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HK1188145B - Novel fused pyridine compounds as casein kinase inhibitors - Google Patents

Novel fused pyridine compounds as casein kinase inhibitors Download PDF

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Publication number
HK1188145B
HK1188145B HK14101403.3A HK14101403A HK1188145B HK 1188145 B HK1188145 B HK 1188145B HK 14101403 A HK14101403 A HK 14101403A HK 1188145 B HK1188145 B HK 1188145B
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Hong Kong
Prior art keywords
methyl
alkyl
pyrazol
fluorophenyl
dihydro
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HK14101403.3A
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Chinese (zh)
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HK1188145A1 (en
Inventor
T．W．巴特勒
R．Y．钱德拉塞卡兰
S．R．曼特
C.萨布拉曼亚姆
T．T．瓦格尔
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生物基因Ma公司
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Priority claimed from PCT/IB2011/055489 external-priority patent/WO2012085721A1/en
Publication of HK1188145A1 publication Critical patent/HK1188145A1/en
Publication of HK1188145B publication Critical patent/HK1188145B/en

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Description

Novel fused pyridine compounds as casein kinase inhibitors
Technical Field
The present invention relates generally to agents useful in the treatment and/or prevention of diseases and disorders associated with the central nervous system. More particularly, the invention includes compounds for treating a patient having a disease or disorder ameliorated by inhibiting casein kinase I delta (CK 1) or CK1 epsilon (CK 1) activity by administration of a series of substituted fused pyridine compounds. More particularly, the invention relates to aryl substituted 5-membered heteroaryl compounds substituted with an optionally substituted (2, 3-fused pyridin-4-yl) group, and related analogs that are inhibitors of human CK1 or CK1 phosphorylation.
Background
The circadian clock links our sleep-activity daily cycle with the external environment. The deregulation of the circadian clock has been implicated in a number of human disorders including depression, seasonal affective disorders, and metabolic disorders. In mammals, the circadian rhythm is controlled by the mother clock located in the supracrossing nucleus of the hypothalamus (Antle and Silver, Trends Neurosci28: 145-151). At the cellular level, molecular events after a clock cycle are described by regular increases and decreases in mRNAs and proteins that define the feedback loop, resulting in a cycle of approximately 24 hours. The cross-supranuclear is primarily directly regulated or generated by light rays passing through the hypothalamic tract of the retina. The periodic output of the nucleus at the cross (not fully identified) regulates multiple downstream rhythms such as those in sleep and wakefulness, body temperature, and hormone secretion (Ko and Takahashi, Hum Mol Gen15: R271-R277). In addition, diseases such as depression, seasonal affective disorder, and metabolic disorders may have circadian rhythms (Barnard and Nolan, PLoS Genet.2008May;4(5): e 1000040.).
Phosphorylation of circadian clock proteins is an essential element in controlling the cyclic rhythm of the clock. CK1 and CK1 are closely related Ser-Thr protein kinases that act as key clock regulators, as evidenced by mammalian mutations in each kinase that significantly alter the circadian cycle (Lowrey et al, Science288: 483-492). Therefore, the CK 1/inhibitor has utility in the treatment of circadian rhythm disorders. It is therefore an object of the present invention to provide compounds of formula I which are inhibitors of CK1 or CK 1. This and other objects of the present invention will become apparent from the following detailed discussion of the invention.
Disclosure of Invention
The present invention is directed to compounds having the structure of formula I:
wherein X and Y are independently = N-, -NR1-、CR1or-S-, with the proviso that at least one of X and Y is CR1；
Ring A is a 4-to 7-membered cycloalkyl or heterocycloalkyl or 5-to 6-membered heteroaryl group, wherein up to 2 carbon atoms are selected from = N-, -NR2A heteroatom of-O-, -S, and where valency permits any remaining carbon atom may be replaced by R3Substitution;
each R1Independently is H, C1-4Alkyl radical, C3-6Cycloalkyl, -CF3、-(CH2)1-3CF34-to 10-membered heterocycloalkyl, wherein said heterocycloalkyl may be substituted with up to two substituents independently selected from halogen, OH, oxo, cyano, C1-6Alkyl or C1-6alkyl-O-C1-6An alkyl group;
each R2Independently is H, C1-6Alkyl radical, C4-10-bicycloalkyl, - (CH)2)t-CN、-SO2C1-6Alkyl, -SO2(CH2)tC3-6Cycloalkyl, -C1-6alkyl-O-C1-6Alkyl, -C1-6alkyl-C (O) O-C1-6Alkyl, -C3-6cycloalkyl-C (O) O-C1-6Alkyl, -C (O) - (O)u-C1-6Alkyl, -C (O) -C1-6alkyl-O-C1-6Alkyl, -C (O) - (O)u-(CH2)t-(C6-10Aryl), - (CH)2)t-(C6-10Aryl), -C (O) - (O)u-(CH2)t- (5-to 10-membered heteroaryl), - (CH)2)t-C(O)-NR5R6、-(CH2)t- (5-to 10-membered heteroaryl), -C (O) - (O)u-(CH2)t- (3-to 10-membered heterocycloalkyl), - (CH)2)t- (4-to 10-membered heterocycloalkyl), -C (O) - (O)u-(CH2)t- (3-to 10-membered cycloalkyl) or- (CH)2)t- (3-to 10-membered cycloalkyl),
wherein R is2Said aryl, heteroaryl, cycloalkyl and heterocycloalkyl may be substituted with up to two substituents independently selected from halogen, OH, cyano, C1-6Alkyl, C (O) -O-C1-3Alkyl or C1-6alkyl-O-C1-6An alkyl group, a carboxyl group,
and wherein R is, where valence permits2Any alkyl, cycloalkyl and heterocycloalkyl of (a) may be further substituted by oxo;
each R3Independently is absent, C1-3Alkyl, halogen, oxo, -NR5R6OR-OR5；
Each R4Independently halogen, -CF3、C1-3Alkyl, - (CH)2)t-C3-4Cycloalkyl, - (CH)2)t-O-C1-3Alkyl, - (CH)2)t-cyano or- (CH)2)t-a hydroxyl group;
each R5Independently is H or C1-6An alkyl group;
each R6Independently is H or C1-6An alkyl group;
R7is H, halogen or C1-3An alkyl group;
n is 0, 1 or 2;
each t is independently 0, 1 or 2;
each u is independently 0 or 1;
and pharmaceutically acceptable salts thereof.
The invention also includes pharmaceutically acceptable salts, hydrates, solvates, isomers, crystalline and amorphous, isomorphous, polymorphs, and metabolites of the compound of formula I. The invention also includes all tautomers and stereochemically isomeric forms of these compounds.
The present invention relates generally to agents and pharmaceutically acceptable salts thereof useful for the treatment and/or prevention of diseases and disorders associated with the central nervous system. More particularly, the invention includes compounds for treating a patient having a disease or disorder ameliorated by inhibiting CK1 or CK1 activity by administering a series of substituted fused pyridine compounds of formula I.
When introducing elements of the present invention or one or more of its exemplary embodiments, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements. Although the present invention has been described in terms of specific embodiments, the details of these embodiments are not to be construed as limitations of the present invention; the scope of the invention is defined by the appended claims.
Detailed description of the invention
One embodiment of the present invention are the compounds of formula I described above.
Another embodiment of the compounds of formula I include, wherein each R is R1Independently is H or C1-4An alkyl group;
each R2Independently is H, C1-6Alkyl, -SO2C1-6Alkyl, -SO2(CH2)tC3-6Cycloalkyl, -C1-6alkyl-O-C1-6Alkyl, -C (O) - (O)u-C1-6Alkyl, - (CH)2)t-(C6-10Aryl), -C (O) - (O)u-(CH2)t- (5-to 10-membered heteroaryl), - (CH)2)t-C(O)-NR5R6、-(CH2)t- (5-to 10-membered heteroaryl), - (CH)2)t- (4-to 10-membered heterocycloalkyl) or- (CH)2)t- (3-to 10-membered cycloalkyl),
wherein R is2Said aryl, heteroaryl, cycloalkyl and heterocycloalkyl of (a) may be substituted with up to two substituents independently selected from halogen, OH, cyano, -C1-6Alkyl, -C (O) -O-C1-3Alkyl or C1-6alkyl-O-C1-6An alkyl group, a carboxyl group,
and wherein R is, where valence permits2Any alkyl, cycloalkyl and heterocycloalkyl of (a) may be further substituted by oxo;
each R3Independently is absent, C1-3Alkyl, oxo, -NR5R6OR-OR5；
Each R4Is halogen;
each R5Is H;
each R6Independently is H or C1-6An alkyl group;
R7is H;
n is 1;
each t is independently 0, 1 or 2;
each u is independently 0 or 1;
x, Y and A are as defined in any other embodiment of formula I;
and pharmaceutically acceptable salts thereof.
The present invention also relates to compounds wherein a of formula I in any of the embodiments discussed herein is any of the following structures:
wherein R is2And R3As defined for the embodiments of formula I or any group of definitions set forth herein, it is to be understood that as much R as is allowed by valence3Substituents, although only one R has been drawn for simplicity3And (4) a substituent. Further, when A is unsubstituted on carbon, then R3Is absent.
Another embodiment of the compounds of formula I include those in which A of formula I is substituted with R at the available nitrogen2Is substituted in which R2Independently is H, -CH3Or SO2CH3(ii) a And A of the formula I is substituted by R on the available carbon3Is substituted in which R3Independently absent or oxo. Another embodiment is, wherein A of formula I is further substituted on at least one carbon by R3Is substituted in which R3As described herein in any embodiment of formula I.
Another embodiment of the present invention includes compounds of formula I wherein X is NR1Wherein R is1Is C1-4Alkyl or C3-4A cycloalkyl group; y is CR1Wherein R is1Is H or CH3(ii) a A is a lactone, lactam, or isoindolinyl group, substituted as permitted in any embodiment of formula I; r4Is F, and R7Is H. Another way of representing this embodiment of the present invention with the moiety for A is where X is NR1Wherein R is1Is C1-4Alkyl or C3-4A cycloalkyl group; y is CR1Wherein R is1Is H or CH3(ii) a A is:
or
Substituted as permitted in any of the embodiments of formula I; r4Is F, and R7Is H.
It must be understood that the compounds of formula I and pharmaceutically acceptable salts thereof also include hydrates, solvates and polymorphs of said compounds of formula I and pharmaceutically acceptable salts thereof, as discussed below.
In one embodiment, the invention also relates to each of the individual compounds, described herein as examples 1 to 52 (including the free base or pharmaceutically acceptable salts thereof).
In another embodiment, the present invention relates to any one compound or compound of any group selected from the group consisting of:
6-benzyl-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -5, 6-dihydro-7H-pyrrolo [3,4-b ] pyridin-7-one;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -7, 8-dihydro-1, 7-naphthyridin-6 (5H) -one;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -5,6,7, 8-tetrahydro-1, 7-naphthyridine;
7- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -2-methyl [1,3] oxazolo [5,4-b ] pyridine;
7- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -2-methyl [1,3] oxazolo [4,5-b ] pyridine;
7- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -1-methyl-1H-pyrazolo [4,3-b ] pyridine;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -1H-pyrazolo [3,4-b ] pyridine;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -2-methyl-2H-pyrazolo [3,4-b ] pyridine;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -1-methyl-1H-pyrazolo [3,4-b ] pyridine;
7-acetyl-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-6,7,8, 9-tetrahydro-5H-pyrido [2,3-d]Aza derivatives；
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-7- (methylsulfonyl) -6,7,8, 9-tetrahydro-5H-pyrido [2,3-d]Aza derivatives；
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-6,7,8, 9-tetrahydro-5H-pyrido [2,3-d]Aza derivatives；
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -5,6,7, 8-tetrahydro-1, 6-naphthyridine;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid ethyl ester;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -7, 8-dihydro-1, 6-naphthyridin-5 (6H) -one; and
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6-methyl-7, 8-dihydro-1, 6-naphthyridin-5 (6H) -one; or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention relates to a method of inhibiting casein kinase 1CK1 or CK1 activity in a patient comprising administering a therapeutically effective amount of an inhibitor of casein kinase 1CK1 or CK 1.
In another embodiment, the invention relates to methods of inhibiting casein kinase CK1 or CK1 activity, which methods result in an extension of the circadian cycle.
In another embodiment, the invention relates to a method of treating a mood disorder or a sleep disorder, or for the preparation of a medicament for treating said disorder, comprising administering a therapeutically effective amount of an inhibitor of casein kinase 1CK1 or CK 1. In one embodiment, the present invention relates to a method of treating sleep disorders. In a further embodiment, the sleep disorder is a circadian rhythm sleep disorder. In yet another embodiment, the circadian sleep disorder is selected from the group consisting of shift work sleep disorder, jet lag syndrome, early sleep phase syndrome, and delayed sleep phase syndrome.
In a further embodiment, the present invention relates to a method of treating a mood disorder selected from the group consisting of depressive disorder and bipolar disorder, or a method of preparing a medicament for treating said mood disorder. In another embodiment of the invention, the depressive disorder is major depressive disorder. In a further embodiment of the invention, the mood disorder is a bipolar disorder. In another embodiment, the bipolar disorder is selected from the group consisting of bipolar I disorder and bipolar II disorder.
In another embodiment, the invention provides a method of treating a neurological and psychiatric disorder, or a method of making an agent for treating said disorder, comprising: administering to the mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat the disorder. Neurological and psychiatric disorders include, but are not limited to, the following in mammals: acute neurological and psychiatric disorders such as brain defects following heart bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal injury, dementia, AIDS-induced dementia, vascular dementia, dementia of mixed type, age-related memory impairment, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive disorders (including cognitive disorders associated with schizophrenia and bipolar disorders), idiopathic and drug-induced Parkinson's disease, muscle spasms and disorders associated with muscle spasticity including tremor, epilepsy, convulsions, migraine (migaine), migraine (migaine adache), urinary incontinence, substance-induced Parkinson's disease, idiopathic and drug-induced Parkinson's disease, muscle spasticity and disorders associated with muscle spasticity including tremor, epilepsy, convulsions, migraine (migaine), migraine (migaine adache), urinary incontinence, substance-induced incontinenceTolerance, substance withdrawal, opioids, nicotine, tobacco products, alcohol, benzodiazepinesExamples of such cognitive disorders include but are not limited to cocaine, withdrawal from sedatives and hypnotics, psychosis, mild cognitive disorders, amnestic cognitive disorders, multi-domain cognitive disorders, obesity, schizophrenia, anxiety, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, mood disorders, depression, mania, bipolar disorder, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, cerebral edema, pain, acute and chronic pain states, severe pain, intractable pain, neuropathic pain, post-traumatic pain, tardive dyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactivity disorder, autism, Asperger's disease, and behavioral disorders. Accordingly, in one embodiment, the present invention provides a method of treating a condition selected from the above-mentioned conditions in a mammal (e.g. a human) comprising administering to said mammal a compound of formula I. The mammal is preferably a mammal in need of such treatment.
As an example, the present invention provides a method of treating attention deficit hyperactivity disorder, schizophrenia and alzheimer's disease or a method of preparing a medicament for treating such disorders.
In another embodiment, the present invention provides a method of treating neurological and psychiatric disorders comprising: administering to a patient in need of such treatment an amount of a compound of formula I effective to treat the disorder. The compounds of formula I are optionally used in combination with another active agent. Such an agent may be, for example, an atypical antipsychotic, a cholinesterase inhibitor, Dimebon, or an NMDA receptor antagonist. Such atypical antipsychotics include, but are not limited to, ziprasidone, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, paliperidone; such NMDA receptor antagonists include, but are not limited to, memantine; such cholinesterase inhibitors include, but are not limited to, donepezil and galantamine.
The invention also relates to pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier. The composition may be, for example, a composition for treating a condition selected from the group consisting of: neurological and psychiatric disorders including, but not limited to: acute neurological and psychiatric disorders such as brain deficits following cardiac bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal injury, dementia caused by AIDS, vascular dementia, dementia of mixed type, age-related memory impairment, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive disorders (including cognitive disorders associated with schizophrenia and bipolar disorders), idiopathic and drug-induced parkinson's disease, muscle spasms and disorders associated with muscle spasticity including tremor, epilepsy, convulsions, migraine (migaine), migraine (migaine headeache), urinary incontinence, substance tolerance, substance withdrawal, opioids, nicotine, tobacco products, alcohol, benzodiazepines(iii) cocaine, withdrawal from sedatives and hypnotics, psychosis, mild cognitive disorders, amnestic cognitive disorders, multi-domain cognitive disorders, obesity, schizophrenia, anxiety, generalized anxiety disorder, social anxiety disorder, panic disorder, post traumatic stress disorder, obsessive compulsive disorder, mood disorders, depression, mania, bipolar disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, cerebral edema, pain, acute and chronic pain states, severe pain, intractable pain, neuropathic pain, post traumatic pain, tardive dyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactivity disorder, autism, Asperger's disease, and behavioral disorders; the composition comprises administering an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The composition may optionally beOne step comprises an atypical antipsychotic, a cholinesterase inhibitor, Dimebon, or an NMDA receptor antagonist. Such atypical antipsychotics include, but are not limited to, ziprasidone, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, paliperidone; such NMDA receptor antagonists include, but are not limited to, memantine; such cholinesterase inhibitors include, but are not limited to, donepezil and galantamine.
The compounds of the invention are also suitable for therapeutic use as antiproliferative agents (e.g., cancer), anti-neoplastic (e.g., potent anti-solid tumor) agents in mammals, particularly humans. In particular, the compounds of the present invention are useful in the prevention and treatment of a wide variety of human hyperproliferative disorders (both malignant and benign abnormal cell growth).
The compounds, compositions, and methods provided herein are useful for treating cancer and for the preparation of medicaments for treating cancer, including but not limited to:
circulatory systems, for example, the heart (sarcomas [ angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma ], myxoma, rhabdomyoma, fibroma, lipoma and teratoma), mediastinum and pleura, and other internal organs of the chest, vascular tumors and vascular tissue associated with tumors;
respiratory tract, e.g., nasal cavity and middle ear, paranasal sinuses, larynx, trachea, bronchi and lungs such as Small Cell Lung Carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, hamartoma, mesothelioma;
gastrointestinal tract, e.g. esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucinoma, gastrinoma, carcinoid tumor, pancreatic tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);
genitourinary tract, e.g., kidney (adenocarcinoma, Wilm's tumor [ nephroblastoma ], lymphoma, leukemia), bladder and/or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, lipoma);
liver, e.g., hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatoadenoma, hemangioma, pancreatic endocrine tumors (e.g., pheochromocytoma, insulinoma, vipoma, islet cell tumor of pancreas, and glucagon tumor);
bone, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronofroma (osteochondral exostosis), benign osteochondrosis, chondroblastoma, chondromas myxofibroma (chondromoxofibroma), osteoid osteoma and giant cell tumor;
a neoplasm of the nervous system, e.g., the Central Nervous System (CNS), primary CNS lymphoma, cancer of the head (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymal tumor, germ cell tumor [ pinealoma ], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);
reproductive systems, e.g., gynecological, uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [ serosal cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma ], granulosa-thecal cytoma, Sertoli-Leydig cytoma, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma) and other sites associated with the female genitalia, placenta, penis, prostate, testis, and other sites associated with the male genitalia;
blood, e.g., blood (myeloid leukemia [ acute and chronic ], acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma [ malignant lymphoma ];
oral cavity, e.g., lips, tongue, gums, bottom of mouth, palate, and other parts of the mouth, parotid gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform crypt, hypopharynx, and other parts of the lips, oral cavity, and pharynx;
skin, e.g., malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloid scars;
adrenal gland: neuroblastoma; and
cancers involving other tissues, including connective and soft tissues, retroperitoneal and peritoneal membranes, eyes, intraocular melanoma, and adnexa, breast, head or/and neck, anal region, thyroid, parathyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasms of lymph nodes, secondary malignant neoplasms of respiratory and digestive systems, and secondary malignant neoplasms of other sites.
More specifically, examples of "cancer" as used herein in connection with the present invention include cancers selected from the group consisting of: lung cancer (NSCLC and SCLC), head or neck cancer, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, gastric cancer, breast cancer, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the Central Nervous System (CNS), primary CNS lymphoma, non-hodgkin's lymphoma, spinal tumors (spinal axis tumors), or a combination of one or more of the foregoing cancers.
More specifically, examples of "cancer" as used herein in connection with the present invention include cancers selected from the group consisting of: lung cancer (NSCLC and SCLC), breast cancer, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, or a combination of one or more of the foregoing cancers.
In one embodiment of the invention, non-cancerous conditions include such proliferative conditions as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH).
As indicated above, the compounds of the invention may be used in combination with one or more other anti-cancer agents, as described below. When combination therapy is employed, the one or more other anti-cancer agents may be administered sequentially or simultaneously with the compounds of the invention. In one embodiment, the additional anti-cancer agent is administered to the mammal (e.g., a human) prior to administration of the compound of the invention. In another embodiment, the additional anti-cancer agent is administered to the mammal after administration of the compound of the invention. In another embodiment, the additional anti-cancer agent is administered to the mammal (e.g., a human) concurrently with the administration of the compound of the invention.
The present invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of formula I as hereinbefore defined (including hydrates, solvates and polymorphs of said compound or a pharmaceutically acceptable salt thereof) in combination with one or more, preferably one to three, anti-cancer agents selected from the group consisting of angiogenesis inhibitors and signal transduction inhibitors, wherein the active agent and the combined anti-cancer agents are considered as a whole in amounts therapeutically effective for the treatment of said abnormal cell growth, and a pharmaceutically acceptable carrier.
Definition of
The term "alkyl" refers to a straight or branched chain saturated hydrocarbon substituent (i.e., a substituent obtained by removing hydrogen from a hydrocarbon), which contains one to twenty carbon atoms; in one embodiment, from one to twelve carbon atoms; in another embodiment, from one to ten carbon atoms; in another embodiment, one to six carbon atoms; and in yet another embodiment, from one to four carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isopentyl, hexyl and the like. In some cases, the number of carbon atoms in a hydrocarbyl substituent (i.e., alkyl, alkenyl, cycloalkyl, aryl, etc.) is preceded by the prefix "Ca-b"means where a is the minimum number and b is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-6Alkyl "refers to an alkyl substituent containing 1 to 6 carbon atoms.
"alkenyl" refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight, branched, or cyclic groups having at least one carbon-carbon double bond. Preferably, it is a medium-sized alkenyl group having 2 to 6 carbon atoms. For example, the term "C" as used herein2-6Alkenyl "represents a straight or branched chain unsaturated group of 2 to 6 carbon atoms, including but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionally substituted with 1 to 5 suitable substituents as defined hereinbefore (e.g. fluoro, chloro, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoroMethoxy or C1-C6Alkyl) is substituted. When the compound of the present invention contains C2-6When alkenyl, the compound may be present in pure e (entgegen), pure z (zusammen), or any mixture thereof.
"alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight, branched, or cyclic groups having at least one carbon-carbon triple bond. Preferably, it is a lower alkynyl group having 2 to 6 carbon atoms. For example, the term "C" as used herein2-6Alkynyl "is used herein to denote a straight or branched hydrocarbon chain alkynyl group as defined above having 2 to 6 carbon atoms and one triple bond.
The term "cycloalkyl" refers to a carbocyclic substituent obtained by removal of a hydrogen atom from a saturated carbocyclic molecule and having three to fourteen carbon atoms. In one embodiment, the cycloalkyl substituent has three to ten carbon atoms. Cycloalkyl groups may be monocyclic, which typically contains from 3 to 6 ring atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternatively, the cycloalkyl group may be 2 or 3 rings fused together, such as bicyclo [4.2.0] octane and decalinyl, and may also be referred to as "bicycloalkyl".
The term "cycloalkyl" also includes fused to C6-C10A substituent on an aromatic ring or fused to a 5-to 10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent is bonded to a carbon atom of the cycloalkyl group. When such a fused cycloalkyl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bonded to a carbon atom of the cycloalkyl group. Said condensed C6-C10The aromatic or 5-10-membered heteroaromatic ring may optionally be substituted by halogen, C1-6Alkyl radical, C3-10Cycloalkyl or = O.
The term "aryl" refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may beCan have six to eighteen carbon atoms. As an example, the aryl substituent may have six to fourteen carbon atoms. The term "aryl" may refer to substituents such as phenyl, naphthyl and anthracenyl. The term "aryl" also includes such substituents as phenyl, naphthyl and anthracenyl, which are substituted with C4-10Carbocyclic (e.g. C)5Or C6Carbocyclic ring) or with a 4-to 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bonded to an aromatic carbon of the aryl group. When such a fused aryl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bonded to an aromatic carbon of the fused aryl group. Said condensed C4-10The carbocycle or 4-to 10-membered heterocycle may optionally be substituted by halogen, C1-6Alkyl radical, C3-10Cycloalkyl or = O. Thus, examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl (also referred to as "tetralinyl"), indenyl, isoindolyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthylenyl (also referred to as "phenalkenyl"), and fluorenyl groups.
In some cases, the number of atoms in a cyclic substituent containing one or more heteroatoms (i.e., heteroaryl or heterocycloalkyl) is indicated by the prefix "a-B-member," where a is the minimum number of atoms that make up the cyclic moiety of the substituent and B is the maximum number. Thus, for example, a 5-to 8-membered heterocycloalkyl group refers to a heterocycloalkyl group containing from 5 to 8 atoms (including one or more heteroatoms) in the cyclic moiety of the heterocycloalkyl group.
The term "hydrogen" refers to a hydrogen substituent and may be described as — H.
The term "hydroxy" refers to-OH. The prefix "hydroxy", when used in combination with another term, indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds having a carbon attached to one or more hydroxyl substituents include, for example, alcohols, enols, and phenols.
The term "cyano" (also referred to as "nitrile") refers to — CN, which may also be represented as:
the term "halogen" refers to fluorine (which may be represented by-F), chlorine (which may be represented by-Cl), bromine (which may be represented by-Br), or iodine (which may be represented by-I). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is bromine.
The term "heterocycloalkyl" refers to a substituent obtained by removing hydrogen from a saturated or partially saturated ring structure containing a total of 4 to 14 ring atoms, wherein at least one of the ring atoms is a heteroatom selected from oxygen, nitrogen or sulfur. For example, the term "4-to 10-membered heterocycloalkyl" as used herein means that the substituent is a single ring having from 4 to 10 total ring atoms. Heterocycloalkyl groups can also contain 2 or 3 rings fused together, where at least one such ring contains a heteroatom (i.e., nitrogen, oxygen, or sulfur) as a ring atom. In a group having a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent that is bonded to the group can be at least one heteroatom, or it can be a ring carbon atom, where the ring carbon atom can be in the same ring as the at least one heteroatom or where the ring carbon atom can be in a different ring from the at least one heteroatom. Similarly, if, in turn, the heterocycloalkyl substituent is substituted with a group or substituent, that group or substituent may be bonded to the at least one heteroatom, or it may be bonded to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
The term "heterocycloalkyl" also includes alkyl groups with C6-10An aromatic ring or a substituent fused to a 5-to 10-membered heteroaromatic ring, having as a substituentSuch fused heterocycloalkyl group of substituents is bonded to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group. When such a fused heterocycloalkyl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bonded to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group. Condensed C6-C10The aromatic ring or 5-to 10-membered heteroaromatic ring may optionally be substituted by halogen, C1-6Alkyl radical, C3-10Cycloalkyl radical, C1-6Alkoxy or = O.
The term "heteroaryl" refers to an aromatic ring structure containing 5 to 14 ring atoms, wherein at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Heteroaryl groups can be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include, but are not limited to: 6-membered ring substituents such as pyridyl, pyrazole (pyrazyl), pyrimidinyl and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3, 4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothienyl, isobenzothienyl, benzisoxazolyl, benzoxazolyl, purinyl and anthrenyl; and 6/6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1, 4-benzoxazinyl. In a group having a heteroaryl substituent, the ring atom of the heteroaryl substituent that is bonded to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if, in turn, the heteroaryl substituent is substituted with a group or substituent, the group or substituent may be bonded to the at least one heteroatom, or it may be bonded to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom, or where the ring carbon atom may be in a different ring from the at least one heteroatom. The term "heteroaryl" also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring.
Examples of monocyclic heteroaryl and heterocycloalkyl groups include, but are not limited to, furyl, dihydrofuryl, tetrahydrofuryl, thiophenyl (also referred to as "thienyl"), dihydrothienyl, tetrahydrothienyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, oxathiazolyl, oxadiazolyl (including oxadiazolyl, 1,2, 4-oxadiazolyl (also referred to as "azoximyl"), 1,2, 5-oxadiazolyl (also referred to as "furazanyl"), or 1,3, 4-oxadiazolyl), pyranyl (including 1, 2-pyranyl or 1, 4-pyranyl), dihydropyranyl, pyridinyl (also referred to as "azinyl"), piperidinyl, diazinyl (including pyridazinyl (also referred to as "1, 2-diazinyl"), pyrimidinyl (also referred to as "1, 3-diazinyl" or "pyrimidady") or pyrazinyl (also referred to as "1, 4-diazinyl")), piperazinyl, triazinyl (including s-triazinyl (also referred to as "1, 3, 5-triazinyl"), meta-triazinyl (also referred to as 1,2, 4-triazinyl) and s-triazinyl (also referred to as "1, 2, 3-triazinyl")), morpholinyl, aza-triazinylOxygen radical and oxygen radicalBasic, sulfur heteroRadicals and diazepinesAnd (4) a base.
Examples of 2-fused ring heteroaryl groups include, but are not limited to, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridyl (including pyrido [3,4-b ] -pyridyl, pyrido [3,2-b ] -pyridyl, or pyrido [4,3-b ] -pyridyl), and pteridinyl, indolyl, isoindolyl, benzimidazolyl, benzoxazinyl, phthalazinyl, quinoxalyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothioxanyl, benzoxazolyl, indoxazinyl, anthrenyl, benzodioxolyl (benzodioxolyl), benzodioxanyl, benzooxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, pteridinyl, and the like, Benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.
Examples of 3-fused ring heteroaryl or heterocycloalkyl include, but are not limited to, 5, 6-dihydro-4H-imidazo [4,5,1-ij]Quinoline, 4, 5-dihydroimidazo [4,5,1-hi]Indole, 4,5,6, 7-tetrahydroimidazo [4,5,1-jk ]][1]Benzazepine compoundsAnd a dibenzofuranyl group.
Other examples of fused ring heteroaryls include, but are not limited to, benzo-fused heteroaryls such as indolyl, isoindolyl (also referred to as "isobenzopyrrol" or "isoindolmimetic"), isoindolyl (also referred to as "indolizinyl"), isoindolyl (also referred to as "benzopyrazolyl"), benzoxazinyl (including quinolyl (also referred to as "1-benzoxazinyl") or isoquinolyl (also referred to as "2-benzoxazinyl")), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also referred to as "1, 2-benzodioxazinyl") or quinazolinyl (also referred to as "1, 3-benzodioxazinyl"), benzopyranyl (including "chromanyl" or "isobenzodihydropyranyl"), benzothiophenyl (also referred to as "dihydrobenzothiophenyl"), "benzothiazolyl"), Benzoxazolyl, indoxazinyl (also referred to as "benzisoxazolyl"), anthrenyl, benzodioxolyl (benzodioxolyl), benzodioxanyl, benzooxadiazolyl, benzofuranyl (also referred to as "coumaronyl"), isobenzofuranyl, benzothienyl (also referred to as "benzothienyl", "thioindenyl", or "benzothienyl"), isobenzothienyl (also referred to as "isobenzothienyl", "isothioindenyl", or "isobenzothienyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3, 2-benzoxazinyl, 1,4, 2-benzoxazinyl, 2,3, 1-benzoxazinyl, or 3,1, 4-benzoxazinyl), benzisoxazinyl (including 1, 2-benzisoxazinyl or 1, 4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, pyranthnyl, and acridinyl.
The term "heteroaryl" also includes substituents such as pyridyl and quinolyl, which react with C4-10Carbocyclic (e.g. C)5Or C6Carbocyclic ring) or with a 4-10-membered heterocyclic ring, wherein a group having such a fused heteroaryl group as a substituent is bonded to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. When such a fused heteroaryl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bonded to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. Said condensed C4-10The carbocycle or 4-10-membered heterocycle may optionally be substituted by halogen, C1-6Alkyl radical, C3-10Cycloalkyl or = O.
Additional examples of heteroaryl and heterocycloalkyl groups include, but are not limited to: 6, 7-dihydro-5H-pyrrolo [3, 4-b)]Pyridin-5-one, 6, 7-dihydro-5H-pyrrolo [3,4-b ]]Pyridyl, furo [3,4-b ]]Pyridin-5 (7H) -one, 2,3,4, 5-tetrahydropyrido [2,3-f][1,4]Oxazazepine6, 7-dihydro-5H-cyclopenta [ b ]]Pyridyl, 5,6,7, 8-tetrahydro-1, 7-naphthyridinyl, furo [3,4-b]Pyridine-7 (5)H) -one, 7, 8-dihydro-1, 7-naphthyridin-6 (5H) -one, 5H-pyrrolo [3,4-b ]]Pyridin-7 (6H) -one, 7, 8-dihydro-1, 6-naphthyridin-5 (6H) -one, 1H-pyrazolo [3,4-b]Pyridyl, 5,6,7, 8-tetrahydro-1, 6-naphthyridinyl, 2H-pyrazolo [4,3-b]Pyridyl, 6,7,8, 9-tetrahydro-5H-pyrido [2,3-d ]]Aza derivativesOxazolo [4,5-b]Pyridyl, oxazolo [5,4-b]Pyridyl, 3-1H-benzimidazol-2-one, (1-substituted) -2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1, 3H-benzimidazol-2-one]Dioxolanyl, [1,3]]Dithiopentcyclyl, [1,3]]-dioxanyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-benzimidazolonyl (1-phthalimidinyl), benzoxazinyl (benzoxanyl), benzo [1,3] benzoxazinyl]Dioxins, benzo [1,4 ]]Dioxins, benzopyrrolidinyl, benzopyridyl, benzooxolane, benzothiepilane, 4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridine, benzothienyl, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepinyl, thietanyl, oxaazanylRadical diazaThio-aza radicalA base group and a side chain, wherein the base group is 1,2,3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolane, pyrazolinyl, dithianyl, dithiopentyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0]Hexane radical, 3-azabicyclo [4.1.0 ]]Heptenyl, 3H-indolyl, quinolizinyl, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridyl. The above groups derived from the groups listed above may be C-linked or N-linked (where possible). For example, a group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, the groups derived from imidazole may be imidazol-1-yl (N-linked) or imidazol-2-yl (C-linked).
A substituent is "substitutable" if it contains at least one carbon or nitrogen atom bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen and cyano are not within the scope of this definition.
If a substituent is described as "substituted," then a non-hydrogen substituent is present at the position of the hydrogen substituent on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is at the position of a hydrogen substituent on the alkyl substituent. For purposes of illustration, a monofluoroalkyl is an alkyl substituted with one fluorine substituent, and a difluoroalkyl is an alkyl substituted with two fluorine substituents. It will be appreciated that if there is more than one substitution on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise specified).
If a substituent is described as "may be substituted" or as "optionally substituted," that substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a series of substituents, then one or more hydrogens on the carbon (to the extent any hydrogen is present) may be replaced individually and/or together with an independently selected optional substituent. If a substituent nitrogen is described as optionally substituted with one or more of a series of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent. One exemplary substituent may be described as-NR 'R ", where R' and R", together with the nitrogen atom to which they are attached, may form a heterocyclic ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur, where the heterocycloalkyl moiety may be optionally substituted. The heterocyclic ring formed by R' and R "together with the nitrogen atom to which they are attached may be partially or fully saturated, or aromatic. In one embodiment, the heterocyclic ring is composed of 4 to 10 atoms. In another embodiment, the heterocycle is selected from the group consisting of: piperidinyl, morpholinyl, azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, and thiazolyl.
The present specification uses the terms "substituent", "group" and "group" interchangeably.
If a group of substituents is described collectively as optionally substituted with one or more of a series of substituents, then the group may include: (1) non-substitutable substituents, (2) substitutable substituents which are not substituted by said optional substituents, and/or (3) substitutable substituents which are substituted by one or more of said optional substituents.
If a substituent is described as "may" or "optionally" substituted with up to a specified number of non-hydrogen substituents, then that substituent may be (1) unsubstituted; or (2) substituted with up to the specified number of non-hydrogen substituents or up to the maximum number of substitutable positions on the substituent (whichever is smaller). Thus, for example, if a substituent is described as a heteroaryl group optionally substituted with up to 3 non-hydrogen substituents, then any heteroaryl group having less than 3 substitutable positions is optionally substituted up to only as many non-hydrogen substituents as the heteroaryl group has substitutable positions. For purposes of illustration, a tetrazolyl group (which has only one substitutable position) will optionally be substituted with up to one non-hydrogen substituent. For further illustration, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen substituents, then if the amino nitrogen is a primary nitrogen, that nitrogen will optionally be substituted with up to 2 non-hydrogen substituents, and if the amino nitrogen is a secondary nitrogen, that amino nitrogen will optionally be substituted with up to only 1 non-hydrogen substituent.
The prefix attached to the substituent of the multiple structural moiety applies only to the first structural moiety. For purposes of illustration, the term "alkylcycloalkyl" contains two moieties: alkyl and cycloalkyl groups. Thus, C1-6C on alkylcycloalkyl1-6-prefix indicates that the alkyl moiety of said alkylcycloalkyl contains from 1 to 6 carbon atoms; said C is1-6The prefix does not describe a cycloalkyl moiety. For further illustration, the prefix "halo" on a haloalkoxyalkyl indicates that the alkoxyalkyl substituent isOnly byThe alkoxy moiety is substituted with one or more halogen substituents. If halogen is substitutedOnly byOccurring on the alkyl moiety, then the substituent is described as an "alkoxy haloalkyl". "if halogen substitution occurs on both the alkyl moiety and the alkoxy moiety, the substituent is described as a" haloalkoxy haloalkyl ". "
If multiple substituents are described as being "independently selected from" a group, the selection of each substituent is not affected by the other substituent or substituents. Thus, each substituent may be the same or different from one or more other substituents.
As used herein, the term "formula I" may be referred to hereinafter as "a compound of the invention. "such terms are also defined to include all forms of the compounds of formula I, including hydrates, solvates, isomers, crystalline and amorphous, polymorphs, and metabolites thereof. For example, a compound of formula I or a pharmaceutically acceptable salt thereof may exist in unsolvated as well as solvated forms. When the solvent or water is intimately bound, the complex will have a well-defined stoichiometry, independent of humidity. However, when the solvent or water is weakly bound, as in the case of the channel solvates and hygroscopic compounds, the water/solvent content will depend on the humidity and drying conditions. In these cases, the non-stoichiometry would be normal.
The compounds of formula I may exist in the form of clathrates or other complexes. Included within the scope of the present invention are complexes such as clathrates, drug-subject inclusion complexes wherein the drug and subject are present in stoichiometric or non-stoichiometric amounts as compared to the aforementioned solvates. Complexes of formula I containing two or more organic and/or inorganic components that may be stoichiometric or non-stoichiometric are also included. The resulting complex may be ionized, partially ionized or non-ionized. For an overview of such complexes see J.Pharm.Sci.,64(8),1269-1288, the author Haleblian (August 1975).
The compounds of formula I may have asymmetric carbon atoms. Solid lines may be used hereinSolid wedge wireOr virtual wedge lineCarbon-carbon bonds of the compounds of formula I are depicted. The use of a solid line to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. The use of solid or dashed wedge lines to depict bonds to asymmetric carbon atoms is intended to indicate that only the stereoisomers shown are intended to be included. It is possible that the compounds of formula I may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers are to be included. For example, unless otherwise indicated, it is intended that the compounds of formula I may exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of solid lines to depict bonds to one or more asymmetric carbon atoms in a compound of formula I and solid or dashed wedge lines to depict bonds to other asymmetric carbon atoms in the same compound is intended to indicate that a mixture of diastereomers is present.
Stereoisomers of formula I include cis and trans isomers of compounds of formula I (including compounds that exhibit more than one type of isomerization), optical isomers such as the R and S enantiomers, diastereomers, geometric isomers, rotamers, conformational isomers, and tautomers; and mixtures thereof (e.g., racemates and diastereomeric pairs). Also included are acid addition or base addition salts in which the counterion is optically active, e.g., D-lactate or L-lysine, or racemic, e.g., DL-tartrate or DL-arginine.
When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) mentioned above, in which a homogeneous form of crystals is produced, containing both enantiomers in equimolar amounts. The second type is a racemic mixture or assemblage (conglomerate) in which two forms of crystals, each containing a single enantiomer, are produced in equimolar amounts.
The compounds of formula I may exhibit tautomerism and structural isomerism. For example, the compounds of formula I may exist in several tautomeric forms (including enol and imine forms and ketone and enamine forms) and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of formula I. Tautomers exist as mixtures of tautomeric groups in solution. In solid form, usually one tautomer predominates. Although one tautomer may be described, the present invention includes all tautomers of the compounds of formula I.
The invention also includes isotopically-labelled compounds which are identical to those recited above for formula I, except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F and36and (4) Cl. Certain isotopically-labeled compounds of formula I, e.g. into which a radioactive isotope has been incorporated (e.g. by3H and14C) those compounds of (a), are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., due to its detection limit and ease of preparation)3H) And carbon-14 (i.e.14C) Isotopes are particularly preferred. In addition, heavier isotopes are used (e.g. deuterium, i.e.2H) Alternatively, certain therapeutic advantages may be obtained due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Isotopically labeled compounds of formula I can generally be prepared by carrying out the procedures disclosed in the schemes below and/or in the examples and preparations by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, salts of the compounds may be advantageous because of one or more of their physical properties, such as improved drug stability in different temperatures and humidities, or desirable solubility in water or oil. In some cases, salts of compounds may also be used as an adjunct in the isolation, purification and/or resolution of the compounds.
Where it is desired to administer the salt to a patient (as opposed to, for example, being used in vitro), the salt is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by mixing a compound of formula I with an acid or a base, the anion of which is generally considered suitable for human use. Pharmaceutically acceptable salts are particularly useful as the product of the process of the invention because of their greater aqueous solubility relative to the parent compound. For pharmaceutical use, salts of the compounds of the present invention are non-toxic "pharmaceutically acceptable salts. Salts "comprised within the scope of the term" pharmaceutically acceptable salts "refer to non-toxic salts of the compounds of the present invention, which salts are typically prepared by reacting the free base with a suitable organic or inorganic acid.
Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include, where possible, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid, sulfonic acid and sulfuric acid, and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothiocarboxylic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid and trifluoroacetic acid. Suitable organic acids generally include, but are not limited to, organic acids of the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic types.
Specific examples of suitable organic acids include, but are not limited to, acetic acid, trifluoroacetic acid, formic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, digluconate (digluconate), lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid (sulfamilate), cyclohexylsulfamic acid, alginic acid (algenic acid), beta-hydroxybutyric acid, galactaric acid, galacturonic acid, adipic acid, alginic acid, butyric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, dodecylsulfuric acid, glycerheptonic acid, Glycerophosphoric acid, heptanoic acid, hexanoic acid, nicotinic acid, 2-naphthalenesulfonic acid (2-naphthalsulfonate), oxalic acid, palmitic acid (palmoate), pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, thiocyanic acid, and undecanoic acid.
Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, for example, calcium or magnesium salts; and salts with suitable organic ligands, for example, quaternary ammonium salts. In another embodiment, the base salts are formed from bases that can form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diethanolamine, glycine, lysine, meglumine, ethanolamine, tromethamine, and zinc salts.
Organic salts may be prepared from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Basic nitrogen-containing groups may be quaternized with agents such as: lower alkyl (C)1-C6) Halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides(i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and the like.
In one embodiment, hemisalts of acids and bases, for example, hemisulfate and hemicalcium salts, may also be formed.
Typically, the compounds of the present invention are administered in an amount effective to treat the conditions described herein. The compounds of the present invention are administered by any suitable route, in the form of pharmaceutical compositions adapted to such route and in dosages effective for the intended treatment. The therapeutically effective dose of the compound required to treat the progression of a medical condition is readily determined by one of ordinary skill in the art using preclinical and clinical methods well known in the medical arts. The term "therapeutically effective amount" as used herein refers to an amount of a compound that is administered to alleviate to some extent one or more of the symptoms of the disorder being treated.
The verb "treat" as used herein, unless otherwise specified, refers to reversing, alleviating, inhibiting the progression of, or inhibiting the progression of, one or more symptoms of the disorder or condition to which the verb is directed. The term "treat" as used herein, unless otherwise indicated, refers to the action of the verb "treat," which is defined immediately above. The verb "treat" also includes adjuvant and neoadjuvant treatment of a subject.
The compounds of the present invention may be administered orally. Oral administration may include swallowing, whereupon the compound enters the gastrointestinal tract; alternatively, buccal or sublingual administration may be employed, whereby the compound enters the blood stream directly from the mouth.
In another embodiment, the compounds of the invention may be administered directly into the bloodstream, into muscle, or into internal organs. Suitable methods of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include needle (including micro-needle) syringes, needle-free syringes, and infusion techniques.
In another embodiment, the compounds of the present invention may also be applied topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the invention may also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, the compounds of the present invention may also be administered directly to the eye or ear.
The dosage regimen for the compound and/or the composition containing the compound is based on a variety of factors including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; as well as the activity of the particular compound employed. Thus, the dosage regimen may vary widely. Dosage levels on the order of from about 0.01mg to about 100mg per kilogram of body weight per day are useful for treating the conditions indicated above. In one embodiment, the total daily dose of a compound of the present invention (administered as a single dose or divided doses) is generally from about 0.01 to about 100 mg/kg. In another embodiment, the total daily dose of a compound of the invention is from about 0.1 to about 50mg/kg, and in another embodiment, from about 0.5 to about 30mg/kg (i.e., mg of a compound of the invention per kg of body weight). In one embodiment, the dose administered is from 0.01 to 10 mg/kg/day. In another embodiment, a dose of from 0.1 to 1.0 mg/kg/day is administered. Dosage unit compositions may contain such amounts or about the number thereof (subunits) to make up the daily dosage. In many cases, administration of the compound will be repeated multiple times (typically no more than 4 times) throughout the day. If desired, multiple doses per day may be employed to increase the total daily dose.
For oral administration, the compositions may be provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. Medicaments typically contain from about 0.01mg to about 500mg of the active ingredient, or in another embodiment, from about 1mg to about 100mg of the active ingredient. For intravenous administration, the dosage may range from about 0.1 to about 10 mg/kg/minute during constant rate infusion.
Suitable subjects according to the invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, etc., but also mammals in the uterus. In one embodiment, the human is a suitable subject. The human subject may be of either sex and at any stage of development.
In another embodiment, the invention includes the use of one or more compounds of the invention in the manufacture of a medicament for the treatment of the conditions described herein.
For the treatment of the above conditions, the compounds of the invention may be administered as the compound itself. Alternatively, pharmaceutically acceptable salts are suitable for pharmaceutical use because of their greater aqueous solubility relative to the parent compound.
In another embodiment, the invention encompasses pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the present invention in the presence of a pharmaceutically acceptable carrier. The carrier can be a solid, a liquid, or both, and can be formulated with the compound as a unit dosage composition, e.g., a tablet, which can contain from 0.05% to 95% by weight of the active compound. The compounds of the invention may be combined with suitable polymers as targetable drug carriers. Other pharmacologically active substances may also be present.
The compounds of the invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the intended treatment. For example, the active compounds and compositions may be administered orally, rectally, parenterally or topically.
Oral administration of solid dosage forms, for example, is provided in the form of discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, oral administration may be in powder or granular form. In another embodiment, the oral dosage form is a sublingual dosage form, e.g., a lozenge. In such solid dosage forms, the compound of formula I is typically combined with one or more excipients. Such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents or may be prepared with an enteric coating.
In another embodiment, oral administration may be in the form of a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art (i.e., water). Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweetening agents), and/or perfuming agents.
In another embodiment, the invention encompasses parenteral dosage forms. "parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be prepared according to known techniques using suitable dispersing, wetting and/or suspending agents.
In another embodiment, the present invention includes a topical dosage form. "topical administration" includes, for example, transdermal administration (e.g., via a transdermal patch or iontophoresis device), intraocular administration, or intranasal or inhalational administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. When administering the compounds of the present invention via transdermal means, the administration will be carried out using a reservoir and a patch of the porous membrane type or solid matrix type. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated-see, for example, Finnin and Morgan, J.pharm.Sci., 88(10), 955-958 (1999).
Formulations suitable for topical administration to the eye include, for example, eye drops wherein a compound of the invention is dissolved or suspended in a suitable carrier. Typical formulations suitable for ocular or otic administration may be in the form of drops of micronized suspension or solution in isotonic, pH adjusted, sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particulate or vesicular systems, such as niosomes or liposomes (liposomes). Polymers (e.g., crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid), cellulosic polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose), or heteropolysaccharide polymers (e.g., agarose gel) may be incorporated with preservatives (e.g., benzalkonium chloride). Such formulations may also be delivered by iontophoresis.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the following manner: delivered as a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray from a nebulizer or atomizer with an appropriate propellant. Formulations suitable for intranasal administration are generally administered as a dry powder (alone; as a mixture, e.g. in dry mixture with lactose; or as a particulate admixture of components, e.g. with a phospholipid such as phosphatidylcholine) from a dry powder inhaler, or as an aerosol spray from a pressurised container, pump, nozzle, nebuliser (preferably one which uses electrohydrodynamics to produce a fine mist) or nebuliser, with or without a suitable propellant (e.g. 1,1,1, 2-tetrafluoroethane or 1,1,1,2,3,3, 3-heptafluoropropane). For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
In another embodiment, the invention encompasses rectal dosage forms. Such rectal dosage forms may be, for example, in the form of suppositories. The mouth fat is a conventional suppository base, but various alternative materials may be used as appropriate.
Other carrier materials and modes of administration known in the pharmaceutical art may also be employed. The pharmaceutical compositions of the present invention may be prepared by well-known pharmaceutical techniques (e.g., effective formulation and administration procedures). The above considerations regarding effective formulation and application procedures are well known in the art and are described in standard texts. For example, the formulation of drugs is discussed in the following documents: hoover, John e., Remington's Pharmaceutical Sciences, Mack publishing co, Easton, Pennsylvania, 1975; coded by Liberman et al, pharmaceutical dosage Forms, Marcel Decker, New York, n.y., 1980; and the Kibbe et al eds, Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.
The compounds of the present invention may be used to treat various conditions or disease states, either alone or in combination with other therapeutic agents. One or more compounds of the invention and one or more other therapeutic agents may be administered simultaneously (in the form of the same dosage form or in separate dosage forms) or sequentially. An exemplary therapeutic agent can be, for example, a metabotropic glutamate receptor agonist.
By "administering two or more compounds in combination" is meant that the two compounds are administered sufficiently close in time that the presence of one compound alters the biological effect of the other compound. The two or more compounds may be administered simultaneously, concurrently or sequentially. In addition, simultaneous administration may be performed by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomical sites or using different routes of administration.
The terms "concurrent administration", "co-administration", "simultaneous administration" and "simultaneous administration" mean that the compounds are administered in combination.
The invention further comprises a kit of parts suitable for carrying out the above-mentioned method of treatment. In one embodiment, the kit of parts comprises: a first dosage form comprising one or more of the compounds of the invention and a container for said dosage, in an amount sufficient to carry out the method of the invention.
In another embodiment, the kit of the invention comprises one or more compounds of the invention.
In another embodiment, the present invention relates to novel intermediates useful in the preparation of the compounds of the present invention.
General synthetic route
The compounds of formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry or modifications and derivations familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or can be prepared by conventional METHODS known in the art (e.g., those disclosed in standard reference books, such as the compound organic SYNTHETIC METHODS, vol.i-VI (Wiley-Interscience). Preferred methods include, but are not limited to, those described below.
During any of the synthetic sequences described below, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be done by means of conventional protecting groups, such as those described in the following documents: greene, Protective group in Organic Chemistry, John Wiley & Sons, 1981; T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons,1991, and T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons,1999, which are incorporated herein by reference.
The compounds of formula I or their pharmaceutically acceptable salts may be prepared according to the reaction schemes discussed below. Substituents in each route are as defined above unless otherwise indicated. Isolation and purification of the product is accomplished by standard procedures well known to those of ordinary skill in the art.
It will be understood by those of skill in the art that the various symbols, superscripts and subscripts used in the schemes, methods and examples are used for ease of presentation and/or to reflect the order in which they are introduced into the schemes, and are not intended to necessarily correspond to the symbols, superscripts and subscripts in the appended claims. The routes are representative of methods useful for synthesizing the compounds of the invention. They are not intended to limit the scope of the invention in any way.
Experimental procedures and working examples
Route 1
Wherein Alkyl represents an Alkyl group.
The compounds of formula I can be synthesized following the general procedure shown in scheme 1. The picoline of formula V can be treated with a suitably strong, non-nucleophilic base such as LDA, NaHMDS or LiHMDS in Tetrahydrofuran (THF) or diethyl ether, and then reacted with the benzoate ester of formula IV to produce ketone III. By using pure or non-reactive solvents such as CH2Cl2Brederecks reagent of (1)DMF-DMA treatment of ketone III affords vinylamide II. Adding R in an alcoholic solvent such as ethanol (EtOH), isopropanol or methanol (MeOH) at a temperature in the range from room temperature to 100 ℃1Substituted hydrazines to produce pyrazoles of formula I.
Route 2
Wherein Halo represents halogen.
The compounds of formula I can also be synthesized following the general procedure shown in scheme 2. When M is a boronic acid or pinacolborane, the formation of intermediate VI can be achieved first by halogen-metal exchange with an alkylmetal reagent such as n-butyllithium, sec-butyllithium or tert-butyllithium or alkyl grignard (of which isopropyl magnesium chloride-lithium chloride complex is preferred) on the halogen compound of formula VIII. Treatment of this metal species with a trialkoxyboronate or 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane affords the corresponding boronic acid or pinacol borane VI. In the presence of a palladium catalyst (preferably Pd (dppf) Cl2) In the presence of a base (e.g. KF, K)2CO3、K3PO4Or preferably Cs2CO3) In a polar solvent such as dimethylacetamide or preferably Dimethylformamide (DMF) at a temperature in the range of from 50 ℃ to 120 ℃, preferably 80 ℃ to 100 ℃ among others, by means of a reaction with bis (pinacolato) diboron]The pinacolborane can also be prepared from the corresponding halide VIII by coupling. The boronic acid or pinacolborane VI may be coupled with the halide/triflate VII under standard palladium catalyzed cross-coupling reaction conditions well known to those of ordinary skill in the art to provide the compound of formula I. [ Suzuki, A., Journal of Organometallic Chemistry,576, 147-.]More specifically, in a suitable organic solvent such as DMFAryl iodates, bromates or triflates of formula VII are reacted with 1 to 3 equivalents of aryl pinacol borane and an appropriate base [ e.g., 2 to 5 equivalents of Cs2CO3]And (4) combining. Adding a palladium catalyst, e.g. 0.02 equivalents of tris (dibenzylideneacetone) dipalladium (0) [ tris (dibenzylideneacetone) dipalladium (0)]The reaction mixture is heated to a temperature in the range of from 60 ℃ to 100 ℃ for 1 to 24 hours. The reaction is not limited to the use of such solvents, bases or catalysts, as many other conditions may be used.
Route 3
Wherein Alkyl represents an Alkyl group.
7-amino-6, 7-dihydro-5H-cyclopenta [ b ] of formula I-a can be prepared as shown in scheme 3]Pyridine. Oxidizing agents, such as hydrogen peroxide in acetic acid, or in a suitably inert solvent (e.g., CH) may be used2Cl2) M-chloroperbenzoic acid in (a), compound I-b (prepared according to the general procedure described in scheme 1 or 2) is converted to N-oxide XIII. Treatment of XII with acetic anhydride at a temperature in the range from room temperature to 110 deg.C, with 75 deg.C to 110 deg.C being preferred, gives the acetate of formula XII. The hydrolysis of XII to alcohol X can be achieved with an aqueous inorganic base (e.g. sodium or potassium hydroxide or sodium or potassium carbonate) and an alcohol co-solvent (e.g. MeOH or EtOH) at a temperature in the range from room temperature to 100 ℃. Can be carried out at a temperature in the range of-20 ℃ to 50 ℃ (with 0 ℃ to room temperature being preferred) in a solvent (e.g., CH)2Cl2THF or acetonitrile) and conversion of X to mesylate IX was achieved with methanesulfonic anhydride (methanesulfonyl anhydride) or methanesulfonyl chloride. Mesylate IX is treated with an alkylamine in a polar, non-nucleophilic solvent (e.g., THF or dioxane) to afford I-a.
Route 4
Lactones of formula I-c and lactams of formula I-d can be prepared as described in scheme 4. Fluoropyridine XXII (prepared using the general methods described in schemes 1 and 2) can be converted to N-oxide XXI using the general methods described in the description of scheme 3. Treatment of XXI with tetramethylsilylcyano in THF at a temperature from 0 deg.C to reflux of the solvent, with or without a catalytic amount of dimethylcarbamyl chloride, affords the nitrile of formula XX. Dinitrile XIX may be prepared by treating XX with a cyanide source, for example a tetraalkylammonium cyanide such as tetrabutylammonium cyanide or potassium or sodium cyanide, in THF, dimethyl sulfoxide (DMSO) or DMF at a temperature in the range from room temperature to 50 ℃. The conversion of XIX to the dibasic acid XVIII can be achieved by treatment with aqueous sodium hydroxide or potassium hydroxide solution (of which potassium hydroxide is preferred) at a temperature in the range of 0 ℃ to 110 ℃ (of which 75 ℃ to 100 ℃ is preferred). The anhydride XVII can be obtained by treating the dibasic acid XVIII with pure acetic anhydride or acetic anhydride containing acetic acid as a solvent at 75 to 100 ℃. Reduction of XVII with sodium borohydride/acetic acid affords the alcohol-acid XXIII, which is then cyclized with acetic acid/acetic anhydride as described by Inoue et al (Synthesis, 1,113,1997) to yield the lactone 1-c. The lactone l-c can also be prepared from the common anhydride intermediate XVII by regioselective reduction with zinc in acetic acid at 25 ℃ to 100 ℃ (with 50 ℃ to 80 ℃ being preferred).
Lactams I-d can be prepared as follows. Reaction of XVII with ammonia or a primary amine in acetic acid at a temperature of 75 ℃ to 110 ℃ with or without catalytic amounts of acetic anhydride produces a phthalic amide of formula XVI. Using zinc in acetic acid at 25 ℃ to 100 ℃ (with 50 ℃ to 80 ℃ being preferred)Regioselective reduction of XVI to give the lactam of formula I-d. I-d can also be prepared by stepwise reduction of XVI with a hydride reagent such as sodium borohydride in an alcoholic solvent such as MeOH to produce a mixture of alcohols of formula XIV and XV. These substances can be chromatographed, possibly followed by a suitably strong acid such as pure or containing CH as a co-solvent2Cl2Further reduction of XIV using a hydride source such as triethylsilane in trifluoroacetic acid (TFA) affords I-d. This transition can be accomplished from room temperature to reflux temperature.
Route 5
Preparation of oxaazepines of formula I-e as shown in scheme 5. The fluorocyano compound XX is treated with the anion of N-Boc ethanolamine, generated with the sodium or lithium salt of hexamethiselazine, or preferably sodium hydride, in a non-nucleophilic, non-reactive solvent such as THF or dioxane at a temperature in the range of from 0 ℃ to 50 ℃, with 10 ℃ to 25 ℃ being preferred, to yield the ether XXVI. Compounds of formula XXVI can also be prepared as follows: compound XX is obtained by treatment of Compound XX with 2- (methylsulfonyl) ethanol and sodium hydride according to the procedure described in Ismail et al (Syn. Comm,34,751,2004), which can then be converted to XXVI [ Mitsunobu, O., Synthesis,1-28 (1981) under standard coupling conditions well known to those of ordinary skill in the art]. More specifically, the hydroxyaryl compound of formula XXa is combined with 1 to 2 equivalents of N-Boc ethanolamine, 1 to 2 equivalents of triphenylphosphine and 1 to 2 equivalents of diisopropyl diazaphosphate in a suitable organic solvent (e.g., THF). The reaction mixture is stirred at a temperature ranging from 0 ℃ to room temperature for 1 to 24 hours. By using TFA/CH2Cl2Or HCl/MeOHRemoval of the Boc group gives the acid salt XXV, thereby preparing the free amine. Treatment of XXV with aqueous sodium or potassium hydroxide at 25 ℃ to 100 ℃ (with 75 ℃ to 90 ℃ being preferred) affords lactam XXIV. Reduction of XXIV to oxazazepine can be accomplished by using a hydride reducing agent such as Lithium Aluminum Hydride (LAH) or borane in an inactive solvent such as THF, or by using zinc in acetic acid at temperatures from 50 deg.C to reflux, with 100 deg.C being preferredI-e。
Route 6
Imidazoles of I-f can be prepared as shown in scheme 6. By reacting aldehydes XXVI and R in a suitably inert solvent, such as diethyl ether or preferably tert-butyl methyl ether, at from 0 ℃ to 50 ℃, preferably at room temperature1Reaction of substituted primary amines to give imines XXVII. Tosylmethyl isocyanide [ tosmic ] was prepared according to the two-step general procedure described in the literature]Reagent XXIX (Organic Syntheses; Wiley)&Sons, New York, 2004; collect.vol.10, p.692). Next, imine XXVII and tosmic agent XXIX are reacted with a carbonate base (e.g. Na) in an appropriately polar, inert solvent (e.g. dimethylacetamide, 1-methyl-2-pyrrolidone (NMP) or preferably DMF) at from 0 ℃ to 50 ℃ (preferably at room temperature)2CO3Or preferably K2CO3) Reaction to form imidazole XXVIII. Intermediate XXVIII can be further reacted according to the general procedures described in schemes 3-5 to provide compounds of formula I-f.
Route 7
The preparation of dimethylimidazoles of the formulae I-g and thiazoles of the formulae I-h is described in scheme 7. Treatment of XXXII, typically with aldehyde XXXI, thiazolium catalyst and triethylamine, following the procedure described in j.a.murray et al (j.am.chem.soc.2001, 123, 9696-9697) yields amidoketone XXX, which is used without isolation. Condensation with methylamine in the presence of acetic acid in an alcoholic solvent (e.g. MeOH or EtOH) gives XXIIb, which can be further reacted according to the general procedure described in schemes 3 to 5 to give compounds of formula I-g. Treatment of the amidoketone XXX with Lawesson's reagent in toluene at reflux also provides thiazole intermediate XXXIII, which can be further reacted according to the general procedure described in schemes 3 to 5 to provide compounds of formula I-h.
Route 8
Compounds of formula I-I can be prepared as described in scheme 8. The 5H-pyrrolo [3,4-b ] can be treated with an oxidizing agent (e.g., m-chloroperbenzoic acid or hydrogen peroxide/acetic acid)]Pyridine-6 (7H) -carboxylic acid ethyl ester XXXIX to give the N-oxide XXXVIII. Chlorination with phosphorus or preferably oxalyl chloride in a suitably polar but inert solvent such as DMF or NMP at temperatures from 0 ℃ to 50 ℃, of which 0 ℃ to room temperature is preferred, affords a mixture of 2-chloro and 4-chloro (formula XXXVII) derived products. The intermediate XXXVII can be coupled with the metal pyrazole VI according to the general procedure described in scheme 2 to give compounds of formula XXXV. Intermediate XXXVII can also be converted to the corresponding iodide XXXVI by refluxing with sodium iodide in acetonitrile. The iodide XXXVI can also be coupled with a metal pyrazole VI according to the general procedure described in scheme 2 to give compounds of formula XXXV. Treatment of carbamate XXXV with aqueous potassium hydroxide or sodium hydroxide in an alcoholic solvent (e.g., EtOH or MeOH) at room temperature to reflux, with reflux being preferred, affords amine XXXIV. This material can be converted into the N-alkylamines, acylates of the compounds of the formula I-IAmines and sulfonamides. For example, R in the formula can be prepared by coupling of a substituted carboxylic acid with XXXIV in a solvent such as THF or ethyl acetate (EtOAc) using an amide coupling reagent, with propylphosphonic anhydride (T3P) along with triethylamine being preferred2A compound (amide) of formula I-I which is a substituted carbonyl group. Also, by reacting in the presence of a non-nucleophilic base (e.g., diisopropylethylamine or triethylamine) in a non-reactive solvent (e.g., THF or CH)2Cl2) In which R is a group of formula2A compound of formula I-I (sulfonamide) which is a substituted sulfonyl group.
Route 9
Compounds of I-j can be prepared as shown in scheme 9. In THF or CH2Cl25,6,7, 8-tetrahydro-1, 6-naphthyridine XLV is converted into ethyl carbamate XLIV using ethyl chloroformate and a non-nucleophilic base (e.g., triethylamine). This intermediate can be converted to compounds of formula I-j following the general procedure described in scheme 8 for the preparation of compounds I-I.
Route 10
Lactams of formula I-k are prepared as described in scheme 10. In a closed tube, at a temperature of from about 75 ℃ to about 125 ℃, in a mixture of toluene and water, at 2 to 5 equivalents of Cs2CO3And a catalytic amount (0.01 to 0.10 equivalents) of Pd (dppf) Cl2With 1 to 2 equivalents of potassium trifluoroborate salt L in the presence ofChlorocyanomethylpyridine XLIX, or by microwave heating, gives the compound XLVIII. With the proviso that the compound is pure or in CH2Cl2Either TFA in solution or HCl in MeOH or EtOH removes the Boc protecting group to give compound XLVII, which can then be cyclized by heating in aqueous NaOH from 50 ℃ to 100 ℃ to form lactam XLVI. Compound XLVI can be converted to compounds of formula I-k following the general procedure detailed in scheme 1 for preparing compounds of formula I.
Route 11
5H-pyrrolo [3,4-b ] of formula I-1 can be prepared as shown in scheme 11]Pyridin-7 (6H) -one. Hydrolysis of 2-cyano-3-methylpyridine of formula LIV (prepared according to the general procedure shown in scheme 2) with aqueous sodium or potassium hydroxide (with MeOH or EtOH as co-solvent) at elevated temperature affords the acid of formula LII. Esterification with MeOH in the presence of catalytic amounts of sulfuric acid at from 50 ℃ to 100 ℃ gives compound LII. Can be carried out at from 50 ℃ to 85 ℃ in the presence of carbon tetrachloride or CH with a catalytic amount of a free radical initiator such as benzoyl peroxide or 2 '2' -azobis (2-methylpropionitrile) (AIBN)2Cl2This material LII was brominated with N-bromosuccinimide to give compound LI. By reacting R with a compound of formula (I) in an inert polar solvent such as THF or acetonitrile containing a non-nucleophilic base such as potassium or sodium carbonate or preferably diisopropylethylamine or triethylamine at a temperature of from 0 ℃ to 50 ℃ (with room temperature being preferred)5-treatment of LI with a substituted primary amine, compound I-1 can be formed.
Route 12
7, 8-dihydro-1, 7-naphthyridin-6 (5H) -ones of formula I-m and 5,6,7, 8-tetrahydro-1, 7-naphthyridine of formula I-n were synthesized as shown in scheme 12. Compound LVII is reacted with 1 to 1.5 equivalents of sodium dimethylmalonate in a polar solvent such as NMP or DMF at from 50 ℃ to 110 ℃ to give the diester of formula LVI. Decarboxylation of this material was achieved by heating between 50 ℃ and 100 ℃ with 2 equivalents of water and 1 to 1.5 equivalents of lithium chloride in DMSO to give ester LV. Hydrogenolysis of LV in acetic acid containing palladium on activated carbon gives lactam I-m, which can be converted into compounds of formula I-n by treatment with hydride reducing agents such as borane-THF complex or lithium aluminum hydride in THF from room temperature to reflux
Route 13
Preparation of 6,7,8, 9-tetrahydro-5H-pyrido [2,3-d ] of formula I-o as shown in scheme 13]Aza derivatives. With pure or in a suitably inactive solvent (e.g. CH)2Cl2) Compound LXII (prepared according to the general procedure described in WO2007140213, substituting N-benzyl-4-piperidone for N-Boc-4-piperidone) is treated with a brominating agent (e.g., phosphorus tribromide or phosphorus oxybromide) to produce compound LXI. The compound LX can be prepared from the bromide LXI and the pinacolborane of formula VI according to the general procedure shown in scheme 2. By reaction with pure or in a suitably inactive solvent (e.g. CH)2Cl2) The conversion of LX to LVIX can be achieved by reaction of a brominating agent (e.g., phosphorus tribromide or phosphorus oxybromide). Hydrodehalogenation by hydrogenation with Raney nickel or palladium on carbon to form compounds of formula LVIII may be performed in accordance with the method used for the synthesis of compounds I-IIn a similar manner to that described in scheme 8, the compounds of formula LVIII are further derivatized to provide compounds of formula I-o.
Route 14
Preparation of oxazolo [4,5-b ] of formula I-p as shown in scheme 14]Pyridine. Treatment of the fluoronitrile compound LVII with sodium benzylate (sodium benzoate) under standard conditions will yield the benzyl ether LXVII. The hydrolysis of the nitrile to the corresponding acid LXVI can be performed using an aqueous solution of an inorganic base (e.g., KOH) and a suitable solvent (e.g., MeOH or EtOH). Subsequently, Curtius rearrangement was performed using diphenylphosphoryl azide (diphenylphosphoryl azide) in tert-butanol to give the BOC-protected amine LXV. Treatment of LXV with an acid (e.g., HCl or TFA) will yield LXIV. Cleavage of the benzyl ether by hydrogenolysis in the presence of a catalyst (e.g., palladium on carbon) will yield the hydroxy intermediate LXIII. Finally, in the presence of an acid (e.g. toluene sulfonic acid), with R as appropriate3Treatment of LXIII with a substituted orthoformate as solvent will yield the desired target I-p.
Route 15
Regioisomerized oxazoles I-q can be prepared as described in scheme 15. Suzuki coupling of the known chloropyridine XI (bioorg. Med. chem. Lett.125 (2003)) with an alkyl boronic ester of the LXX type (prepared according to the general method shown in scheme 2) in the presence of a Pd (0) catalyst such as palladium tetrakistriphenylphosphine (0) (palladiumtetra-phenylphosphinophosphine (0)) and a base such as potassium fluoride in a solvent such as MeOH, at a temperature from room temperature to 100 deg.C, preferably under reflux, will yield the nitro derivative LXIX. Can be carried out in the presence of a suitable catalyst (such as Pd on carbon or palladium hydroxide)The conversion of LXIX to give the amino alcohol LXVIII is accomplished by hydrogenation in a solvent (e.g. MeOH or EtOH). Finally, LXVII is reacted with suitably R as solvent in the presence of an acid (e.g. toluene sulphonic acid)3Condensation of substituted orthoformates will give the desired target oxazolo [5,4-b]Pyridine I-q.
Route 16
Azaindazoles of the type I-r/I-r can be prepared as described in scheme 16. Known iodides LXXII [ prepared as described in WO07002293 ] in the presence of a Pd (0) catalyst such as bis dibenzylidene palladium (0) (bis dibenzylidene palladium (0)) and an added phosphine ligand such as tricyclohexylphosphine and a base such as potassium phosphate in a solvent such as DMF at a temperature in the range from room temperature to 120 ℃ (preferably at 100 ℃ to 120 ℃)]Suzuki coupling with a hydrocarbylboronic ester of the LXX type will yield an azaindazole LXXI. In the presence of a base (e.g. sodium hydride or Cs)2CO3Preferably Cs2CO3) The conversion of LXXI to regioisomerized alkylated derivatives I-r and I-s can be achieved by alkylation in a solvent (e.g. THF or DMF, preferably THF) at a temperature in the range from room temperature to reflux (preferably 50 ℃), using an appropriate alkyl halide or tosylate. The regioisomerized alkyl derivatives thus produced can be separated by general or reversed phase column chromatography.
Route 17
Compounds of formula I-t/I-u can be prepared as described in scheme 17. In the presence of a base (e.g. sodium hydride or Cs)2CO3Preferably Cs2CO3) In the presence of a solvent (e.g. THF or DMF, preferablyTHF) at a temperature in the range from room temperature to reflux (preferably 50 ℃), known chloro-indazoles LXXV (prepared as described in EP 151962) are alkylated with the appropriate alkyl halides or tosylates to give regioisomerized alkyl derivatives LXXIII and LXXIV, which can be separated by general or reverse phase column chromatography. Suzuki coupling of LXXIII and LXXIV with an LXX type hydrocarbyl borate ester in the presence of a Pd (0) catalyst such as bis-dibenzylidene palladium (0) and an added phosphine ligand such as tricyclohexylphosphine and a base such as potassium phosphate in a solvent such as DMF at a temperature in the range from room temperature to 120 ℃ (preferably at 100 ℃ to 120 ℃) will yield a compound of formula I-t/I-u.
The synthesis of various compounds of the invention is illustrated below. Additional compounds within the scope of the invention may be prepared using the methods illustrated in these examples, alone or in combination with techniques well known in the art
Experiments are generally carried out under an inert atmosphere (nitrogen or argon), particularly where oxygen-sensitive or moisture-sensitive reagents or intermediates are employed. Commercial solvents and reagents are generally used without further purification, including where appropriate anhydrous solvents (generally Sure-Seal)TMProduct from Aldrich Chemical Company, Milwaukee, Wisconsin). Mass spectrometry data are reported from liquid chromatography-mass spectrometry (LCMS), Atmospheric Pressure Chemical Ionization (APCI), or gas chromatography-mass spectrometry (GCMS) instruments. Chemical shifts for Nuclear Magnetic Resonance (NMR) data are expressed in parts per million (ppm,) with reference to the residual peak of the deuterated solvent used. Coupling constants (J values) are reported in hertz.
For the synthesis, the reference procedure, reaction conditions (reaction time and temperature) in other examples or methods may be changed. Generally, the reaction is followed by thin layer chromatography or mass spectrometry, and workup is carried out as appropriate. The purification can vary between different experiments: in general, the solvent and solvent ratio for the eluent/gradient is adjustedColumn select to provide the appropriate Rf' s or retention time (RetT).
Examples
EXAMPLE 14- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) furo [3,4-b ] pyridin-5 (7H) -one
Step 1 preparation of 3- (4-fluorophenyl) -1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole
A solution of 4-bromo-3- (4-fluorophenyl) -1-methyl-1H-pyrazole (700g,2.74mol) in THF (1.4L) was cooled to 15 deg.C and the lithium isopropylmagnesium chloride complex (1.3M in THF, 3.8L,4.94mol) was added slowly while maintaining the reaction temperature below 25 deg.C. The mixture was stirred at 20 ℃ for 3 hours, and a 10 ℃ solution of 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (610g,3.28mol) in THF (1.4L) was added dropwise while maintaining the internal temperature below 20 ℃. The resulting green/brown cloudy solution was stirred between 10 ℃ and 20 ℃ for 1 hour, after which time it was cooled to 10 ℃. Water (5.6L) cooled to 10 ℃ was slowly added to the reaction mixture so that the reaction temperature remained below 25 ℃. Celite (1.4kg) was added followed by 2-methyltetrahydrofuran (7L) and the mixture was stirred at 20 ℃ for 15 min. The mixture was filtered through celite and the pad rinsed with 2-methyltetrahydrofuran (8L). The organic phase was separated and washed with brine (5.6L) and then concentrated under vacuum to a low stirred volume. The material was diluted with EtOH (3L) and then concentrated again. The material was redissolved in EtOH (3.5L) and water (4.2L) was added over 30min with vigorous stirring. The resulting slurry was stirred at 15 ℃ for 1 hour, filtered and washed with 4 volumes of water. The resulting cake was blow dried and then placed in a vacuum oven at 40 deg.CFurther drying yielded 0.4kg (48%) of the product of example 1-step 1 as a white solid: APCI MS M/z303.2(M +1);1H NMR(400MHz,CDCl3)7.91(dd,J=8.9,5.6,2H),7.70(s,1H),7.03(dd,J=8.8,8.8,2H),3.90(s,3H),1.29(s,12H)。
step 2 preparation of 3-fluoro-4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) methylpyridinecarbonitrile (picolininonitril)
The product from example 1-step 1 (14.5g,48mmol) and 3-fluoro-4-iodomethylpyridinonitrile (picolininitril) e (9.92g,40.0mmol) were mixed in 100mL DMF and charged with Cs2CO3(19.90g,61.2 mmol). The resulting suspension was treated with nitrogen sparge for 20min and treated with a single portion of tris (dibenzylideneacetone) dipalladium (0) (1.51g,1.6 mmol). The nitrogen bubbling was continued for another 20min and the dark suspension was stirred continuously at room temperature for 30 min. The reaction mixture was warmed to 50 ℃ for 6 hours and allowed to cool to room temperature overnight. The concentrated slurry was added to 150mL EtOAc and the suspension was diluted with 50mL 50% saturated aqueous sodium chloride followed by treatment with DARCO and stirred at room temperature for 1 hour. The mixture was filtered through celite, the layers were separated and the organic layer was washed with 3 × 30mL 50% saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4Dried and concentrated in vacuo to give 18g of a pasty orange solid. The solid was dissolved in a minimum amount of CH loaded onto a 100g SNAP column2Cl2In 340g SNAP column, elute the crude material with a gradient of 5-80% EtOAc/heptane of 4.8L or more. The appropriate fractions were combined and concentrated. During concentration, a white solid precipitated out. This precipitated material was collected to give 6.93g (59%) of the product of example 1-step 2 as a white solid: APCI MSm/z297.0(M +1);1H NMR(400MHz,CDCl3)8.28(d,J=5.1,1H),7.84(d,J=2.9,1H),7.40(dd,J=5.3,2.2,2H),7.25(dd,J=5.8,4.9,1H),7.09(dd,J=8.6,8.6,2H),4.02(s,3H)。
step 3 preparation of 4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) pyridine-2, 3-dicarbonitrile
The product of example 1-step 2 (10.00g,33.75mmol) was dissolved in DMSO (100mL) with gentle heating. Potassium cyanide (2.35g,35.0mmol) was added, heated to 50 ℃ and stirred. After 2 hours, cool in an ice bath and add 0.1N aqueous NaOH (50 mL). The resulting slurry was stirred for 5min and the solids were collected, rinsed with water and air dried to yield 10.34g of the product of example 1-step 3 as a light cream solid:1H NMR(400MHz,CDCl3)8.56(d,J=5.2,1H),8.02(s,1H),7.33(dd,J=8.9,5.2,2H),7.24(d,J=5.5,1H),7.06(dd,J=8.6,8.6,2H),4.02(s,3H)。
step 4 preparation of 4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) pyridine-2, 3-dicarboxylic acid in the form of the dipotassium salt
A mixture of the product of example 1-step 3 (10.34g,34.1mmol) and aqueous KOH (28.3g,504mmol, dissolved in 100mL of water) was heated at 100 deg.C for 24 h. The mixture was cooled in ice to precipitate a thick white solid. The material was warmed to room temperature, filtered and air dried to yield 12.47g (88%) of the product of example 1-step 4 as a cream colored solid: LCMS M/z342.1(M + 1).
Step 5-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl-monohydrochloride form]Furo [3,4-b ]]Preparation of pyridin-5 (7H) -one the product of example 1-step 4 (5.00g,12.0mmol) was slurried with acetic acid (35mL) and acetic anhydride (12.5mL) and heated to 110 ℃ for 3 hours. The resulting homogeneous mixture is cooled and concentrated, slurried with 50mL of diethyl ether, and reconcentrated to give 4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -6-methyl-5H-pyrrolo [3, 4-b%]Pyridine-5, 7(6H) -dione as a viscous yellow solid. The solid material was slurried in THF (70mL), sodium borohydride (568mg,15.0mmol) was added, and acetic acid (1.7mL,2.5mmol) was added dropwise over a period of one minute. After stirring for 90min, the reaction mixture was concentrated to a thick yellow paste, acetic acid (90mL) and acetic anhydride (45mL) were added, and the mixture was heated at 110 ℃ for two hours to give a homogeneous solution. The heat was removed and the mixture was stirred at room temperature overnight and concentrated. The residue was partitioned between EtOAc and water, the organics were separated, and the aqueous phase was re-extracted with EtOAc. Combining the extractsWashed with brine and dried (MgSO)4) And concentrated to give a thick yellow oil. Silica gel chromatography eluting with 50% EtOAc/heptane yielded 2.06g (55%) of the product of example 1-step 5 as a waxy white solid. This material was dissolved in EtOAc (100mL) and treated with 1.2 equivalents of 2N HCl/diethyl ether to yield 1.91g of the product of example 1-step 5 as a yellow solid: MS (APCI)310.0M/z (M +1);1H NMR(400MHz,DMSO-d6)8.64(d,J=5.3,1H),8.17(s,1H),7.32(dd,J=8.8,5.5,2H),7.11(dd,J=9.0,9.0,2H),7.08(d,J=5.0,1H),5.32(s,2H),3.92(s,3H)。
3-fluoro-4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) methylpyridine nitrile (picolininonitril) (see step 2) was also prepared by the following route:
step 6 preparation of 1- (4-fluorophenyl) -2- (3-fluoropyridin-4-yl) ethanone
Lithium hexamethyisilazide (1.0M in THF, 17.9mL,17.9mmol) was cooled to 0 deg.C and 3-fluoro-4-methylpyridine (1.00g,0.926mmol) in THF (50mL) was added dropwise, maintaining the solution temperature below 5 deg.C. Subsequently, the mixture was stirred at 0 ℃ for 1 hour, and ethyl 4-fluorobenzoate in THF (50mL) was added dropwise. The reaction mixture was allowed to warm slowly to room temperature with stirring overnight. Aqueous ammonium chloride was added and the mixture poured into EtOAc. The organic phase was separated and dried (Na)2SO4) And concentrating. Silica gel chromatography with a gradient of 10-50% EtOAc/heptane yielded 1.83g (89%) of the product of example 1-step 6 as a white solid: LCMS M/z234.4(M +1);1H NMR(400MHz,MeOH-d4)8.41(d,J=1.71H),8.32(d,J=4.8,1H),8.14(dd,J=8.9,5.4,2H),7.38(dd,J=5.9,5.1,1H),7.25(dd,J=9.0,9.0,2H),4.52(s,2H)。
step 7 preparation of 3- (dimethylamino) -1- (4-fluorophenyl) -2- (3-fluoropyridin-4-yl) prop-2-en-1-one
Example 1-step 6 product (1.35g,5.79mmol), dimethylformamide dimethyl acetal (0.77g,5.79mmol) and THF (20mL) were stirred at 80 ℃ for 2 hours, then at 100 ℃ for one hour, and then concentrated to give 1.6g of the product of example 1-step 7 as a yellow oil which was used without purification: LCMS M/z289.4(M + 1).
Step 8 preparation of 3-fluoro-4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) pyridine
The product from example 1-step 7 (1.6g,5.55mmol) was dissolved in EtOH (75mL) and cooled to 0 ℃. Methylhydrazine (0.35mL,6.66mmol) was added dropwise and the mixture was allowed to warm slowly to room temperature with stirring overnight, then concentrated. LCMS of the crude product showed a mixture of two N-methylpyrazole regioisomers (regiomers) separated by silica gel chromatography eluting with a 1:1 mixture of heptanes and 7:2:1 heptanes: diethylamine: MeOH. The product of example 1-step 8 was isolated as a light yellow solid (900mg, 60%): LCMS M/z272.5(M +1);1H NMR(400MHz,MeOH-d4)8.41(d,J=2.5,1H),8.20(d,J=5.1,1H),8.01(d,J=1.7,1H),7.39(dd,J=8.8,5.3,(2H),7.19(dd,J=6.7,5.1,1H),7.09(dd,J=8.8,8.8,2H),3.98(s,3H)。
step 9 preparation of 3-fluoro-4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) pyridine 1-oxide
The product of example 1-step 8 (900mg,3.32mmol) was dissolved in CH2Cl2(20mL) and treated with m-chloroperbenzoic acid (85%, 1.35g,6,64mmol) and stirred at room temperature for 5 h. The mixture was concentrated and purified by silica gel chromatography. Using column CH2Cl2Rinsed, then with 0-50% EtOAc/CH2Cl2Rinse, final rinse with EtOAc, followed by removal of the desired N-oxygen with 20% MeOH/EtOAc and 1% triethylamineAnd (4) melting the mixture. The desired N-oxide was obtained as a yellow oil (1.06g, quantitative yield): LCMS M/z288.5(M +1);1H NMR(400MHz,MeOH-d4)8.42(dd,J=5.4,1.7,1H),8.04-8.06(ddd,J=6.7,1.8,0.8,1H),8.02(d,J=2.1,1H),7.42(dd,J=8.8,5.3,2H),7.24(dd,J=8.7,6.8,1H),7.12(dd,J=8.7,8.7,2H),3.97(s,3H)。
step 10 preparation of 3-fluoro-4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) methylpyridinecarbonitrile (picolininonitril)
The product of example 1-step 9 (1.06g,3.69mmol), triethylamine (1.03mL,7.38mmol) and trimethylsilyl cyanide (0.615mL,4.61mmol) were stirred in acetonitrile (10mL) at 70 ℃ for 3 days. LCMS indicated that the N-oxide was still present, so an additional 1.5mL of trimethylsilyl cyanide and 2.5mL of triethylamine were added and heating continued for an additional 24 hours. The mixture was cooled, concentrated and purified by silica gel chromatography using 10-100% EtOAc/heptane and 1% triethylamine modifier (modifier) to yield 600mg (55%) of example 1-step 10 as a yellow solid. The spectral data were consistent with those of the material prepared using the procedure in step 2 above.
Example 24- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6-methyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one
Step 1 preparation of 4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -6-methyl-5H-pyrrolo [3,4-b ] pyridine-5, 7(6H) -dione
A mixture of the product of example 1-step (275.29g,659.41mmol), acetic acid (2.06L) and acetic anhydride (137.65mL,1456mmol) was heated at 110 deg.C for 1 hour, cooled to 80 deg.C, and methylamine (2.0M/THF,659.41mL;567.09g) was added over a period of more than 20min, with the temperature maintained at 80 deg.C. White smoke was observed during the addition. Adding the reaction mixtureIt was heated to 100 ℃ overnight and concentrated to about 500mL to give a net yellow solution. Water (200mL) was added over a period of longer than 10min with stirring. Acetic acid (about 100mL) and another 200mL of water were added to assist stirring. The solids were removed by filtration using a buchner funnel with filter cloth and the solids were washed with 250mL of water. Air-dry for 1 hour then dry in a vacuum oven overnight at 60 ℃ to yield 206.47g (93.10%) of the product of example 2-step 1 as a light yellow solid: LCMSM/z337.1(M +1);1H NMR(400MHz,MeOH-d4)8.59(d,J=5.4,1H),8.26(s,1H),7.42(dd,J=8.8,5.3,2H),7.25(d,J=5.3,1H),7.10(dd,J=8.9,8.9,2H),4.02(s,3H),3.15(s,3H)。
step 2 preparation of 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6-methyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one
To a flask equipped with overhead stirring were added the product of example 2-step 1 (202.00g,600.61mmol) and zinc powder (Zn powder: (wt.))<10 microns) (357.04g,5.41mol) followed by the addition of acetic acid (2.02L). The mixture was heated to 105 ℃, stirred for 4.5 hours, and then cooled to room temperature. Celite was added to the reaction mixture and the mixture was filtered to remove zinc. The filter pad was rinsed with EtOAc, the filtrate was concentrated to-300 mL and 200mL of water was added. The resulting solid was collected, rinsed with water, and dried overnight in vacuo to give 103.23g (53%) of example 2 as a solid: LCMSM/z323.2(M +1);1H NMR(400MHz,CDCl3)8.38(d,J=5.5,1H),8.28(s,1H),7.41(dd,J=8.8,5.5,2H),7.03(dd,J=8.6,8.6,2H),6.96(d,J=5.2,1H),4.44(s,2H),4.01(s,3H),3.24(s,3H)。
EXAMPLE 3 4- [3- (4-chlorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6-methyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one
Step 1 preparation of 4-bromo-3- (4-chlorophenyl) -1H-pyrazole
N-Bromosuccinimide (10.4g,56.0mmol) was added portionwise to 3- (4-chlorophenyl) -1H-pyrazole (10.0g,56.0mmol) in CH2Cl2(140 mL). The mixture was stirred for 10min, water and another portion of CH were added2Cl2The mixture was stirred for 5 min. The organic phase was separated, washed with brine and dried (MgSO)4) And concentrated to give 15.0g of the product of example 3-step 1 as a pale yellow solid:1H NMR(400MHz,CDCl3)7.68(d,J=8.6,2H),7.59(s,1H),7.35-7.39(m,2H)。
step 2 preparation of 4-bromo-3- (4-chlorophenyl) -1-methyl-1H-pyrazole
Mixing Cs2CO3(38.0g,116.0mmol) was added to a solution of the product from example 3-step 1 (15.0g,58.0mmol) in DMF (63 mL). Methyl iodide (3.74mL,58.2mmol) was added and the resulting pink solution was stirred at room temperature for 2 hours. The mixture was concentrated and the residue partitioned between EtOAc and water. The organic phase was separated, washed with brine and dried (MgSO)4) And concentrated. With 40% heptane/CH2Cl2Silica gel chromatography of (2) gave 10.1g (64%) of the product of example 3-step 2 as a white solid.1H NMR (CDCl3) showed 5% of the corresponding regioisomer (4-bromo-5- (4-chlorophenyl) -1-methyl-1H-pyrazole). The identity of the two regioisomers was confirmed by means of NMR NOE (nuclear Vouhauser effect) experiments. This material was used without further purification.1H NMR(400MHz,CDCl3)7.80-7.82(m,2H),7.43(s,1H),7.35-7.38(m,2H),3.90(s,3H)。
Preparation of example 3:
the example 3-step 2 product was converted to example 3 following the general procedure described in example 1 (steps 1-5) and then example 2 (steps 1 and 2): LCMSM/z339.1(M +1);1H NMR(400MHz,CDCl3)8.34(d,J=5.3,1H),8.18(s,1H),7.30-7.33(m,2H),7.23-7.25(m,2H),6.91(d,J=5.2,1H),4.38(s,2H),3.94(s,3H),3.17(s,3H)。
EXAMPLE 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one
Step 14 preparation of 3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [3,4-b ] pyridine-5, 7(6H) -dione
4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -6-methyl-5H-pyrrolo [3, 4-b)]Pyridine-5, 7(6H) -dione (intermediate from example 1, step 5, 190mg,0.588mmol) and 28-30% aqueous ammonium hydroxide (4mL) were heated to vigorous reflux for 30min, then concentrated. The residue was dissolved in 1:1 acetic acid/acetic anhydride (20mL), heated at 120 ℃ for 2 hours, and concentrated. The residue was dissolved in EtOAc and passed through a short silica gel plug (short silica gel plug) to give 176mg (92%) of the product of example 4-step 1 as a white solid, which was used without further purification: LCMSM/z323.1(M +1);1H NMR(400MHz,CDCl3)8.63(d,J=5.2,1H),8.15(s,1H),7.37(dd,J=8.8,5.5,2H),7.17(d,J=5;3,1H),7.04(dd,J=8.6,8.6,2H),4.01(s,3H)。
step 2 example 4:
following the general procedure described in example 2, step 2, using 5 equivalents of zinc powder and heating for 1.5 hours, example 4 was prepared from the example 4-step 1 product in 71% yield: LCMSM/z309.1(M +1);1H NMR(400MHz,CDCl3)8.40(d,J=5.4,1H),8.21(s,1H),7.37-7.49(m,2H),6.95-7.03(m,3H),6.14(brs,1H),4.74(s,2H),3.98(s,3H)。
EXAMPLE 5 6-benzyl-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one
Step preparation of 16-benzyl-4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [3,4-b ] pyridine-5, 7(6H) -dione
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]Furo [3,4-b ]]Pyridin-5 (7H) -one (example 1, step 5,472mg,1.46mmol) and benzylamine (0.167mL,1.53mmol) in acetic acid (4.7mL) were heated at reflux for 18H, cooled, and then concentrated to a brown solid. This material was stirred with ether (20mL) for 10min and then filtered to give 450mg (75%) of the product of example 5-step 1 as a brown solid: LCMSM/z413.5(M +1);1H NMR(400MHz,CDCl3)8.57(d,J=5.2,1H),8.15(s,1H),7.26-7.42(m,7H),7.13(d,J=5.3,1H),7.01(dd,J=8.6,8.6,2H),4.87(s,2H),4.00(s,3H)。
step preparation of 26-benzyl-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one
Boron trifluoride-diethyl etherate (Boron trifluoride-diethyl etherate) (0.18mL,1.45mmol) was added to a solution of the product of example 5-step 1 (100mg,0.242mmol) in THF (2.4 mL). After stirring at room temperature for 30min, borane THF complex (1.0M/THF,1.21mL,1.21mmol) was added and the mixture was heated to 40 ℃ overnight. A few drops of 6NHCl were added and the mixture was refluxed for 1 hour, cooled and concentrated. Silica gel chromatography of the resulting material with a gradient of 5-10% MeOH/EtOAc yielded 6mg (6%) of example 5 as a gum: LCMSM/z399.5(M +1);1H NMR(400MHz,MeOH-d4)8.44(d,J=5.5,1H),8.14(s,1H),7.20-7.36(m,7H),7.12(d,J=5.2,1H),7.03(dd,J=8.8,8.8,2H),4.72(s,2H),4.33(s,2H),3.96(s,3H)。
EXAMPLE 6-benzyl-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine
Lithium Aluminum Hydride (LAH) (1.0M/THF,1.10mL,1.10mmol) was added dropwise to a solution of example 5(114mg,0.276mmol) in THF (2.8 mL). The mixture was stirred at room temperature overnight, cooled to 0 ℃ and treated with a few drops of Na2SO4Quenching with saturated aqueous solution. Reacting the mixture with CH2Cl2(3X50mL) extraction, filtration (Celite) over MgSO4Drying and concentrating. This material was poured onto a Phenomenex Phenyl Hexyl column (150 × 3.0mm,5 μ) with a gradient of 5-100% MeOH in water with 0.1% formic acid to yield 5mg (5%) of the title compound, which was converted to the hydrochloride salt: LCMSM/z399.5(M +1);1H NMR(400MHz,MeOH-d4)8.49(d,J=4.7,1H),8.01(s,1H),7.44-7.52(m,5H),7.32-7.38(m,3H),7.14(dd,J=8.6,8.6,2H),4.76(brs,2H),4.57(brs,2H),4.31(brs,2H),4.00(s,3H)。
example 7- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-2,3,4, 5-tetrahydropyrido [2,3-f][1,4]Oxazazepine
Step 1 preparation of tert-butyl 2- (2-cyano-4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) pyridin-3-yloxy) ethylcarbamate
60% sodium hydride (1.35g,33.8mmol) was added to a solution of N-Boc-ethanolamine (2.62mL,16.9mmol) in THF (85 mL). After stirring at room temperature for 5min, the product of example 1-step 2 (5.0g,17.0mmol) was added with stirring. The mixture was stirred for 30min, then saturated NH was used4Quenching with aqueous Cl and EtOAc (100mL) dilution. The organic phase was separated and dried (MgSO)4) And concentrated to give 1.4g of a viscous oil. Purification by silica gel chromatography with 40-60%% EtOAc/heptane afforded 3.35g (45%) of the product of example 7-step 1 as a white solid: LCMS M/z438.6(M +1);1H NMR(400MHz,CDCl3)8.17(d,J=5.1,1H),7.76(s,1H),7.30(dd,J=8.8,5.5,2H),7.14(d,J=4.9,1H),6.95(dd,J=8.8,8.8,2H),5.01(br s,1H),3.94(s,3H),3.91(t,J=5.3,2H),3.30(q,J=5.5,2H),1.33(s,9H)。
step 2 preparation of 3- (2-Aminoethoxy) -4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) methylpyridinecarbonitrile (picolininitril) e
Ethanolated HCl (1.25M,33mL,41mmol) was added to the product of example 7-step 1 (3.35g,7.7mmol), and the resulting solution was refluxed for 30min, followed by concentration to yield 2.90g (92%) of the product of example 7-step 2, isolated as the dihydrochloride salt as a white solid: MS (APCI) M/z338.0(M +1);1H NMR(400MHz,MeOH-d4)8.33(d,J=4.9,1H),8.16(s,1H),7.42(dd,J=8.8,5.3,2H)7.38(d,J=5.1,1H),7.10(dd,J=8.7,2H);4.14(t,J=5.2,2H),4.03(s,3H),3.22(t,J=5.1,2H)。
step 3 (9- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -3, 4-dihydropyrido [2, 3-f)][1,4]Oxazazepine-5(2H) -one
The product from example 7-step 2 (2.90g,7.07mmol) and 1N aqueous NaOH (29mL,29mmol) were stirred at 85 ℃ for 2 h. The reaction mixture was cooled to room temperature and the precipitate was collected, rinsed with water and air dried to yield 1.92g (80%) of the product of example 7-step 3 as a light brown solid: MS (APCI) M/z (M +1)338.8;1H NMR(400MHz,DMSO-d6)8.47(t,J=6.1,1H),8.27(d,J=4.7,1H),7.33(dd,J=9.0,5.7,2H),7.11-7.17(m,3H),3.89(s,3H),3.84(t,J=5.3,2H),3.15(dt,J=5.5,4.7,2H)
step 4 example 7:
lithium Aluminum Hydride (LAH) (1.0M in THF,11.4mL,11.4mmol) was added to a solution of the product from example 7-step 3 (1.92g,5.68mmol) in THF (56mL) and the resulting mixture was refluxed for 1 hour. After cooling to room temperature, excess LAH was quenched with a minimal amount of water and diluted with EtOAc. The resulting slurry was filtered through celite, and the filtrate was concentrated to yield 1.8g of a light yellow solid. With 5% MeOH/CH2Cl2Silica gel chromatography of (2) yielded 650mg (35%) of example 7 as a light yellow gum. The dihydrochloride salt was prepared in EtOAc with 2N HCl/diethyl ether to give 537mg of a pale peach solid: MS (APCI) M/z325.0(M +1);1H NMR(400MHz,MeOH-d4)8.29(d,J=5.7,1H),8.15(s,1H),7.45(d,J=5.7,1H),7.41(dd,J=8.8,5.3,2H),7.13(dd,J=8.9,8.9,2H),4.68(s,2H),4.21-4.24(m,2H),3.99(s,3H),3.66-3.68(m,2H)。
example 8- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-2-methyl-2, 3,4, 5-tetrahydropyrido [2,3-f][1,4]Oxazazepine
Step 1 preparation of 4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -3-hydroxymethylpyridinecarbonitrile (picolininonitril) e
Sodium hydride (60%, 4.05mg,10.1mmol) was added to a solution of the product of example 1, step 2 (1.00g,3.38mmol) and 2- (methylsulfonyl) ethanol (629mg,5.06mmol) in THF (20mL) at 0 ℃. The mixture was warmed to room temperature and stirred for 18 hours. Saturated aqueous ammonium chloride was added to quench excess sodium hydride and the mixture was extracted into EtOAc. The organic phase was separated and dried (MgSO)4) And concentrating. Silica gel chromatography with a gradient of 20% to 100% EtOAc/heptane yielded the product of example 8-step 1 in quantitative yield: LCMS M/z295.1(M +1);1H NMR(400MHz,CDCl3)8.19(d,J=4.7,1H),7.74(s,1H),7.40(dd,J=8.8,5.3,2H),7.23(d,J=4.7,1H),7.05(dd,J=8.6,8.6,2H),4.03(s,3H)。
step 2 preparation of tert-butyl 2- (2-cyano-4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) pyridin-3-yloxy) propylcarbamate
Diisopropyl azodicarboxylate (0.78mL,3.70mmol) was added to an ice-cold solution of the product from example 8-step 1 (990mg,3.36mmol), tert-butyl 2-hydroxypropyl carbamate (590mg,3.36mmol), and triphenylphosphine (1.06g,4.04 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was loaded onto silica gel and purified by chromatography using a gradient of 10-60% EtOAc/heptane to yield 1.48g of the-75% pure product of example 8-step 2 as a yellow gum, which was used without further purification: LCMS M/z452.2(M + 1).
Step 3-9- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -2-methyl-3, 4-dihydropyrido [2,3-f ]][1,4]OxazazepinePreparation of (2H) -5-ketones
The example 8-step 3 product was prepared from the example 8-step 2 product, which was-75% pure, following the general procedure described in example 6 (steps 2 and 3): LCMS M/z353.2(M +1);1H NMR(400MHz,CDCl3)8.39(d,J=4.9,1H),7.72(s,1H),7.41(dd,J=8.8,5.4,2H),7.35(br t,J=6.7,1H),7.20(d,J=4.9,1H),7.04(dd,J=8.6,8.6,2H),4.31-4.38(m,1H),4.02(s,3H),3.40(ddd,J=15.6,6.4,3.7,1H),3.14(ddd,J=15.6,6.1,6.1,1H),1.15(d,J=6.4,3H)。
step 4, example 8:
zinc powder (121mg,1.84mmol) and the product of example 8-step 3 (130mg,0.37mmol) were stirred in acetic acid (10mL) at 110 ℃ for 18 h. LCMS shows the title compound and its N-acetyl derivative (1- (9- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -2-methyl-2, 3-dihydropyrido [2, 3-f)][1,4]Oxazazepine-4(5H) -yl) ethanone). The reaction mixture was cooled to 25 ℃, filtered (celite), and rinsed with acetic acid. The filtrate was concentrated, then 6N HCl (5mL) and MeOH (6mL) were added and the mixture refluxed for 20 hours. The reaction mixture was concentrated, redissolved in 3:1 chloroform/isopropanol and saturated K2CO3The aqueous solution, water and brine were washed and then dried (MgSO)4) And concentrating. Using 100% CH2Cl2To 10% MeOH/CH2Cl2Gradient chromatography yielded 83mg (66%) of example 8 as a racemic mixture. The individual enantiomers were separated by chiral HPLC (Chiralpak AD-H,4.6 mm. times.25 25 cm; mobile phase 85/15 carbon dioxide/EtOH; flow rate 2.5 mL/min; modifier 0.2% isopropylamine).
Enantiomer # 1: RetT =5.30min, LCMS M/z339.2(M +1);1H NMR(400MHz,CDCl3)8.05(d, J =5.1,1H),7.69(s,1H),7.43(dd, J =8.9,5.4,2H),7.02(dd, J =8.8,8.8,2H),6.94(d, J =5.1,1H),4.20(AB quartet, J)AB=15.0,ΔνAB=13.4,2H),4.00(s,3H),3.72-3.76(m,1H),3.17(dd,J=14.0,1.9,1H),2.95(dd,J=14.3,4.7,1H),1.12(d,J=6.4,3H)。
Enantiomer # 2: RetT =5.84min, LCMS M/z339.2(M +1);1h NMR, same as for enantiomer # 1.
Example 9- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-3-methyl-2, 3,4, 5-tetrahydropyrido [2,3-f][1,4]Oxazazepine
Following the same general procedure described in example 7, substituting tert-butyl 1-hydroxypropan-2-ylcarbamate for tert-butyl 2-hydroxypropylcarbamate in step 2, example 9 was prepared, and the enantiomers were separated by chiral HPLC (Chiralpak AD-H,10mm x250 cm; mobile phase 80/20 carbon dioxide/EtOH; flow rate 10 mL/min; modifier 0.2% isopropylamine):
enantiomer # 1: RetT =4.30min, LCMS M/z339.2(M +1);1H NMR(400MHz,CDCl3)8.06(d,J=4.8,1H),7.65(s,1H),7.41(dd,J=8.8,5.5,2H),7.03(dd,J=8.8,8.8,2H),6.93(d,J=5.1,1H),4.30(s,2H),4.07(dd,J=11.9,2.5,1H),4.00(s,3H),3.25-3.30(m,1H),3.17-3.22(m,2H),1.04(d,J=6.5,3H)。
enantiomer # 2: RetT =4.73min, LCMSM/z339.2(M +1);1h NMR, same as for enantiomer # 1.
EXAMPLE 10- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6- (methylsulfonyl) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine
Step 1 preparation of 6- (methylsulfonyl) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine
Methanesulfonyl chloride (0.97mL,12.4mmol) was added dropwise to diisopropyl-ethylamine (5.16mL,31.1mmol) and 6, 7-dihydro-5H-pyrrolo [3,4-b ]]Pyridine (2.0g,10.0mmol) in CH2Cl2(20mL) at-10 ℃. The mixture was stirred at room temperature overnight with CH2Cl2Diluted (300mL) and washed with saturated aqueous sodium bicarbonate. The organic phase was separated and dried (MgSO)4) Filtration through a short pad of silica gel was performed, rinsing with EtOAc. The filtrate was concentrated to give 2.15g (quantitative) of the product of example 10-step 1 as a solid, which was used without further purification: LCMS M/z199.2(M +1);1H NMR(400MHz,CDCl3)8.54(d, J =4.9,1H),7.61(d, J =7.8,1H),7.25(dd, J =7.8,5.1,1H),4.75(AB quartet, J)AB=2.1,ΔνAB=7.8,4H),2.94(s,3H)。
Step 2 preparation of 6- (methylsulfonyl) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine 1-oxide
Following the general procedure described in example 1, step 9, the example 10-step 2 product was prepared from the example 10-step 1 product in 95% yield as a white solid: LCMS M/z215.01(M +1);1H NMR(400MHz,CDCl3)8.16(d,J=6.5,1H),7.29(dd,J=7.5,7.5,1H),7.18(d,J=7.8,1H),4.82-4.89(m,4H),2.96(s,3H)。
step 3 preparation of 4-chloro-6- (methylsulfonyl) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine
Oxalyl chloride (0.415mL,4.67mmol) was added dropwise to a suspension of the product of example 10-step 2 (500mg,2.33mmol) in DMF (40mL) at 0 ℃. The resulting mixture was warmed to room temperature and stirred for 18 hours. Water was slowly added to quench excess oxalyl chloride and the mixture was extracted into CH2Cl2(250 mL). The extract was washed with brine and dried (MgSO)4) And concentrated to give a brown gum which is then purified by silica gel chromatography using a gradient of 100% heptane to 50% EtOAc/heptane. First, 2-chloro-6- (methylsulfonyl) -6, 7-dihydro-5H-pyrrolo [3,4-b ] is eluted from the column]Pyridine (76mg, 14%) followed by elution of the product of example 10-step 3 (240mg, 44%, white solid):1H NMR(400MHz,CDCl3)8.45(d,J=5.5,1H),7.26(d partially obscured by residual CHCl3peak,1H),4.80(br s,4H),2.97(s,3H)。
step 4, example 10:
the product of example 10-step 3 (100mg,0.43mmol), the product of example 1-step 1, (156mg,0.516mmol), LiOH (30.9mg,1.29mmol) and dichloro1,1 '-bis (diphenylphosphino) ferrocenepalladium (II) (dichoro 1, 1' -bis (diphenylphosphino) ferrocenepalladium (II)) (35.1mg,0.043mmol) were mixed as a solid and degassed by evacuation and backfilling with nitrogen (3 times). DMF (30mL) was added and the mixture was heated at 100 ℃ for 2 hours. After cooling to room temperature, addEtOAc was added and the mixture was filtered (celite) and rinsed with EtOAc. The filtrate was washed with water and brine, dried (MgSO)4) And concentrating. Silica gel chromatography with a 40-80% EtOAc/heptane gradient yielded 102mg (64%) of example 10 as a light brown solid: LCMSM/z373.1(M +1);1H NMR(400MHz,MeOH-d4)8.47(d,J=6.4,1H),8.28(s,1H),7.42-7.48(m,3H),7.15(dd,J=8.8,8.8,2H),4.96-4.97(m,2H),4.77-4.79(m,2H),4.02(s,3H),3.00(s,3H)。
EXAMPLE 11 6- (ethylsulfonyl) -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine
Step 1 preparation of 4-chloro-5H-pyrrolo [3,4-b ] pyridine-6 (7H) -carboxylic acid ethyl ester
Example 11-step 1 product was prepared using the general procedure described in example 10 (steps 1-3) substituting ethyl chloroformate for methanesulfonyl chloride in step 1. The material was obtained as a pink solid: MS (APCI) M/z226.9(M +1);1h NMR showed a mixture of rotamers (400MHz, CDCl)3)8.43(d, J =5.4,1H),7.23-7.26(m,1H),4.75-4.85(m,4H),4.26(q, J =7.1,2H),1.31-1.36 (overlapping triplets, J =7.2,3H overall). This material was converted to the hydrochloride salt for use in the next step.
Step 2 preparation of 4-iodo-5H-pyrrolo [3,4-b ] pyridine-6 (7H) -carboxylic acid ethyl ester
Sodium iodide (3.93g,26.2mmol) and the product of example 11-step 1, hydrochloride salt (step 1,2.30g,8.74mmol) were refluxed in acetonitrile (20mL) for 3 days. The reaction mixture was cooled, concentrated and washed with water and brine2Cl2And saturated aqueous sodium bicarbonate. Separating the two phases, and adding CH to the aqueous phase2Cl2Re-extracted twice (total volume 750 mL). The solution was passed through layers with diatomaceous earth (0.5')Silica gel (0.5') plug using 1:1EtOAc/CH2Cl2Elution was carried out to yield 1.98g (71%) of the product of example 11-step 2 as a brown solid:1h NMR showed a 1:1 mixture of rotamers (400MHz, CDCl)3)8.08-8.11 (overlapping doublet, 1H all), 7.61(br d, J =5.3,1H),4.89/4.84 (wide doublet, 2H all), 4.68/4.64 (wide singlet, 2H all), 4.23-4.29 (overlapping quartet, 2H all), 1.32-1.37 (overlapping triplet, 3H all).
Step 3 preparation of ethyl 4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [3,4-b ] pyridine-6 (7H) -carboxylate
Following the general procedure described in example 10 (step 4), 4-iodo-5H-pyrrolo [3,4-b ] was used]Pyridine-6 (7H) -carboxylic acid ethyl ester instead of 4-chloro-6- (methylsulfonyl) -6, 7-dihydro-5H-pyrrolo [3,4-b ]]Pyridine, replacing LiOH with 2 equivalents of cesium fluoride, prepared the product of example 11-step 3 in 68% yield as a light brown solid: LCMS M/z367.2.1(M +1);1H NMR(400MHz,MeOH-d4) 1:1 mixture of rotamers, 8.47-8.50(2 overlapping doublets, 1H),8.28(br s,1H),7.44-7.52(m,3H),7.15-7.19(2 overlapping doublets, 2H),4.97/5.00 (broad singlet, 2H),4.77/4.80 (broad singlet, 2H),4.20-4.27(2 overlapping quartets, 2H),4.05(br s,3H),1.30-1.35(2 overlapping triplets, 3H).
Step 4 preparation of 4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine
Aqueous KOH (10M,10.3mL,103mmol), the product of example 11-step 3 (1.51g,4.12mmol), MeOH (15mL), and water (15mL) were heated at 90 deg.C for 18 h. After cooling to room temperature, water (10mL) was added and the mixture was extracted twice with 3:1 chloroform/isopropanol. The extract was concentrated to give 1.2g (99%) of the product of example 11-step 4 as a pink solid: MS (APCI) M/z295.0.1, (M +1);1H NMR(400MHz,CDCl3)8.34(d,J=5.3,1H),7.47(s,1H),7.39(dd,J=9.0,5.5,2H),7.02(dd,J=8.8,8.8,2H),6.94(d,J=5.3,1H),4.28(br s,2H),3.97(br s,2H)。
step 5 example 11 as the hydrochloride salt
Ethanesulfonyl chloride (24. mu.L, 0.26mmol) was added to the product of example 11-step 4 (75mg,0.26mmol) and triethylamine (106. mu.L, 0.77mmol) in CH2Cl2(8 mL). After stirring for 5min, the reaction mixture was washed with CH2Cl2Diluted, washed with saturated aqueous sodium bicarbonate and dried (Na)2SO4) And concentrated to give 89mg (91%) of example 11, which was converted to the hydrochloride salt: LCMSM/z387.1(M +1);1H NMR(400MHz,CDCl3)8.43(d,J=5.0,1H),7.51(s,1H),7.38(dd,J=8.2,5.6,2H),7.02-7.06(m,3H),4.76(br s,2H),4.46(brs,2H),4.02(s,3H),3.00(q,J=7.5,2H),1.34(t,J=7.3,3H)。
example 12 6- (cyclopropylsulfonyl) -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine,
following the general procedure described in example 11, step 5, substituting cyclopropanesulfonyl chloride for ethylsulfonyl chloride, example 12 was prepared to give the hydrochloride salt in 88% yield: LCMS M/z399.1(M +1);1H NMR(400MHz,MeOH-d4) Mixture of rotamers, 8.54(br s,1H),8.31(br s,1H),7.57(br s,1H),7.47(br s,2H),7.19(br s,2H),5.06(br s,2H),4.79(br s,2H),4.05(br s,3H),2.70(br s,1H),1.14(br s,2H),1.06(br s, 2H).
EXAMPLE 13- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6-propionyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine
A solution (50% wt, 360. mu.L, 0.60mmol) of triethylamine (142. mu.L, 1.02mmol), propionic acid (22.9. mu.L, 0.31mmol) and propylphosphonic anhydride (T3P) was added to a solution of example 11(75mg,0.26mmol) in EtOAc (4 mL). The resulting slurry was stirred at room temperature for 2 hours, followed by CH2Cl2Diluting with saturated K2CO3Washed with an aqueous solution and dried (Na)2SO4) And concentrating. The residue was redissolved in EtOAc and treated with excess 2N HCl in ether to yield 113mg of the hydrochloride salt of example 12 as a solid in quantitative yield: LCMS M/z351.1(M +1);1H NMR(400MHz,MeOH-d4) Mixture of rotamers, 8.52(br d, J =6.3,1H),8.32/8.36 (singlet, 1H),7.45-7.54(m,3H),7.15-7.21(m,2H),4.98/5.03/5.20(3 broad singlet, 4H total), 4.06/4.07 (singlet, 3H total), 2.43-2.52(m,2H),1.16-1.21(2 overlapping triplets, 3H).
Examples 14 to 22:
examples 14 to 22 in Table 1 were prepared following the general procedure described in example 13, where R2From:
TABLE 1
EXAMPLE 23- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-cyclopenta [ b ] pyridine
4-chloro-6, 7-dihydro-5H-cyclopenta [ b ] in DMF (5mL)]Pyridine (350mg,2.28mmol), product of step 1 of example 1 (688mg,2.28mmol), K2CO3(661mg,4.78mmol), 1-bis (diphenylphosphino) ferrocene palladium dichloride (1, 1-bis (diphenylphosphino) ferrocene palladium dichloride) (84mg,0.144mmol) was placed in a microwave vial and microwaved at 150 ℃ for 10 min. Reacting the mixture with CH2Cl2(10mL) and water (5 mL). Separating the two layers, and adding CH to the aqueous phase2Cl2And (5) extracting again. The combined organic phases were washed with water and brine4Dried, filtered and concentrated to give a brown solution. Chromatography on 40g of silica gel eluting with 9:1, 4:1 and 1:1 heptane EtOAc provided example 23 as a light brown oil which solidified upon standing (290mg, 43%). LCMS M/z294.5(M + 1).1H NMR(400MHz,CDCl3)8.23(d,J=5.3,1H),7.45(s,1H),7.36(dd,J=9.8,5.4,2H),6.97(dd,J=8.8,8.8,2H),6.85(d,J=5.1,1H),3.98(s,3H),3.00(t,J=7.6,2H),2.59(t,J=7.3,2H),1.93-2.02(m,2H)。
EXAMPLE 24- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-7-ol
Step 1 preparation of 4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridine 1-oxide
According to example 1, in step 9The general procedure described is to subject 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-6, 7-dihydro-5H-cyclopenta [ b]Pyridine is converted to the N-oxide. Silica gel chromatography of using a 9:1 to 4:1 mixture of EtOAc/MeOH yielded 54% of the product of example 24-step 1 as a yellow solid: LCMS M/z310.5(M +1);1H NMR(400MHz,CDCl3)7.97(d,J=6.6,1H),7.45(s,1H),7.35(dd,J=8.9,5.4,2H),7.00(dd,J=8.7,8.7,2H),6.89(d,J=6.6,1H),3.97(s,3H),3.17(t,J=7.6,2H),2.67(t,J=7.6,2H),2.02-2.09(m,2H)。
step 2 preparation of 4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -6, 7-dihydro-5H-cyclopenta [ b ] pyridin-7-yl acetate
The product from example 24-step 1 (155mg,0.50mmol) was heated in acetic anhydride (10mL) at 105 ℃ overnight. Cooling the mixture with CH2Cl2Diluted and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO)4) And concentrated to give a brown oil. Silica gel chromatography with a gradient of 10% to 90% EtOAc/heptane yielded 109mg (62%) of the product of example 24-step 2 as a white solid: LCMS M/z352.5(M +1);1H NMR(400MHz,CDCl3)8.41(d,J=5.1,1H),7.49(s,1H),7.36(dd,J=8.2,5.4,2H),6.95-7.04(m,3H),6.11(dd,J=7.2,5.3,1H),3.99(s,3H),2.69-2.79(m,1H),2.49-2.59(m,2H),2.13(s,3H),1.89-1.97(m,1H)。
step 3 example 24:
the product of example 24-step 2 (105mg,0.299mmol) was partially dissolved in 1.5mL of MeOH. 1.5mL of 10% K was added2CO3The aqueous solution was stirred at room temperature for 3 days. The reaction mixture was concentrated, redissolved in EtOAc, washed with saturated sodium bicarbonate solution and brine. In Na2SO4Dry, filter and concentrate to give example 24 as a brown solid (95mg, quantitative yield) LCMS M/z310.5(M +1);1H NMR(400MHz,CDCl3)8.33(d,J=5.1,1H),7.48(s,1H),7.32-7.39(m,2H),6.95-7.01(m,3H),5.19(dd,J=7.0,7.0,1H),3.98(s,3H),3.76(br s,1H),2.70-2.79(m,1H),2.40-2.52(m,2H),1.86-1.97(m,2H)。
EXAMPLE 25- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -N-methyl-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-7-amine
Will be in CH2Cl2Example 23(50mg,0.16mmol) in (2mL) was cooled to 0 ℃. Triethylamine (0.027mL,0.194mmol) was added, followed by methanesulfonyl chloride (0.013mL,0.170 mmol). The resulting mixture was stirred at 0 ℃ for 30 min. LCMS showed the starting alcohol was still present, so additional portions of triethylamine and methanesulfonyl chloride were added and stirring continued until LCMS indicated the starting material was consumed. Adding water, separating the organic phase, drying and concentrating to obtain crude methanesulfonic acid 4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) -6, 7-dihydro-5H-cyclopenta [ b]Pyridin-7-yl ester (62mg, 99%) as a purple solid. THF (1mL) was added to this crude mesylate followed by 1mL of methylamine (2M in THF,2mmol) to give a brown solution. The reaction mixture was stirred at room temperature for 16 hours and then purified by silica gel chromatography. Elution with 1:3, 1:1 and 1:3 heptane/EtOAc followed by EtOAc and 95:5EtOAc/MeOH gave 12mg of 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-6, 7-dihydro-5H-cyclopenta [ b]Pyridin-7-ol. Further elution with 95:5EtOAc/2M ammonia in MeOH afforded 11mg of a brown gummy material which was dissolved in EtOAc and treated with excess 4M HCl/dioxane, stirring for 10 minutes. Filtration afforded example 25 as a gray solid dihydrochloride (6mg, 9%): LCMS M/z323.5(M +1);1H NMR(400MHz,MeOH-d4)8.43(d,J=5.5,1H),8.01(s,1H),7.37(dd,J=9.0,5.8,2H),7.26(d,J=5.5,1H),7.08(dd,J=8.6,8.6,2H),4.76-4.82(m,1H),3.99(s,3H),2.92-2.99(m,1H),2.84(s,3H),2.73-2.81(m,1H),2.58-2.67(m,1H),2.06-2.15(m,1H)。
examples 26 to 52
Examples 26 to 52 were prepared by the following scheme:
method of producing a composite material
Reacting 4- [3- (4-fluoro-phenyl) -1-methyl-1H-pyrazol-4-yl]-furo [3,4-b]A solution of pyridine-5, 7-dione (0.1mmol) in acetic acid (0.1mL) was added to a vial containing the appropriate amine (0.1 mmol). The vial was heated to 120 ℃ for 10min, at which time zinc powder was added and the vial was heated to 110 ℃ for 7 hours, then shaken at room temperature for 16 hours. The reaction solution was filtered through an empty SPE cartridge to remove the zinc dust, washed with EtOAc, and concentrated. The residue was dissolved in DMSO (1mL) and reverse phase HPLC (column: Waters Atlantis C) was used184.6 × 50mm,5 μm; mobile phase A: 0.05% TFA (v/v) in water; mobile phase B: 0.05% TFA (v/v) in acetonitrile; gradient: 5% to 95% B) for purification.
R in the following Table 22Based on:
TABLE 2
And (4) kinase determination. In the presence of 1. mu.l of CKI inhibitor or 4% DMSO in a final volume of 40. mu.l in a medium containing 50mM Tris (pH 7.5), 10mM MgCl2CK1 kinase assay was performed in buffer with 1mM dithiothreitol, 100. mu.g/mL BSA with 10. mu.M ATP, 2nM CKI wild type and 42. mu.M peptide substrate PLRTLpSVASLPGL (Flotow et al, 1990). Incubating the reaction at 25 ℃ for 85 min; the assay was performed as for the Kinase-Glo assay (Promega). The luminescence output was measured on a Perkin elmer envision plate reader (plate reader) (Perkin elmer, Waltham, MA).
In the presence of 1. mu.l of CKI inhibitor or 4% DMSO in a final volume of 40-. mu.l in a medium containing 50mM Tris (pH 7.5), 10mM MgCl2CK1 kinase assay was performed in buffer with 1mM dithiothreitol, 100. mu.g/mL BSA with 10. mu.M ATP, 2.5nM CKI wild type and 42. mu.M peptide substrate PLRTLpSVASLPGL (flow et al, 1990). Incubating the reaction at 25 ℃ for 70 min; the assay was performed as for the Kinase-Glo assay (Promega). The luminescence output was measured on a Perkin elmer envision plate reader (Perkin elmer, Waltham, MA).
CK1WCA HCS nuclear translocation assay. At 37 ℃ in 5% CO2Cos7 cells were maintained in Dulbecco's Modified Eagle Medium (Gibco 11995) supplemented with 10% fetal bovine serum. Cells in log phase were de-logarithmized using 5min TrypLE Express (Gibco 12605) treatment and viable cell counts were determined using a Cedex cell counter. Cells were diluted in DMEM medium to a density of 1.5e5 viable cells/mL in a volume of 2/3 of the final volume of the final transfected cell mixture. Two substances were used according to the manufacturer's recommendations using Lipofectamine2000 reagent (Invitrogen)The cells were co-transfected with plasmid DNA, mouse Per3-GFP (green fluorescent protein) in pd2EGFP-N1 vector and human CKI in pcDNA4/hisA vector (1: 5 for CK 1; 1:11 for CK 1). The transfection mixture contained approximately 0.83. mu.g/mL of DNA and 6. mu.L/mL of Lipofectamine2000, totaling 1/3 of the final transfection volume in Opti-MEM I medium (Invitrogen). After 20min at room temperature, the cell mixture was combined with the DNA transfection mixture according to the manufacturer's instructions. The transfected cell suspension was dispensed into Greiner 384-well Cellcoat (PDL) plates (Greiner # 781946) at 50. mu.L per well using a multi-drop dropper (Multidrop dispenser).
Compounds were dissolved in 100% DMSO and diluted 4x concentration with Opti-MEM I before being added to plated cells. At 37 ℃ in CO2After overnight exposure in the incubator, cells were fixed by adding 12% paraformaldehyde (Electron microscopical Sciences, Hatfield, PA) to 4% final concentration in Phosphate Buffered Saline (PBS) containing 20% sucrose, and then cultured at room temperature for 30 min. The fixative was removed and the cells were washed with PBS and then stained with 0.4. mu.g/ml Hoechst dye (Invitrogen) in blocking buffer containing 4% goat serum (Vector Labs-1000) and 0.1% TritonX (Sigma T8787) for 1 h. The cells were washed again with PBS and stored in PBS at 4 ℃ or immediately scanned with Cellomics ArrayScan VTI. The CKI-dependent nuclear localization of GFP-tagged mPer3 protein was quantified using the Cellomics ArrayScan VTI system, and the nuclear-cytoplasmic intensity difference was calculated using the Cytoplasm-to-Nucleus translocation Bio-application (cytoplast to Nuclear translocation Bioapplication). Inhibitors of CK 1/were tested across dose response curves to assess the ability of these inhibitors to inhibit the translocation of mPer3-GFP to the nucleus. mPER3 cells with a total intensity of GFP expression equal to or greater than 20,000 were included in the assay.
Table 3 provides biological data for examples 1 to 52.
TABLE 3

Claims (11)

1. A compound of formula I:
wherein:
x is-NR1-, said R1Is C1-4Alkyl or C3-6A cycloalkyl group;
y is CR1Said R is1Is H, C1-4Alkyl or C3-6Cycloalkyl radicals；
Wherein A is one of the following:
each R2Independently is H, C1-6Alkyl radical, C4-10-bicycloalkyl, - (CH)2)t-CN、-SO2C1-6Alkyl, -SO2(CH2)tC3-6Cycloalkyl, -C1-6alkyl-O-C1-6Alkyl, -C1-6alkyl-C (O) O-C1-6Alkyl, -C3-6cycloalkyl-C (O) O-C1-6Alkyl, -C (O) - (O)u-C1-6Alkyl, -C (O) -C1-6alkyl-O-C1-6Alkyl, -C (O) - (O)u-(CH2)t-(C6-10Aryl), - (CH)2)t-(C6-10Aryl), -C (O) - (O)u-(CH2)t- (5-to 10-membered heteroaryl), - (CH)2)t-C(O)-NR5R6、-(CH2)t- (5-to 10-membered heteroaryl), -C (O) - (O)u-(CH2)t- (3-to 10-membered heterocycloalkyl), - (CH)2)t- (4-to 10-membered heterocycloalkyl), -C (O) - (O)u-(CH2)t- (3-to 10-membered cycloalkyl), or- (CH)2)t- (3-to 10-membered cycloalkyl),
wherein R is2Said aryl, heteroaryl, cycloalkyl and heterocycloalkyl may be substituted with up to two substituents independently selected from halogen, OH, cyano, C1-6Alkyl or C1-6alkyl-O-C1-6An alkyl group, a carboxyl group,
and wherein R is, where valence permits2Any alkyl, cycloalkyl and heterocycloalkyl of (a) may be further substituted by oxo;
each R3Independently is absent, C1-3Alkyl, halogen, oxo, -NR5R6OR-OR5；
Each R4Independently is halogen;
each R5Independently is H or C1-6An alkyl group;
each R6Independently is H or C1-6An alkyl group;
R7is H;
n is 1;
each t is independently 0, 1 or 2; and
each u is independently 0 or 1.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
x is-NR1-, said R1Is C1-4An alkyl group;
y is CR1Said R is1Is H;
each R2Independently is H, C1-6Alkyl, -SO2C1-6Alkyl, -SO2(CH2)tC3-6Cycloalkyl, -C1-6alkyl-O-C1-6Alkyl, -C (O) - (O)u-C1-6Alkyl, - (CH)2)t-(C6-10Aryl), -C (O) - (O)u-(CH2)t- (5-to 10-membered heteroaryl), - (CH)2)t-C(O)-NR5R6、-(CH2)t- (5-to 10-membered heteroaryl), - (CH)2)t- (4-to 10-membered heterocycloalkyl) or- (CH)2)t- (3-to 10-membered cycloalkyl),
wherein R is2Said aryl, heteroaryl, cycloalkyl and heterocycloalkyl of (a) may be substituted with up to two substituents independently selected from halogen, OH, cyano, -C1-6Alkyl, -C (O) -O-C1-3Alkyl or C1-6alkyl-O-C1-6An alkyl group, a carboxyl group,
and where valency permits R2Any alkyl, cycloalkyl and heterocycloalkyl of (a) may be further substituted by oxo;
each R3Independently is absent, C1-3Alkyl, oxo, -NR5R6OR-OR5；
R4Is halogen;
each R5Is H;
each R6Independently is H or C1-6An alkyl group;
R7is H;
n is 1;
each t is independently 0, 1 or 2;
each u is independently 0 or 1;
a is as defined in claim 1.
3. A compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2Independently is H, -CH3Or SO2CH3(ii) a And R is3Independently absent or oxo.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is NR1And R on said N1Is C1-4Alkyl or C3-4A cycloalkyl group;
y is CR1And R on said C1Is H or CH3；
R4Is F;
a is
And R is7Is H.
5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is N-C1-4Alkyl and Y is CH.
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein X is N-CH3And Y is CH.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is
4- (3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl) furo [3,4-b ] pyridin-5 (7H) -one;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6-methyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
6-benzyl-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
9- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-2,3,4, 5-tetrahydropyrido [2,3-f][1,4]Oxazazepine；
9- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-2-methyl-2, 3,4, 5-tetrahydropyrido [2,3-f][1,4]Oxazazepine；
9- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl]-3-methyl-2, 3,4, 5-tetrahydropyrido [2,3-f][1,4]Oxazazepine；
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6- (methylsulfonyl) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine;
6- (ethylsulfonyl) -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6-propionyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridine;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -N-methyl-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-7-amine;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6- [ (1-methyl-1H-pyrazol-4-yl) methyl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6- (tetrahydrofuran-3-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
6- [ (1, 5-dimethyl-1H-pyrazol-3-yl) methyl ] -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
6-cyclopentyl-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
6-ethyl-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
6- [ (1, 5-dimethyl-1H-pyrazol-4-yl) methyl ] -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
6- (cyclopropylmethyl) -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6- [2- (3-methyl-1, 2, 4-oxadiazol-5-yl) ethyl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
3- {4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -5-oxo-5, 7-dihydro-6H-pyrrolo [3,4-b ] pyridin-6-yl } propionitrile;
3- ({4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -5-oxo-5, 7-dihydro-6H-pyrrolo [3,4-b ] pyridin-6-yl } methyl) benzonitrile;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6- [ (1R,5S,6R) -3-oxabicyclo [3.1.0] hex-6-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
6-bicyclo [1.1.1] pent-1-yl-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6- (pyridin-3-ylmethyl) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one;
6- (3-ethoxypropyl) -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one; or
4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl ] -6- [ (6-methylpyridin-3-yl) methyl ] -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one.
8. Use of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of neurological and psychiatric diseases or disorders in a mammal, wherein the disease or disorder is sleep disorder, dementia, alzheimer's disease, huntington's chorea, idiopathic and drug-induced parkinson's disease, schizophrenia, mood disorders, or autism.
9. The use of claim 8, wherein the disease or disorder is a mood disorder or a sleep disorder.
10. The use of claim 9, wherein the mood disorder is selected from the group consisting of depressive disorders and bipolar disorders.
11. A pharmaceutical composition comprising a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
HK14101403.3A 2010-12-20 2011-12-06 Novel fused pyridine compounds as casein kinase inhibitors HK1188145B (en)

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