ES2365259T3 - HETEROCYCLIC COMPOUNDS AS C-FMS KINASE INHIBITORS. - Google Patents

Abstract

A compound of Formula I: ** Formula ** where: W is ** Formula ** where R4 = H, F, Cl, Br, I, OH, OCH3, OCH2CH3, -C (1-3 ), -CO2R5, CONR6R7, C≡CR8 or CN; wherein R5 = H, or -C (1-3) alkyl; R6 = H, or -C (1-3) alkyl; R7 = H, or -C (1-3) alkyl; and R8 = H, -CH2OH; or -CH2CH2OH; R2 is cycloalkyl, spiro-substituted cycloalkenyl, heterocyclyl, spiro-substituted piperidinyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, any of which may be independently substituted with one or two each of the following: chlorine, fluorine, C (1-3) hydroxyalkyl and C (1-4) alkyl; wherein the cycloalkyl groups are saturated or partially unsaturated rings composed of 3 to 8 carbon atoms and wherein said ring may be substituted with up to four alkyl substituents; wherein the spiro substituted cycloalkenyl groups are cycloalkyl rings sharing a single carbon atom and wherein at least one of the rings is partially unsaturated; X is selected from the group consisting of: ** Formula ** wherein R1 and R10 are independently H, -CH3, or C2-C5 alkyl, optionally substituted with one or two of: Me, Et, OH, NH2, NHMe, NMe2, NHEt, NEt2, pyrrolidinyl, pyridyl, morpholino, CONH2 or COOH and in such a way that when any of two heteroatoms is attached to said C2 to C5 alkyl group there are at least two carbon atoms between them, and R3 is -SO2Me, SO2Et, -CO2R9, -NO2 or -CN; wherein R9 is H or C (1-3) alkyl; Z is H, F, Cl, Br, C1-C3 alkyl or -CH2OH; and J is CH or N; or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

Description

Background of the invention

The invention relates to new compounds that act as protein tyrosine kinase inhibitors. More particularly, the invention relates to new compounds that act as c-fms kinase inhibitors.

Protein kinases are enzymes that serve as key components of the signal transduction pathway by catalyzing the transfer of the terminal adenosine 5'-triphosphate (ATP) phosphate to the hydroxy group of tyrosine, serine, and threonine residues of proteins. As a consequence, protein kinase inhibitors and substrates are valuable tools for evaluating the physiological consequences of protein kinase activation. Overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been shown to play significant roles in the development of many diseases, including cancer and diabetes.

Protein kinases can be divided into two classes: those that preferentially phosphorylate thiorsine residues (protein tyrosine kinases) and those that preferentially phosphorylate serine and / or threonine residues (protein serine / threonine kinases). Protein tyrosine kinases perform a variety of functions that range from stimulating cell growth and differentiation to arresting cell proliferation. They can be classified as receptor protein tyrosine kinases or intracellular protein tyrosine kinases. Receptor protein tyrosine kinases, which possess an extracellular ligand-binding domain and an intracellular catalytic domain with intrinsic tyrosine kinase activity, are distributed among 20 subfamilies.

Receptor tyrosine kinases of the epidermal growth factor ("EGF") family, which includes HER-1, HER-2 / neu, and HER-3 receptors, contain an extracellular binding domain, a transmembrane domain, and a cytoplasmic catalytic domain. intracellular. Binding to the receptor leads to the initiation of multiple intracellular tyrosine kinase-dependent phosphorylation processes, ultimately resulting in transcription of oncogenes. Breast, colorectal, and prostate cancers have been linked to this family of receptors.

The insulin receptor ("IR") and the insulin-like growth factor receptor I ("IGF-1R") are structurally and functionally related but exert different biological effects. IGF-1R overexpression has been associated with breast cancer.

Platelet-derived growth factor ("PDGF") receptors mediate cellular responses that include proliferation, migration, and survival and include PDGFR, stem cell factor receptor (c-kit), and c-fms. These receptors have been linked to diseases such as atherosclerosis, fibrosis, and proliferative vitreoretinopathy.

Fibroblast growth factor receptors ("FGR") consist of four receptors that are responsible for blood vessel production, limb growth, and growth and differentiation of numerous cell types.

Vascular endothelial growth factor ("VEGF"), a potent endothelial cell mitogen, is produced in high amounts by many tumors, including ovarian carcinomas. Known receptors for VEGF are designated VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3 (Flt-4). A related group of receptors, tie-1 and tie-2 kinases, have been identified in vascular endothelium and hematopoietic cells. VEGF receptors have been linked to vasculogenesis and angiogenesis.

Intracellular protein tyrosine kinases are also known as non-receptor protein tyrosine kinases. More than 24 such kinases have been identified and classified into 11 subfamilies. Serine / threonine protein kinases, such as cellular protein tyrosine kinases are predominantly intracellular.

Diabetes, angiogenesis, psoriasis, restenosis, eye diseases, schizophrenia, rheumatoid arthritis, cardiovascular disease, and cancer are examples of pathogenic conditions that have been linked to abnormal protein tyrosine kinase activity. Therefore, there is a need for potent and selective protein tyrosine kinase inhibitor small molecules. US Patent Nos. 6,383,790; 6,346,625; 6,235,746;

6,100,254 and International PCT Applications WO 01/47897, WO 00/27820 and WO 02/068406 are indicative of recent attempts to synthesize such inhibitors.

US 2005/113566 discloses compounds that act as protein tyrosine kinase inhibitors, more specifically, c-fms kinase inhibitors. Documents WO 2006/047277, WO 2006/047504 and US 2006/148812, disclose compounds that act as inhibitors of protein tyrosine kinase, more specifically, inhibitors of c-fms kinase and methods for treating autoimmune diseases, diseases with an inflammatory component, metastasis, pain, osteoporosis, Paget's disease, and diseases in which bone resorption mediates morbidity.

image 1

Summary of the Invention

The invention addresses the current need for selective and potent protein tyrosine kinase inhibitors by providing potent inhibitors of c-fms kinase. The invention relates to the new compounds of Formula I:

image2

or to a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: W is

image2

wherein R4 = H, F, Cl, Br, I, OH, OCH3, OCH2CH3, -C (1-3) alkyl -, -CO2R5, CONR6R7, C≡CR8 or CN;

in which

R5 = H or -C (1-3) alkyl; R6 = H or -C (1-3) alkyl; R7 = H or -C (1-3) alkyl; and R8 = H, -CH2OH, or -CH2CH2OH;

R2 is cycloalkyl (including cyclohexenyl and cycloheptenyl), spiro-substituted cycloalkenyl (including

15 spiro [2.5] oct-5-enyl, spiro [3.5] non-6-enyl, spiro [4.5] dec-7-enyl and spiro [5.5] undec-2-enyl), heterocyclyl (including piperidinyl), piperidinyl spiro -substituted (including 3-aza-spiro [5.5] undecanyl and 8-azaspiro [4.5] decanyl), thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, either of which may be independently substituted with one or two of each of the following: chlorine, fluorine, C (1-3) hydroxyalkyl and C (1-4) alkyl (including said substituted cycloalkyls 4,4-dimethylcyclohexenyl, 4,4

Diethylcyclohexenyl, 4-methylcyclohexenyl, 4-ethylcyclohexenyl, 4-n-propylcyclohexenyl, 4-isopropylcyclohexenyl and 4-tertbutylcyclohexenyl; said substituted piperidinyls including 4-methylpiperidinyl, 4-ethylpiperidinyl, 4- (1-hydroxyeth-2-yl) piperidinyl and 4,4-dimethylpiperidinyl);

X is selected from the group consisting of:

image2

Wherein R1 and R10 are independently H, -CH3, or -C2 to C5 alkyl optionally substituted with one or two of: Me, Et, OH, NH2, NHMe, NMe2, NHEt, NEt2, pyrrolidinyl, pyridyl, morpholino , CONH2 or COOH and in such a way that when any two heteroatoms are attached to said C2 to C5 alkyl group, there are at least two carbon atoms between them, and R3 is -SO2Me, SO2Et, -CO2R9, -NO2 or -CN ;

image3

wherein R9 = H or C (1-3) alkyl; Z is H, F, Cl, Br, C1-C3 alkyl or -CH2OH; and J is CH or N.

herein and throughout the present application, the terms "Me", "Et", "Pr" and "Bu" refer to methyl, ethyl, propyl and butyl, respectively.

Detailed description of the invention

The invention relates to the new compounds of Formula I:

image2

or to a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, in which: 10 Wes

image2

wherein R4 = H, F, Cl, Br, I, OH, OCH3, OCH2CH3, -C (1-3) alkyl -, -CO2R5, CONR6R7, C≡CR8 or CN;

in which

R5 = H or -C (1-3) alkyl; R6 = H or -C (1-3) alkyl;

R7 = H or -C (1-3) alkyl; and

R8 = H, -CH2OH or -CH2CH2OH;

R2 is cycloalkyl (including cyclohexenyl and cycloheptenyl), spiro-substituted cycloalkenyl (including

spiro [2.5] oct-5-ene, spiro [3.5] non-6-ene, spiro [4.5] dec-7-ene and spiro [5.5] undec-2-ene), heterocyclyl (including piperidinyl), piperidinyl spiro -substituted (including 3-aza-spiro [5.5] undecane and 8-aza-spiro [4.5] decane),

thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which may

be substituted independently with one or two of each of the following: chlorine, fluorine, C (1-3) hydroxyalkyl and

C (1-4) alkyl (including said substituted cycloalkyls 4,4-dimethylcyclohexenyl, 4,4-diethylcyclohexenyl, 4

methylcyclohexenyl, 4-ethylcyclohexenyl, 4-n-propylcyclohexenyl, 4-isopropylcyclohexenyl and 4-tert-butylcyclohexenyl; 25 including said substituted piperidinyls 4-methylpiperidinyl, 4-ethylpiperidinyl, 4- (1-hydroxyeth-2-yl) piperidinyl and 4,4

dimethylpiperidinyl);

X is selected from the group consisting of: where R1 and R10 are independently H, -CH3 or -C2 to C5 alkyl optionally substituted with one or two of: Me, Et, OH, NH2, NHMe, NMe2, NHEt , NEt2, pyrrolidinyl, pyridyl, morpholino, CONH2 or COOH and in such a way that when any two heteroatoms are attached to said C2 to C5 alkyl group, there are at least two carbon atoms between them, and

image4

R3 is -SO2Me, SO2Et, -CO2R9, -NO2, or -CN; wherein R9 = H or C (1-3) alkyl; Z is H, F, Cl, Br, C1-C3 alkyl or -CH2OH; and J is CH or N.

In a preferred embodiment of the invention:

10 Wes

image5

X is selected from the group consisting of:

image6

image2

wherein R1 and R10 are independently H, -CH3 or -C2 to C5 alkyl optionally substituted with one or two of: Me, Et, OH, NH2, NHMe, NMe2, NHEt, NEt2, pyrrolidinyl, pyridyl, morpholino, CONH2 or COOH and in such a way that when any two heteroatoms are attached to said C2 to C5 alkyl group, there are at least two atoms

5 carbon between them, and R3 is -SO2Me, SO2Et, -CO2R9, -NO2 or -CN; where R9 = H or C (1-3) alkyl; Z is H, F, Cl, Br, C1-C3 alkyl or -CH2OH; and J is CH or N.

10 as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.

In another embodiment of the invention:

W is X is selected from the group consisting of:

image7

image8

image2

image2

wherein R1 is independently H, -CH3, or -C2 to C5 alkyl optionally substituted with one or two of: Me,

5 Et, OH, NH2, NHMe, NMe2, NHEt, NEt2, pyrrolidinyl, pyridyl, morpholino, CONH2 or COOH and in such a way that when any two heteroatoms are attached to said C2 to C5 alkyl group, there are at least two carbon atoms carbon between them, and R3 is -SO2Me, SO2Et, -CO2R9, -NO2 or -CN; wherein R9 = H or C (1-3) alkyl;

Z is H, C1-C3 alkyl or -CH2OH; and J is CH or N. and pharmaceutically acceptable solvates, hydrates, tautomers, and salts thereof.

In another embodiment of the invention:

W is

image9

R2 is

image10

image2

Z is H or -CH2OH; J is CH; X is selected from the group consisting of

image2

Wherein R1 is H, -CH2CH3, -CH2CH2OH, or -CH3; and R3 is -SO2CH3, -CO2CH3, -NO2 or -CN; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof. In another embodiment of the invention: 10 Wes

image2

R2 is

image11

image2

Z is H or -CH2OH; J is CH; X is selected from the group consisting of

image12

R3 is -SO2CH3 or -CN; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.

One embodiment of the invention are compounds selected from the group consisting of the compounds of Examples 1 and 3 to 53, solvates, hydrates, tautomers, and pharmaceutically acceptable salts of these compounds, and any combination thereof.

Yet another embodiment are compounds selected from the group consisting of:

image2

image13

image2

image2

image2

and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof. The compounds of this embodiment are in Examples 1-15.

Yet another embodiment is a compound selected from the group consisting of: and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof. The compounds of this embodiment are in Examples 3, 8, 9 and 11.

image14

image2

Another embodiment is the compound

image2

5

and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof. The compound of this embodiment is Example 54.

The invention also relates to compounds of formula I for use in methods of inhibiting protein tyrosine kinase activity in a mammal by administering a therapeutically effective amount of

10 at least one compound of Formula I. A preferred tyrosine kinase is c-fms.

The invention is considered to include the enantiomeric, diastereomeric and tautomeric forms of all compounds of Formula I as well as their racemic mixtures. In addition, some of the compounds represented by Formula I may be prodrugs, that is, derived from an action drug that possesses superior release capabilities and therapeutic value compared to the action drug. Prodrugs are transformed

15 in drugs active by enzymatic or chemical processes in vivo.

Definitions

The term "alkyl" refers to straight and branched chain radicals of up to 12 carbon atoms, preferably up to 6 carbon atoms, unless otherwise indicated, and includes, but is not limited to, methyl, ethyl, propyl, isopropyl , butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl,

Octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl.

image15

5

10

fifteen

twenty

25

30

35

40

Four. Five

The term "hydroxyalkyl" refers to straight or branched chain radicals of up to 6 carbon atoms, in which a hydrogen atom has been replaced by an OH group.

The term "hydroxyalkylamino" refers to a hydroxyalkyl group in which a hydrogen atom in the carbon chain has been replaced by an amino group, in which nitrogen is the point of attachment to the rest of the molecule.

The term "cycloalkyl" refers to a saturated or partially unsaturated ring comprised of 3 to 8 carbon atoms. Up to four alkyl substituents may be present on the ring. Examples include cyclopropyl, 1,1-dimethylcyclobutyl, 1,2,3-trimethylcyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and 4,4-dimethylcyclohexenyl.

The term "aminoalkyl" refers to at least one primary or secondary amino group attached to any carbon atom along an alkyl chain, where an alkyl group is the point of attachment to the rest of the molecule.

The term "alkylamino" refers to an amino with an alkyl substituent, where the amino group is the point of attachment to the rest of the molecule.

The term "dialkylamino" refers to an amino with two alkyl substituents, where the amino group is the point of attachment to the rest of the molecule.

The term "heteroaromatic" or "heteroaryl" refers to monocyclic aromatic ring systems of 5 to 7 members or bicyclic 8 to 10 members, any of these rings may consist of one to four heteroatoms selected from N, O or S where the Nitrogen and sulfur atoms can exist in any allowed oxidation state. Examples include benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl, and thienyl.

The term "heteroatom" refers to a nitrogen atom, an oxygen atom, or a sulfur atom in which the nitrogen and sulfur atoms can exist in any permitted oxidation state.

The term "alkoxy" refers to straight or branched chain radicals of up to 12 carbon atoms, unless otherwise indicated, attached to an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

The term "aryl" refers to monocyclic or bicyclic aromatic ring systems containing 6 to 12 ring carbons. There may optionally be alkyl substituents present on the ring. Examples include benzene, biphenyl, and naphthalene.

The term "aralkyl" refers to a C1-6 alkyl group containing an aryl substituent. Examples include benzyl, phenylethyl, or 2-naphthylmethyl.

The term "sulfonyl" refers to the group -S (O) 2Ra, where Ra is hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. A "sulfonylating agent" adds the group -S (O) 2Ra to a molecule.

The term "spiro-substituted cycloalkenyl" refers to a pair of cycloalkyl rings that share a single carbon atom and in which at least one of the rings is partially unsaturated, for example:

image2

The term "spiro-substituted heterocyclyl" refers to a ring of heterocyclyl and cycloalkyl that share a single carbon atom, for example:

image2

Therapeutic uses

The compounds of Formula I represent new potent inhibitors of protein tyrosine kinases, such as cfms, and may be useful in the prevention and treatment of disorders that result from the actions of these kinases.

The invention also provides compounds of Formula I for use in methods of inhibiting a protein tyrosine kinase which comprises contacting the protein tyrosine kinase with an effective inhibitory amount of at least one of the compounds of Formula I. A preferred tyrosine kinase is c -fms. The compounds of the present invention are also inhibitors of FLT3 tyrosine kinase activity. In one embodiment to inhibit a protein tyrosine kinase, at least one of the compounds of Formula I is combined with a known tyrosine kinase inhibitor.

image16

In various embodiments of the invention, the protein tyrosine kinases inhibited by the compounds of Formula I are localized in cells, in a mammal, or in vitro. In the case of mammals, including humans, a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formula I is administered.

The invention further provides compounds of Formula I for use in methods of treating cancer in mammals, including humans, by administering a therapeutically effective amount of a pharmaceutically acceptable composition of at least one compound of Formula I. Exemplary cancers include, but are not limited to without limitation, acute myeloid leukemia, acute lymphocytic leukemia, ovarian cancer, uterine cancer, prostate cancer, lung cancer, breast cancer, colon cancer, stomach cancer and hairy cell leukemia. The invention also provides methods for treating certain precancerous lesions including myelofibrosis. In one embodiment of the invention, an effective amount of at least one compound of Formula I is administered in combination with an effective amount of a chemotherapeutic agent.

The invention further provides compounds of Formula I for use in methods of treating and preventing metastases arising from cancers including, but not limited to, ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, cancer. colon, stomach cancer and hairy cell leukemia.

The invention further provides compounds of Formula I for use in methods for treating osteoporosis, Paget's disease and other diseases in which bone resorption mediates morbidity including rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthetic failure, sarcoma. osteolytic, myeloma, and tumor metastasis to bone as frequently occurs in cancers including, but not limited to, breast cancer, prostate cancer, and colon cancer.

The invention also provides compounds of Formula I for use in methods of treating pain, in particular skeletal pain caused by tumor metastasis or osteoarthritis, as well as visceral, inflammatory and neurogenic pain.

The invention also provides compounds of Formula I for use in methods of treating cardiovascular, inflammatory and autoimmune diseases in mammals, including humans, by administering a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formula I Examples of diseases with an inflammatory component include glomerulonephritis, inflammatory bowel disease, prosthetic failure, sarcoidosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, psoriasis, diabetes, tumor-related angiogenesis, macular degeneration age-related, diabetic retinopathy, restenosis, schizophrenia or Alzheimer's dementia. These can be effectively treated with compounds of the present invention. Other diseases that can be effectively treated include, but are not limited to, atherosclerosis and cardiac hypertrophy.

Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and other forms of inflammatory arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis, or uveitis can also be treated with compounds of the present invention.

The term "therapeutically effective amount" as used herein, means the amount of active compound or pharmaceutical agent that induces the biological or medical response in a human, animal or tissue system that is sought by a researcher, veterinarian, doctor. in medicine or other clinical specialist, which includes relief, prevention, treatment or delay of the appearance or progression of the symptoms of the disease or disorder to be treated.

When employed as protein tyrosine kinase inhibitors, the compounds of the invention can be administered in an effective amount within the dosage range of about 0.5 mg to about 10 g, preferably between about 0.5 mg to about 5 g in doses. single or divided daily. The dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of treatment, and the presence of concurrent and unrelated treatments.

It is also apparent to one skilled in the art that the therapeutically effective dose for compounds of the present invention or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, the optimal dosages to be administered can be readily determined by one of ordinary skill in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the progression of the disease. Furthermore, factors associated with the particular subject being treated, including the subject's age, weight, diet, and timing of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are therefore exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are required and these are within the scope of the present invention.

image17

The compounds of Formula I can be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carrier. Exemplary carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial and antifungal agent, and isotonic agents. Exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents, and lubricants.

The pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts that are formed from organic or inorganic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate, and tartrate. Basic salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamino salts, and salts with amino acids such as arginine. In addition, the basic nitrogen-containing groups can be quaternized with, for example, alkylhalides.

The pharmaceutical compositions of the invention can be administered by any means that achieve their intended purpose. Examples include parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular administration. Alternatively or simultaneously, administration can be orally. Formulations suitable for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions, and cyclodextrin inclusion complexes.

The present invention also encompasses a process for preparing a pharmaceutical composition which comprises mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention. Additionally, the present invention includes pharmaceutical compositions prepared by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

Polymorphs and Solvates

In addition, the compounds of the present invention may have one or more crystalline amorphous or polymorphous forms and are therefore intended to be included within the scope of the invention. In addition, the compounds can form solvates, for example with water (ie hydrates) or common organic solvents. As used herein, the term "solvate" refers to a physical association of the compounds of the present invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvate may be isolated, for example when one or more solvent molecules are incorporated into the crystal structure of the crystalline solid. The term "solvate" is intended to include solution phase solvates and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

The present invention is intended to include within its scope solvates of the compounds of the present invention. Therefore, in the treatment methods of the present invention, the term "administer" shall include the meaning to treat, ameliorate, or prevent a syndrome, disorder, or disease described herein with the compounds of the present invention or a solvate of the same, which could obviously be included within the scope of the invention although not specifically disclosed.

image18

Preparation Procedures

Scheme 1

image2

Scheme 1 describes the synthesis of compounds of Formula 1 where X is

image19

image2

(Y is CO and SO2 in Scheme 1).

Commercially available 2-phenyl-propane-1,2-diol can be converted to 1-1 aminodiol in which J is CH according to the procedure described in Journal of Medicinal Chemistry 40 (25), 4030-4052, (1997). It is understood that when J is N, a similar procedure can be used, starting with (2-pyridyl) propanediol (Tetrahedron: Asymmetry 8 (13), 2175-2187, (1997)).

Conversion of aminodiol 1-1 to compound 1-2 is accomplished using standard protecting group chemistry. Examples of suitable N-protecting groups P1 can be found in "Protective Groups in Organic Synthesis," by Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons. Inc, NY, (1999). The preferred protecting group is tert-butyloxycarbonyl (BOC) which can be introduced by reacting the aminodiol 1-1 with di-tert-butyl bicarbonate ((BOC) 2O) in tetrahydrofuran (THF) and Na2CO3 aq. Conversion of diol 1-2 to diamine 1-5 can be accomplished via diazide 1-4 which can be prepared by displacement of leaving groups L1 from intermediate 1-3 with azide anion and reduction to give diamine 1-5 with known procedures such as Ph3P or preferably catalytic hydrogenation. Examples of suitable L1 leaving groups are mesylates, tosylates, triflates and halogens such as Br or I. The L1 in intermediate 1-3 can be introduced by conversion of the diol function of intermediate 1-2 using known literature procedures. The preferred leaving group is mesylate which can be prepared by reacting the diol 1-2 with mesyl chloride (MsCl) and a tertiary amine base such as triethylamine (Et3N) in DCM. Alternatively, intermediate 1-2 can be converted to 1-5 in one step using known synthetic protocols such as Ph3P / NaN3 (Synthetic Communications 30 (12), 2233, (2000)) or a suitable modification of such protocols.

The transformation of diamine 1-5 to cyclic urea 1-6 (where Y is CO) can be accomplished by reacting the diamine with carbonizing agents ("phosgene equivalents"), such as S, S-dithiocarbonate. dimethyl (DMDTC) (J. Org. Chem., 61, 4175, (1996)), bis (4-nitrophenyl) carbonate (Helvetica Chimica Acta 82 (8), 1195, (1999)), urea (J. Chem. Soc., Perkin Trans2, 317, (1981)), benzyl succinimidocarbonate (Bull. Chem. Soc., Jpn., 71, 699, (1998)), hexachloroacetone (Liebigs Annalen / Recueilo, (5), 925, ( 1997)), triphosgene (Tett. Lett., 32, 4185, (1991)) and carbodiimidazole (J. Med. Chem., 40, 1707, (1997)) at appropriate temperatures and in appropriate solvents or using complexes of metals from transition such as tungsten (J. Org. Chem., 67, 4086, (2002)), Ni (J. Organomet. Chem., 419, 251, (1991)), Pd (Macromolecules, 26, 1784, (1993) ), Ru (J. Mol. Catal. A: Chem., 122, 103, (1997)), Mn (Inorg. Chem. 4, 293, (1965,) and J. Organomet. Chem., 134, 203, (1977)) or Co (J. Mol. Catal ., 60, 41, (1990)). Main group elements such as S (J. Org. Chem. 26, 3306 and 3309, (1961,)) and Se (Bull. Chem. Soc., Jpn., 60, 1793, (1987)) can also be used to catalyze this transformation.

The preferred procedure for the synthesis of cyclic urea 1-6 (Y is CO) is the reaction of diamine 1-5 with bis (4-nitrophenyl) carbonate in 1,2-dichloroethane. Sulfonylurea 1-6 (Y is SO2) can be produced analogously by replacing the carbonylating agent with sulfonylating agents such as sulfuryl chloride (Acta. Chem. Scand, 17, 2141, (1963)) and sulfonamide (Bioorganic and Medicinal Chemistry , 13, 755, (2005)). Therefore, a reaction of the diamine 1-5 with sulfonamide in pyridine can be used to produce the sulfonylurea 1-6.

Sulfonylureas and ureas 1-6 can be N-alkylated using known literature procedures (Synthetic Communications, 18 (5), 487-494 (1988)), WO 9600708, DE 4028040). Preferred alkylation procedures include, but are not limited to, thermal reaction with alkylating agents, such as alkyl halides R1L2 (L2 is halogen) and sulfates (R1OSO2OR1) in the presence of a suitable phase transfer catalyst such as tetrabutylammonium salts, in solvents such as toluene and dioxane to produce intermediate 1-8 where Y is CO or SO2, and R1 is alkyl.

Protecting group P1 of intermediate 1-8 (where Y is CO, SO2) can be removed under appropriate conditions to mask amine function. For removal of a BOC group in intermediate 1-8 (where Y is CO, SO2), TFA can be used and the resulting aniline can be isolated as its TFA salt or free base.

Compounds of Formula 1-10, where Y is CO or SO2, can be obtained by ortho-halogenation, preferably bromination, of the deprotected amino compound, followed by metal-catalyzed coupling reactions of the bromoamino intermediate 1-9 with boronic acids. or boronate esters (Suzuki reactions, where R2M1 is R2B (OH) 2 or a boronic ester) or tin reagents (Stille reactions, where R2M1 is R2Sn (alkyl) 3) (for recaps, see N. Miyaura, A. Suzuki, Chem. Rev., 95: 2457 (1995), JK Stille, Angew. Chem, Int. Ed. Engl., 25: 508024 (1986) and A. Suzuki in Metal-Catalyzed Coupling Reactions, F Deiderich, P. Stang, Eds., Wiley-VCH, Weinheim (1988)). Similarly, the BOC-protected intermediate 1-6 can be orthohalogenated to obtain intermediate 1-7 which can then be deprotected under acidic conditions to produce intermediate 1-9 in which R1 is H, and Y is CO, or SO2.

image20

Preferred conditions for the above bromination are N-bromosuccinimide (NBS) in a suitable solvent such as N, N-dimethylformamide (DMF), dichloromethane (DCM) or preferably acetonitrile. Metal catalyzed couplings, preferably Suzuki reactions, can be performed according to the conventional methodology described above, preferably in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) (Pd (PPh3) 4), a base aqueous such as aq. Na2CO3, and a suitable solvent such as toluene, ethanol, dimethoxyethane (DME), or DMF.

The amino group of compound 1-10 can then be coupled with a heterocyclic acid P2-WCOOH (or a corresponding salt thereof P2-WCOOM2, M2 is Li, Na or K), according to conventional procedures for the formation of amide bonds ( for a recap, see: M. Bodansky and A. Bodansky, The Practice of Peptide Synthesis, Springer-Verlag, NY (1984)) or by reaction with WCOC1 acid chlorides or WCO2Rq activated esters (where Rq is a leaving group, such as pentafluorophenyl or N-succinimide) to form product 1-11. The preferred reaction conditions for the coupling with P2-WCOOH or P2-WCOOM2 are: when W is a furan (optional protecting group P2 not present), oxalyl chloride in dichloromethane (DCM) with DMF as a catalyst to form the acid chloride WCOC1 and then coupling in the presence of a trialkylamine such as N, N-diisopropylethylamine (DIEA); when W is a pyrrole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole-6-sulfonamidomethyl hydrochloride (HOBt); and when W is an imidazole or triazole, the preferred conditions are bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP) and DIEA in a solvent, such as DCM or DMF.

When W in compound 1-11 contains a protecting group P2 as mentioned previously, it can be removed at this point. For example, when W is optionally nitrogen-protected imidazole with 2 (trimethylsilyl) ethoxymethyl (SEM), the SEM group can be removed with acidic reagents such as trifluoroacetic acid TFA or fluoride sources such as tert-butylammonium fluoride (TBAF) to obtain the desired end product 112 (Y is CO, SO2). The preferred reaction conditions for this deprotection are treatment of the substrate with TBAF in the presence or absence of ethylenediamine in a suitable solvent, such as DMF to produce the final product 1-12.

Scheme 2

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An alternative synthetic route for the preparation of intermediates of formula 1-6 where Y is CO or SO2 is shown in Scheme 2. The key intermediate in this synthetic route is 2-2 4-substituted phenyl glutanitrile which can be prepared from of the corresponding 4-formyl compound 2-1 according to literature procedures (EP 24776). It is understood that Rx in this synthetic route can be an appropriately protected amine or a functional group that can be converted to an amine such as NO2. Rx may be present in the starting material or may be introduced in an appropriate step as described in Scheme 1. The nitrile functions of phenylglutanitrile 2-2 can be hydrolyzed to obtain phenylglutaramide 2-3 according to appropriate literature procedures (For For reference, see "Comprehensive Organic Transformations", by Richard C. Larock, John Wiley and Sons. Inc, NY, (1999) In addition, the diester intermediate 2-6 (Ry is alkyl), which can be prepared

10 using procedures analogous to bibliographic procedures (Journal of the Indian Chemical Society, 55 (9), 897901, (1978)), it can also be converted to phenylglutaramide 2-3 according to bibliographic procedures (Synthesis, (11), 973- 4, (1982)).

Phenylglutaramide 2-3 can be converted to the desired cyclic urea 1-6 (Y is CO) by Hoffman rearrangement through the carbamate intermediate 2-5 with or without isolation (US 6022968). Furthermore, it is also understood that cyclic urea 1-6 (Y is CO) can be obtained directly from intermediate 2-3 when Hoffman rearrangement is initiated with reagents such as Pb (OAc) 4 implementing minor modifications (WO document 9943659). It is apparent to those skilled in the art that Rx can be manipulated at the appropriate stage to install the amino function at intermediate 1-6 (Y is CO, SO2). Furthermore, carbamate 2-5 (Rz is t-Bu) can also be converted to diamine 2-4 under acidic conditions, preferably TFA. Then diamine 2-4

20 can be used as a precursor for the synthesis of cyclic ureas and cyclic sulfonylureas 1-6 by the various procedures described for the formation of 1-6 in Scheme 1.

Scheme 3

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Scheme 3 illustrates another synthetic route for the preparation of cyclic ureas, cyclic sulfonylureas, where X is

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image2

and cyclic guanidines of Formula 1 where X is

image2

For illustration of the synthetic strategy in this scheme, reagents and conditions are defined for the substrate where J is CH. As mentioned above in Scheme 1, it is understood that similar synthetic procedures can be used with minor modification when J is N.

Commercially available 2-phenyl-propane-1,2-diol 3-1 can be used as the starting material in this synthetic sequence which is protected to give 3-2. Examples of suitable O-protecting groups can be found in "Protective Groups in Organic Synthesis", by Theodora W. Greene and Peter G. M. Wuts, John Wiley & Sons. Inc, NY, (1999). The preferred protection of the diol is conversion to the corresponding 3-2 diacetate, where P3 is Ac (Tetrahedron, 46 (20), 7081, (1990)).

Conversion of intermediate 3-2 to amine 3-4 can be accomplished by two procedures. In one process, halogenation, preferably bromination, of 3-2 followed by metal-catalyzed amination of the intermediate halo 3-3 (where Rx is halogen) may be employed (for reviews see: SL Buchwald, et al, Top. Curr Chem., 219: 131-209 (2001) and JF Hartwig in "Organopalladium Chemistry for Organic Synthesis," Wiley Interscience, NY (2002)). In the other procedure, compound 3-2 can be nitrated and then nitro intermediate 3-3 (where Rx is NO2) reduced (For references see; The Nitro Group in Organic Synthesis "by Noboru Ono, John Wiley & Sons Inc,). The preferred procedure for this transformation is nitration of intermediate 3-2 with conc. HNO3 to obtain compound 3-3 (Rx is NO2), followed by catalytic hydrogenation to convert the nitro group to the corresponding amino group at 3-4.

Compounds of formula 3-6 can be obtained by ortho-halogenation, preferably bromination, of aniline stratum 3-4 to obtain intermediate 3-5 (L3 is halogen), followed by metal-catalyzed complement reaction of the latter with a partner suitable as previously described in Scheme 1 for introducing R2. Preferred conditions for the bromination of intermediate 3-4 are NBS in a suitable solvent such as DMF, DCM or acetonitrile. Metal-catalyzed couplings, preferably Suzuki reactions, can be performed according to conventional methodology as described in Scheme 1, preferably in the presence of a palladium (0) catalyst such as tris (dibenzylideneacetone) dipaladium (Pd2 (dba) 3) in the presence of a non-aqueous base such as K3PO4 and a phosphine ligand, such as 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl (S-Phos) in suitable solvents such as toluene, DME or dioxane.

Compounds of Formula 3-7 can be prepared by reacting compounds of Formula 3-6 with carboxylic acids P2-WCOOH as previously described. The protecting group P3 in intermediate 3-7 can then be removed to unmask the diol function. The preferred deprotection procedure involves saponification of 3-7 diacetate (P3 is Ac) with inorganic bases such as KOH in suitable solvents such as ethyl alcohol (EtOH). The diol function of intermediate 3-8 can be converted to diamine 3-10 as previously described in Scheme 1, via diazide 3-9, replacing catalytic hydrogenation with an appropriate reduction procedure that does not reduce an olefin. , such as Zn / NH4Cl.

When X is a cyclic guanidine, the diamine can be reacted with appropriate guanidinylating reagents, such as S, S'-dimethyl cyanodithiomidocarbonate, N- [bis (methylthio) methylene] methanesulfonamide and dimethyl N-nitroimidodithiocarbonate (Australian Journal of Chemistry, 46 (6), 873, (1993), dimethyl N-nitroimidodithiocarbonate (WO 9204329) and methyl [bis (methylthio) methylene] carbamate (US 3839416) to provide compound 3-11 (Q is NR3).

When W in compound 3-11 contains an optional protecting group P2 as previously mentioned, it can be removed at this point as previously described in Scheme 1, to obtain the final product 3-12.

When Q is a cyclic urea or sulfonylurea, diamine 3-10 can also be reacted with carbonizing reagents and sulfonylating reagents as described in Scheme 1 followed again by removal of P2 if present.

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Scheme 4

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A synthetic route for the preparation of cyclic imides of Formula 1 in which X is

image2

5 is shown in Scheme 4. It is clear to those skilled in the art that, although the reagents and conditions are defined for the substrate where J is CH in order to illustrate synthetic methodology, similar synthetic procedures can be used with modifications. of little importance when J is N.

4-Nitrophenylglutaric acid 4-4 can be used as a key intermediate in this synthetic route. This material can be prepared by direct nitration of phenylglutaric acid 4-5. The preferred condition for this transformation is the treatment of phenylglutaric acid 4-5 with conc. HNO3. (WO 9923063). Alternatively, this substrate can be prepared starting from 4-nitrobenzaldehyde 4-1 through intermediates 4-2 and 4-3, using preparative procedures described in the literature for the synthesis of phenylglutaric acid (Journal of Medicinal Chemistry, 47 (8 ), 1900, (2004)). The construction of the imide ring structure can be done by conversion of the

image23

Nitrophenylglutaric acid 4-4 in the corresponding anhydride 4-6 followed by ring opening with an amine R1NH2 and subsequent ring closure of the resulting acidic amide intermediate to give 4-7. 4-nitrophenylglutaric acid 4-4 can also be directly converted to imide 4-7 (R1 is H) by fusing it with urea (Chemistry-A European Journal, 7 (20), 4512, (2001)). In some cases, R1 is the desired group in the final product. When the

5 amine R1NH2 used in this reaction contains a protecting group such as p-methoxybenzyl (PMB), the unsubstituted imide 4-7 (R1 is H) can be obtained by removal of the p-methoxybenzyl group by known bibliographic procedures (for examples of procedures for deprotection see: Theodora W. Greene and Peter GM Wuts, John Wiley and Sons, Inc., NY (1991)). The preferred procedure for this transformation is to treat intermediate 4-7 (R1 is p-methoxybenzyl) with ammonium cerium (IV) nitrate (CAN) (Bull. Chem. Soc. Jpn. 58, 1413, (1985)).

The conversion of the nitro group of intermediate 4-7 to obtain the amino compound 4-8 can be carried out by known literature procedures as previously described in Scheme 2. The preferred procedure for this transformation is catalytic hydrogenation. The R2 substituent can be introduced by orthohalogenation of intermediate 4-8 and metal catalyzed coupling reactions of the resulting product 4-9 (where L1 is halogen, preferably Br) as previously described to give 4-10.

Compound 4-11 can be prepared by reacting compound 4-10 with carboxylic acids P2-WCOOH as previously described in Scheme 1. When W in compound 4-11 contains optional protection of P2 as previously mentioned, can be removed as described in Scheme 1 to obtain the final product 4-12.

Scheme 5

image24

A synthetic route for the preparation of compounds of Formula 1 in which X is

image2

is shown in Scheme 5. It is clear to those skilled in the art that although the reagents and conditions are defined for the substrate where J is H, for the purpose of illustrating synthetic methodology, they can be used in 5 similar synthetic procedures. with minor modifications when J is N.

2-Phenyl-1-propene-1,3-disulfonic acid 5-1 (J. Amer. Chem. Soc., 66, 1105-9, (1944)) can be used as starting material in this synthesis (J is CH). This material can be subjected to catalytic hydrogenation to obtain 5-2 which can then be nitrated as described in Scheme 4 to obtain intermediate 5-3. Intermediate 5-3 can be converted to anhydride 5-4 according to literature procedure (Chem. Ber. 91, 1512-15, 10 (1958)). Cyclic sulfonamides 5-5 can be obtained from intermediate 5-4 using the synthetic methodology described in Scheme 4 for the conversion of anhydride 4-6 to cyclic imide 4-7. In some cases, cyclization of a sulfonamidosulfonic acid intermediate may require the use of procedures described in the literature (Ann., 657, 86-94 (1962)), preferably using POCl3. The nitro group of intermediate 5-5 can be reduced to give an amino group to obtain intermediate 5-6 which can be carried through the following 4 steps using the

Described chemistry for the conversion of intermediate 4-8 to 4-12 as described in Scheme 4.

Scheme 6

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5

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40 l Scheme 6 illustrates the synthetic route for the preparation of cyclic carbonates of Formula 1 in which X is

image2

and alternative routes for the preparation of cyclic ureas and cyclic sulfonylureas of Formula 1 where X is

image2

(R1 is H), respectively, and for cyclic guanidines of Formula 1 where X is

image2

(R1 is H). The starting material 6-1 is a dihalonitrile compound in which the leaving group L4 is chlorine or preferably fluorine and in which L5 is bromine or iodine. Compound 6-1 can be reacted with a dialkyl malonate, for example diethyl malonate (Rx is Et) or preferably dimethyl malonate (Rx is Me), in a polar aprotic solvent, such as N, N-dimethylacetamide (DMA ), dimethylsulfoxide (DMSO) or preferably N, N-dimethylformamide (DMF), in the presence of a base, such as KH, LiH, KOtBu or preferably NaH to provide compound 6-2.

The second halide L5 * in compound 6-2 may then undergo a metal-catalyzed complement reaction with a boronic acid or boronate ester (Suzuki reactions where R2M1 is R2B (OH) 2, for example, cyclohexane acid- 1-enylboronic or R2B (OR) 2 where (OR) 2 is pinacholate, respectively) or with tin reagents (Stille reactions, in which R2M1 is R2Sn (alkyl) 3) in the presence of a suitable palladium catalyst such as Pd (Ph; P) 4 or preferably dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (Pd (dppf) Cl2) and an appropriate base, such as Cs2CO3 or preferably K3PO4 to give compound 6- 3. For recaps of these coupling reactions, see N. Miyaura, A. Suzuki, Chem. Rev., 95, 2457 (1995), J. K. Stille, Angew. Chem, Int. Ed. Engl., 25, 508-24 (1986) and A. Suzuki in Metal-Catalyzed Coupling Reactions, F. Deiderich, P. Stang, Eds., Wiley-VCH, Weinheim (1988).

The nitro group of compound 6-3 can be reduced to an amino group with a reducing agent that will not reduce an olefin, such as iron powder in the presence of NH4Cl in a solvent such as aqueous ethanol, to form amine 6-4.

The amino group in compound 6-4 can then be coupled with a P2-WCOOH heterocyclic acid (or a corresponding salt thereof P2-WCOOM2, M2 is Li, Na, or K), according to procedures for amide bond formation as described in Scheme 1 to form amide product 6-5 (P2 is an optional protecting group as defined in Scheme 1). The optional protecting group in W, if present, in compound 6-5, such as 2- (trimethylsilyl) ethoxymethyl (SEM) optionally used to protect a nitrogen when W contains an imidazole or triazole, can be removed under the conditions described in Scheme 1, preferably acidic conditions and most preferably trifluoroacetic acid, to give compound 6-6. Alternatively, the optional protecting group P2 can be removed with a fluoride reagent, preferably tetrabutylammonium fluoride in a suitable solvent such as DMF or THF.

The two ester groups of compound 6-6 can be selectively reduced with an appropriate reducing agent, such as sodium borohydride in the presence of suitable solvents, such as a mixture of methanol and tert-butanol, to form compound 6-7.

The diol 6-7 can be reacted with an appropriate carbonylating agent, such as phosgene, carbonyldiimidazole, bis (4-nitrophenyl) carbonate, or preferably triphosgene, in the presence of a base, such as pyridine or lutidine, in an organic solvent, such as THF, to give compound 6-8.

Diol 6-7 can also serve as a precursor for diamine 6-9 by the methodology described in Scheme 3 for the conversion of diol 3-8 to diamine 3-10. Diamine 6-9 is useful for the synthesis of cyclic urea 6-10 (R1 is H) and cyclic sulfonylureas 6-11 (R1 is H) as described for the synthesis of compound 1-6 in Scheme 1 and for the synthesis of the cyclic guanidines 6-12 (R1 is H) as described for the synthesis of compound 3-10 in Scheme 3).

image26

Scheme 7

image2

5 An alternative route to intermediate 6-4 of Scheme 6 is illustrated in Scheme 7 and is particularly useful for the synthesis of compounds 6-8, 6-10, 6-11 and 6-12 as shown in Scheme 6 where J is N.

Compound 7-1 can serve as a starting material where L1 is chlorine or preferably fluorine and can be substituted with a malonate ester as described in Scheme 6 to give compound 7-2. The reduction of nitro compound 7-2 to amine 7-3 can be accomplished by any of a number of reduction procedures.

10 conventional (as recapitulated in M. Hudlicky, "Reductions in Organic Chemistry," Wiley, NY (1984)), preferably with hydrogen over a suitable catalyst, such as palladium on carbon in an appropriate solvent, such as ethanol.

Halogenation, preferably bromination, of amine 7-3 to introduce L2 can be performed as described in Scheme 1 for the preparation of compound 1-9. Suzuki coupling with a boronic acid or

Boronic ester R2M1 as described in Scheme 6 can then provide intermediate 6-4 which is carried over to the final compounds as also described in Scheme 6.

Scheme 8

image2

Scheme 8 illustrates a route for the preparation of 2-imidazole carboxylates of Formula 8-5 wherein Ra is H 20 or C (1-4) alkyl, and Rd is H, alkyl, -CN or -CONH2, that are used as intermediates in the synthesis of compounds of the

image27

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40

Formula I where W is imidazole.

The imidazoles of Formula 8-1, in which Ra is H or C (1-4) alkyl, and Rc is H, C (1-4) alkyl or -CN are commercially available or, where Rc is -CN, they are readily available from commercially available aldehydes (8-1 where Rc is CHO) by reaction with hydroxylamines followed by dehydration with a suitable reagent such as phosphorous oxychloride or acetic anhydride (Synthesis, 677 , 2003). Imidazoles of Formula 8-1 are protected with a suitable group (P1) such as a methoxymethylamine (MOM) or preferably an SEM group to give compounds of Formula 8-2 (see Theodora W. Greene and Peter GM Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., NY (1991)).

The imidazoles of Formula 8-2, in which Rc is -CN, are halogenated with a suitable reagent, such as N-bromosuccinimide or N-iodosuccinimide under electrophilic conditions in a solvent such as DCM or CH3CN or under radical conditions in the presence of an initiator such as azobis (isobutyronitrile) (AIBN) in a solvent such as CCl4 to give compounds of Formula 8-3 where L8 is a leaving group (preferably bromine or iodine). The halogen-magnesium exchange in compounds of Formula 8-3 provides the organomagnesium species, which is then reacted with an electrophile to provide compounds of Formula 8-4. The preferred conditions for the halogen-magnesium exchange are to use an alkyl magnesium reagent, preferably isopropyl magnesium chloride in a suitable solvent such as THF at temperatures between -78 ° C -0 ° C. The preferred electrophiles are ethyl chloroformate or ethyl cyanoformate. For examples of halogen-magnesium exchange over cyanoimidazoles see J. Org. Chem. 65, 4618, (2000).

For imidazoles of Formula 8-2, where Rc is not -CN, these can be converted directly to imidazoles of Formula 8-4 by deprotonation with a suitable base, such as an alkyl lithium followed by reaction with an electrophile as described above. described above for the organomagnesium species. Preferred conditions are to treat the imidazole with n-butyllithium in THF at -78 ° C and inactivate the resulting organolithium species with ethyl chloroformate (for examples, see Tetrahedron Lett., 29, 3411-3414, (1988)).

The esters of Formula 8-4 can then be hydrolyzed to give carboxylic acids (M is H) or carboxylate salts (M is Li, Na, or K,) of Formula 8-5 using one equivalent of an aqueous solution of metal hydroxide ( MOH), preferably potassium hydroxide in a suitable solvent, such as ethanol or methanol. The synthesis of compounds of Formula 8-5 in which Rd is -CONH2 is performed by first treating compounds of Formula 8-4, in which Rc is -CN, with an appropriate alkoxide, such as potassium ethoxide to convert the cyano group to an imidate group (Pinner reaction) followed by hydrolysis of the ester and imidate groups with two equivalents of an aqueous metal hydroxide solution.

Scheme 9

image2

Scheme 9 illustrates a route to give 2-imidazolecarboxylates of Formula 9-3 or 9-5 where Re is chlorine or bromine, and M is H, Li, K, or Na, which are used as intermediates in the synthesis of compounds. of Formula I, where W is imidazole.

Compounds of Formula 9-1 are first prepared by protection of commercially available ethyl imidazole carboxylate according to the procedures outlined in Scheme 8, preferably with a SEM group.

Compounds of Formula 9-2 are prepared by reacting compounds of Formula 9-1 with one equivalent of an appropriate halogenating reagent, such as NBS or N-chlorosuccinimide (NCS) in a suitable solvent such as CH3CN, DCM, or DMF at 25 ° C. Compounds of Formula 9-4 are prepared by reacting compounds of Formula 9-1 with two equivalents of an appropriate halogenating reagent, such as NBS or NCS in a suitable solvent such as CH3CN or DMF at temperatures between 30 ° C to 80 ° C. ºC. The imidazoles of Formula 9-3 and 9-5 are then obtained from the respective esters by hydrolysis as described in Scheme 8.

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Scheme 10

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Scheme 10 illustrates a process for the preparation of imidazoles of Formula 10-3 in which Rf is -SCH3, SOCH3 or -SO2CH3, M is H, Li, K or Na which are used as intermediates in the synthesis of compounds of Formula I where W is imidazole. Imidazole 10-1 (WO 1996011932) is protected according to the procedures described in Scheme 8, preferably with a SEM protecting group to give compounds of Formula 10-2. Hydrolysis of the ester according to the procedure of Scheme 8 gives compounds of Formula 10-3 in which Rf

10 is -SCH3. Oxidation of 2-methylthioimidazoles of Formula 10-2 with one equivalent of an appropriate oxidant, followed by hydrolysis of the ester according to the procedure in Scheme 8 gives the compounds of Formula 103, where Rf is -SOCH3. Oxidation with two equivalents of an appropriate oxidant, followed by hydrolysis of the ester according to the procedure of Scheme 8 gives the compounds of Formula 10-3 where Rf is -SO2CH3. The preferred reagent for oxidation is MCPBA in DCM. When the compounds of Formula I contain a

Acyclic or cyclic sulfide, the sulfide can be further oxidized to give the corresponding sulfoxides or sulfotes. Sulfoxides can be obtained by oxidation using an appropriate oxidant, such as an equivalent of metachloroperobenzoic acid (MCPBA) or by treatment with NaIO4 (see, for example, J. Med. Chem., 46: 4676-86 (2003)) and can be obtained sulfones using two equivalents of MCPBA or by treatment with 4-methylmorpholine N-oxide and catalytic osmium tetraoxide (see, for example, PCT application WO 01/47919).

In addition, both sulfoxides and sulfotes can be prepared using one equivalent and two equivalents of H2O2 respectively, in the presence of titanium (IV) isopropoxide (see, for example, J. Chem. Soc., Perkin Trans. 2, 1039- 1051 (2002)).

Examples

The following examples are for exemplary purposes only and are not intended to limit the invention in any way.

Example 1

4-Cyano-1H-imidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4- (2,6-dioxo-piperidin-4-yl) -phenyl] -amide

image2

a) 1- (2-Trimethylsilanyl-ethoxymethyl) -1H-imidazole-4-carbonitrile

image2

One flask filled with imidazole-4-carbonitrile (0.50 g, 5.2 mmol) (Synthesis, 677, 2003), 2- (trimethylsilyl) ethoxymethyl chloride (SEMCI) (0.95 ml, 5.3 mmol) , K2CO3 (1.40 g, 10.4 mmol) and acetone (5 ml) were stirred for 10 h at RT. The mixture was diluted with ethyl acetate (EtOAc) (20 ml) and washed with water (20 ml) and brine (20 ml) and the organic phase was dried over MgSO4. The crude product was eluted on a 20-g SPE cartridge (silica) with 30% EtOAc / hexane to give 0.80 g (70%) of the title compound as a colorless oil: Mass spectrum (Cl (CH4), m / z) Calcd. For C10H17N3OSi, 224.1 (M + H), found 224.1.

image29

b) 2-Bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-4-carbonitrile

image2

A solution of 1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-4-carbonitrile (0.70 g, 3.1 mmol) (as prepared in the previous step) in CCl4 (10 ml) was given N-bromosuccinimide (NBS) (0.61 g, 3.4 mmol) and azobis (isobutyronitrile) (AIBN, catalytic) were added and the mixture was heated at 60 ° C for 4 h. The reaction was diluted with EtOAc

10 (30 ml), washed with NaHCO3 (2 x 30 ml) and brine (30 ml) and the organic phase was dried over Na2SO4 and then concentrated. The title compound was eluted on a 20-g SPE cartridge (silica) with 30% EtOAc / hexane, yielding 0.73 g (77%) of a yellow solid: Mass spectrum (Cl (CH4) , m / z) Calcd. For C10H16BrN3OSi, 302.0 / 304.0 (M + H), found 302.1 / 304.1.

c) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester

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To a solution of 2-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-4-carbonitrile (0.55 g, 1.8 mmol) (as prepared in the previous step) in tetrahydrofuran (THF ) (6 ml) at -40 ° C a solution of 2M isopropylmagnesium chloride (i-PrMgCl) in THF (1 ml) was added dropwise. The reaction was allowed to stir for 10 min at -40 ° C, then cooled to -78 ° C and ethyl chloroformate (0.30 g, 3.0 mmol) was added. The reaction was allowed

20 reached RT and stirred for 1 hr. The reaction was quenched with aq. NH4Cl. sat. It was diluted with EtOAc (20 ml) and washed with brine (2 x 20 ml). The organic phase was dried over Na2SO4 and then concentrated. The title compound was eluted on a 20-g SPE cartridge (silica) with 30% EtOAc / hexane, yielding 0.40 g (74%) of a colorless oil: Mass spectrum (ESI, m / z) : Calcd for C13H21N3O3Si, 296.1 (M + H), found 296.1.

d) Potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate

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To a solution of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester (0.40 g, 1.3 mmol) (as prepared in the previous step) 6M KOH solution (0.2 ml) was added in ethanol (3 ml), the reaction was stirred for 10 min and then concentrated to give 0.40 g (100%) of the title compound as a yellow solid: 1H NMR (CD3OD; 400 MHz): δ 7.98 (s, 1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H ),

0.00 (s, 9H). Mass spectrum (ESI neg, m / z): Calcd. For C11H16KN3O3Si, 266.1 (M-K), found 266.0.

e) 2- (4-Nitro-benzylidine) -malonic acid diethyl ester

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A solution of 3.00 g (19.9 mmol) of 4-nitro-benzaldehyde in toluene (30 ml) was treated with 3.62 ml (23.8 mmol) of diethyl malonic acid and 0.5 ml of piperidine. The mixture was heated to 100 ° C for 24 h, cooled to room temperature (RT), diluted with toluene (80 ml) and washed with water (1 x 100 ml), saturated aqueous NaHCO3 (1 x 100 ml) and 1.0 M aqueous HCl (1 x 100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 25% EtOAc-hexane provided 5.09 g (87%) of the title compound: 1H NMR (CDCl3; 400 MHz): δ 8.25 (d, 2H, J = 8 , 8 Hz), 7.77 (s 1H), 7.63 (d, 2H, J = 8.8 Hz), 4.35 (cd, 4H, J = 7.2, 2.0 Hz), 1 , 30 (t, 6H, J = 7.2 Hz).

f) 2,4-Bis-ethoxycarbonyl-3- (4-nitro-phenyl) -pentanedioic acid diethyl ester

image2

10

A solution of 1.42 g (20.8 mmol) of solid NaOEt in EtOH (30 ml) was treated with 3.43 ml (22.6 mmol) of malonic acid diethyl ester at RT for 20 min. This mixture was treated with a solution of 5.09 g (17.4 mmol) of 2- (4-nitro-benzylidino) -malonic acid diethyl ester (as prepared in the previous step) at RT for 6

h. AcOH (5 ml) was added and the mixture was stirred for 5 min. The mixture was partitioned between water (50 ml) and CH2Cl2 (125

15 ml). The organic phase was separated, dried (MgSO4) and concentrated in vacuo, yielding 7.32 g (93%) of the title compound: 1H NMR (CDCl3; 400 MHz): δ 8.12 (d, 2H, J = 8.8 Hz), 7.58 (d, 2H, J = 8.8 Hz), 5.30 (s, 1H), 4.34-4.28 (m, 1H), 4.26-4 , 11 (m, 9H), 1.32-1.20 (m, 12H).

g) 3- (4-nitro-phenyl) -pentanedioic acid

image2

20 A suspension of 7.32 g (16.1 mmol) of 2,4-bis-ethoxycarbonyl-3- (4-nitro-phenyl) -pentanedioic acid diethyl ester (as prepared in the previous step) in HCl concentrate (15 ml) was heated at 100 [deg.] C. for 22 h. The mixture was cooled to RT and the resulting precipitate was filtered, washed with cold water and air dried to provide 3.58 g (88%) of the title compound as an off-white solid: 1H NMR (CD3OD ; 400 MHz): δ 8.12 (d, 2H, J = 8.8 Hz), 7.58 (d, 2H, J = 8.8 Hz), 3.77-3.68 (m, 1H) , 2.87-2.66 (m, 4H).

25 h) 4- (4-Nitro-phenyl) -piperidine-2,6-dione

image31

image2

A mixture of 250 mg (0.987 mmol) of 3- (4-nitro-phenyl) -pentanedioic acid (as prepared in the previous step) and 119 mg (1.98 mmol) of urea was heated at 150 ° C for 40 min (until all solid melted and gas evolution stopped). The mixture was cooled to RT, taken up in EtOAc (70 ml), washed with NaHCO3

5 aqueous saturated (2 x 40 mL), dried (MgSO4) and concentrated in vacuo to provide 52.0 mg (22%) of the title compound as a brown solid: 1H NMR (CDCh; 400 MHz ): δ 8.28 (d, 2H, J = 8.8 Hz), 7.44 (d, 2H, J = 8.8 Hz), 3.64-3.54 (m, 1H), 3, 04-2.96 (m, 2H), 2.86-2.76 (m, 2H).

Alternatively, the title compound can be obtained as follows: a solution of 500 mg (1.97 mmol) of 3- (4-nitro-phenyl) pentanedioic acid (as prepared in the previous step) in 50 ml of dioxane was cooled to 10 ° C and treated with 229 µl (2.96 mmol) of methyl chloroformate and 936 µl (6.71 mmol) of triethylamine for 7.2 h. A solution of 0.5 M ammonia in dioxane (15.8 ml, 7.90 mmol) was added at 10 ° C and the mixture was stirred at RT for 72 h. The mixture was filtered through Celite, the filter cake was washed with EtOAc, and the solvents were evaporated in vacuo. The residue was treated with 1.30 g (15.8 mmol) of solid NaOAc and acetic anhydride (4 ml) and heated at 100 ° C for 1 h. The mixture was cooled to RT and concentrated to half the original volume.

The residue was taken up in EtOAc (100 ml) and washed with saturated aqueous NaHCO3 (1 x 75 ml), brine (1 x 75 ml), and water (1 x 75 ml). The organic phase was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50 g Varian MegaBond Elut SPE column with 50-60% EtOAc-hexane provided 197 mg (43%) of the title compound as an off-white solid (see spectrum previous).

i) 4- (4-Amino-phenyl) -piperidine-2,6-dione

twenty

image2

A solution of 197 mg (0.841 mmol) of 4- (4-nitro-phenyl) -piperidine-2,6-dione (as prepared in the previous step) in methyl alcohol (MeOH) (15 ml) was hydrogenated over 10% Pd / C at 0.14 MPa (20 psi) for 5 h at RT. The mixture was filtered through Celite, the filter cake was washed with MeOH, and the solvents evaporated in vacuo to provide 106 mg (62%) of the title compound as an off-white solid: Spectrum of

Mass (ESI, m / z): Calcd. For C11H12N2O2, 205.1 (M + H), found 205.1.

j) 4- (4-Amino-3-bromo-phenyl) -piperidine-2,6-dione

image2

A solution of 106 mg (0.519 mmol) of 4- (4-amino-phenyl) -piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (20 ml) was cooled to 0 ° C and treated with 92.4 mg (0.519 mmol) of NBS for 35 min. The mixture was diluted with CH2Cl2 (50 ml) and washed with saturated aqueous NaHCO3 (2 x 40 ml) and water (1 x 40 ml). The organic phase

image32

5

10

fifteen

twenty

25

30

dried (MgSO4) and concentrated in vacuo to provide 138 mg (94%) of the title compound as a tan solid: Mass spectrum (ESI, m / z): Calcd. for C11H11N2O2Br, 283.0 / 285.0 (M + H), found 283.1 / 285.1.

k) 4- (4-Amino-3-cyclohex-1-enyl-phenyl) -piperidine-2,6-dione

image2

A solution of 69.0 mg (0.244 mmol) of 4- (4-amino-3-bromo-phenyl) -piperidine-2,6-dione (as prepared in the previous step) in toluene (10 ml) and Dioxane (10 ml) was treated with 30.7 mg (0.244 mmol) of cyclohex-1enylboronic acid, 104 mg (0.487 mmol) of K3PO4, and 34.2 mg (0.0975 mmol) of 2- (dicyclohexylphosphino) biphenyl. The mixture was degassed by sonication, placed under an Ar atmosphere, treated with 5.50 mg (0.0244 mmol) of Pd (OAc) 2 and heated at 90 ° C for 5 h. The mixture was diluted with EtOAc (30 ml) and washed with water (2 x 20 ml). The organic phase was dried (MgSO4) and concentrated in vacuo to provide 73.5 mg (106%, some trapped solvent) of the title compound as a tan solid: Mass spectrum (ESI, m / z ): Calcd for C17H20N2O2, 285.2 (M + H), found 285.2.

l) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) 1H- [2-Cyclohex-1-enyl-4- (2,6-di-oxo-piperidin-4-yl) -phenyl] -amide imidazole-2-carboxylic

image2

A solution of 73.5 mg (0.259 mmol) of 4- (4-amino-3-cyclohex-1-enyl-phenyl) -piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 ( 20 ml) was treated with 64.4 mg (0.388 mmol) of PyBroP, 86.8 mg (0.284 mmol) of potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate (as prepared in this Example, step (d)) and 135 µl (0.775 mmol) of DIEA at RT for 2 h. The mixture was diluted with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (2 x 30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to provide 70.0 mg (51%) of the title compound as an off-white solid: Mass spectrum (ESI, m / z): Calcd. For C28H35N5O4Si, 534.3 (M + H), found 534.2.

m) 4-Cyano-1H-imidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4- (2,6-dioxo-piperidin-4-yl) -phenyl] -amide

A solution of 70.0 mg (0.131 mmol) of [2-cyclohex-1-enyl-4- (2,6-dioxo-piperidin-4-yl) -phenyl] -amide of 4-cyano1- (2- Trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step) in CH2Cl2 (10 ml) was treated with EtOH (2 drops) and TFA (3 ml) at RT for 1.5 h. Solvents were removed in vacuo. Purification of the residue by reverse phase high pressure liquid chromatography (RP-HPLC) (C18) with 10-80% CH3CN in 0.1% TFA / H2O for 30 min provided 5.3 mg (8%) of the Title compound as a white solid: 1H NMR (CD3OD; 400 MHz): δ 8.18 (d, 1H, J = 8.4 Hz), 8.01 (s, 1H), 7.24 (dd, 1H, J = 8.4, 2.4 Hz), 7.15 (d, 1H, J = 2.4 Hz), 5.85-5.78 (m, 1H), 3.48- 3.38 (m, 1H), 2.90-2.7 (m, 4H), 2.32-2.22 (m, 4H), 1.90-1.73 (m, 4H). Mass Spectrum (ESI, m / z): Calcd. For C22H21N5O3, 404.2 (M + H), found 404.0.

image33

Example 2

Another process for the preparation of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2,6-di-oxo-piperidin-4-yl) -phenyl] -amide from Example 1

image2

a) 3- (4-Nitro-phenyl) -pentanedioic acid

image2

A flask charged with concentrated H2SO4 (400 ml) was cooled to 0 ° C and treated in portions with 50.0 g (240 mmol) of 3-phenyl-pentanedioic acid for 20 min and with fuming HNO3 (10 ml) dropwise for 20 min. The mixture was stirred at RT for 3 h, poured onto ice (amount equivalent to 1000 ml) and the precipitate was filtered, washed with

10 cold water, air dried and dried in a vacuum desiccator. The solid was triturated with a minimal amount of CH3CN, filtered and air dried. The filtrate was concentrated and triturated again with a minimal amount of CH3CN, filtered and air dried to provide a second batch. The two batches were combined to provide 56.9 g (94%) of the title compound as an off-white solid: 1H NMR (DMSO-d6; 400 MHz): δ 8.15 (d, 2H, J = 8.8 Hz), 7.58 (d, 2H, J = 8.8 Hz), 3.62-3.50 (m, 1H), 2.79-2.57 (m, 4H).

15 b) 4- (4-Nitro-phenyl) -dihydro-pyran-2,6-dione

image2

A flask was charged with 20.0 g (79.0 mmol) of 3- (4-nitro-phenyl) -pentanedioic acid (as prepared in the previous step) and 22.4 ml (237 mmol) of acetic anhydride . The mixture was heated to 80 ° C for 1 hr, cooled to RT and slowly treated with ether until the product began to precipitate. After allowing the solid to precipitate

Completely, the solid was filtered, washed with ether, and air dried to provide 13.0 g (70%) of the title compound as an off-white solid: 1H NMR (CDCl3; 400 MHz): δ 8 , 28 (d, 2H, J = 8.8 Hz), 7.41 (d, 2H, J = 8.8 Hz), 3.64-3.53 (m, 1H), 3.22-3, 13 (m, 2H), 2.96-2.85 (m, 2H).

image34

c) 1- (4-Methoxy-benzyl) -4- (4-nitro-phenyl) -piperidine-2,6-dione

image2

A solution of 12.6 g (53.6 mmol) of 4- (4-nitro-phenyl) -dihydro-pyran-2,6-dione (as prepared in the previous step) in THF (160 ml) was treated with 9.04 ml (6.96 mmol) of 4-methoxy-benzylamine at RT for 2 h. The 5 solvents were evaporated in vacuo. The residue was dissolved in 1.0N HCl (200 ml) and extracted with EtOAc (2 x 250 ml). The combined organic phases were washed with water (1 x 200 ml), dried (MgSO4) and concentrated in vacuo. The residue was treated with acetic anhydride (200 ml) and triethylamine (30 ml) and heated at 85 ° C for 1.5 h. The mixture was concentrated in vacuo, treated with 1.0N HCl (200 ml) and extracted with EtOAc (3 x 200 ml). The combined organic phases were washed with saturated aqueous NaHCO3 (1 x 200 ml) and water (1 x 200 ml), dried (MgSO4), and

10 concentrated in vacuo. The solid was triturated with hexane using sonication, filtered and air dried to provide 16.5 g (87%) of the title compound as a light brown solid: Mass spectrum (ESI, m / z) : Calcd for C19H21N2O, 325.1 (M-OCH3 + 2H), found 325.0.

d) 4- (4-Nitro-phenyl) -piperidine-2,6-dione

image2

15 A suspension of 22.8 g (64.2 mmol) of 1- (4-methoxy-benzyl) -4- (4-nitro-phenyl) -piperidine-2,6-dione (as prepared in step above) in CH3CN (150 ml) was treated with 70.4 g (128 mmol) of cerium ammonium nitrate (CAN) as a solution in water (100 ml). The mixture was stirred at RT for 5 h, diluted with water (100 ml) and extracted with EtOAc (2 x 150 ml). The combined organic phases were washed with saturated aqueous NaHCO3 (1 x 100 ml) and water (1 x 100 ml). The combined aqueous phases were extracted with EtOAc (1 x 100 ml). The phases

The combined organics were dried (MgSO4) and concentrated in vacuo. The solid residue was triturated with a minimal amount of CH3CN, filtered and air dried. The filtrate was concentrated and triturated again with a minimal amount of CH3CN, filtered and air dried as a second batch. The two batches were combined to provide 7.00 g (47%) as an off-white solid: 1H NMR (CDCl3; 400 MHz): δ 8.26 (d, 2H, J = 8.8 Hz), 7 , 97 (bs, 1H), 7.42 (d, 2H, J = 8.8Hz), 3.62-3.52 (m, 1H), 3.02-2.93 (m, 2H), 2.84-2.74 (m, 2H).

E) 4-Cyano-1H-imidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4- (2,6-dioxo-piperidin-4-yl) -phenyl] -amide

The title compound was prepared from 4- (4-nitro-phenyl) -piperidine-2,6-dione (as prepared in the previous step) using the same procedures found in Example 1, steps ( i) - (m). The spectra are identical to the spectra of Example 1, step (m).

image35

Example 3

4-Cyano-1H-imidazole-2-carboxylic acid [2- (4,4-Dimethyl-cyclohex-1-enyl) -4- (2,6-dioxo-piperidin-4-yl) -phenyl] -amide

image2

a) 4- [4-Amino-3- (4,4-dimethyl-cyclohex-1-enyl) -phenyl] -piperidine-2,6-dione

image2

A solution of 600 mg (2.12 mmol) of 4- (4-amino-3-bromo-phenyl) -piperidine-2,6-dione (as prepared in Example 1, step (j)) in toluene (20 ml) and dioxane (20 ml) were treated with 900 mg (4.24 mmol) of K3PO4, 424 mg (2.76 mmol) of 4,4-dimethyl-cyclohex-1-enylboronic acid and 297 mg ( 0.848 mmol) of 2- (dicyclohexylphosphino) biphenyl. The mixture was degassed by sonication, placed under an Ar atmosphere, treated with 47.6 mg (0.212 mmol) of Pd (OAc) 2 and heated at 80 ° C for 2.5 h. The mixture was diluted with EtOAc (100 ml) and washed with water (2 x 70 ml). The organic phase was extracted with EtOAc (100 ml) and the combined organic phases were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50 g Varian MegaBond Elut SPE column with 25-50% EtOAc-hexane provided 140 mg (21%) of the title compound as a solid of

Brown color: Mass spectrum (ESI, m / z): Calcd. For C19H24N2O2, 313.2 (M + H), found 313.1.

b) 4-Cyano-1- (2- trimethylsilanylethoxymethyl) -1H-imidazole-2-carboxylic

image2

A 140 mg (0.448 mmol) solution of 4- [4-amino-3- (4,4-dimethyl-cyclohex-1-enyl) -phenyl] -piperidine-2,6-dione (as

20 has been prepared in the previous step) in CH2Cl2 (10 ml) was treated with 313 mg (0.672 mmol) of PyBroP, 151 mg (0.493 mmol) of potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate (as prepared in Example 1, step (d)) and 234 µl (1.34 mmol) of DIEA at RT for 30 min. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1 x 30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 10-42% EtOAc-hexane provided 192 mg (76%) of the title compound as an off-white solid: Mass spectrum (ESI, m / z): Calc. for C30H39N5O4Si, 562.3 (M + H), found 562.0.

image36

c) 4-Cyano-1H-imidazole-25 acid [2- (4,4-Dimethyl-cyclohex-1-enyl) -4- (2,6-dioxo-piperidin-4-yl) -phenyl] -amide carboxylic

A 190 mg (0.338 mmol) solution of [2- (4,4-dimethyl-cyclohex-1-enyl) -4- (2,6-dioxo-piperidin-4-yl) -phenyl] -amide of acid 4 -cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step) in CH2Cl2 (10 ml) treated with MeOH (200 µl) and TFA (3 ml) at RT for 1.5 h. MeOH (30 ml) was added, the mixture was concentrated to half its volume, MeOH (15 ml) was added and the solvents were removed.

10 completely under vacuum at <35 ° C. Silica gel chromatography of the residue with 25-75% EtOAc -hexane provided 92.9 mg (64%) of the title compound as a white solid: 1H NMR (CD3OD; 400 MHz): δ 8 , 22 (d, 1H, J = 8.4 Hz), 8.02 (s, 1H), 7.26 (dd, 1H, J = 8.4, 2.4 Hz), 7.18 (d, 1H, J = 2.4 Hz), 5.79-5.75 (m, 1H), 3.52-3.42 (m, 1H), 2.93-2.76 (m, 4H), 2 , 37-2.30 (m, 2H), 2.12-2.07 (m, 2H), 1.62 (t, 2H, J = 5.6 Hz), 1.10 (s, 6H). Mass Spectrum (ESI, m / z): Calcd. For C24H25N5O3, 432.2 (M + H), found 432.1.

15 Example 4

[2-Cyclohex-1-enyl-4- (2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide 4-cyano-1H-imidazole-2-carboxylic acid trifluoroacetic acid salt

image2

a) [4- (2-Hydroxy-1-hydroxymethylethyl) -phenyl] -carbamic acid tert-butyl ester

image2

twenty

A mixture of 2- (4-amino-phenyl) -propane-1,3-diol (1.6 g, 9.6 mmol, J. Med. Chem., 40 (25), 4030-4052, (1997) ), di-tert-butyl dicarbonate (BOC) 2O (2.30 g, 10.5 mmol), THF (200 ml), water (100 ml) and Na2CO3 (1.12 g, 10.5 mmol) are stirred at RT overnight. The reaction mixture was diluted with EtOAc (200 ml) and saturated brine (200 ml). The organic phase was separated and the aqueous phase was extracted with EtOAc (2 x 100 ml). The organic phases are

25 combined, dried (Na2SO4), and concentrated. The obtained residue was purified on silica (20100% EtOAc-hexane), obtaining the title compound (1.2 g, 47%): Mass spectrum (ESI, m / z): Calcd. For C14H21NO4, 290.3 ( M + Na), found 290.0.

b) [4- (2-Amino-1-aminomethylethyl) -phenyl] -carbamic acid tert-butyl ester

image37

image2

To a suspension of [4- (2-hydroxy-1-hydroxymethyl-ethyl) -phenyl] -carbamic acid tert-butyl ester (267 mg, 1.00 mmol, as prepared in the previous step) in DCM ( 10 ml) and Et3N (0.35 ml, 2.5 mmol), methanesulfonyl chloride (MsCl) (0.15 ml, 2.0 mmol) was added dropwise at 0 ° C. The resulting mixture was stirred at RT for 30

5 min, it was diluted with DCM (10 ml) and washed with saturated NaHCO3 (20 ml). The organic phase was separated, dried (Na2SO4) and concentrated to give 2- (4-tert-butoxycarbonylamino-phenyl) -3-methanesulfonyloxy-propyl methanesulfonic acid ester, which was dried under vacuum and used directly in the following step: Mass spectrum, (ESI, m / z): Calcd. for C16H25NO8S2, 446.1 (M + Na), found 446.0.

To a solution of 2- (4-tert-butoxycarbonylamino-phenyl) -3-methanesulfonyloxy-propyl methanesulfonic acid ester in

Crude 10 (as prepared above) in DMF (10 mL), NaN3 (130 mg, 2.00 mmol) was added. The resulting mixture was heated to 70 ° C overnight. The reaction mixture was allowed to cool to RT, diluted with ether (10 ml) and washed with water (3x10 ml). The organic phase was separated, dried (Na2SO4) and concentrated. The obtained residue was purified on silica (10% EtOAc -hexane), yielding [4- (2-azido-1-azidomethylethyl) -phenyl] -carbamic acid tert-butyl ester (206 mg, total 65%): NMR 1H (CD3OD; 400 MHz): δ 7.33 (d, 2H, J = 8.6 Hz), 7.07 (d, 2H, J = 8.6

15Hz), 3.48 (m, 4H), 2.93 (m, 1H), 1.42 (s, 9H).

[4- (2-Azido-1-azidomethyl-ethyl) -phenyl] -carbamic acid tert-butyl ester (240 mg, 0.757 mmol, as prepared above) was hydrogenated with H2 at 0.41 MPa (40 psi ) on 10% Pd / C (120 mg) for 1 h. The reaction mixture was filtered through a pad of Celite, concentrated, and dried in vacuo to provide [4- (2-amino-1-aminomethyl-ethyl) -phenyl] -carbamic acid tert-butyl ester (169 mg , 64%): 1H NMR (CD3O; 400 MHz): δ 7.35

20 (d, 2H, J = 8.6 Hz), 7.12 (d, 2H, J = 8.6 Hz), 2.90 (m, 2H), 2.79 (m, 2H), 2, 69 (m, 1H), 1.42 (s, 9H).

c) [4- (2-Oxo-hexahydro-pyrimidin-5-yl) -phenyl] -carbamic acid tert-butyl ester

image2

A solution of [4- (2-amino-1-aminomethyl-ethyl) -phenyl] -carbamic acid tert-butyl ester (as prepared in the previous step, 739 mg, 2.78 mmol) and bis carbonate of 4-nitrophenyl (850 mg, 2.79 mmol) in 1,2-dichloroethane

25 (250 ml) was refluxed for 24 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified on silica (50% EtOAc -hexane-5% MeOH -EtOAc) to provide the title compound (437 mg, 53%): Mass spectrum (ESI , m / z): Calcd. for C15H21N3O3, 292.3 (M + H), found 292.0.

image38

d) [2-Bromo-4- (2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -carbamic acid tert-butyl ester

image2

To a solution of [4- (2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -carbamic acid tert-butyl ester (as prepared in the previous step, 29 mg, 0.10 mmol) in CH3CN (1 ml), NBS (19.5 mg, 0.100 mmol) was added. The resulting mixture was stirred overnight and concentrated to half volume. The resulting precipitate was collected by filtration to obtain the title compound (12 mg, 32%): Mass spectrum (ESI, m / z): Calcd. For C15H20BrN3O3 370.0 and 372.0 (M + H), found 370.1 and 372.1.

e) 5- (4-Amino-3-cyclohex-1-enyl-phenyl) -tetrahydro-pyrimidin-2-one

image2

10 [2-Bromo-4- (2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -carbamic acid tert-butyl ester (99 mg, 0.26 mmol, as prepared in step above) in TFA (1 ml). The resulting mixture was stirred at RT for 30 min and concentrated in vacuo. The residue obtained was dried under vacuum for 1h and dissolved in EtOH (0.5 ml) and toluene (1 ml). To this solution of cyclohex-1-enyl boronic acid (20.5 mg, 0.16 mmol), 2 M Na2CO3 (0.5 ml, 1 mmol) and Pd (PPh3) 4 (30 mg, 0.025 mmol) were added ). The resulting mixture was heated to 80 ° C overnight. The mixture of

The reaction was allowed to cool to RT and extracted with EtOAc (2 x 10 mL). The EtOAc phases were combined, dried (Na2SO4), and concentrated in vacuo. The obtained residue was purified on silica (2% MeOH -EtOAc), yielding the title compound (31 mg) contaminated with Ph3PO, which was used in the next step without further purification: Mass spectrum (ESI, m / z) : Calcd for C16H21N3O, 272.1 (M + H), found 272.1.

f) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole acid [2-Cyclohex-1-enyl-4- (2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide- 2-carboxylic

image2

5- (4-amino-3-cyclohex-1-enyl-phenyl) -tetrahydro-pyrimidin-2-one (22 mg, as prepared in the previous step) was coupled to 4-cyano-1- (2 -trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic, potassium salt (as prepared in Example 1, step (d), 27.2 mg, 0.0890 mmol) as described in Example 1, Step (1) to obtain the title compound (14 mg, in two steps) after purification on silica (3% MeOH -EtOAc): Mass spectrum (ESI, m / z): Calcd. for C27H36N6O3Si, 521 , 2 (M + H), found 521.1.

image39

g) 4-Cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide trifluoroacetic acid salt

5 4-Cyano-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole acid [2-cyclohex-1-enyl-4- (2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide was dissolved 2-carboxylic acid (as prepared in the previous step, 14 mg, 0.026 mmol) in DCM (1 ml), EtOH (30 µl) and TFA (0.3 ml). The resulting mixture was stirred overnight and concentrated. The obtained residue was subjected to RP-HPLC eluting with 20% to 100% CH3CN in 0.1% TFA / H2O for 20 min on a C18 column to obtain the title compound (1.1 mg, 8%): 1H NMR (CD3OD / CDCl3; 400 MHz): δ 8.23 (d, 1H, J

10 = 8.0 Hz), 7.90 (s, 1H), 7.20 (dd, 1H, J = 8.0, 2.2 Hz), 7.09 (d, 1H, J = 2.2 Hz), 5.75 (bs, 1H), 3.47 (4H, m), 3.17 (m, 1H), 2.22-2.33 (m, 4H), 1.72-1.83 (m, 4H). Mass Spectrum (ESI, m / z): Calcd. For C21H22N6O2, 391.3 (M + H), found 391.2.

Example 5

4-Cyano-1H-imidazole-215 carboxylic acid [2-cyclohex-1-enyl-4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -amide

image2

a) [4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -carbamic acid tert-butyl ester

image2

[4- (2-Amino-1-aminomethyl-ethyl) -phenyl] -carbamic acid tert-butyl ester (as described above) was heated to reflux.

20 prepared in Example 4, step (b), 30.4 mg, 0.114 mmol) and sulfamide (15.4 mg, 0.802 mmol) in pyridine (0.7 ml) for 4 h. The reaction mixture was concentrated in vacuo, and the residue was purified on silica (20% EtOAc -70% hexane), obtaining the title compound (24 mg, 64%): 1H NMR (DMSO-d6; 400 MHz) : δ 9.35 (bs, 1H); 7.45 (m, 2H), 7.15 (m, 2H), 6.73 (m, 2H), 3.52 (m, 2H), 3.27 (m, 2H), 2.85 (m , 1H), 1.52 (s, 9H).

b) 2-Bromo-4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenylamine

image40

image2

[4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -carbamic acid tert-butyl ester (as prepared in the previous step, 100 mg , 0.305 mmol) in TFA (1 ml). The resulting solution was stirred at RT for 30 min and concentrated in vacuo. The residue obtained (74.3 mg) was dried under vacuum for 1 h and dissolved in HOAc (2 ml). The resulting mixture was cooled to 0 ° C and NBS (42.6 mg, 0.239 mmol) was added. The resulting mixture was stirred for 30 min, washed with aqueous NaHCO3 (2 mL), and concentrated. The residue was purified on silica (20 100% EtOAc-hexane) to obtain the title compound (49 mg, 52%): 1H NMR (CD3OD; 400 MHz): δ 7.23 (d, 1H, J = 2.0 Hz ), 6.93 (dd, 1H, J = 8.2, 2.0 Hz), 6.78 (d, 1H, J = 8.2 Hz), 3.63 (m, 2H), 3.32 (m, 2H), 2.82 (m, 1H).

c) 2-Cyclohex-1-enyl-4- (1,1-dioxo-1 image41 6- [1,2,6] thiadiazinan-4-yl) -phenylamine

image2

10

2-Bromo-4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenylamine (as prepared in the previous step, 46.9 mg, 0.153 mmol ) with cyclohexane-1-enyl boronic acid (24.1 mg, 0.191 mmol) according to the Suzuki coupling procedure of Example 4, step (e) and purified on silica (20-100% EtOAc -hexane) yielding the title compound (30.7 mg, 65%): Mass spectrum (ESI, m / z): Calcd. for C15H21N3O2S,

308.1 (M + H), found 308.1.

d) [2-Cyclohex-1-enyl-4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -amide of 4-cyano-1- (2 -trimethylsilanylethoxymethyl) -1H-imidazole-2-carboxylic

image2

2-Cyclohex-1-enyl-4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenylamine (as prepared in step

20 above, 30.7 mg, 0.100 mmol) to 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d ), 33.6 mg, 0.260 mmol) as described in Example 1, step (1), obtaining the title compound (14 mg, 25%) after purification on silica (20-50% EtOAc hexane ): Mass spectrum (ESI, m / z): Calcd. For C26H36N6O4SSi, 557.2 (M + H), found 556.8.

e) 4-Cyano-1H-imidazole acid [2-cyclohex-1-enyl-4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -amide- 225 carboxylic

To a [2-cyclohex-1-enyl-4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -amide solution of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step, 17.8 mg, 0.0320 mmol) in DMF (35 µl) and ethylenediamine (13 µl, 0.18 mmol) , Solid tetrabutylammonium fluoride (TBAF) (25 mg, 0.090 mmol) was added. The resulting solution was stirred at 60 [deg.] C. for 12 h. The reaction mixture was concentrated in vacuo and the resulting residue purified on silica (20-100% EtOAc -hexane) to provide the title compound (9.3 mg, 68%): 1H NMR (CD3OD; 400 MHz): δ 8.19 (d, 1H, J = 8.7 Hz), 8.05 (s, 1H), 7.18 (dd, 1H, J = 8.7, 2.2 Hz), 7.08 (d , 1H, J = 2.2 Hz), 5.81 (bs, 1H), 3.62 (m, 2H), 3.35 (m, 2H), 2.93 (m, 1H), 2.24 -2.34 (m, 4H), 1.82-1.90 (m, 4H). Mass Spectrum (ESI, m / z): Calcd. For C20H22N6O3S, 427.1 (M + H), found 427.2.

image42

Example 6

[2-Cyclohex-1-enyl-4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -5-hydroxymethyl-phenyl-amide of 4-cyano-1Himidazol-2 acid -carboxylic

image2

10 TFA (0.3 ml) was added to a solution of [2-cyclohex-1-enyl-4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid amide (as prepared in Example 5, step (d), 21 mg, 0.030 mmol) in DCM (1 ml) and EtOH (30 µl). The resulting mixture was stirred at RT for 2 h and concentrated in vacuo. The residue obtained was purified on silica (20-50% EtOAc -hexane), obtaining the compound

15 of the title (8.0 mg, 46%): 1H NMR (CD3OD; 400 MHz): δ 8.10 (s, 1H), 8.05 (s, 1H), 7.11 (s, 1H), 5.78 (bs, 1H), 4.7 (ABc, 1H, J = 16Hz), 4.48 (ABc, 1H, J = 16Hz), 4.3 (m, 1H), 3.87 ( m, 1H), 3.52 (m, 1H), 3.6 (m, 1H), 3.18 (m, 1H), 2.62 (bs, 1H), 2.22-2.34 (m , 4H), 1.72-1.90 (m, 4H). Mass Spectrum (ESI, m / z): Calcd. For C21H24N6O4S, 439.1 (M-H2O + H), found 439.2.

Example 7

20 4-Cyano1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide salt

image2

a) [4- (1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -carbamic acid tert-butyl ester

image2

A mixture of [4- (2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -carbamic acid tert-butyl ester (as prepared in Example 4, step (c), 376 mg, 1, 29 mmol), K2CO3 powder (744 mg, 5.39 mmol), Bu4NBr (41.9 mg, 0.130 mmol), 1,2-dichloroethane (8 ml) and Me2SO4 (0.5 ml) was heated to 60 ° C in a sealed tube overnight. The reaction mixture was allowed to cool to RT and the inorganic solids were filtered off. The filter cake was washed with dioxane 1: 1 / DCM (3 x 20 ml). The organic phases were combined and concentrated in vacuo. The obtained residue was purified on silica (20-100% EtOAc-hexane) affording the title compound (259 mg, 63%): Mass spectrum (ESI, m / z): Calcd. For C17H25N3O3, 320.2 (M + H), found 320.0.

b) 5- (4-amino-3-bromo-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-one trifluoroacetic acid salt

image2

10 [4- (1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -carbamic acid tert-butyl ester (as prepared in the previous step, 106 mg, 0.333 mmol) in TFA (2 ml). The resulting mixture was stirred at RT for 30 min and concentrated. The residue obtained was dried under vacuum for 30 min and redissolved in DCM (5 ml). The resulting solution was cooled to 0 ° C and NBS (64 mg, 0.35 mmol) was added. The reaction mixture was stirred at RT for 30 min and treated with DCM (20 ml) and saturated aqueous NaHCO3 (20 ml). The organic phase was separated, dried

15 (Na2SO4) and concentrated to provide the title compound (92 mg, 92%), which was used directly in the next step without further purification. Mass Spectrum (ESI, m / z): Calcd. For C12H16BrN3O, 298.0 and 300.0 (M + H), found 298.2 and 300.2.

c) 5- (4-Amino-3-cyclohex-1-enyl-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-one

image2

20 The trifluoroacetic acid salt of 5- (4-amino-3-bromo-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-one was reacted (as prepared in the previous step, 92 mg, 0 , 30 mmol) with cyclohex-1-enyl boronic acid (48.7 mg, 0.375 mmol) according to the Suzuki coupling procedure of Example 4, step (e) and purified on silica (2% MeOH -EtOAc) yielding the title compound (35 mg, 38%): Mass spectrum (ESI, m / z): Calcd. for C18H25N3O, 300.2 (M + H), found 300.3.

D) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl acid [2-Cyclohex-1-enyl-4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide ) -1H-imidazole-2-carboxylic

image2

4-Cyano-1- (2-cyano-1- (2

image43

trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step, 41 mg, 0.13 mmol) to the potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) - 1H-imidazole-2-carboxylic (as prepared in Example 1, step (d), 50 mg, 0.16 mmol) as described in Example 1, step (1) obtaining the title compound (66 mg , 87%) after purification on silica (EtOAc 50-100% -hexane): Mass spectrum (ESI, m / z):

5 Calcd for C29H40N6O3Si, 549.2 (M + H), found 549.2.

e) Trifluoroacetic acid salt of 4-cyano-1H- [2-cyclohex-1-enyl-4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide imidazole-2-carboxylic

To a [2-cyclohex-1-enyl-4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide solution of 4-cyano-1- (2-trimethylsilanyl- ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step, 66 mg, 0.12 mmol) in 10 DMF (2 ml) was added solid TBAF (109 mg, 0.410 mmol). The resulting mixture was stirred at 60 [deg.] C. for 6 h. DMF was removed in vacuo and the resulting residue was purified by RP-HPLC eluting with 20% to 100% CH3CN in 0.1% TFA / H2O for 20 min on a C18 column, obtaining the title compound (26 mg , 52%): 1H NMR (CDCl3; 400 MHz): δ 9.50 (s, 1H), 8.45 (d, 1H, J = 8.4 Hz), 7.75 (s, 1H), 7 , 24 (dd, 1H, J = 8.4, 2.0 Hz), 7.08 (d, 1H, J = 2.0 Hz), 5.87 (bs, 1H), 3.62 (m, 2H), 3.35 (m, 3H), 2.94 (s, 6H), 2.22-2.34 (m, 4H), 1.72-1.90 (m, 4H). Spectrum of

Mass (ESI, m / z): Calcd. For C23H26N6O2, 419.2 (M + H), found 419.3.

Example 8

4-Cyano-1-enyl acid [2- (4,4-Dimethyl-cyclohex-1-enyl) -4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide -2-carboxylic

image2

20 a) 5- [4-Amino-3- (4,4-dimethyl-cyclohex-1-enyl) -phenyl] -1,3-dimethyl-tetrahydro-pyrimidin-2-one

image2

The title compound was prepared according to the Suzuki coupling procedure of Example 4, step (e), using 4,4-dimethyl-cyclohex-1-enyl boronic acid in place of cyclohex-1-enylboronic acid: Mass spectrum (ESI, m / z): Calcd. For C28H29N3O, 328.2 (M + H), found 328.3.

25 b) [2- (4,4-Dimethyl-cyclohex-1-enyl) -4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide 4- cyano1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic

image44

image2

The title compound was synthesized from 5- [4-amino-3- (4,4-dimethyl-cyclohex-1-enyl) -phenyl] -1,3-dimethyl-tetrahydropyrimidin-2-one (as described prepared in the previous step) as described in Example 1, step (1): Mass spectrum (ESI, m / z): Calcd. for C31H44N6O3Si, 577.3 (M + H), found 577.2.

5 c) [2- (4,4-Dimethyl-cyclohex-1-enyl) -4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide trifluoroacetic acid salt 4-cyano-1H-imidazole-2-carboxylic acid

The title compound was synthesized from [2- (4,4-dimethyl-cyclohex-1-enyl) -4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin5-yl) -phenyl] -amide of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step) as described in Example 7, step (e). 1H NMR (CDCl3; 400 MHz): δ 9.55 (s, 1H), 8.43 (d,

10 1H, J = 8.4 Hz), 7.73 (s, 1H), 7.24 (dd, 1H, J = 8.4, 2.1 Hz), 7.06 (s, 1H), 5 , 82 (bs, 1H), 3.60 (m, 2H), 3.33 (m, 3H), 3.13 (s, 6H), 2.28-2.35 (m, 2H), 2, 08-2.17 (m, 2H), 1.62 (m, 2H), 1.16 (s, 6H); Mass Spectrum (ESI, m / z): Calcd. For C25H30N6O2, 447.2 (M + H), found 447.3.

Example 9

4-Cyano-1H-imidazole-215 carboxylic acid [2-Cyclohept-1-enyl-4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide

image2

a) 5- (4-Amino-3-cyclohept-1-enyl-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-one

image2

A trifluoroacetic acid salt solution of 5- (4-amino-3-bromo-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-one

20 (as prepared in Example 7, step (b), 105 mg, 0.352 mmol), cyclohepten-1-yl boronic acid (74 mg, 0.52 mmol), K3PO4 (224 mg, 1.05 mmmol) , tris (dibenzylideneacetone) dipalladium (0) (Pd2 (dba) 3) (32 mg, 0.034 mmol) and 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (S-Phos) (57.5 mg, 0.350 mmol) in Toluene (0.7 ml) was heated at 100 [deg.] C. in an Ar atmosphere for 1 h. The reaction mixture was allowed to cool to RT and filtered. The filter cake was washed

image45

5

10

fifteen

twenty

25

30

35

with DCM (2 x 10 ml). The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The obtained residue was purified on silica (20-100% EtOAc -hexane), yielding the title compound (95 mg, 86%): Mass spectrum (ESI, m / z): Calcd. For C19H27N3O, 314.2 (M + H), found 314.3.

b) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) [2-Cyclohept-1-enyl-4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide -1H-imidazole-2-carboxylic

image2

5- (4-amino-3-cyclohept-1-enyl-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-one (as prepared in the previous step, 47.5 mg, 0.151 mmol ) to 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d), 27.2 mg, 0.0890 mmol ) as described in Example 1, step (1), obtaining the title compound (82 mg, 96%) after purification on silica (20-100% EtOAc -hexane): Mass spectrum (ESI, m / z): Calcd. for C30H42N6O3Si, 563.3 (M + H), found 563.1.

c) Trifluoroacetic acid salt of 4-cyano-1H-imidazole acid [2-cyclohept-1-enyl-4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] amide -2-carboxylic

To a solution of [2-cyclohept-1-enyl-4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide of 4-cyano-1- (2-trimethylsilanyl- ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step, 86 mg, 0.15 mmol) in DMF (2 ml) was added solid TBAF (213 mg, 0.816 mmol). The resulting mixture was stirred at 60 [deg.] C. for 6 h. DMF was removed in vacuo and the resulting residue was purified by RP-HPLC eluting with 20-100% CH3CN in 0.1% TFA / H2O for 20 min on a C18 column to obtain the title compound (39 mg, 47 %): 1H NMR (CD3OD; 400 MHz): δ 8.15 (d, 1H, J = 8.4 Hz), 8.02 (s, 1H), 7.22 (dd, 1H, J = 8, 4, 2.1 Hz), 7.13 (d, 1H, J = 2.1 Hz), 5.98 (t, 1H, J = 6.4 Hz), 3.53-3.38 (m, 5H), 2.96 (m, 6H), 2.54 (m, 2H), 2.42 (m, 2H), 1.92 (m, 2H), 1.65-1.83 (m, 4H ). Mass Spectrum (ESI, m / z): Calcd. For C24H28N6O2, 433.2 (M + H), found 433.2.

Example 10

4-Cyano-1H-pyrrole-2-carboxylic acid [2-Cyclohept-1-enyl-4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -phenyl] -amide

image2

A mixture of 5- (4-amino-3-cyclohept-1-enyl-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-one (as prepared in Example 9, step (a), 21 mg, 0.067 mmol), 4-cyanopyrrolocarboxylic acid (Canadian J. Chum. 59: 2673 (1981)). (24.6 mg, 0.180 mmol), EDCI (19.4 mg, 0.101 mmol), HOBt (9.2 mg, 0.068 mmol), DIEA (35 µl, 0.20 mmol) in DCM (0.5 ml) stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue was purified by RP-HPLC eluting with 20% to 100% CH3CN in 0.1% TFA / H2O for 20 min on a C18 column, obtaining the title compound (4 , 2 mg, 14%): 1H NMR (CD3OD; 400 MHz): δ 7.58 (d, 1H, J = 1.5 Hz), 7.44 (d, 1H, J = 8.2 Hz), 7.15-7.24 (m, 3H), 5.93 (t, 1H, J = 6.5 Hz), 3.38-3.61 (m, 5H), 2.96 (m, 6H) , 2.48 (m, 2H), 2.28 (m, 2H), 1.82 (m, 2H), 1.45-1.23 (m, 4H); Mass Spectrum (ESI, m / z): Calcd. For C25H29N5O2, 432.2 (M + H), found 432.2.

Example 11 [2-Cyclohex-1-enyl-4- (2,6-dimethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) phenyl] -amide of 4-cyano acid -1Himidazole-2-carboxylic

image46

image2

a) [4- (2,6-Dimethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -carbamic acid tert-butyl ester

5

image2

A mixture of [4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -carbamic acid tert-butyl ester (as prepared in Example 5, step (a), 327 mg, 1.00 mmol), K2CO3 powder (1.88 g, 10.0 mmol) and MeI (0.64 ml, 15 mmol) in DMF (10 ml) was heated at 50 ° C for 12 h in a hermetically sealed tube. The reaction mixture was allowed to cool to RT and the organic solids were filtered off. The filter cake was washed with dioxane / DCM 1: 1

10 (3 x 20 ml). The organic phases were combined and concentrated in vacuo. The residue obtained was purified on silica (20-100% EtOAc -hexane) to provide the title compound (233 mg, 65.6%): Mass spectrum (ESI, m / z): Calcd for C16H25N3O4S, 356, 1 (M + H), found 356.1.

b) [2-Bromo-4- (2,6-dimethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -carbamic acid tert-butyl ester

image2

The title compound was prepared from [4- (2,6-dimethyl-1,1-dioxo-1λ6 [1,2,6] thiadiazinan-4-yl) -phenyl] - acid tert-butyl ester carbamic (as prepared in the previous step) according to the procedure described in Example 5, step (b): Mass spectrum (ESI, m / z): Calcd. for C11H16BrN3O2S, 334.0 and 336.0 (M + H), found 334.0 and 336.0.

c) 2-Cyclohex-1-enyl-4- (2,6-dimethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenylamine

image2

The title compound was prepared from [2-bromo-4- (2,6-dimethyl-1,1-dioxo-1λ6 [1,2,6] thiadiazinan-4-yl) - acid tert-butyl ester phenyl] -carbamic (as prepared in the previous step) according to the procedure described in Example 4, step (e): Mass spectrum (ESI, m / z): Calcd. for C17H25N3O2S, 336, (M + H), found 336.2.

5 d) [2-Cyclohex-1-enyl-4- (2,6-dimethyl-1,1-dioxo-1 image41 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid 6- [1,2,6] thiadiazinan-4-yl) -phenyl] -amide

image2

The title compound was prepared from 2-cyclohex-1-enyl-4- (2,6-dimethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan4-yl) -phenylamine ( as prepared in the previous step) according to the procedure described in Example

10 1, step (1): Mass spectrum (ESI, m / z): Calcd. For C28H40N6O4SSi, 585.2 (M + H), found 584.9.

e) [2-cyclohex-1-enyl-4- (2,6-dimethyl-1,1-dioxo-1) trifluoroacetic acid salt image41 6- [1,2,6] thiadiazinan-4-yl) -phenyl] 4-cyano-1H-imidazole-2-carboxylic acid amide

The title compound was prepared from [2-cyclohex-1-enyl-4- (2,6-dimethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) phenyl] 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid amide (as prepared in

15 previous step) according to the SEM deprotection procedure described in Example 9, step (b): 1H NMR (CDCl3; 400 MHz): δ 11.85 (sa, 1H), 9.54 (s, 1H, ), 8.37 (d, 1H, J = 8.4 Hz), 7.73 (d, 1H, J = 2.1 Hz), 7.38 (dd, 1H, J = 8.4, 2, 1Hz), 7.04 (s, 1H), 5.98 (m, 1H), 3.85 (m, 2H), 3.46 (m, 2H), 3.33 (m, 2H), 2 , 35-2.20 (m, 4H), 1.65-1.92 (m, 4H): Mass spectrum (ESI, m / z): Calcd for C22H26N6O2S, 455.1 (M + H), found 455.2.

Example 12

20 [4- (2-Cyanoimino-hexahydro-pyrimidin-5-yl) -2-cyclohex-1-enyl-phenyl] -amide 4-cyano-1H-imidazole-2-carboxylic acid

image2

a) 3-Acetoxy-2- (4-amino-3-cyclohex-1-enyl-phenyl) -propyl ester of acetic acid

image2

image47

To a solution of 3-acetoxy-2- (4-aminophenyl) -propyl ester of acetic acid (Tetrahedron, 46 (20), 7081, (1990), 1.2 g, 5.0 mmol) in DCM ( 50 ml) was added NBS (903 mg, 5.07 mol) at 0 ° C. The resulting mixture was stirred at RT for 2 h and subjected to the usual treatment, obtaining 3-acetoxy-2- (4-amino-3-bromo-phenyl) -propyl ester of acetic acid (1.4 g, 89%) which it was used directly in the next stage.

The title compound was prepared according to the Suzuki coupling procedure of Example 9, step (a) using 3-acetoxy-2- (4-amino-3-bromo-phenyl) -propylyl acetic acid ester (as shown prepared above) and cyclohex-1-enyl boronic acid: Mass spectrum, (ESI, m / z): Calcd. for C19H25NO4, 332.1 (M + H), found 332.1.

b) Ester 3-acetoxy-2- (4 - {[4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] -amino} -3-cyclohex-110 enyl-phenyl) - acetic acid propyl

image2

Acetic acid 3-acetoxy-2- (4-amino-3-cyclohex-1-enyl-phenyl) -propyl ester (as prepared in the previous step) was coupled to 4-cyano-1- (2- trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic, potassium salt (as prepared in Example 1, step (d)) as described in Example 1, step (1), obtaining the compound of

Titer: Mass Spectrum (ESI, m / z): Calcd. For C30H40N4O6Si, 581.2 (M + H), found 581.0.

c) 4-Cyano-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4- (2-hydroxy-1-hydroxymethyl-ethyl) -phenyl] -amide

image2

To a solution of 3-acetoxy-2- (4 - {[4-cyano-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2-carbonyl] -amino} -3

20 cyclohex-1-enyl-phenyl) -propyl acetic acid (as prepared in the previous step, 580 mg, 1.00 mmol) in i-PrOH (15 ml), 2N NaOH (1 ml , 2 mmol). The reaction mixture was stirred at RT for 1 hr and DCM (200 ml) and water (200 ml) were added. The organic phase was separated, dried (Na2SO4) and concentrated. The residue was purified on silica (40% EtOAc -hexane), obtaining the title compound (312 mg, 63%): Mass spectrum (ESI, m / z): Calcd. For C26H36N4O4Si, 497.2 (M + H), found 497.0.

D) 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl /) 1H-imidazole-2 acid [4- (2-Amino-1-aminomethylethyl /) -2-cyclohex-1-enyl-phenyl] -amide -carboxylic

image48

image2

[2-Cyclohex-1-enyl-4- (2-hydroxy-1-hydroxymethyl-ethyl) -phenyl] -amide was converted to 4-cyano-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step) in the corresponding diazide, [4 (2-azido-1-azidomethyl-ethyl) -2-cyclohex-1-enyl-phenyl] -amide of acid 4-cyano-1- ( 2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2

5 carboxylic acid as previously described in Example 4, step (b), which was used directly in the next step without further purification.

4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) 1H-imidazole-2- carboxylic acid (as prepared above, 546 mg, 1.00 mmol) in THF (1 ml), water (2 ml) and MeOH (10 ml). To this solution, NH4Cl (534 mg, 25.0 mmol) and Zn powder (653 mg,

10 10.0 mmol). The resulting mixture was stirred at RT for 30 min and filtered through a plug of Celite. The filter cake was washed with MeOH (2 x 10 ml). The filtrate was concentrated, dissolved in 5% i-PrOH / DCM, and washed with saturated aqueous NaHCO3 (20 mL). The organic phase was dried (Na2SO4) and concentrated to obtain the title compound (207 mg, 42%): Mass spectrum (ESI, m / z): Calcd. For C26H38N6O2Si, 495.3 (M + H), found 495.2.

e) 4-Cyano-1- (215 trimethylsilanyl-ethoxymethyl) -1H-imidazole acid [4- (2-Cyanoimino-hexahydro-pyrimidin-5-yl) -2-cyclohex-1-enyl-phenyl] -amide 2-carboxylic

image2

To a solution of [4- (2-amino-1-aminomethyl-ethyl) -2-cyclohex-1-enyl-phenyl] -amide of 4-cyano-1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2 acid -carboxylic (as prepared in the previous step, 15 mg, 0.030 mmol) in DCM (10 ml) was added dimethyl N-cyanodithioimino carbonate (4.2 mg, 0.28 mmol). The resulting solution was heated to

Reflux for 4 h. The reaction mixture was allowed to cool to RT and concentrated in vacuo. The residue obtained was purified on silica (20-100% EtOAc -hexane) to obtain the title compound (11 mg, 62%): Mass spectrum (ESI, m / z): Calcd. For C28H36N8O2Si, 545.3 ( M + H), found 545.1.

f) 4-cyano-1H-imidazole-2-carboxylic acid [4- (2-cyanoimino-hexahydro-pyrimidin-5-yl) -2-cyclohex-1-enyl-phenyl] -amide

25 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole acid [4- (2-cyanoimino-hexahydro-pyrimidin-5-yl) -2-cyclohex-1-enyl-phenyl] -amide was subjected to 2-carboxylic (as prepared in the previous step) to deprotected SEM as described in Example 9, step (c) obtaining the title compound: 1H NMR (CD3OD / CDCl3; 400 MHz): δ 8.25 ( d, 1H, J = 8.4 Hz), 7.73 (s, 1H), 7.24 (dd, 1H, J = 8.4, 2.1 Hz), 7.08 (d, 1H, J = 2.1 Hz), 5.85 (bs, 1H), 3.4-3.6 (m, 4H), 3.1-3.2 (m, 1H), 2.22-2.34 ( m, 4H), 1.77-1.90 (m, 4H): Mass spectrum, (ESI, m / z): Calcd. for

C22H27N8O2, 415.2 (M + H), found 415.2.

image49

Example 13

4-Cyano-1-Himidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4 (2-methanesulfonylimino-hexahydro-pyrimidin-5-yl) -phenyl] -amide

image2

a) 4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2 acid [2-Cyclohex-1-enyl-4- (2-methanesulfonylimino-hexahydro-pyrimidin-5-yl) -phenyl] -amide -carboxylic

image2

A solution of [4- (2-amino-1-aminomethyl-ethyl) -2-cyclohex-1-enyl-phenyl] -amide of 4-cyano-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2- carboxylic (as prepared in Example 12, step (d), 250 mg, 0.506 mmol) and N

10 (bis-methylsulfanylmethylene) -methanesulfonamide (Australian Journal of Chemistry, 46 (6), 873, (1993), 100 mg, 0.506 mmol) in 1,2-dichloroethane (20 ml) was heated under reflux for 4 h. The reaction mixture was concentrated and the residue was purified on silica (20-100% EtOac -hexane), obtaining the title compound (117 mg, 39%): Mass Spectrum, (ESI, m / z): Calc for C28H39N7O4SSi, 598.2 (M + H), found 598.2.

b) 4-Cyano-1H15 imidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4 (2-methanesulfonylimino-hexahydro-pyrimidin-5-yl) -phenyl] -amide

4-Cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2 acid [2-cyclohex-1-enyl-4- (2-methanesulfonylimino-hexahydro-pyrimidin-5-yl) -phenyl] -amide -carboxylic (as prepared in the previous step) to SEM deprotection as described in Example 9, step (c), obtaining the title compound: 1H NMR (DMSO-d6; 400 MHz): δ 14.2 (bs, 1H), 9.69 (s, 1H), 8.25 (s, 1H), 7.82 (d, 1H, J = 8.4Hz), 7.44 (s, 1H), 7 , 17 (dd, 1H, J = 8.4, 2.2 Hz), 7.08 (d,

1H, J = 2.2 Hz), 5.65 (bs, 1H), 3.32-3.36 (m, 4H), 2.98-3.05 (m, 1H), 2.68 ( s, 3H), 2.02-2.18 (m, 4H), 1.45-1.68 (m, 4H): Mass spectrum (ESI, m / z): Calcd for C22H25N7O3S, 468.2 (M + H), found 468.3.

Example 14

4-Cyano-1H-imidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4- (1-methyl-2,6-dioxo-piperidin-4-yl) -phenyl] -amide

image2

25 a) 1-Methyl-4- (4-nitro-phenyl) -piperidine-2,6-dione

image50

image2

A 399 mg (1.70 mmol) solution of 4- (4-nitro-phenyl) -dihydro-pyran-2,6-dione (as prepared in Example

2, step (b)) in THF (8 ml) was treated with 1.10 ml (2.21 mmol) of 2.0 M methylamine in THF. The mixture was stirred at RT

for 45 min, it was concentrated in vacuo, taken up in aqueous 1N HCl (10 mL) and extracted with EtOAc (2 x 20 mL). The

5 combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was taken up in anhydride

acetic (7 ml), treated with triethylamine (1 ml) and heated at 80 ° C for 1 h. Solvents were removed in vacuo.

The residue was taken up in EtOAc (20 mL) and washed successively with 1N aqueous HCl, saturated aqueous NaHCO3, and

water (1 x 10 ml each). The organic phase was dried (MgSO4) and concentrated in vacuo. Gel chromatography

Silica from the residue with 25-50% EtOAc -hexane provided 348 mg (83%) of the title compound as an off-white solid: 1H NMR (CDCl3; 400 MHz): δ 8.25 (d, 2H , J = 8.8 Hz), 7.40 (d, 2H, J = 8.8 Hz), 3.56-3.45

(m, 1H), 3.21 (s, 3H), 3.10-3.01 (m, 2H), 2.88-2.77 (m, 2H).

b) 4- (4-Amino-phenyl) -1-methyl-piperidine-2,6-dione

image2

A 348 mg (1.40 mmol) suspension of 1-methyl-4- (4-nitro-phenyl) -piperidine-2,6-dione (as prepared in the

15 step above) in MeOH (10 mL) was hydrogenated over 10% Pd / C at 0.14 MPa (20 psi) for 1 hr at RT. The mixture was filtered through Celite, the filter cake was washed with MeOH and the solvents evaporated in vacuo to provide 289 mg (94%) of the title compound as an off-white solid: Mass spectrum (ESI , m / z): Calcd. for C12H14N2O2, 219.1 (M + H), found 219.1.

c) 4- (4-Amino-3-bromo-phenyl) -1-methyl-piperidine-2,6-dione

twenty

image2

A solution of 289 mg (1.32 mmol) of 4- (4-amino-phenyl) -1-methyl-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (15 ml) was treated portionwise with 224 mg (1.29 mmol) of solid NBS for 20 min. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (2 x 30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc -hexane

25 provided 265 mg (67%) of the title compound as a tan solid: Mass spectrum (ESI, m / z): Calcd for C12H13N2O2Br, 297.0 / 299.0 (M + H), found 297.0 / 299.0.

d) 4- (4-Amino-3-cyclohex-1-enyl-phenyl) -1-methyl-piperidine-2,6-dione

image51

image2

5

10

fifteen

twenty

25

30

A suspension of 265 mg (0.892 mmol) of 4- (4-amino-3-bromo-phenyl) -1-methylpiperidine-2,6-dione (as prepared in the previous step) in toluene (15 ml) and Dioxane (15 ml) was treated with 379 mg (1.78 mmol) of K3PO4, 146 mg (1.16 mmol) of cyclohex-1-enylboronic acid and 125 mg (0.357 mmol) of 2- (dicyclohexylphosphino) -biphenyl. The mixture was degassed by sonication, placed under an Ar atmosphere, treated with 20.0 mg (0.00892 mmol) of Pd (OAc) 2 and heated at 80 ° C for 2.5 h. The mixture was diluted with EtOAc (70 ml) and washed with water (2 x 50 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50 g Varian MegaBond Elut SPE column with 25-50% EtOAc -hexane provided 266 mg (100%) of the title compound as a tan solid: Mass spectrum (ESI, m / z): Calcd. For C18H22N2O2, 299.2 (M + H), found 299.1.

e) 4-Cyano-1- (2-trimethylsilanylethoxymethyl) -1H [2-Cyclohex-1-enyl-4- (1-methyl-2,6-dioxo-piperidin-4-yl) -phenyl] -amide -imidazole-2-carboxylic

image2

A solution of 266 mg (0.891 mmol) of 4- (4-amino-3-cyclohex-1-enyl-phenyl) -1-methyl-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (10 ml) was treated with 623 mg (1.34 mmol) of PyBroP, 300 mg (0.981 mmol) of potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate (as prepared in Example 1, step (d)) and 466 µl (2.67 mmol) of DIEA at RT for 16 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1 x 30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50 g Varian MegaBond Elut SPE column with 25% EtOAc-hexane provided 130 mg (27%) of the title compound as an off-white solid: Mass Spectrum (ESI , m / z): Calcd. for C29H37N5O4Si, 548.3 (M + H), found 547.9.

f) 4-Cyano-1H-imidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4- (1-methyl-2,6-dioxo-piperidin-4-yl) -phenyl] -amide

A 130 mg (0.237 mmol) solution of 4-cyano-1 acid [2-cyclohex-1-enyl-4- (1-methyl-2,6-dioxo-piperidin-4-yl) -phenyl] -amide - (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step) in CH2Cl2 (10 ml) was treated with MeOH (200 µl) and TFA (3 ml) at RT for 1 , 25 h. MeOH (30 ml) was added, the mixture was concentrated to half volume, MeOH (20 ml) was added and the solvents were completely removed in vacuo at <35 ° C. Silica gel chromatography of the residue on a 50 g Varian MegaBond Elut SPE column with 25-50% EtOAc -hexane and by RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA / H2O for 30 min provided 8.0 mg (8%) of the title compound as a white solid: 1H NMR (CD3OD; 400 MHz): δ 8.19 (d, 1H, J = 8.4 Hz ), 8.03 (s, 1H), 7.24 (dd, 1H, J = 8.4, 2.4 Hz), 7.16 (d, 1H, J = 2.4 Hz), 5.87 -5.82 (m, 1H), 3.47-3.37 (m, 1H), 3.16 (s, 3H), 2.96-2.91 (m, 4H), 2.33-2 , 25 (m, 4H), 1.92-1.77 (m, 4H). Mass Spectrum (ESI, m / z): Calcd. For C23H23N5O3, 418.2 (M + H), found 418.1.

Image52

Example 15 4-Cyano-1H-imidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4- (2-oxo- [1,3] dioxan-5-yl) -phenyl] -amide

image2

a) 2- (3-Bromo-4-nitro-phenyl) -malonic acid dimethyl ester

5

image2

To a suspension of NaH (364 mg, 9.08 mmol) in 10 ml of DMF at 0 ° C was added acid dimethyl ester (519 µl, 4.54 mmol). The resulting mixture was warmed to RT and stirred for 0.5 h under an atmosphere of Ar. 2-Bromo-4-fluoro-1-nitro-benzene (500mg, 2.27mmol) was added to the mixture and the reaction was stirred at RT for 16h under an Ar atmosphere. The mixture was then treated with 2 ml of aq NH4Cl. sat. followed by 10 ml of H2O and extracted with 10 DCM (3 x 10 ml). The combined extracts were washed with water (10 ml) and brine (5 ml), and dried (Na2SO4). Removal of the solvent in vacuo followed by flash chromatography of the residue on silica gel (hexane-DCM 1: 4) gave 604 mg (80%) of a yellow-green oil containing the pure title compound as a mixture. mixture of diester (A) and its enol tautomer (B): 1H NMR (CD3OD; 400 MHz): A: δ 8.48 (d, 1H, J = 2.5 Hz), 8.21 (dd, 1H, J = 8.8, 2.5Hz), 7.85 (d, 1H, J = 8.8Hz), 5.34 (s, 1H), 3.81 (s, 6H). B: δ 7.85 (d, 1H, J = 8.4 Hz), 7.82 (d, 1H,

J = 1.9 Hz), 7.54 (dd, 1H, J = 8.4, 1.9 Hz), 4.68 (s, 1H), 3.80 (s, 6H).

b) 2- (3-Cyclohex-1-enyl-4-nitro-phenyl) -malonic acid dimethyl ester

image2

To a mixture of 2- (3-bromo-4-nitro-phenyl) -malonic acid dimethyl ester (as prepared in the previous step, 300 mg, 0.903 mmol), cyclohexane-1-enyl boronic acid (125 mg , 0.994 mmol) and dichloromethane adduct of dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (Pd (dppf) Cl2-CH2Cl2) (66.0 mg, 0.0903 mmol) in 5 ml of DMF was added K3PO4 (765 mg, 3.61 mmol). The resulting mixture was stirred at 60 [deg.] C. for 9 h in an Ar atmosphere. After cooling to RT, the mixture was treated with 50 ml of EtOAc, washed with H2O (3 x 10 ml) and brine (10 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with 10% EtOAc-hexane to provide 210 mg (70%) of the title compound as a

Yellow oil: Mass spectrum (ESI, m / z): Calcd. For C17H19NO6, 334.1 (M + H), found 334.0.

image53

c) 2- (4-amino-3-cyclohex-1-enyl-phenyl) -malonic acid dimethyl ester

image2

A mixture of 2- (3-cyclohex-1-enyl-4-nitro-phenyl) -malonic acid dimethyl ester (as prepared in the previous step, 200 mg, 0.600 mmol), iron powder (168 mg, 3.00 mmol) and NH4Cl (321 mg, 6.00 mmol) in 6 ml of

Ethanol was stirred at 80 [deg.] C. for 16 h. After cooling to RT, the mixture was treated with 30 ml of H2O and extracted with EtOAc (3 x 20 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30% EtOAc -hexane) to give 129 mg (71%) of the title compound as a pale yellow oil: Mass spectrum (ESI, m / z ): Calcd for C17H21NO4, 304.2 (M + H), found 304.1.

D) 1- (4 - {[4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-1-carbonyl] -amino} -3-cyclohex-1-enyl-phenyl) -malonic acid dimethyl ester

image2

To a mixture of 2- (4-amino-3-cyclohex-1-enyl-phenyl) -malonic acid dimethyl ester (as prepared in the previous step, 100 mg, 0.330 mmol), 4-cyano-1- Potassium (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 106 mg, 0.346 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) (154 mg, 0.330 mmol) in 3 ml of DMF was added N, N-diisopropylethylamine (DIEA) (0.172 ml, 0.990 mmol). After stirring at RT for 16 h, the mixture was treated with 50 ml of EtOAc, washed with H2O (2 x 15 ml) and brine (15 ml) and dried (Na2SO4). The organic solvent was evaporated and the residue was purified by flash chromatography on silica gel (5-10% EtOAc -hexane) to give 118 mg (85%) of the title compound as

A colorless oil: Mass spectrum (ESI, m / z): Calcd. For C28H36N4O6Si, 553.2 (M + H), found 552.6.

e) 2- {4 - [(4-cyano-1H-imidazole-2-carbonyl) -amino] -3-cyclohex-1-enyl-phenyl} -malonic acid dimethyl ester

image2

To a solution of 2- (4 - {[4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carbonyl] amino} -3-cyclohex-1-enyl-phenyl) acid dimethyl ester -malonic (as prepared in the previous step, 145 mg, 0.262 mmol) in 1.0 ml

25 of DCM (CH2Cl2) was added 1.0 ml of TFA. After stirring at RT for 4 h, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (20-30% EtOAc -hexane) to give 93 mg (84%) of the title compound as a white solid: Mass spectrum (ESI, m / z): Calcd. for C22H22N4O5, 423.1 (M + H), found 422.8.

image54

f) 4-Cyano-1H-imidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4- (2-hydroxy-1-hydroxymethyl-ethyl) -phenyl] -amide

image2

To a mixture of 2- {4 - [(4-cyano-1H-imidazole-2-carbonyl) -amino] -3-cyclohex-1-enyl-phenyl} malonic acid dimethyl ester (as prepared in step above, 30.0 mg, 0.0710 mmol) and NaBH4 (13.4 mg, 0.355 mmol) in 15 ml of tert-butyl alcohol (t-BuOH) at 80 ° C, MeOH (50 µl) was added for 5 min. The resulting mixture was stirred at 80 [deg.] C. for 16 h in an Ar atmosphere. After cooling to RT, the mixture was treated with aq. Citric acid. 10% at pH 7. The mixture was then treated with 30 ml of EtOAc, washed with H2O (5 ml) and brine (10 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with 1-5% MeOH-DCM to provide 14.1 mg (61%) of the title compound as a solid of

10 white color: 1H NMR (CD3OD; 400 MHz): δ 8.00 (s, 1H), 7.54 (dd, 1H, J = 8.2, 2.3 Hz), 7.46 (d, 1H , J = 2.3 Hz), 7.27 (d, 1H, J = 8.2 Hz), 5.59 (m, 1H), 3.71-3.84 (m, 4H), 3.29 (m, 1H), 2.15-2.29 (m, 4H), 1.67-1.84 (m, 4H). Mass Spectrum (ESI, m / z): Calcd. For C20H22N4O3, 367.2 (M + H), found 366.8.

g) 4-Cyano-1H-imidazole-2-carboxylic acid [2-Cyclohex-1-enyl-4- (2-oxo- [1,3] dioxan-5-yl) -phenyl] -amide

To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4- (2-hydroxy-1-hydroxymethyl-ethyl) -phenyl]

15 amide (as prepared in the previous step, 5.4 mg, 0.015 mmol) and pyridine (3.0 µl, 0.037 mmol) in 0.5 ml of THF at -78 ° C, a triphosgene solution ( 1.8 mg, 0.0061 mmol) in 0.5 ml of DCM. The resulting mixture was warmed to RT and stirring was continued for 1h under an atmosphere of Ar. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-2% MeOH-DCM) gave 2.8 mg (48%) of the title compound as a white solid: NMR 1H (CD3OD; 400 MHz): δ 8.01 (s, 1H),

7.66 (dd, 1H, J = 8.6, 2.3 Hz), 7.59 (d, 1H, J = 2.3 Hz), 7.29 (d, 1H, J = 8.6 Hz), 5.66 (m, 1H), 4.65 (dd, 2H, J = 10.9, 10.9 Hz), 4.45 (dd, 2H, J = 10.9, 4.9 Hz ), 3.72 (m, 1H), 2.24 (m, 4H), 1.70-1.88 (m, 4H). Mass Spectrum (ESI, m / z): Calcd. For C21H20N4O4, 393.2 (M + H), found 393.1.

The following examples were produced according to the procedures of the previous examples with the corresponding reagents listed below in the table:

Example No.

Name Structure Procedure Reference Reagents

16

4-Cyano-1H-imidazole-2-carboxylic acid {4- [1,3-bis- (2-Hydroxy-ethyl) -2oxo-hexahydro-pyrimidin-5-yl] -2-cyclohex-1-enyl-phenyl} -amide Ex. 4, steps (a) (c); Ex. 7 Br (CH2) 2OSi-tBuMe2 (Aldrich Chemical Co.)

image55

(Cont.)

Example No.

Name Structure Procedure Reference Reagents

17

4-Cyano-1H-imidazole-2-carboxylic acid [4- (1,3-Diethyl-2-oxohexahydro-pyrimidin-5-yl) -2 (4,4-dimethyl-cyclohex-1enyl) -phenyl] -amide Ex. 4, steps (a) - (c); Ex. 7 EtI; (Combi-Blocks, Inc.)

18

4Cyano-1H-imidazole-2-carboxylic acid [2- (4,4-Diethyl-cyclohex-1enyl) -4- (1,3-dimethyl-2-oxohexahydro-pyrimidin-5-yl) phenyl] -amide image2 Ex. 4, steps (a) - (c); Ex. 7 (WO 2005063705)

19

[4- (1,1-Dioxo-1λ6 - [1,2,6] thiadiazinan-4-yl) -2- (4-ethyl-cyclohex-1-enyl) -phenyl] 4-cyano1H-imidazole-2 acid amide -carboxylic image2 Ex. 4, steps (a) - (b); Ex. 5 (WO 2005063705)

twenty

Cyan acid [4- (2,6-Dimethyl-1,1-dioxo1λ6- [1,2,6] thiadiazinan-4-yl) 2-spiro [4.5] dec-7-en-8-ylphenyl] -amide -1H-imidazole-2-carboxylic image2 Ex. 4, steps (a) - (b); Ex. 5, step (a); Ex. 11 (WO 2005063705)

image56

twenty-one

4-cyano-1H-pyrrole-2-carboxylic acid [2-Cyclohex-1-enyl-4- (2,6-dimethyl-1,1-dioxo1λ6 [1,2,6] thiadiazinan-4-yl) phenyl] -amide Ex. 11 (Canadian J. Chem. 59, 2673 (1981))

22

Cyan acid [4- (2,6-Dimethyl-1,1-dioxo1λ6- [1,2,6] thiadiazinan-4-yl) 2-spiro [2.5] oct-5-en-6-ylphenyl] -amide -1H-imidazole-2-carboxylic Ex. 4, steps (a) - (b); Ex. 5, step (a); Ex. 11 (WO 2005063705)

2. 3

4-chloro-1H-imidazole-2-carboxylic acid [4- (2,6-Dioxo-piperidin-4-yl) -2-spiro [3.5] non-6-en-7yl-phenyl] -amide image2 Ex. 2 (WO 2005063705); (Example 44, step (b))

Image57

24

5-cyano-furan-2 acid {2- (4,4-Dimethyl-cyclohex-1enyl) -4- [1- (2-hydroxy-ethyl) 2,6-dioxo-piperidin-4-yl] phenyl} -amide -carboxylic image2 Ex. 15 H2N (CH2) 2OH; (Combi-Blocks, Inc.); (WO 2004096795 A2)

Example 25

[2- (4,4-Dimethyl-cyclohex-1-enyl) -4- (2-methyl-1,1,3,3-tetraoxo-1λ6,3λ6- [1,3,2] dithiazinan-5-yl 5-cyano-1H-imidazole-2-carboxylic acid) -phenyl] -amide

image2

b) 2-phenyl-propane-1,3-disulfonic acid

image2

To 2-phenyl-propene-1,3-disulfonic acid (J. Amer. Chem. Soc., 66, 1105-9 (1944)) in THF-water (1: 1) was added 10% by weight of palladium to 5% on carbon and the mixture was hydrogenated on a Parr shaker under a pressure of 0.10 MPa (15 lb) of hydrogen until the reaction was complete by thin layer chromatography (TLC). The mixture was filtered (Celite) and concentrated in vacuo to provide the title compound.

c) 2- (4-Nitro-phenyl) -propane-1,3-disulfonic acid

Image58

image2

2-Phenyl-propane-1,3-disulfonic acid (as prepared in the previous step) was treated with concentrated H2SO4 and fuming HNO3 according to the procedure of Example 2, step (a) to provide the title compound.

c) 4- (4-nitro-phenyl) - [1,2,6] oxaditiano 2,2,6,6-tetraoxide

5

image2

2- (4-Nitro-phenyl) -propane-1,3-disulfonic acid (as prepared in the previous step) was treated with POCl3 as described in Chem. Berichte., 91, 1512-15 (1958) and the title compound was isolated and used in the next step without further purification.

d) 2- (4-methoxy-benzyl) -5- (4-nitro-phenyl) - [1,3,2] dithiazinane 1,1,3,3-tetraoxide

10

image2

A solution of 2,2,6,6-tetraoxide of 4- (4-nitro-phenyl) - [1,2,6] oxaditiano (as prepared in the previous step) was treated with 4-methoxy-benzylamine of according to the procedure of Example 2, step (c), to provide the title compound.

e) 1,1,3,3-Tetraoxide of 5- (4-nitro-phenyl) - [1,3,2] dithiazinane

image2

2- (4-methoxy-benzyl) -5- (4-nitro-phenyl) - [1,3,2] dithiazinane was treated 1,1,3,3-tetraoxide (as prepared in the previous step) with cerium ammonium nitrate (CAN) according to the procedure of Example 2, step (d), providing the title compound.

image59

f) [2- (4,4-Dimethyl-cyclohex-1-enyl) -4- (2-methyl-1,1,3,3-tetraoxo-1λ6,3λ6- [1,3,2] dithiazinan-5 5-Cyano-1H-imidazole-2-carboxylic acid -yl) -phenyl] -amide

The title compound was prepared from 5- (4-nitro-phenyl) - [1,3,2] dithiazinano 1,1,3,3-tetraoxide (as prepared in the previous step) using similar procedures to those found in Example 1, steps (i) (m).

The following compounds were prepared by procedures similar to the previous examples and with the corresponding reagents as indicated in the table.

26

[2-Cyclohex-1-enyl-4- (2-ethyl-1,1,3,3-tetraoxo-1λ6,3λ6- [1,3,2] dithiazinan5-yl) -phenyl] -amide of acid 4-methyl1H- imidazole-2-carboxylic Ex. 25 above, steps (a) (c), (e) - (f) EtNH2; (Example 28, step (c))

27

[2-Spiro [5.5] undec-2-en-3-yl-4 (1,1,3,3-tetraoxo-1λ6,3λ6 - [1,3,2] dithiazinan-5-yl) -phenyl] - 4-Cyano-1H-pyrrole-2-carboxylic acid amide image2 Ex 25 above (WO 2005063705); (Canadian J. Chem. 59, 2673 (1981))

10 Example 28

[4- (2,6-Diethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -2- (4-methyl-piperidin-1-yl) -phenyl] -amide 4-methyl-1Himidazole-2-carboxylic acid

image2

a) 5-Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole

image60

image2

To a solution of 4-methylimidazole (2.70 g, 33.0 mmol) in 10 ml of acetonitrile at 0 ° C was added triethylamine (NEt3)

(4.00 g, 39.6 mmol) and acetyl chloride (2.80 g, 36.3 mmol). The mixture was allowed to reach RT, then filtered

to remove ppt and the filtrate was concentrated to give 1- (4-methyl-imidazol-1-yl) -ethanone, which was used without purification

5 additional in the next stage. To a solution of 1- (4-methyl-imidazol-1-yl) -ethanone (4.10 g, 33.0 mmol) in 15 ml of

Acetonitrile SEM-Cl (5.80 g, 35.0 mmol) was added and the solution was stirred at 25 ° C for 10 h. Solvents are

They were removed by evaporation, 100 ml of 2.5 M NaOH was added to the residue and the mixture was stirred at 25 ° C for 1 h.

The reaction mixture was then extracted with ether (3 x 100 mL), dried over Na2SO4, and concentrated. The

Title compound was purified by silica gel chromatography eluting with 75% EtOAc / hexanes, yielding 4.30 g (61%) of a colorless oil: Mass spectrum (ESI, m / z): Calcd for C10H20N2O4Si , 213.1 (M + H),

found 213.1.

b) 5-Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester

image2

To a solution of 5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole (as prepared in the previous step,

0.320 g, 1.50 mmol) in 5 ml of THF at -78 ° C was added n-BuLi (0.80 ml, 2M in cyclohexane), the mixture was allowed to reach RT and stirred for 30 min . The mixture was cooled to -78 ° C, ethyl cyanoformate (0.160 g, 1.65 mmol) was added and the mixture was allowed to stir for 10 h at RT. The reaction was diluted with 15 ml of EtOAc and washed with NaHCO3 (2 x 15 ml) and brine (15 ml). The title compound was eluted from a 20 g SPE with 50% EtOAc / hexanes, yielding 0.160 g (38%) of a light brown oil: Mass Spectrum (ESI, m / z): Calc. For

C13H24N2O3Si, 285.2 (M + H), found 284.9.

c) 5-Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic

image2

To a solution of 5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester (as prepared in the previous step, 0.090 g, 0.32 mmol) in 2 ml of ethyl alcohol (EtOH) at RT was added 0.16 ml of 2N KOH. The mixture was stirred for 1 h and then concentrated and dried in vacuo to give the title compound as a solid which was used without further purification.

d) [4- (2,6-Diethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -carbamic acid tert-butyl ester

image2

The title compound was prepared from N- [4- (1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -acetamide (as prepared in Example 5, step (a)) and EtI following the procedure of Example 11, step (a).

image61

e) [2-Bromo-4- (2,6-diethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -phenyl] -carbamic acid tert-butyl ester

image2

The title compound was prepared from [4- (2,6-diethyl-1,1-dioxo-1λ6 [1,2,6] thiadiazinan-4-yl) -phenyl] -carbamic acid tert-butyl ester (as prepared in the previous step) following the procedure of Example 11, step (b).

f) 4- (2,6-Diethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -2- (4-methyl-piperidin-1-yl) -phenylamine

image2

The title compound was prepared from [2-bromo-4- (2,6-diethyl-1,1-dioxo-1λ6 [1,2,6] thiadiazinan-4-yl) - acid tert-butyl ester phenyl] -carbamic (as prepared in the previous step) and 4-methylpiperidine following the

10 Buchwald bibliography procedure (Org. Lett., 4, 2885-8 (2002)). The residue obtained was purified by chromatography on silica gel with a mixture of suitable solvents. After isolation, removal of the BOC protecting group from the resulting intermediate was accomplished by stirring at RT in TFA-DCM (1: 2), monitoring its completion by TLC, and then concentrating in vacuo.

g) [4- (2,6-Diethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -2- (4-methyl-piperidin-1-yl) -phenyl] -4-methyl-1H15 imidazole-2-carboxylic acid amide

The title compound was prepared from 4- (2,6-diethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -2- (4-methyl-piperidin-1yl ) -phenylamine (as prepared in the previous step) and potassium salt of 5-methyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared earlier in this example, step (c )) following the procedure of Example 11, steps (d) - (e).

The following compounds were prepared by procedures similar to those of the previous example, with or without additional procedures, and with the corresponding reagents listed in the table.

image62

Example No.

Name Structure Procedure Reference Reagents

29

4-Cyano-1H-imidazole-2-carboxylic acid [4- (1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -2- (4-methylpiperidin-1-yl) -phenyl] -amide image2 Example 7, step (a); Example 4, step (b); Example 7, step (d); Example 28, steps (e) - (f) (Example 7, step (a))

30

5-Cyano-furan-2-carboxylic acid [4- (1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -2- (4,4-dimethylpiperidin-1-yl) -phenyl] -amide image2 Example 29 (US 2003236247); (WO 2004096795 A2)

image63

(cont.) (cont.) (cont.)

image64

Example No.

Name Structure Procedure Reference Reagents

31

4-Cyano-1H- [4- (1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -2- (4,4-dimethyl-piperidin-1-yl) phenyl] -amide pyrrole-2-carboxylic image2 Example 29 (US 2003236247) (Canadian J. Chem. 59,2673 (1981))

image65

Example No.

Name Structure Procedure Reference Reagents

32

5-Cyano acid [2- (8-Aza-spiro [4.5] dec-8-yl) -4- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) phenyl] -amide 2H- [1,2,4] triazole-3-carboxylic image2 Example 29 (J. Med. Chem., 8, 76676 (1965)); (Hecheng Huaxue, 11 (4), 351353 (2003))

33

[4- (2,6-Dimethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -2- (4,4-dimethyl-piperidin-1-yl) -phenyl] -amide 4-cyano-1H-imidazole-2-carboxylic acid image2 Example 28 (US 2003236247)

image66

Example No.

Name Structure Procedure Reference Reagents

3. 4

{4- (2,6-Dimethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -2- [4- (2-hydroxy-ethyl) piperidin-1-yl] 4-Hydroxy-1H-imidazole-2-carboxylic acid -phenyl} -amide image2 Example 28 (WO 9811086 A1); Berichte, 58B, 1346-53 (1925)

The following compounds were prepared by procedures similar to the previous examples with additional procedures and with the corresponding reagents listed in the table.

Example No.

Name Structure Procedure Reference Reagents

35

4-cyano-1H-imidazole-2-carboxylic acid [4- (2,6-Dioxopiperidin-4-yl) -2-piperidin-1-yl-phenyl] amide Example 1, steps (a) - (j); Example 28, step (e); Example 1, steps (l) - (m) image2

36

4-Cyano-1H-imidazole2-carboxylic acid [4- (2,6-Dioxopiperidin-4-yl) -2- (4-methyl-piperidin-1-yl) phenyl] -amide Example 1, steps (a) - (j); Example 28, step (e); Example 1, steps (1) - (m)

37

4-Cyano-1H-pyrrole-2-carboxylic acid {4- (1,6-Dioxopiperidin-4-yl) -2- (4-methyl-piperidin-1-yl) phenyl] -amide Example 1, steps (a) - (j); Example 28, step (e); Example 1, steps (1) - (m) (Canadian J. Chem. 59, 2673 (1981))

image67

(Cont.)

Example No.

Name Structure Procedure Reference Reagents

MeNH2;

38

[2- (4,4-Dimethylpiperidin-1-yl) -4- (1methyl-2,6-dioxopiperidin-4-yl) -phenyl] 5-cyano-furan-2-carboxylic acid amide image2 Example 15, (a) - (b); Example 4, (a) and (d); Example 28, step (e); Example 1, steps (l) - (m) (US 2003236247);

(WO 2004096795 A2)

39

Acid [2- (4-Methyl-piperidin-1-yl) -4- (2-methyl1,1,3,3-tetraoxo-1λ6, 3λ6- [1,3,2] dithiazinan5-yl) -phenyl] -amide 5-cyano-1Himidazole-2-carboxylic acid image2 Example 25, steps (a) - (d); Example 1, step (i); Example 43, step (c); Example 4, step (d); Example 28, step (e); Example 1, steps (1) - (m) MeNH2

40

[2- (8-Aza-spiro [4.5] dec-8-yl) -4 (1,1,3,3-tetraoxo1λ, 636- [1,3,2] dithiazinan-5-yl) -phenyl] amide 5-cyano-4H [1,2,4] triazole-3-carboxylic acid image2 Example 25, steps (a) - (d); Example 15, step (c); Example 43, step (c); Example 4, steps (a) and (d); Example 28, step (e); Example 1, steps (1) - (m); Example 2, step (d) (J. Med. Chem., 8, 766-76 (1965)); (Hecheng Huaxue, 11 (4), 351-353 (2003))

The following compound was prepared by procedures similar to the previous examples with additional procedures and with the corresponding reagents listed in the table.

Image68

Example No.

Name Structure Procedure Reference Reagents

41

[6- (4,4-Dimethyl-cyclohex-1-enyl) 2 ', 6'-dioxo-1', 2 ', 3', 4 ', 5', 6'hexahydro- [2,4 '] bipyridinyl 4-Cyano-1Himidazole-2-carboxylic acid -5-yl] amide image2 Example 2 (WO 9737979 A1); (Combi-Blocks, Inc.)

The following compound was prepared by procedures similar to the previous examples with additional procedures and with the corresponding reagents listed in the table.

Example No.

Name Structure Procedure Reference Reagents

42

(4-Methyl-2 ", 6" -dioxo3,4,5,6,1 ", 2", 3 ", 4", 5 ", 6" decahydro-2H [1,2 ', 6', 4 " ] terpyridin-3'-yl) 4-cyano1H-imidazole-2-carboxylic acid amide image2 Example 2, steps (a) - (d); Example 1, steps (i); Example 4, step (a); Example 43; stage (h); Example 1, steps (1) - (m) (WO 9737979 A1);

Example 43

[6 '- (1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -4,4-dimethyl-3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl- 4-Cyano-1H-imidazole-2-carboxylic acid 3'-yl] -amide

image69

a) 2- (5-Nitro-pyridin-2-yl) -propane-1,3-diol

image2

The title compound was prepared from 2-pyridin-2-yl-propane-1,3-diol (Tetrahedron: Asymmetry 8 (13), 21752187 (1997)) according to the procedure in Example 2, step ( to).

b) 2- (5-Amino-pyridin-2-yl) -propane-1,3-diol

image2

The title compound was prepared from 2- (5-nitro-pyridin-2-yl) -propane-1,3-diol (as prepared in the previous step) according to the procedure in Example 1, stage (i).

c) [6- (2-Hydroxy-1-hydroxymethyl-ethyl) -pyridin-3-yl] -carbamic acid tert-butyl ester

10

image2

The title compound was prepared from 2- (5-amino-pyridin-2-yl) -propane-1,3-diol (as prepared in the previous step) and (BOC) 2O according to conventional procedures found in "Protective Groups in Organic Synthesis", by Theodora W. Greene and Peter GM Wuts, John Wiley & Sons, Inc. NY, (1999).

d) [6- (2-Amino-1-aminomethyl-ethyl) -pyridin-3-yl] -carbamic acid tert-butyl ester

fifteen

image2

The title compound was prepared from [6- (2-hydroxy-1-hydroxymethyl-ethyl) -pyridin-3-yl] carbamic acid tert-butyl ester (as prepared in the previous step) according to the procedure in Example 4, step (b).

e) [6- (2-Oxo-hexahydro-pyrimidin-5-yl) -pyridin-3-yl] -carbamic acid tert-butyl ester

image2

The title compound was prepared from [6- (2-amino-1-aminomethyl-ethyl) -pyridin-3-yl] tert-butyl acid

image70

carbamic (as prepared in the previous step) according to the procedure in Example 4, step (c).

f) [6- (1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -pyridin-3-yl] -carbamic acid tert-butyl ester

image2

The title compound was prepared from [6- (2-oxo-hexahydro-pyrimidin-5-yl) -pyridin-3-yl] -carbamic acid tert-butyl ester (as prepared in the previous step) according to the procedure in Example 7, step (a).

g) [2-Bromo-6- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -pyridin-3-yl] -carbamic acid tert-butyl ester

image2

The title compound was prepared from [6- (1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -pyridin-3-yl] -carbamic acid tert-butyl ester (as prepared in the previous step) according to the procedure in Example 10 4, step (d).

h) 5- (3'-Amino-4,4-dimethyl-3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-6-yl) -1,3-dimethyl-tetrahydro-pyrimidine -2-one

image2

The title compound was prepared from [2-bromo-6- (1,3-dimethyl-2-oxo-hexahydropyrimidin-5-yl) -pyridin-3-yl] -carbamic acid tert-butyl ester (as has been prepared in the previous step) and 4,4-dimethylpiperidine (US

2003236247) following the Buchwald procedure from the literature (Org. Lett., 4, 2885-8 (2002)). The residue obtained was purified by chromatography on silica gel with a mixture of suitable solvents. After isolation, removal of the BOC protecting group from the resulting intermediate was accomplished by stirring at RT in TFA-DCM (1: 2), monitoring its completion by TLC and then concentrating in vacuo.

i) [6 '- (1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl) -4,4-dimethyl-3,4,5,6-tetrahydro-2H- [1,2'] 4-Cyano-1H-imidazole-2-carboxylic acid bipyridinyl-3'-yl] -amide

The title compound was prepared from 5- (3'-amino-4,4-dimethyl-3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-6'-yl) -1 , 3dimethyl-tetrahydro-pyrimidin-2-one (as prepared in the previous step) according to the procedures in Example 1, steps (1) and (m).

Example 44

25 [6 '- (2,6-Diethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -4-methyl-3,4,5,6-tetrahydro-2H- 4-Chloro-1H-imidazole-2-carboxylic acid [1,2 '] bipyridinyl-3'-yl] -amide

image71

image2

a) 4-Chloro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester

image2

The title compound was prepared according to the procedure of Example 51, step (b), substituting N-chlorosuccinimide (NCS) for NBS. Mass Spectrum (ESI, m / z): Calcd. For C12H21ClN2O3Si, 305.1 (M + H), found 304.7.

b) Potassium salt of 4-chloro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate

image2

The title compound was prepared from 4-chloro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester (prepared in the previous step) according to the procedure in Example 1, stage (d). Mass Spectrum (ESI, m / z): Calcd. For C10H16ClKN2O3Si, 277.1 (M + H-K), found 276.7.

c) 6 '- (2,6-Diethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -4-methyl-3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-3'-ylamine

image2

The title compound was prepared from 4-chloro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole ethyl ester

2-carboxylic (prepared in the previous step) according to the procedure in Example 1, steps (a) - (h) substituting EtI for Me2SO4.

d) [6 '- (2,6-Diethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -4-methyl-3,4,5,6-tetrahydro-2H 4-Chloro-1H-imidazole-2-carboxylic acid - [1,2 '] bipyridinyl-3'-yl] -amide

The title compound was prepared from 6 '- (2,6-diethyl-1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -4-methyl-3,4,5 , 6

20 tetrahydro-2H- [1,2 '] bipyridinyl-3'-ylamine (as prepared in the previous step) and potassium salt of 4-chloro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate (as prepared in this example, step (b) following the procedure of Example 1, step (1)) followed by the procedure of Example 1, step (m).

image72

The following compounds were prepared by procedures similar to those of the previous example with the corresponding reagents as indicated in the table.

Example No.

Name Structure Procedure Reference Reagents

Four. Five

[6 '- (1,3-Dimethyl-2-oxohexahydro-pyrimidin-5-yl) -4,4-dimethyl-3,4,5,6-tetrahydro-2H [1,2'] bipyridinyl-3'-yl] -4-Cyano-1Himidazole-2-carboxylic acid amide image2 Example 44 (US 2003236247); (Example 1, stage (d)

46

[6 '- (2,6-Dimethyl-1,1-dioxo1λ6- [1,2,6] thiadiazinan-4-yl) -4-methyl-3,4,5,6-tetrahydro-2H [1,2'] 5-Cyano-2H [1,2,4] triazole-3-carboxylic acid bipyridinyl-3'-yl] -amide Example 44 (Hecheng Huaxue, 11 (4), 351-353 (2003))

The following compounds were prepared by procedures similar to those of the previous examples with modifications and with the corresponding reagents as indicated in the table.

Example No.

Name Structure Procedure Reference Reagents

47

4-Cyano-1H- [2- (4,4-Dimethyl-cyclohex-1enyl) -6- (1,3-dimethyl-2-oxohexahydro-pyrimidin-5-yl) pyridin-3-yl] -amide 2-carboxylic imidazole Example 43, steps (a) - (g); Example 3, steps (a) and (c); Example 1, step (1) - (m) (Combi-Blocks, Inc.)

image73

(Cont.)

Example No.

Name Structure Procedure Reference Reagents

[6- (1,3-Dimethyl-2-oxohexahydro-pyrimidin-5-yl) -2-spiro [4.5] dec-7

Example 43, steps (a) - (g);

48

5-cyano-furan-2-carboxylic acid en-8-yl-pyridin-3-yl] amide Example 3, step (a) and (c); Example 1, step (1) - (m) (WO 2005063705);

(WO 2004096795

A2)

49

[2- (4,4-Dimethyl-cyclohex1-enyl) -6- (2,6-dimethyl-1,1-dioxo-1λ6 - [1,2,6] thiadiazinan-4-yl) pyridin-3-yl] - 4-Cyano-1H-pyrrole2-carboxylic acid amide image2 Example 43, steps (a) (d); Example 5, step (a); Example 11, steps (a) - (d) (Combi-Blocks, Inc.);

(Canadian J. Chem. 59, 2673 (1981))

fifty

[2- (4,4-Dimethyl-cyclohex1-enyl) -6- (2,6-dimethyl1,1-dioxo-1λ6- [1,2,6] thiadiazinan-4-yl) -pyridin3-yl] -amide 4-cyano-1H-imidazole-2-carboxylic acid Example 43, steps (a) (d); Example 5, step (a); Example 11, steps (a) - (e) (Combi-Blocks, Inc.)

image74

Example 51

{5- [4 - [(4-Bromo-1H-imidazole-2-carbonyl) -amino] -3- (4,4-dimethyl-cyclohex-1-enyl) -phenyl] tetrahydro-pyrimidine- 2-ylidene} -carbamic

image2

a) 1- (2-Trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester

image2

One flask filled with 1H-imidazole-2-carboxylic acid ethyl ester (1.03 g, 7.36 mmol), K2CO3 (2.00 g, 14.5 mmol), SEM-Cl (1.56 mL, 8 , 89 mmol) and 20 ml of acetone was stirred for 10 h at RT. The reaction was diluted with EtOAc (100 ml), washed with NaHCO3 (2 x 100 ml) and brine (100 ml), and the organic phase was dried over Na2SO4 and

10 concentrated. The title compound was eluted from a 20 g SPE with 50% EtOAc / hexanes, yielding 1.50 g (76%) of a colorless oil. Mass Spectrum (ESI, m / z): Calcd. For C12H22N3O3Si, 271.1 (M + H), found 271.1.

b) 4-Bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester

image2

To a solution of 1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid ethyl ester (0.20 g, 0.74 mmol)

15 (prepared in the previous step) in 2 ml of CH3CN was added NBS (0.13 g, 0.74 mmol) and the mixture was heated at 60 ° C for 2 h. The mixture was concentrated and the title compound was purified by eluting a 20 g SPE column with 20% EtOAc / hexanes to give 0.10 g (39%) of a colorless oil. Mass Spectrum (ESI, m / z): Calcd. For C12H21BrN2O3Si, 349.0 (M + H), found 348.7.

c) Potassium salt of 4-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate

image2

twenty

The title compound was prepared according to the procedure in Example 1, step (d). Mass Spectrum (ESI, m / z): Calcd. For C10H16BrKN2O3Si, 322.0 (M + H-K), found 322.6.

d) {5- [4 - [(4-bromo-1H-imidazole-2-carbonyl) -amino] -3- (4,4-dimethyl-cyclohex-1-enyl) phenyl] -tetrahydro- pyrimidin-2-ylidene} -carbamic

The title compound was prepared according to the procedures in Example 12, substituting the potassium salt of 4-bromo-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate (as prepared in this example , step (c)) by potassium salt of 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylate and substituting 4,4-dimethylcyclohex-1-enylboronic acid for cyclohex-1-enylboronic acid .

image75

Examples 52 and 53 were prepared by procedures similar to those of the previous example with the corresponding reagents as indicated in the table.

Example No.

Name Structure Procedure Reference Reagents

52

4-cyano-1H-imidazole-2-carboxylic acid [4- (2-Nitroimino-hexahydropyrimidin-5-yl) -2- (4,4-dimethyl-cyclohex-1-enyl) phenyl] -amide image2 Example 51 (Combi-Blocks, Inc.); (Aldrich Chemical Co., Inc.); (Example 1, stage (d)

image76

(Cont.)

Example No.

Name Structure Procedure Reference Reagents

53

{5- [4 - [(4-Cyano-1H-imidazole-2-carbonyl) -amino] -3- (4,4-dimethyl cyclohex-1-enyl) phenyl] -tetrahydro-pyrimidin-2ylidene} -carbamic acid methyl ester image2 Example 51 (Combi-Blocks, Inc.); (Helv. Chim. Acta, 35, 1005-20 (1952)); (Example 1, stage (d)

Example 54

Trifluoroacetic acid salt of 4- [4- (2-cyanoimino-1,3-dimethyl-hexahydro-pyrimidin-5-yl) -2- (4,4-dimethyl-cyclohex-1enyl) -phenyl] -amide cyano-1H-imidazole-2-carboxylic

image2

a.) 5- (4-Bromo-phenyl) -tetrahydro-pyrimidin-2-ylidene-cyanamide

image2

To a stirred suspension of 2- (4-bromo-phenyl) -propane-1,3-diol (462 mg, 2.00 mmol, JACS, 125 (46), 13948) in 10 DCM (50 ml) and Et3N ( 0.7 ml, 5 mmol) MsCl (0.3 ml, 4.0 mmol) was added at 0 ° C. The resulting mixture was left

image77

5

10

fifteen

twenty

25

30

35

40

warm to RT, stir for 4 h and treated with sat. NaHCO3. (50 ml). The DCM phase was separated and the aqueous phase was extracted twice with DCM (2 x 20 ml). The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The resulting bismesylate was dried under high vacuum for 2 h and redissolved in DMF (5 ml). NaN3 (0.52 g, 8.0 mmol) was added to this mixture. The resulting mixture was heated to 70 ° C overnight. The reaction mixture was allowed to cool to RT and was treated with water (10 ml). The product was then extracted with EtOAc (3x10 ml). The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The resulting diazide was dried under high vacuum for 2 h and used in the next step without further purification. The diazide (280 mg, 1 mmol) was dissolved in MeOH (5 ml) and Et3N (1.4 ml, 10 mmol) and the resulting solution was placed under an atmosphere of N2. To this solution was added propanedithiol (1.0 ml, 10 mmol). The resulting mixture was stirred at RT overnight and concentrated to obtain a viscous oil which was dried under high vacuum for 2 h, dissolved in ether (20 ml) and treated with 2M HCl in ether (10 ml, 20 mmol). The resulting suspension was sonicated for 5 min and stirred for 5 h. The precipitate formed was collected by suction filtration and dried under vacuum, obtaining 2- (4-bromo-phenyl) -propane-1,3-diamine dihydrochloride which was used directly in the next step without further purification. The dihydrochloride salt (302 mg, 1 mmol) was added to a solution of Et3N (0.7 ml, 5 mmol) and dimethyl N-cyanodithioiminocarbonate (146 mg, 1.00 mmol) in EtOH (10 ml). The resulting mixture was heated to 80 ° C overnight. The reaction mixture was allowed to cool to RT and stirred for a further 2 h. The formed precipitate was collected by suction filtration, obtaining 92 mg (33%) of the title compound. Mass Spectrum (ESI, m / z): Calcd. For C11H11BrN4, 279.0 (M + H), found 279.1.

b) 5- (4-Bromo-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide

image2

To a suspension of NaH (80 mg, 2 mmol) in dry DMF (10 ml), 5- (4-bromophenyl) tetrahydro-pyrimidin-2-ylidene-cyanamide (279 mg, 1.00 mmol) was added dropwise , as prepared in the previous step) in DMF (5 ml) at 0 ° C. The resulting mixture was stirred at RT for 30 min, cooled back to 0 ° C and treated with MeI (0.24 ml, 4.0 mmol). The mixture was allowed to warm to RT, stirred for 2 h, diluted with water (10 ml) and extracted with DCM (3 x 20 ml). The DCM phases were combined, dried (Na2SO4), and concentrated. The solid obtained was suspended in hexane, sonicated for 5 min and the precipitate was collected by suction filtration 173 mg, 62%. Mass Spectrum (ESI, m / z): Calcd. For C13H15BrN4, 307.0 (M + H), found 307.4.

c) 5- (4-Amino-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide

image2

In a screw cap vial containing tri-tert-butylphosphine (5.0 mg, 0.025 mmol), Pd2 (dba) 3 (14.3 mg, 0.0250 mmol), Zn [N (SiMe3) 2] 2 ( 116 mg, 0.300 mmol) and LiCl (12.6 mg, 0.300 mmol) in an atmosphere of Ar was added 5- (4-bromo-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide (153 mg 0.500 mmol), as prepared in the previous step) in THF (1 ml). The reaction mixture was then stirred at 60 ° C overnight, allowed to cool to RT, and treated with 1N HCl (0.2 ml). The reaction mixture was then transferred to a separatory funnel, diluted with DCM (10 ml), and washed with 1N NaOH (5 ml). The DCM phases were combined, dried (Na2SO4), and concentrated. The obtained solid was purified on silica (50% -100% EtOAc / hexane), obtaining 40 mg, 33% of the title compound. Mass Spectrum (ESI, m / z): Calcd. For C13H17N5, 244.10 (M + H), found 244.2.

d) 5- (4-Amino-3-bromo-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide

image2

The title compound was prepared according to the bromination procedure of Example 1, step (j), using 5 (4-amino-phenyl) -1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide as the starting material. starting point: Mass spectrum (ESI, m / z): Calcd. for C13H16BrN5, 322.1 (M + H), found 322.2.

c) 5- [4-Amino-3- (4,4-dimethyl-cyclohex-1-enyl) -phenyl] -1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide

image78

image2

5

10

fifteen

twenty

25

30

35

The title compound was prepared according to the Suzuki coupling procedure of Example 3, step (a), using 4,4-dimethyl-cyclohex-1-enyl boronic acid and 5- (4-amino-3-bromophenyl) -1,3-dimethyl-tetrahydro-pyrimidine-2ylidene-cyanamide. Mass spectrum (ESI, m / z): Calcd. For C21H29N5, 352.2 (M + H), found 352.4

f) 4-cyano-1 acid [4- (2-Cyanoimino-1,3-dimethyl-hexahydro-pyrimidin-5-yl) -2- (4,4-dimethyl-cyclohex-1-enyl) -phenyl] -amide - (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic

image2

5- [4-amino-3- (4,4-dimethyl-cyclohex-1-enyl) -phenyl] -1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide (as prepared in previous step) to 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1) as described in Example 1, step ( 1), obtaining the title compound: Mass spectrum (ESI, m / z): Calcd. For C32H44NRO2Si, 601.3 (M + H), found 601.3.

g) Trifluoroacetic acid salt of acid [4- (2-cyanoimino-1,3-dimethyl-hexahydro-pyrimidin-5-yl) -2- (4,4-dimethylcyclohex-1-enyl) -phenyl] -amide 4-cyano-1H-imidazole-2-carboxylic

The title compound was synthesized from [4- (2-cyanoimino-1,3-dimethyl-hexahydro-pyrimidin-5-yl) -2- (4,4-dimethylcyclohex-1-enyl) -phenyl] -amide 4-cyano-1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-carboxylic acid (as prepared in the previous step) as described in Example 7, step (e): 1H NMR ( CD3OD; 400 MHz): δ 8.22 (d, 1H, J = 8.4 Hz), 8.01 (s, 1H), 7.25 (dd, 1H, J = 8.4, 2.1 Hz ), 7.08 (d, 1H, J = 2.1 Hz), 5.82 (bs, 1H), 3.4-3.6 (m, 4H), 3.25 (s, 6H), 3 , 1-3.2 (m, 1H), 2.38 (m, 2H), 2.15 (m, 2H), 1.62 (m, 2H), 1.15 (s, 6H); Mass Spectrum (ESI, m / z): Calcd. For C26H30N8O, 471.2 (M + H), found 471.3.

IV. Results

Fluorescence Polarization Competition Immunoassay

A fluorescence polarization competition immunoassay was used to measure inhibition by the compound of phosphorylation of CSF-1R by tyrosine on a synthetic peptide CSF-1R555-568 (SYEGNSYTFIDPTQ). The assay was performed in black 96-well microplates (Cat # 42-000-0117, Molecular Devices, Sunnyvale, CA). In each well, 5 µl of compound (in 4% DMSO) was mixed with 2 µl of 3.5 nM CSF-1R, 25 mM MgCl2 in assay buffer (100 mM HEPES, pH 7.5, 1 mM DTT, Tween- 0.01%), and 2 µl of 1540 µM peptide in assay buffer. The kinase reaction was started by adding 1 µl of 10 mM ATP in assay buffer. Final concentrations in the 10 µl reaction mix were 100 mM HEPES, pH 7.5, 1 mM DTT, 0.01% Tween-20, 2% DMSO, 308 µM SYEGNSYTFIDPTQ, 1 mM ATP, 5 mM MgCl2, and CSF-1R 0.7 nM. Positive and negative control wells were included in each plate, in which 4% DMSO in assay buffer replaced the compound; in addition, the positive control wells received 1.2 µl of 50 mM EDTA before the start of the reaction.

The plates were covered and incubated at room temperature for 80 minutes. Reactions were stopped by the addition of 1.2 µl of 50 mM EDTA. Each well then received 10 µl of a 1: 1: 3 mixture of 10X antiphosphotyrosine antibody, 10X PTK green indicator, and FP dilution buffer, respectively (Cat. # P2837, Invitrogen, Carlsbad, CA). The plates were covered, incubated for 30 minutes at room temperature and the fluorescence polarization was read on an Analyst plate reader (Molecular Devices). The instrument settings were: excitation 485 nm, emission 530 nm, with a cutoff filter of 505 nm; height Z: middle of the well; factor G: 0.93. Under these conditions, the fluorescence polarization values for positive and negative controls were approximately 290 and 160, respectively, and were used to define 100% and 0% inhibition of the CSF-1R reaction. The indicated IC50 values are the average of three of at least three determinations.

image79

CSF-1-directed Mouse Bone Marrow Derived Macrophage Assay

The macrophages were derived by culturing mouse bone marrow in alpha-MEM supplemented with 10% FCS (fetal calf serum) and 50 ng / ml recombinant mouse CSF-1 on bacteriological plates. On the sixth day, macrophages were removed from the plates, washed, and resuspended at 0.1 million cells / ml in alpha-MEM containing 10% FCS. One hundred µl of cell suspension was distributed per well in 96-well culture plates. The wells were further supplemented with the addition of 50 µl of medium containing 15 ng / ml CSF-1, Indomethacin 3

10 µM and 3X of a series of dilutions of test compounds. The cells are cultured for 30 hours at 37 ° C and 5% CO2. During the final six hours, cultures are supplemented with an additional 30 µl of medium containing a 1: 500 dilution of bromodeoxyuridine (BrDU). At the end of the culture period, the medium is removed and replaced with 200 fixing solution for 30 minutes at room temperature. The fixative is then removed from the plates and the plates are allowed to air dry. Incorporation of BrDU into dry fixed cells is quantified

15 using a specific ELISA (Cat X1327K) from Exalpha Corporation (Watertown MA). Background values are determined from wells without BrDU reagent. IC50 values are calculated based on the signal from cells stimulated with CSF-1 with no compound present.

Table 1 lists the test results for representative compounds of the invention.

TABLE 1

Example Number

IC50 (µM) BMDM (Mouse) with mCSF-driven proliferation (µM)

1

0.001 0.01

3

0.001 0.007

4

0.003 0.07

5

0.003 0.06

6

0.01 0.06

7

0.001 0.01

8

0.0004 0.003

9

0.001 0.005

10

N / A 0.1

eleven

0.002 0.002

12

0.003 0.04

13

0.002 0.1

14

0.001 0.004

fifteen

> 0.3 N / A

54

0.00042 0.039

image80

Claims (15)

1. A compound of Formula I: image 1 where: W is image 1 wherein R4 = H, F, Cl, Br, I, OH, OCH3, OCH2CH3, -C (1-3) alkyl, -CO2R5, CONR6R7, C≡CR8 or CN; in which R5 = H, or -C (1-3) alkyl; R6 = H, or -C (1-3) alkyl; R7 = H, or -C (1-3) alkyl; and R8 = H, -CH2OH; or -CH2CH2OH; R2 is cycloalkyl, spiro-substituted cycloalkenyl, heterocyclyl, spiro-substituted piperidinyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl or dihydropyranyl, any of which may be independently substituted with one or two each of the following: chlorine, fluorine, C (1-3) hydroxyalkyl and alkyl 15 C (1-4); wherein the cycloalkyl groups are saturated or partially unsaturated rings composed of 3 to 8 carbon atoms and wherein said ring may be substituted with up to four alkyl substituents; wherein the spiro substituted cycloalkenyl groups are cycloalkyl rings sharing a single carbon atom and wherein at least one of the rings is partially unsaturated; 20 X is selected from the group consisting of: image 1 wherein R1 and R10 are independently H, -CH3, or C2-C5 alkyl, optionally substituted with one or two of: Me, Et, OH, NH2, NHMe, NMe2, NHEt, NEt2, pyrrolidinyl, pyridyl, morpholino, CONH2, or COOH and in such a way that when any of two heteroatoms is attached to said C2 to C5 alkyl group there are at least two 25 carbon atoms between them, and R3 is -SO2Me, SO2Et, -CO2R9, -NO2 or -CN; wherein R9 is H or C (1-3) alkyl; Z is H, F, Cl, Br, C1-C3 alkyl or -CH2OH; and J is CH or N; or 30 a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. image2 2. A compound of claim 1, wherein: R2 is selected from the group consisting of: cyclohexenyl, 4,4-dimethyl cyclohexenyl, 4,4-diethyl cyclohexenyl, 4-methyl cyclohexenyl, 4-ethyl cyclohex-enyl, 4-npropyl cyclohexenyl, 4-iso-propyl cyclohexenyl, 4-tert-butyl cyclohexenyl, cycloheptenyl, spiro [2.5] oct-5-enyl, spiro [3.5] non-6-enyl, spiro [4.5] dec-7-enyl, spiro [5.5] undec-2-enyl, 3-aza-spiro [5.5] undecanyl, 8 -azaspiro [4.5] decanyl, 4-methyl piperidinyl, 4-ethyl piperidinyl, 4- (1'hydroxye-2'yl) piperidinyl and 4,4 dimethyl piperidinyl thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl and dihydro-pyranyl. 3. A compound of claim 1, wherein: W is R2 is image 1 4. A compound of claim 3, wherein: R2 is image3 image 1 X is selected from the group consisting of: image 1 image 1 Wherein R1 is H, -CH3 or C2 to C5 alkyl, optionally substituted with one or two of: Me, Et, OH, NH2, NHMe, NMe2, NHEt, NEt2, pyrrolidinyl, pyridyl, morpholino, CONH2 or COOH, such that when any of two heteroatoms is attached to said C2-C5 alkyl group there are at least two carbon atoms between them; R3 is SO2Me, SO2Et, -CO2R9, -NO2 or -CN; wherein R9 = H or C (1-3) alkyl; and Z is H, C1-C3 alkyl or -CH2OH. 5. A compound of claim 4, wherein: 10 R2es image4 image 1 Z is H or -CH2OH; X is selected from the group consisting of image 1 where R1 is H, -CH2CH3, -CH2CH2OH, or -CH3; and R3 is -SO2CH3, -CO2CH3, -NO2 or -CN. 6. A compound of claim 5, wherein: W is R2 is image 1 X is selected from the group consisting of image5 image 1 R3 where R1 is H or -CH3; y is -SO2CH3 or -CN. 7. A compound of claim 1 selected from the group consisting of: image 1 image6 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 and solvates, tautomeric hydrates, and pharmaceutically acceptable salts thereof.

8.

A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9.

At least one compound of claim 1, for use in a method of treating inflammation in a mammal.

10.

At least one compound of claim 1, for use in a method of treating cancer or cardiovascular disease in a mammal.

eleven.

At least one compound of claim 1, for use in a method of treating a disease with an inflammatory component in a mammal, wherein the disease is selected from the group consisting of: glomerulonephritis, inflammatory bowel disease, prosthetic failure, sarcoidosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, psoriasis, diabetes, tumor-related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, and Alzheimer's dementia.

12.

At least one compound of claim 1, for use in a method of treating pain selected from the group consisting of: skeletal pain caused by tumor metastasis or osteoarthritis, visceral, inflammatory and neurogenic pain, in a mammal.

13.

At least one compound of claim 1, for use in a method of treating osteoporosis, Paget's disease and other diseases in which bone resorption mediates morbidity including rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthetic failure, sarcoma osteolytic, myeloma and tumor metastasis to bone.

14.

At least one compound of claim 1, for use in a method of treating and preventing metastases from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer and hairy cell leukemia in a mammal.

fifteen.

At least one compound of claim 1, for use in a method of treating autoimmune diseases selected from the group consisting of: systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis and uveitis in a mammal.