US20100041663A1 - Organic Compounds as Smo Inhibitors - Google Patents

Organic Compounds as Smo Inhibitors Download PDF

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US20100041663A1
US20100041663A1 US12/503,565 US50356509A US2010041663A1 US 20100041663 A1 US20100041663 A1 US 20100041663A1 US 50356509 A US50356509 A US 50356509A US 2010041663 A1 US2010041663 A1 US 2010041663A1
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compound
mmol
dimethyl
methyl
alkyl
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Feng He
Stefan Peukert
Karen Miller-Moslin
Naeem Yusuff
Zhuoliang Chen
Bharat Lagu
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Novartis AG
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Novartis AG
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Publication of US20100041663A1 publication Critical patent/US20100041663A1/en
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, ZHUOLIANG, YUSUFF, NAEEM, HE, FENG, MILLER-MOSLIN, KAREN, PEUKERT, STEFAN, LAGU, BHARAT
Priority to US13/553,870 priority patent/US8481542B2/en
Priority to US13/905,686 priority patent/US9409871B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention includes compounds of formula (I) wherein R4 is C(O)OC 1-8 alkyl, CF 3 , C(O)OR6, C(O)NR6R8, C 1-8 haloalkyl, C 1-8 alkylOH, C(O)R6, SO 2 R6, C(O)NHC 1-8 alkylR6, C(CH 3 )(CH 3 )(OH), C(O)CH 3 , C(CH 2 )CH 3 , or C(CH 3 )(CH 2 OH)OH; and R6 and R8 are independently H, C 1-8 alkyl, C 1-8 alkenyl, C 3-14 cycloalkyl, a C 6-14 aryl group, a 5-14 membered heteroaryl group, or a 3-14 membered cycloheteroalkyl group.
  • the present invention includes compounds of formula (I) wherein R7 is
  • R6 and R8 are independently H, C 1-8 alkyl, such as methyl, ethyl, propyl, or butyl; C 2-8 alkenyl, such as alkenyl, propenyl; C 3-14 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; a C 6-14 aryl group, such as phenyl; a 5-14 membered heteroaryl group, such as pyridinyl or pyrimidinyl; a 3-14 membered cycloheteroalkyl group, such as morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl; C 1-8 haloalkyl, such as CF 3 ; C 1-8 alkylOH, C 1-8 alkoxy, such as methoxy or ethoxy; or two R6, or R6 and R8 on one atom can form a
  • R4 is C(O)CH 3 , C(O)NH-phenyl, C(O)OH, CF 3 , C(CH 3 )(CH 3 )OH, C(O)OCH 3 , CF 3 , or C(O)OCH 2 CH 3 .
  • the present invention includes compounds of formula (I) wherein R1 is
  • the present invention includes compounds of formula (I) wherein R4 is C(O)OC 1-8 alkyl, CF 3 , C(O)OR6, C(O)NR6R8, C 1-8 haloalkyl, C 1-8 alkylOH, C(O)R6, SO 2 R6, C(O)NHC 1-8 alkylR6, C(CH 3 )(CH 3 )(OH), C(O)CH 3 , CH 2 —CH 2 —CH 3 , or C(CH 3 )(CH 2 OH)OH.
  • R6 and R8 are independently H, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl, CF 3 , methoxy, two R6, or R6 and R8 on one atom can form a heteroatom containing ring, such as a 5-14 membered heteroaryl group, such as pyridinyl or pyrimidinyl; or a 3-14 membered cycloheteroalkyl group, such as piperidinyl or piperazinyl.
  • the present invention includes compounds of formula (I) wherein R4 is
  • Y is a bond, C 1-8 alkylene, such as methylene, ethylene, propylene —C(O)—, —C(O)O—, —CH(OH)—, or —C(O)NR10, where R10 is C 1-8 alkyl, such as methyl, ethyl, propyl, or butyl, or H.
  • R10 is C 1-8 alkyl, such as methyl, ethyl, propyl, or butyl, or H.
  • Y is a bond, methylene, —C(O)O—, or C(O)NH.
  • Y is a bond.
  • the methods of the present invention may employ compounds of the invention (e.g., a compound of Formula I) as formulated as pharmaceutical preparations comprising a pharmaceutically acceptable excipient or carrier, and said preparations may be administered to a patient to treat conditions involving unwanted cell proliferation such as cancers and/or tumors (such as medulloblastoma, basal cell carcinoma, etc.), and non-malignant hyperproliferative disorders.
  • compounds of the invention e.g., a compound of Formula I
  • pharmaceutical preparations comprising a pharmaceutically acceptable excipient or carrier
  • said preparations may be administered to a patient to treat conditions involving unwanted cell proliferation such as cancers and/or tumors (such as medulloblastoma, basal cell carcinoma, etc.), and non-malignant hyperproliferative disorders.
  • Hedgehog gain-of-function refers to an aberrant modification or mutation of a Ptc gene, Hedgehog gene, or smoothened gene, or a change (e.g., decrease) in the level of expression of such a gene, which results in a phenotype which resembles contacting a cell with a Hedgehog protein, e.g., aberrant activation of a Hedgehog pathway.
  • Transcriptional and translational control sequences are DNA regulatory sequences, such as promoters, enhancers, terminators, and the like, that provide for the expression of a coding sequence in a host cell.
  • polyadenylation signals are control sequences.
  • inhibitors refer to inhibitory molecules identified using in vitro and in vivo assays for Hh pathway function, e.g., Smo antagonists.
  • inhibitors and antagonists refer to compounds or agents that decrease signaling that occurs via the Hh pathway.
  • Inhibitors may be compounds that decrease, block, or prevent, signaling via this pathway.
  • malignant hyperproliferative disorder(s) includes but is not limited to cancers, neuronal proliferative disorders, bone marrow proliferative diseases and leukemias.
  • Perhaloalkyl groups i.e., alkyl groups wherein all of the hydrogen atoms are replaced with halogen atoms (e.g., CF 3 and C 2 F 5 ), are included within the definition of “haloalkyl.”
  • a C 1-10 haloalkyl group can have the formula —C i H 2i+1 ⁇ j X j , wherein X is F, Cl, Br, or I, i is an integer in the range of 1 to 10, and j is an integer in the range of 0 to 21, provided that j is less than or equal to 2i+1.
  • cycloalkyl refers to a non-aromatic carbocyclic group including cyclized alkyl, alkenyl, and alkynyl groups.
  • a cycloalkyl group can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, adamantyl, and spiro[4.5]decanyl groups, as well as their homologs, isomers, and the like.
  • aryl refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system where at least one of the rings in the ring system is an aromatic hydrocarbon ring and any other aromatic rings in the ring system include only hydrocarbons.
  • a monocyclic aryl group can have from 6 to 14 carbon atoms and a polycyclic aryl group can have from 8 to 14 carbon atoms.
  • the aryl group can be covalently attached to the defined chemical structure at any carbon atom(s) that result in a stable structure.
  • isotopes suitable for inclusion in the compounds of the invention comprises isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • hydrogen such as 2 H and 3 H
  • carbon such as 11 C, 13 C and 14 C
  • chlorine such as 36 Cl
  • fluorine such as 18 F
  • iodine such as 123 I and 125 I
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 O, 17 O and 18 O
  • phosphorus such as 32 P
  • sulphur such as 35 S.
  • the methods of the present invention include the use of compounds of Formula I which agonize Ptc inhibition of Hedgehog signaling, such as by inhibiting activation of smoothened or downstream components of the signal pathway, in the regulation of repair and/or functional performance of a wide range of cells, tissues and organs, including normal cells, tissues, and organs, as well as those having the phenotype of Ptc loss-of-function, Hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function.
  • a compound of Formula I can inhibit activation of a Hedgehog pathway by binding to smoothened or its downstream proteins.
  • cells induce their neighbors to differentiate like themselves (homeogenetic induction); in other cases a cell inhibits its neighbors from differentiating like itself.
  • Cell interactions in early development may be sequential, such that an initial induction between two cell types leads to a progressive amplification of diversity.
  • inductive interactions occur not only in embryos, but in adult cells as well, and can act to establish and maintain morphogenetic patterns as well as induce differentiation.
  • N-terminal Hedgehog peptide As a result of the tethering, a high local concentration of N-terminal Hedgehog peptide is generated on the surface of the Hedgehog producing cells. It is this N-terminal peptide which is both necessary and sufficient for short- and long-range Hedgehog signaling activities.
  • lymphoma e.g., e.g., B-cell lymphoma, plasmoblastoma, plasmacytoma or CLL
  • the methods entail administering to the subject a pharmaceutical composition containing an effective amount of a compound of Formula I to inhibit the hedgehog signaling pathway.
  • the subject can be one who is diagnosed with lymphoma, with or without metastasis, at any stage of the disease (e.g., stage I to IV, Ann Arbor Staging System).
  • Lymphomas suitable for treatment with methods of the invention include but are not limited to Hodgkin's disease and non-Hodgkin's disease.
  • Non-Hodgkin's lymphoma includes but is not limited to (1) slow-growing lymphomas and lymphoid leukemia (e.g., chronic lymphocytic leukemia, small lymphocytic leukemia, lymphoplasmacytoid lymphoma, follicle center lymphoma, follicular small cleaved cell, follicular mixed cell, marginal zone B-cell lymphoma, hairy cell leukemia, plasmacytoma, myeloma, large granular lymphocyte leukemia, mycosis fungoides, szary syndrome); (2) moderately aggressive lymphomas and lymphoid leukemia (e.g., prolymphocytic leukemia, mantle cell lymphoma, follicle center lymphoma, follicular small cleaved cell, follicle center lymphoma, chronic lymphocytic leukemia/prolymphocytic leukemia, angiocentric lymphoma, an
  • Some of the therapeutic methods of the invention are particularly directed to treating lymphomas or myelomas which do not express Gli3.
  • Gli1 and Gli2 were expressed in all lymphomas, detectable Gli3 expression was present mainly in lymphomas which were resistant to Hh pathway inhibition by cyclopamine.
  • subjects with lymphomas can be first examined for expression of Gli3 in a lymphoma cell sample obtained from the subject.
  • Compounds of the invention are useful in the treatment of basal cell carcinoma (BCC or rodent ulcer), tumors of the adrenal glands arising from the cortex or the medulla part of the adrenal gland medulla, and ovarian tumors.
  • BCC basal cell carcinoma
  • tumors of the adrenal glands arising from the cortex or the medulla part of the adrenal gland medulla, and ovarian tumors.
  • dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • tumor treatment approaches including surgery, ionizing radiation, photodynamic therapy, implants, e.g. with corticosteroids, hormones, or they may be used as radiosensitizers.
  • implants e.g. with corticosteroids, hormones, or they may be used as radiosensitizers.
  • anti-inflammatory and/or antiproliferative treatment combination with anti-inflammatory drugs is included. Combination is also possible with antihistamine drug substances, bronchodilatatory drugs, NSAID or antagonists of chemokine receptors.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • the free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, and the like.
  • a compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
  • the diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions,” John Wiley And Sons, Inc., 1981.
  • the present invention is further exemplified, but not limited, by the following representative examples, which are intended to illustrate the invention and are not to be construed as being limitations thereon.
  • the structure of final products described herein can be confirmed by standard analytical methods, e.g., spectrometric and spectroscopic methods (e.g. MS, NMR). Abbreviations used are those conventional in the art.
  • Compounds are purified by standard methods, e.g. crystallization, flash chromatography or reversed phase HPLC.
  • reaction mixture is quenched with sat. aq. NH 4 Cl at ⁇ 78° C. and diluted with DCM.
  • the organic solution is washed with brine, dried over Na 2 SO 4 and concentrated to afford the crude material.
  • the resulting solid is purified by prep. HPLC, eluting with 10%-100% acetonitrile in water (both mobile phases modified by 3% n-PrOH). Fractions containing the desired product are combined and freeze-dried to afford a white solid (25 mg, 42%).
  • Example 54 is prepared from example 53 by addition of MeMgI as described for example 52. HR MS (m/z, MH+) meas. 434.2666, calc. 434.2668.
  • ketones XId can act as electrophiles for metallo-organic reagents such as R′′—Li to provide tertiary alcohol examples Il. Transformation of the hydroxyl group with fluorination reagants e.g. Deoxofluor yields further examples In.
  • Ketones X Id can be used in reductive amination reactions with amines and e.g. NaBH(OAc) 3 as reducing agent to yield examples Io.
  • Compound 30 is prepared from compound 10 and piperidine-4-carbonitrile following the procedure similar to what described for compound 3.
  • reaction mixture is allowed to stand for 3.5 h at room temperature and the reaction mixture is then concentrated under reduced pressure to yield a semi-solid which is recrystallized from heptane to yield crude product.
  • Purification by HPLC of the crude product with acetonitrile in water (from 10% to 100% with 3% 1-propanol) at 220 nm wavelength detection provides the desired product as off white powder (28 mg, 22%).
  • This compound as a TFA salt is prepared from compound 24 and 1,2,3,4-tetrahydro-isoquinoline following a procedure used in example 56.
  • Scheme 6 shows a general synthetic scheme for the preparation of compounds of Formula Ip.
  • Substituted 1,4-dichloropyridazines II can be reacted with organo-zinc reagents under palladium catalysis to form intermediates XII.
  • Displacement of the remaining chlorine with an piperazine in the presence of base yields compounds XIII.
  • substituent(s) Z the use of a N-protecting group might be required to block the reactivity of one of the piperazine nitrogens.
  • Intermediates XIII can react depending on the desired linker Y with R3-Cl in a nucleophilic displacement reaction under basic conditions, with R—CHO in a reductive amination with e.g.
  • 4,5-dimethyl-1,2-dihydro-pyridazine-3,6-dione (50 g, 357 mmol) is added to a 1 L flask and POCl 3 (250 mL) is slowly added. The suspension is stirred and heated to reflux and all starting material dissolves. After 2 h approximately 150 mL POCl 3 are removed under vacuum. The viscous, brown solution is poured in small portions slowly onto ice in a 1.5 L beaker under stirring. The orange suspension is neutralized with 28% aqueous ammonia under external cooling. The product is filtered with a Buchner funnel, washed with water and dried at 40° C. under vacuum to yield a off white powder (59 g, 93%).
  • the compound is prepared analogous to compound 37 starting from compound 36.
  • 3-chloro-6-(4-fluoro-benzyl)-4,5-dimethyl-pyridazine is prepared from 4,5-dimethyl-1,4-dichloro-pyridazine and para-fluoro benzyl zinc bromide.
  • Compound 45 is prepared analogous to compound 44 starting from of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (compound 39) and para-fluorobenzyl zinc bromide.
  • Compound 55 is prepared as described above from piperazine and 3,6-dichloro-4,5-dimethyl-pyridazine.
  • Triethylamine (2.0 mL, 14.4 mmol, 2.9 eq) is added to a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (1.25 g, 5.0 mmol, 1 eq), 3-chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (1.20 g, 5.0 mmol, 1 eq) in dichloromethane (40 mL) and the resulting solution is stirred at rt for 2 h.
  • the reaction mixture is diluted with dichloromethane (50 mL) and washed with water (25 mL), then brine (25 mL). The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The desired compound is isolated by silica gel chromatography (10-75% EtOAc/heptane) as a white solid (1.83 g, 82%).
  • the compound is prepared in a similar fashion as described above.
  • Table 7 lists examples of compounds prepared by Grignard addition as described above:
  • example 116 40 mg, 0.10 mmol
  • HATU 73 mg, 0.14 mmole
  • diisopropylethyl amine 37 mg, 0.29 mmol
  • dimethylacetamide 1.5 ml
  • amine 0.14 mmole
  • HPLC acetonitrile/water (3% propanol), 30% ⁇ 100%) to afford the product (examples 133 to 140, 37% ⁇ 55%).
  • Table 8 lists examples of compounds prepared by amide formation as described above:
  • the reaction mixture is diluted with EtOAc (50 mL) and washed with water (2 ⁇ 10 mL) followed by brine (2 ⁇ 10 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure to a white residue.
  • the desired compound is isolated by silica gel chromatography (CH 2 Cl 2 -20% MeOH/CH 2 Cl 2 ) as a white solid (43 mg, 79%).
  • Methyltriphenylphosphonium iodide (410 mg, 1.010 mmol) is added to THF (5.5 mL) and cooled to 5° C. Potassium tert-butoxide (1.1 mL, 1 M in THF, 1.1 mmol) is added dropwise and the reaction is stirred for 30 min.
  • 1-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-ethanone (350 mg, 0.841 mmol) in THF (1.5 mL) is added to the reaction.
  • Table 9 lists examples of compounds prepared by amination as described above:
  • Scheme 7 shows a general synthetic scheme for the preparation of compounds of Formula Iq to Is.
  • Substituted chloro pyridazines IIIa can be reacted with acetonitrile under treatment with a strong base (e.g. LiHMDS) to form intermediates XIVa.
  • a strong base e.g. LiHMDS
  • Hydrolysis of the nitrile functionality provides acid intermediates XIVb and subsequent amid coupling with acid hydrazides yields intermediates XIVc.
  • Intermediates XIVa can be reacted with hydroxylamine and N,N-dimethylformamide-dimethylacetal to examples Iq or can provide tetrazole examples Ir by reaction with sodium azide followed by alkylation (e.g. bromides or iodides).
  • Intermediates XIVc can be condensed e.g. with triphenylphosphine to examples Is.
  • Acetic acid hydrazide (20.6 mg, 0.28 mmol) is added to a round-bottom flask under N 2 followed by DMF (5 mL). Diisopropylethylamine (0.25 mL) is added and the reaction is stirred for 30 min. ⁇ -4,5-Dimethyl-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazin-3-yl ⁇ -acetic acid (110 mg, 0.28 mmol) is added and the reaction is stirred for 1 h. HOBT (42 mg, 0.311 mmol) and HBTU (116.8 mg, 0.31 mmol) are added and the reaction is allowed to stir for 16 h. The crude reaction mixture is purified via flash chromatography on silica gel (0-30% methanol in dichloromethane) to afford the title compound (114 mg, 90%).
  • Methyl iodide (16 ⁇ L, 0.263 mmol) is added dropwise, and the reaction is stirred and allowed to warm to room temperature over 16 h. Cool back to 0° C. and add additional methyl iodide (24 ⁇ L, 0.395 mol). Allow reaction to warm to room temperature over 16 h. Concentrate reaction in vacuo and filter off solids. Wash with MeOH. Remaining solid is dissolved in H 2 O and TFA and is purified by HPLC (CH 3 CN/H 2 O) to afford the title compounds as a 57:43 mixture of regioisomers (22.2 mg, 20%).

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