5 mmol) using a procedure similar to that described for compound 0602-107 (Example 34).
  • Step 49c Methyl 2-(((2-(3-(aminomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl) methyl)(methyl)amino)pyrimidine-5-carboxylate (Compound 0603-137)
  • 0602-137 400 mg, 1.46 mmol
  • 0504-54 522 mg, 1.16 mmol
  • NaHC0 3 368 mg, 4.4 mmol
  • bis(triphenylphosphine)palladium( II ) chloride 104 mg, 0.146 mmol
  • toluene 4 mL
  • ethanol 2 mL
  • water 0.5 mL
  • the title compound 137 was prepared (46 mg, 18%) as a light yellow solid from 0603-137 (250 mg, 0.5 mmol) and freshly prepared hydroxylamine methanol solution (20 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. 173-176 °C.
  • Step 50a (3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol (Compound 0602-138)
  • the title compound, 0602-138 was prepared (300 mg, 43%) as a yellow oil from m- bromobenzyl alcohol (0.56 g, 3 mmol), bis(pinacolato)diboron (1.14 g, 4.5 mmol), potassium acetate (1.32 g, 9 mmol), and Pd(dppf) 2 Cl 2 (490 mg, 0.6 mmol) using a procedure similar to that described for compound 0602-107 (Example 34).
  • Step 50b Ethyl 2-(((2-(3-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5 -carboxylate (0603-138)
  • the title compound, 0603-138 was prepared (140 mg, 90%) as a white solid from 0504-54 (135 mg, 0.30 mmol), 0602-138 (105 mg, 0.45 mmol), NaHC0 3 (76 mg, 0.90 mmol), and Pd(dppf) 2 Ci2 (11 mg, 0.015 mmol) in toluene (2.5 mL), ethanol (1.6 mL), and water (0.7 mL) using a procedure similar to that described for compound 0603-107
  • Step 50c N-hydroxy-2-(((2-(3-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5 -carboxamide
  • the title compound 138 was prepared (30 mg, 44%>) as a light yellow solid from 0603-138 (70 mg, 0.13 mmol) and freshly prepared hydroxylamine methanol solution (10 mL) using a procedure similar to that described for compound 3 (Example 1). mp 160-164 °C.
  • Step 51a l-Bromo-3-(methoxymethyl)benzene (Compound 0601-139) To a solution of m-bromobenzyl alcohol (1.0 g, 5.3 mmol) in THF (10 mL) was added NaH (0.26 g, 10.6 mmol) at 0 °C, stirred for 10 minutes, followed by addition of iodomethane (1.1 g, 7.9 mmol). The resulting reaction mixture was stirred for 1 hour. To the mixture ethyl acetate (30 mL) was added, washed with water, brine, dried over Na 2 S0 4 , filtered, and concentrated under reduced pressure to give the title compound 0601-139 (1.0 g, 93%) as an oil.
  • Step 51c Ethyl-2-(((2-(3-(methoxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5-carboxylate (Compound 0603 - 139)
  • the title compound, 0603-139 was prepared (180 mg, 71%) as a white solid from 0504-54 (210 mg, 0.46 mmol), 0602-139 (174 mg, 0.7 mmol), sodium hydrogen carbonate (118 mg, 1.4 mmol), and bis(triphenylphosphine)palladium( II ) chloride (16 mg, 0.02 mmol) in toluene (8 mL), ethanol (2 mL), and water (1 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 51d N-hydroxy-2-(((2-(3-(methoxymethyl)phenyl)-4-morpholinothieno[3 ,2- d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide (Compound 139)
  • the title compound 139 was prepared (56 mg, 47%) as an orange solid from 0603- 139 (120 mg, 0.22 mmol) and freshly prepared hydroxylamine methanol solution (8 mL) using a procedure similar to that described for compound 3 (Example 1). m.p. 178-181 °C.
  • Step 52a (4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol (compound 0602-140)
  • the title compound, 0602-140 was prepared (670 mg, 94%) as an oil from (4- bromophenyl)methanol (0.56 g, 3 mmol), bis(pinacolato)diboron (1.14 g, 4.5 mmol), potassium acetate (1.32 g, 9 mmol), and PdCl 2 (dppf) 2 (490 mg, 0.6 mmol) using a procedure similar to that described for compound 0602-107 (Example 34).
  • Step 52b Ethyl 2-(((2-(4-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5 -carboxylate (compound 0603-140)
  • the title compound, 0603-140 was prepared (120 mg, 77%) as a white solid from
  • Step 52c N-Hydroxy-2-(((2-(4-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide (compound 140)
  • the title compound 140 was prepared (61 mg, 63%>) as a yellow solid from 0603-
  • Step 53b 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl acetate (Compound 0602- 141)
  • the title compound, 0602-141 was prepared (2.3 g, 80%) as an oil from 0601-141 (2.4 g, 10.5 mmol), bis(pinacolato)diboron (4.1 g, 16.3 mmol), potassium acetate (3.2 g, 32.7 mmol), and PdCl 2 (dppf) 2 (89 mg, 0.11 mmol) using a procedure similar to that described for compound 0602-107 (Example 34).
  • Step 53c Ethyl 2-(((2-(2-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5 -carboxylate (Compound 0603-141)
  • the title compound, 0603-141 was prepared (80 mg, 17%) as a white solid from 0504-54 (420 mg, 0.92 mmol), 0602-141 (386 mg, 1.4 mmol), sodium hydrogen carbonate (236 mg, 2.8 mmol), and bis(triphenylphosphine)palladium( II ) chloride (32 mg, 0.04 mmol) in toluene (8 mL), ethanol (4 mL), and water (2 mL) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 53d N-hydroxy-2-(((2-(2-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methy l)(methyl)amino)pyrimidine-5 -carboxamide (Compound 141)
  • the title compound 141 was prepared (58 mg, 37%) as a yellow solid from 0603-
  • Step 54b 3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (Compound 0602- 142)
  • Step 54c Ethyl 2-(((2-(3-carbamoylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)pyrimidine-5 -carboxylate (Compound 0603-142)
  • the title compound, 0603-142 was prepared (180 mg, 50%>) as a yellow solid from 0504-54 (305 mg, 0.68 mmol), 0602-142 (200 mg, 0.81 mmol), Pd(PPh 3 ) 2 Cl 2 (21 mg, 0.03 mmol), and NaHC0 3 (171 mg, 2.04 mmol) in toluene (5 mL), ethanol (3 ml), and water (1.3 ml) using a procedure similar to that described for compound 0603-107 (Example 30).
  • Step 54d 2-(((2-(3-carbamoylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6- yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide (Compound 142).

Abstract

La présente invention concerne une méthode de traitement d'un cancer associé à une mutation K-ras chez un sujet nécessitant un tel traitement. La méthode comprend les étapes suivantes : (1) identification d'un sujet souffrant d'un cancer associé à une mutation K-ras ; et (2) administration au sujet (i) d'un inhibiteur de PI3 kinase et (ii) d'un inhibiteur de HDAC, l'inhibiteur de PI3 kinase et l'inhibiteur de HDAC étant administrés à des quantités qui constituent ensemble une quantité thérapeutiquement active.
PCT/US2011/032683 2010-04-16 2011-04-15 Traitement de cancers présentant des mutations k-ras WO2011130628A1 (fr)

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CN2011800290564A CN102970868A (zh) 2010-04-16 2011-04-15 具有k-ras突变的癌症的治疗
AU2011239537A AU2011239537A1 (en) 2010-04-16 2011-04-15 Treatment of cancers having K-ras mutations
EP11769663.3A EP2557923A4 (fr) 2010-04-16 2011-04-15 Traitement de cancers présentant des mutations k-ras
CA2795952A CA2795952A1 (fr) 2010-04-16 2011-04-15 Traitement de cancers presentant des mutations k-ras
JP2013505177A JP2013525308A (ja) 2010-04-16 2011-04-15 Ｋ−ｒａｓ変異を有する癌の治療
US13/652,152 US20130102595A1 (en) 2011-04-15 2012-10-15 Treatment of cancers having k-ras mutations

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