EA040842B1 - SUBSTITUTED DIHYDROPYRIDINE DERIVATIVES AS ANDROGEN RECEPTOR AND GLUCOCORTICOID RECEPTOR ANTAGONISTS - Google Patents

Description

The field of technology to which the invention belongs

The present invention relates to new pharmaceutically useful, optionally substituted dihydropyridine derivatives that can be used as modulators of nuclear receptors, such as receptors selected from androgen receptors and glucocorticoid receptors. The compounds are theoretically useful in the treatment of diseases and conditions mediated by nuclear receptors selected from the androgen receptor and the glucocorticoid receptor, such as cancer. The invention also relates to the use of such compounds as medicines, to pharmaceutical compositions containing them, and to methods for their synthetic preparation.

State of the art

Nuclear receptors constitute a large superfamily of ligand-dependent transcription factors involved in a variety of physiological and embryological processes and are associated with a wide range of human diseases. This makes them attractive targets for drug development. In fact, approximately 13% of all FDA-approved drugs act on nuclear receptors. (Mangelsdorf DJ. et al., The nuclear receptor superfamily: the second decade, Cell 1995, 83, 835-839).

Nuclear receptors bind to specific DNA elements in the regulatory regions of genes via a highly conserved DNA binding domain (DBD) and to specific ligands via another highly conserved domain, the ligand binding domain (LBD), which consists of a series of approximately 12 helices forming a hydrophobic pocket. Binding of ligands in the pocket induces conformational changes in the receptor that affect the recruitment of coregulatory molecules (cofactors) that stimulate (coactivators) or repress (corepressors) transcription. (Huang P. et al., Structural overview of the nuclear receptor superfamily: Insights into physiology and therapeutics, Annu Rev Physiol 2010, 72, 247-272).

The androgen receptor (AR) belongs to a subfamily of steroid hormone-activated nuclear receptors that also includes estrogen, glucocorticoid, mineralocorticoid, and progesterone receptors (ER, GR, MR, and PR). In the cytoplasm, ligandless AR is stabilized by heat shock proteins. Upon binding of a testosterone or dihydrotestosterone (DHT) ligand, a conformational change occurs in the AR causing dissociation of specific chaperones, dimerization and phosphorylation of the AR, and translocation of the AR to the nucleus. The DNA binding domain (DBD) in the AR binds to androgen-responsive elements, induces the recruitment of the DNA transcription apparatus and gene transcription. AR is found in various tissues throughout the human body, including the prostate, scalp, skin, and muscles.

The androgen receptor is the primary therapeutic target for prostate cancer, which is a significant public health problem in industrialized countries because it represents the second most common cause of death from malignant neoplasms in men. In newly diagnosed patients, the tumor is often confined to the prostate, from where it can be surgically removed or where it can be treated with radiation therapy. If metastases are detected, or an increased level of the prostate-specific antigen (PSA) biomarker indicates progression of the disease, then the first course of treatment is to reduce the supply of androgens to the tumor (antiandrogen therapy, ADT), because. in the primary stage, prostate tumor growth is dependent on androgens. Androgen levels can be lowered through surgical castration (elimination of testosterone production in the testes) or through drug treatment with antiandrogens (deactivation of the AR), LHRH (luteinizing hormone releasing factor) agonists or antagonists (suppression of testosterone production in the testes), and inhibitors of CYP17 or 5- alphareductase (inhibition of androgen biosynthesis).

Initially, ADT is effective in controlling the disease, but within a few years, tumor cells tend to develop continuous growth mechanisms under conditions of androgen depletion, and malignancy becomes what is known as recurrent or castration-resistant prostate cancer (CRPC). Most of the mechanisms contributing to CRPC are still AR-dependent and include intratumoral androgen synthesis, increased AR expression as a result of gene amplification or overexpression, upregulation of coactivator proteins that increase AR activity, acquisition of mutations in the AR protein that increase its activity in response to antagonists or other steroid hormones, constitutively active AR splicing variants, and alternative signaling pathways (eg, induced by overexpression of the glucocorticoid receptor) (Watson PA. et al., Emerging mechanisms of resistance to AR inhibitors in prostate cancer, Nat Rev Cancer 2015, 15, 701 -711).

CRPC is incurable, and current treatments provide only a modest increase in overall survival of 4–5 months. In 2009, median survival for patients with advanced metastatic prostate cancer who did not benefit from antiandrogen therapy was generally 16 to 20 months (Thoreson GR. et al., Emerging therapies in castration resistant prostate cancer, Can J Urol 2014, 21, 98-105).

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Non-steroidal antiandrogens are preferred over steroid compounds in the case of prostate cancer, because they are more selective and have fewer side effects (Elancheran R, Recent discoveries and developments of androgen receptor based therapy for prostate cancer, Med Chem Commun 2015, 6, 746-768).

Thus, there is a significant need for new therapies, including improved non-steroidal AR antagonists, which can be used to treat primary and especially castration-resistant prostate cancer.

AR antagonists can also be used to treat other androgen receptor regulated conditions, disorders, and diseases, including, but not limited to, breast cancer (Hickey TE et al., Expression of androgen receptor splice variants in clinical breast cancer, Oncotarget 2015, preliminary November 5 publication), epithelial ovarian cancer, benign prostatic hyperplasia, alopecia, and acne (Jie JL, et al., Rational design and synthesis of 4-((1R,2R)-2-hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a novel, nonsteroidal androgen receptor antagonist devoid of phototoxicity for dermatological indications, J Med Chem 2008, 51, 7010-7014), hirsutism and polycystic ovarian syndrome.

As stated above, the glucocorticoid receptor may play a role in one of the mechanisms contributing to CRPC. At first, the hypothesis that GR may confer resistance may seem inconsistent with clinical evidence that glucocorticoid administration may be beneficial in some patients with CRPC. This apparent contradiction is explained by the fact that glucocorticoids inhibit the production of adrenocorticotropic hormone (ACTH) by the pituitary gland, which leads to a decrease in androgen levels. This androgen-lowering activity may explain the decrease in serum PSA levels observed in prednisone-only men, documented in the comparator group in the Phase III clinical trial, leading to the approval of abiraterone for previously chemotherapy-naive CRPC. However, in men with prostate cancer expressing high levels of GR, this beneficial effect of androgen reduction will be counteracted by GR activation in tumor cells. Under these conditions, a more effective treatment strategy may combine AR and GR inhibition, which is currently being investigated in an early-stage clinical trial of enzalutamide in combination with the GR antagonist mifepristone/RU486 (ClinicalTrials.gov ID: NCT02012296). One potential confounding factor in this study is that mifepristone also has a high AR binding affinity and may function as an AR agonist. Thus, treatment with mifepristone may inadvertently activate the AR via agonism, displacing the potent antagonism of enzalutamide (Watson PA. et al., Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer, Nature Reviews Cancer/AOP, published online November 13, 2015 ., and references included therein).

There are studies showing that GR agonists such as dexamethasone are sufficient to induce resistance to enzalutamide, while a GR antagonist can restore sensitivity. Nowadays, with the increasing use of enzalutamide, resistance is becoming an increasingly significant clinical problem in which activation of the glucocorticoid signaling pathway appears to play an important role. These results suggest a role that glucocorticoids may play in stimulating tumor growth. The main result of these studies is that glucocorticoids can promote tumor growth and progression in men whose cancer expresses GR. Thus, new strategies may be needed that can block AR signaling and GR signaling, and attempts to develop GR-specific antagonists that do not have side effects on AR may be useful in preventing or overcoming enzalutamide resistance. Unlike AR inhibition, which can cause unpleasant but tolerable adverse events, general GR inhibition can be lethal (Narayanan S, et al., Androgen-glucocorticoid interactions in the era of novel prostate cancer therapy, NATURE REVIEWS (UROLOGY, doi: 10.1038/nrurol.2015,254 published online December 8, 2015 and references included therein).

Glucocorticoids (GR agonists) are potent immunosuppressive and anti-inflammatory agents that are widely used as an adjunctive treatment in solid tumor therapy to alleviate adverse events, reduce toxicity, and protect normal tissue. However, glucocorticoids can interfere with the therapeutic efficacy of anticancer therapy, for example, by inhibiting apoptosis and promoting proliferation. Thus, it is proposed to minimize the use of glucocorticoids in anticancer therapy. Mechanistically, dexamethasone (an important glucocorticoid drug) has been found to suppress the immune response by upregulating the T cell checkpoint proteins PD-1 and CTLA-4. The GR antagonist mifepristone has been shown to reverse this effect (K. Xing et al., Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy, BMC Immunology 2015, 16, 39; M. Xia et al., Dexamethasone enhances CTLA-4 expression during T cell activation, Cell Mol Life Sci 1999, 55, 1649-1659).

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Thus, GR antagonists having an effect opposite to glucocorticoids can be used as immune system activators for the treatment of solid tumors as monotherapy and in combination with checkpoint inhibitors. Currently, mifepristone is being studied in cancer patients, where stress response mechanisms, including the hypothalamic-pituitary-adrenal (HPA) axis, are often activated and dysregulated.

High levels and altered circadian rhythms of cortisol, a glucocorticoid hormone involved in stress signaling, inflammation, and metabolism, correlate with poor prognosis in patients with end-stage cancers, such as lung, breast, colon, and ovarian cancer (N.M. Kimet al., Random serum cortisol as a predictor for survival of terminally ill patients with cancer, Am J Hosp Pall Med 2016, 33, 281-285 A. Schrepf et al., Diurnal cortisol and survival in epithelial ovarian cancer, Psychoneuroendocrinology 2015 , 53, 256-267).

It has recently been shown that cortisol production is a common feature of a wide variety of malignant cells, and that tumor cortisol inhibits the proliferation of tumor-specific CD8 ⁺ T cells in a GR-specific manner. The effect was inhibited in the presence of the GR antagonist mifepristone/RU486. These data suggest that cortisol production by tumor cells may have an important immunoregulatory function, and that GR antagonists may have therapeutic potential as immune system reactivators (N. Cirillo et al., Characterization of the cancer-associated glucocorticoid system: key role of 11b -hydroxysteroid dehydrogenase type 2, Br. J. Cancer 2017, prepublication online 1-10, doi: 10.1038/bjc.2017.243).

Currently, there are several glucocorticoid receptor antagonists marketed and used in clinical trials. These include mifepristone, a synthetic steroid compound that has been investigated as an antiglucocorticoid drug for the treatment of persistent or recurrent Cushing's disease. Its affinity for the progesterone receptor is a major disadvantage (Schteingart D.E., Drugs in the medical treatment of Cushing's syndrome, Expert Opin. Emerging Drugs (2009) 14(4):661-671). Other glucocorticoid receptor antagonists are in preclinical development (Kach J. et al., Selective glucocorticoid receptor modulators (SGRMs) delay castrate-resistant prostate cancer growth, published on mct.aacrjournals.org April 21, 2017; Hunt H. J. et al., The Identification of the Clinical Candidate (R)(1-(4-fluorophenyl)-6-((1-methyl-lHpyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H -pyrazolo[3,4g]isoquinolin-4a-yl) (4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist, J. Med. Chem, DOI: 10.1021/acs .jmedchem.7b00162, date of publication (website): April 03, 2017).

The listing or discussion of clearly previously published documents in this specification is not necessarily to be considered an endorsement that the document is part of the prior art or is common knowledge.

1,4-Dihydropyridines are an important class of cardiovascular drugs such as nifedipine, nitrendipine, amlodipine and many other analogues that exert their antihypertensive and antianginal effects by blocking L-type calcium channels. The 1,4-dihydropyridine core is also a preferred scaffold that, with appropriate substitution, can interact with different receptors and ion channels, providing different types of biological activity (P. Ioan et al., 1,4-Dihydropyridine scaffold in medicinal chemistry, The story so far and perspectives (Part 1): Action in Ion Channels and GPCRs Curr Med Chem 2011, 18, 4901-4922 E. Carosati et al.,, 1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The story so far and perspectives (Part 2): Action in Other Targets and Antitargets, Curr Med Chem 2012, 19, 4306-4323).

International Patent Application No. WO 2005/016885 A2 describes various dihydropyridines with beta-adrenergic receptor and L-type calcium channel inhibitory activity that can be used to treat heart diseases. However, it is not indicated whether these compounds can be used to treat cancer.

European Patent Application No. EP 0217530 A1 describes dihydropyridine derivatives as vasodilators which can be used in the treatment of stroke, angina pectoris and migraine. In addition, the compounds can be used as anti-asthma agents. Among the compounds described are 4-benzothiophene-1,4-dihydropyridine-3,5-diester derivatives which are inactive as androgen receptor modulators and thus are not included within the scope of the present invention.

US Patent Application No. 2016/0151388 A1 describes a method and compositions relating to a glucocorticoid receptor antagonist in prostate cancer alone or in combination with an androgen receptor antagonist. Prostate cancer can become resistant to antiandrogen therapy, for example, by increasing the expression and/or activity of the glucocorticoid receptor.

The problem that can be solved by the present invention is the provision of compounds as modulators of nuclear receptors selected from the androgen receptor and the glucocorticoid receptor.

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The essence of the invention

In one aspect (aspect 1), the present invention relates to a dihydropyridine derivative of formula (I)

where R ¹ is a group selected from:

a) -COR ⁵ ,

b) -COOR ⁵ ,

c) -CN,

d) -C(O)NH2,

R ⁵ is a group selected from:

a) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from -N(R ⁶ )R ⁷ and -OR ⁶ , halogen atom, C ₃ -C ₆ -cycloalkyl, ethynyl and Me-C^C-,

b) C ₃ -C ₆ -cycloalkyl,

R ² is a group selected from:

a) -COOR ⁸ ,

b) -COR ⁸ ,

c) -C(O)N(R ⁸ )R ⁹ ,

d) -CN,

e) -S(O)nR ⁸ where n is an integer from 1 to 2,

R ⁸ and R ⁹ are independently selected from:

a) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from A ¹ or B ² ,

b) groups A ¹ ,

c) a hydrogen atom, or

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5-6 membered heterocycle optionally containing 1 heteroatom selected from O and N, and said heterocycle is optionally substituted with 1 or 2 groups independently selected from linear or branched C ₁ -C ₄ -alkyl,

R ³ is a group selected from:

a) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from a halogen atom, -N(R ⁶ )R ⁷ and -OR ⁶ ,

b) C ₃ -C ₆ -cycloalkyl, optionally substituted with 1, 2 or 3 halogen atoms,

c) a hydrogen atom,

d) -NH2,

e) -CN,

R ⁴ is a group selected from:

a) groups A ¹ ,

b) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from A ¹ or B ² ,

c) -N(R ⁶ )R ⁷ ,

d) -CN,

e) -CO-H,

f) -CO-Me,

g) -CO-OMe,

h) a hydrogen atom,

X ¹ and X ⁴ are independently selected from C-B ¹ , N and C-H,

X ² , X ³ and X ⁵ are independently selected from C-B ¹ and C-H,

And ¹ is chosen from:

a) C ₃ -C ₆ -cycloalkyl, the ring of which is optionally substituted with 1, 2, 3 or 4 substituents selected from =O and B ³ ;

b) a 3-6 membered saturated heterocyclyl ring containing 1, 2 or 3 heteroatoms selected from O, S and N, and the ring of which is optionally substituted with 1, 2 or 3 substituents selected from =O and B ³ ;

c) a phenyl or 6-membered heteroaryl group containing carbon, hydrogen and one or two N atoms, any of which is optionally substituted with 1, 2 or 3 substituents selected from B ¹ ;

each B ¹ is independently selected from a halogen atom, -CF ₃ -group, 6-membered heteroaryl containing carbon, hydrogen and one or two N atoms, linear or branched C ₁ -C ₆ -alkyl, -CN,

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-N(R ⁶ )R ⁷ , -OR ⁶ , -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )R ⁷ , -OC(=O )-R ⁶ , -N(R ⁶ )C(=O)R ⁷ , -NR7SO2R ⁶ ,

-SO2N(R ⁶ )R ⁷ , -SR ⁶ , -S(O)R ⁶ and -S(O)2R ⁶ each B ² is independently selected from a halogen atom, -CN, -N(R ⁶ )R ⁷ , -OR ⁶ , -C(=O)R ⁶ , -C(=O)OR ⁶ ,

-C(=O)N(R ⁶ )R ⁷ , -OC(=O)-R ⁶ , -N(R ⁶ )C(=O)R ⁷ , -NR7SO2R ⁶ , -SO2N(R ⁶ )R ⁷ , -SR ⁶ , -S(O)R ⁶ , -S(OhR ⁶ , ethinyl and

Me-C C-, each B ³ is independently selected from halogen, linear or branched C1-C ₆ alkyl, -CN, -N(R ⁶ )R ⁷ , -OR ⁶ , -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )R ⁷ , -OC(=O)-R ⁶ , -N(R ⁶ )C(=O)R ⁷ , -NR ⁷ SO2R ⁶ , -SO2N(R ⁶ )R ⁷ , -SR ⁶ , -S(O)R ⁶ , -S(O)2R ⁶ , R ⁶ and R ⁷ are each independently:

hydrogen atom, linear or branched C ₁ -C ₁₂ -alkyl and C ₃ -C ₆ -cycloalkyl, optionally substituted with 1, 2 or 3 substituents selected from =0 (oxo group), halogen atom, hydroxy group, phenyl, C ₃ -C ₆ cycloalkyl, linear or branched C ₁ -C ₆ -alkoxy group, amino group, alkylamino group, dialkylamino group, linear or branched C ₁ -C ₆ -alkylcarbonyl, phenyl or 6-membered heteroaryl group containing carbon, hydrogen and one or two N atoms, optionally substituted with 1, 2 or 3 substituents selected from halogen, cyano, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ haloalkyl, hydroxy, linear or branched C ₁ -C ₆ alkoxy , amino groups, alkylamino groups, dialkylamino groups;

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 3-8 membered ring, optionally containing an additional heteroatom selected from O, N and S, and the ring of which is optionally substituted with 1, 2 or 3 substituents selected from ═O (oxo), linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ haloalkyl, linear or branched C ₁ -C ₆ alkylcarbonyl;

with the proviso that if R ¹ is -COOR ⁵ and R ² is -COOR ⁸ , then R ⁴ is not a methyl group, and pharmaceutically acceptable salts thereof.

Other aspects of the present invention are as follows.

In a second aspect, the present invention relates to methods for preparing compounds according to the first aspect.

In a third aspect, the present invention relates to pharmaceutical compositions containing an effective amount of a compound according to the first aspect.

In a fourth aspect, the present invention relates to a combination product containing the compound according to the first aspect and another therapeutic agent selected from agents for the treatment of prostate cancer, castration-resistant prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian cancer and other solid tumors, melanoma, metastatic malignancies, benign prostatic hyperplasia, polycystic ovarian syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, diseases with muscle atrophy, cachexia and Cushing's syndrome caused by antipsychotic drugs, weight gain, obesity, post-traumatic stress disorder and alcoholism.

In a fifth aspect, the present invention relates to the use of the compounds according to the first aspect for the manufacture of a medicament, in particular for the treatment of diseases that can be improved by modulating nuclear receptors, in particular by androgen receptor and/or glucocorticoid receptor antagonism; disease or condition susceptible to improvement in androgen receptor and/or glucocorticoid receptor antagonism is selected from prostate cancer, castration-resistant prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian and other solid tumors, melanoma, metastatic malignancies, benign prostatic hyperplasia, polycystic ovary syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, muscle wasting disease and cachexia, Cushing's syndrome antipsychotic drug-induced weight gain, obesity, post-traumatic stress disorder, and alcoholism.

In a sixth aspect, the present invention relates to methods of treating diseases that can be improved by modulating nuclear receptors, in particular by androgen receptor and/or glucocorticoid receptor antagonism, by administering compounds according to the first aspect, or pharmaceutical compositions according to the third aspect, or a combination product according to a fourth aspect to an individual in need of said treatment.

In a seventh aspect, the present invention relates to a compound according to the first aspect for use as a medicine.

In an eighth aspect, the present invention relates to a compound according to the first aspect for use in the treatment of a disease or condition selected from the group consisting of malignant neoplasm, prostate cancer, castration-resistant prostate cancer, pancreatic cancer, urinary cancer. bladder, kidney cancer, gastric cancer, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian cancer and other solid tumors, melanoma, metastatic malignancies, benign prostatic hyperplasia, polycystic ovarian syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, muscle atrophy and cachexia disorders, Cushing's syndrome, antipsychotic drug-induced weight gain, obesity, post-traumatic stress disorder, and alcoholism.

As indicated above, the dihydropyridine derivatives of the invention may be used in the treatment or prevention of diseases known to be susceptible to amelioration by treatment with nuclear receptor modulators, in particular nuclear receptor modulators selected from the androgen receptor and the glucocorticoid receptor. Such diseases are selected from, for example, malignant neoplasm, prostate cancer, castration-resistant prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, lung cancer, breast cancer, colon cancer, colorectal cancer, cancer ovarian and other solid tumors, melanoma, metastatic malignant neoplasms, benign prostatic hyperplasia, polycystic ovary syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, diseases with muscle atrophy and cachexia, Cushing's syndrome caused by antipsychotic drugs, weight gain, obesity, post-traumatic stress disorder and alcoholism.

Thus, the derivatives of the present invention and their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and/or salts thereof, can be used in a method for the treatment of pathological conditions or diseases in humans, comprising administering to an individual in need of said treatment, an effective amount of dihydropyridine derivatives according to of the invention or their pharmaceutically acceptable salts.

Within the scope of the invention, the term halogen atom is used to denote an atom selected from the group consisting of a chlorine, fluorine, bromine or iodine atom, preferably a bromine, fluorine or chlorine atom.

Within the scope of the invention, the term alkyl is used to denote linear or branched hydrocarbon radicals (C _n H _2n+1 ) containing from 1 to 12 carbon atoms. Examples include methyl, ethyl, n-propyl, p-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, isopentyl, 1-ethylpropyl, 1.1 -dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3dimethylbutyl, 2 -methylpentyl and 3-methylpentyl, n-heptyl, 3-methylheptyl, n-octyl, 2,2-dimethyloctyl. In a preferred embodiment, said alkyl groups contain from 1 to 6 carbon atoms.

Within the scope of the invention, the term haloalkyl is used to denote C ₁ -C ₆ alkyl substituted with one or more halogen atoms, preferably one, two or three halogen atoms. Haloalkyl groups may be linear or branched. Preferably, the halogen atoms are selected from the group consisting of fluorine or chlorine atoms. In a preferred embodiment, the haloalkyl group is a straight or branched C ₁ -C ₄ alkyl substituted with one, two or three fluorine or chlorine atoms.

Within the scope of the invention, the term cycloalkyl is used to denote hydrocarbon cyclic groups (C _n H _2n - ₁ ) containing from 3 to 6 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like.

Within the scope of the invention, the term heterocyclyl is used to denote saturated rings containing 3 to 6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and N as part of the ring. Heterocyclyl groups include, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.

Within the scope of the invention, the term C ₁ -C ₆ -alkoxy group is used to denote radicals containing a linear or branched C ₁ -C ₆ -alkyl group connected to an oxygen atom (C _n H _2n+1 -O-). Preferred alkoxy radicals include methoxy, ethoxy, n-propoxy, ipropoxy, n-butoxy, sec-butoxy, t-butoxy, trifluoromethoxy, difluoromethoxy, hydroxymethoxy, 2-hydroxyethoxy or 2- a hydroxypropoxy group.

Within the scope of the invention, the term carbonyl group is used to denote a C=O group. Within the scope of the invention, when the term oxo (=O) is used to denote a substituent on a ring, it means that the carbon atom of said ring is in the form of a carbonyl (C=O) group.

Within the scope of the invention, the term heteroaryl group is used to denote a 5- or 6-membered heteroaromatic ring containing carbon, hydrogen, and one or more atoms selected from O, N, and S. These groups may optionally be substituted with 1, 2, or 3 substituents, selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ haloalkyl, a linear or branched C ₁ -C ₆ alkyl, a hydroxy group, a linear or branched C ₁ -C ₆ -alkoxy group, an amino group, an alkylamino group, and a dialkylamino group . Heteroaryl groups may optionally be substituted with substituents such as the substituents defined as R ⁶ and

At ¹ .

Preferred groups are optionally substituted pyridyl and pyrimidinyl. If the heteroaryl radical has 2 or more substituents, the substituents may be the same or different.

Within the scope of the invention, the term alkylamino group is used to denote radicals containing a linear or branched C ₁ -C ₆ -alkyl group connected to a -NH- group. Preferred alkylamino radicals include methylamino-, ethylamino-, n-propylamino-, i-propylamino-, n-butylamino-, sec-butylamino-, tert-butylamino-, trifluoromethylamino-, difluoromethylamino-, hydroxymethylamino-, 2-hydroxyethylamino- or 2-hydroxypropylamino group.

Within the scope of the invention, the term dialkylamino group is used to denote radicals containing two linear or branched C ₁ -C ₆ alkyl groups linked to the nitrogen atom of the group, where the alkyl groups may be identical or different. Preferred dialkylamino radicals include di(methyl)amino-, di(ethyl)amino-, di-(n-propyl)amino-, di-(i-propyl)amino-, di-(n-butyl)amino-, di-(sec- butyl)amino-, di-(tert-butyl)amino-, di-(trifluoromethyl)amino-, di(hydroxymethyl)amino-, di(2-hydroxyethyl)amino-, di(2-hydroxypropyl)amino-, methylethylamino- , methyl-and-propylamino and ethyl-n-propylamino.

Within the scope of the invention, some of the atoms, radicals, chains or cycles present in the general structures of the invention are optionally substituted. This means that these atoms, radicals, chains or cycles may be unsubstituted or substituted in any position with one or more, for example 1, 2, 3 or 4, substituents, while the hydrogen atoms associated with unsubstituted atoms, radicals, chains or cycles , are replaced by chemically acceptable atoms, radicals, chains or cycles. If two or more substituents are present, each substituent may be the same or different.

Within the scope of the invention, the term pharmaceutically acceptable salt is used to refer to salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acids, and organic acids such as citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic , methanesulfonic, ethanesulfonic, benzenesulfonic or rtoluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (eg sodium or potassium) and alkaline earth metal (eg calcium or magnesium) hydroxides and organic bases such as alkylamines, phenylalkylamines and heterocyclic amines.

Other preferred salts of the invention are quaternary ammonium compounds where the anion equivalent (X ^-n ), where -n indicates the negative charge of the anion and is typically -1, -2 or -3, is bonded to a positively charged N atom. X ^-n can be an anion of various inorganic acids, such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, or an anion of an organic acid, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate , malate, mandelate, trifluoroacetate, methanesulfonate and p-toluenesulfonate. X ^-n is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulfonate.

In one of the embodiments of the present invention in the compounds of formula (I) X ¹ , X ² , X ³ and X ⁵ represent a group CH or CB ¹ . In a preferred embodiment, B ¹ is a halogen atom. In a more preferred embodiment, X ¹ , X ³ and X ⁵ are C-H and X ² is C-B ¹ where B ¹ is a halogen atom.

In another embodiment of the present invention, in compounds of formula (I), X ⁴ is a group selected from C-B ¹ and an N atom. In a preferred embodiment, X ⁴ is C-B ¹ . In a more preferred embodiment, B ¹ is selected from the group -CN and a halogen atom.

In another embodiment of the present invention in the compounds of formula (I) R ¹ is a group selected from -COR ⁵ , -COOR ⁵ and the group -CN. In a preferred embodiment, R ⁵ is independently selected from C3-C5 cycloalkyl, -C1-C3 alkyl, where the terminal methyl is unsubstituted or substituted with three fluorine atoms (-CF3), and C1-C3 alkyl is optionally substituted at any position with an alkynyl group. In a more preferred embodiment, each R ⁵ is independently selected from -C 1 -C ₃ alkyl and -C ₃ -C ₅ -cycloalkyl.

In one embodiment of the present invention, in compounds of formula (I), R ² is a group selected from -COR ⁸ and -COOR ⁸ , preferably -COOR ⁸ . In a preferred embodiment, R ⁸ is independently selected from: linear or branched C ₁ -C ₆ alkyl, optionally

- 7 040842 substituted with 1, 2 or 3 substituents selected from A ¹ or B ² , preferably A ¹ where A ¹ is a group selected from phenyl, C ₃ -C ₆ -cycloalkyl, optionally substituted with 1, 2 or 3 C1C ₃ -alkyl and 3-6-membered saturated heterocyclyl rings containing 1, 2 or 3 heteroatoms selected from O, S and N, and where the ring is optionally substituted with 1, 2 or 3 C ₁ -C ₃ -alkyl groups; and B ² represents a halogen atom.

In a more preferred embodiment, R ² is -COOR ⁸ where R ⁸ is independently:

linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from a fluorine atom and C ₃ -C ₅ -cycloalkyl, optionally substituted with 1, 2 or 3 fluorine atoms, or a group A ¹ representing C ₃ -C ₆ -cycloalkyl, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine atoms and C ₁ -C ₃ -alkyl groups.

In another embodiment of the present invention in the compounds of formula (I) R ² represents the group-CN.

In another embodiment of the present invention, in compounds of formula (I), R ³ is a group selected from C3-C6 cycloalkyl optionally substituted with 1, 2 or 3 halogen atoms; and linear or branched C1-C4 alkyl optionally substituted with 1, 2 or 3 substituents selected from a halogen atom, -N(R ⁶ )R ⁷ and -OR ⁶ . In a preferred embodiment, R ⁶ and R ⁷ are selected from hydrogen and linear or branched C1- _C6 alkyl.

In a more preferred embodiment, R ³ is selected from linear or branched C ₁ -C 4 alkyl and C ₃ -C ₆ cycloalkyl. In a more preferred embodiment, R ³ is selected from a methyl or cyclopropyl group optionally substituted with 1, 2 or 3 fluorine atoms.

In another embodiment of the present invention, in compounds of formula (I), R ⁴ is linear or branched C1-C6 alkyl optionally substituted with 1, 2 or 3 substituents selected from A ¹ or B ² . In a more preferred embodiment, A ¹ is C3-C ₆ -cycloalkyl, and B ² is a group selected from a halogen atom, -N(R ⁶ )R ⁷ and OR ⁶ . In a more preferred embodiment, R ⁶ and R ⁷ are selected from hydrogen and linear or branched C1-C6 alkyl. In a more preferred embodiment, R ⁴ is linear or branched C1- _C3 alkyl optionally substituted with 1, 2 or 3 substituents selected from 1, 2 or 3 fluorine atoms and a hydroxyl group.

In another embodiment of the present invention in the compounds of formula (I) R ⁴ represents the group A ¹ . In a more preferred embodiment, A ¹ is C3C6 cycloalkyl optionally containing 1, 2 or 3 heteroatoms selected from O, S and N, and wherein the ring is optionally substituted with C1-C3 alkyl. In a more preferred embodiment, R ⁴ is an A ¹ group which is C3-C ₆ cycloalkyl.

In one of the embodiments of the present invention in the compounds of formula (I) R ⁴ represents the group-N(R ⁶ )R ⁷ . In a more preferred embodiment, R ⁶ and R ⁷ are selected from hydrogen and linear or branched C ₁ -C ₄ alkyl.

In a more preferred embodiment, R ⁴ is a group selected from:

N(R ⁶ )R ⁷ where R ⁶ and R ⁷ are independently selected from a hydrogen atom and a linear or branched C ₁ -C ₃ alkyl group A ¹ representing a C ₃ -C ₆ -cycloalkyl, a linear or branched C ₁ - C ₆ -alkyl optionally substituted with 1, 2 or 3 substituents selected from 1, 2 or 3 fluorine atoms or 1 hydroxyl group,

In one of the embodiments of the present invention in the compounds of formula (I) X ¹ , X ² , X ³ and X ⁵ represent -CH, X ⁴ represents C-B ¹ where B ¹ represents a -CN group or a bromine atom, R ¹ is a group selected from -C(C)CH3, -C(O)OCH3 -C(O)OCH2-alkynyl and CN, R ² is a group selected from -C(O)OCH-linear or branched C1- C ₅ -alkyl group optionally substituted with 1, 2 or 3 fluorine atoms, and C(O)OCH ₂ -cyclopropyl optionally substituted with 1, 2 or 3 fluorine atoms, R ³ is a group selected from linear or branched C 1 -C 3 alkyl and C3-C4 cycloalkyl, and R ⁴ is a group selected from linear or branched C1-C3 alkyl, C3-C ₄ cycloalkyl and -NH2.

The compound according to claim 1, where X ¹ , X ² , X ³ and X ⁵ are -CH, X ⁴ is C-B ¹ , where B ¹ is a -CN group, R ¹ is a group selected from -C (O)CH3, -C(O)OCH3, R ² is a group selected from -C(O)OCH2-cyclopropyl optionally substituted with 1, 2 or 3 fluorine atoms, and -C(O)OCH2-CF ₃ , R ³ is a group selected from methyl and cyclopropyl, and R ⁴ is a group selected from cyclopropyl and -NH2.

In another embodiment of the present invention, in compounds of formula (I), X ¹ , X ³ , X ⁴ and X ⁵ are -CH and X ² is a C-B ¹ group. In a more preferred embodiment, B ¹ is a halogen atom.

In another embodiment of the present invention in the compounds of formula (I) X ¹ , X ² , X ³ , X ⁴ and X ⁵ represent -CH.

- 8 040842

Specific compounds of the present invention include:

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3-carboxylate (enantiomer 1)

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3-carboxylate (enantiomer 2)

5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxamide

1-(4-(benzo[b]thiophen-3-yl)-5-benzoyl-2,6-dimethyl-1,4-dihydropyridin-3-yl)ethan1-one

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-phenyl-1,4-dihydropyridine-3-carboxylate

1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-nicotinoyl-1,4-dihydropyridin-3yl)ethan-1-one

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydro-[2,3'-bipyridine]-3carboxylate

2,2,2-trifluoroethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4d and hydropyride in-3-carboxylate

5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid

-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(4-methylpiperazin-1-carbonyl)-1,4- 9 040842 e ihydropyride in-3-yl)ethan- 1-on

5-acetyl-4-(benzo[b]thiophen-3-yl)-X,X-diethyl-2,6-dimethyl-1,4-dihydropyridine in-3-carboxamide

1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(morpholine-4-carbonyl)-1,4dihydropyride in-3-yl)ethan-1-one

2-methoxyethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyride in 3-carboxylate

3-acetamidopropyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Benzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3-carboxylate

2-morpholinoethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

2-(dimethylamino)ethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine in-3-carboxylate

2-acetamidoethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(methoxymethyl)-6-methyl-1,4dihydropyridine in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-((dimethylamino)methyl)-6-methyl-1,4dihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine in-3-carboxylate

4-methoxybenzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Pyridin-2-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(morpholino-methyl)-1,4dihydropyridine-3-carboxylate

Dimethyl 4-(benzo[b]thiophen-3-yl)-2,6-bis(morpholinomethyl)-1,4-dihydropyridine3,5-dicarboxylate

2-hydroxyethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine in-3-carboxylate

1-(4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2-methyl-1,4dihydropyridine in-3-yl)ethan-1-one

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(1-(tert-butoxycarbonyl)azetidin-3yl)-6-methyl-1,4-dihydropyride in-3-carboxylate ( 1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl-5-acetyl-4-(benzo[b]thiophen-3yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate

Cyclohexylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4- 10 040842 e hydropyride in-3-carboxylate

Methyl 4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-2,6-dicyclopropyl-1,4dihydropyridine-3-carboxylate

5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-L1-phenyl-1,4-dihydropyridine-3-carboxamide

T tetrahydro-2H-pyran-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-d imethyl-1,4dihydropyridine in-3-carboxylate (Tetrahydro-2H- pyran-4-yl)methyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl1,4-dihydropyridine-3-carboxylate

Cyclohexyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(2-methoxy-2-oxoethyl)-6-methyl-1,4dihydropyridine in-3-carboxylate

Methyl 5-acetyl-2,6-dimethyl-4-(2-methylbenzo[b]thiophen-3-yl)-1,4-dihydropyridine3-carboxylate

Cyclopropylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(2-methoxyethyl)-6-methyl-1,4dihydropyridine in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-((benzyloxy)methyl)-6-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(phenoxymethyl)-1,4dihydropyridine-3-carboxylate

Phenethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-d imethyl-1,4-dihydropyridine-3 carboxylate

Methyl 4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2-methyl1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4dihydropyridine in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-benzyl-2-methyl-1,4-dihydropyridine in-3-carboxylate

Methyl 4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(2-phenylacetyl)-1,4d and hydropyride in-3-carboxylate

Methyl 4-(benzo[b]thiophen-3-yl)-5-(2-methoxyacetyl)-2,6-dimethyl-1,4dihydropyridine in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-(methoxymethyl)-2-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(fluoromethyl)-6-methyl-1,4d ihydropyride in-3-carboxylate

Cyclopropylmethyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4- 11 040842 e hydropyride in-3-carboxylate

1-(tert-Butoxycarbonyl)piperidin-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate

Cyclopentylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Cyclopropylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

1-methylpiperidin-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4d and hydropyride in-3-carboxylate

Cyclopentyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

4,4-dimethylcyclohexyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Cyclobutyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-2,6-dimethyl-4-(thieno[3,2-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-methyl-6-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate

Cyclopropylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Cyclohexylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Cyclohexylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Cyclopentylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

Cyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

Cyclopentyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate

Benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3carboxylate (Tetrahydro-2H-pyran-4-yl)methyl- 5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3yl)-1,4-dihydropyridine-3-carboxylate

Benzyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin- 12 040842

3-carboxylate

Benzyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine in3-carboxylate (Tetrahydro-2H-pyran-4-yl)methyl- 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate (Tetrahydro-2H-pyran-4-yl)methyl-5-acetyl- 4-(5-fluorobenzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate

Benzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4d and hydropyride in-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

4-fluorobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4d and hydropyride in-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4d and hydropyride in-3-carboxylate

1,1'-(4-(benzo[b]thiophen-3-yl)-2-benzyl-6-methyl-1,4-dihydropyridine-3,5 diyl)bis(ethan-1-one)

-(5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3-yl)-2phenylethan-1-one

Methyl 5-acetyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-2-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate

1-(2-methyl-5-(piperidine-1-carbonyl)-4-(thieno[2,3-b]pyridin-3-yl)-6(trifluoromethyl)-1,4-dihydropyridin-3-yl )ethane-1-one

4-(((5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine in-3carbonyl)oxy)methyl)benzoic acid

Benzyl-5-acetyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-2-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,b-dimethyl-1,4dihydropyridine in-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine in-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4d and hydropyride in-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

4-(cyclopropylcarbamoyl)benzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl- 13 040842

1,4-dihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4d ihydropyr idine-3-carboxylate

4-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

-bromobenz yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

2-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate (3-fluoropyridin-4-yl )methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

Pyrimidin-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridin-3-carboxylate (5-bromopyridin-3-yl) methyl 5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3yl)-1,4-dihydropyridine-3-carboxylate

2-phenylpropan-2-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

-cyanobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridine-3-yl)-1,4dihydropyridine in-3-carboxylate

4-cyanobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridine-3-yl)-1,4dihydropyridine in-3-carboxylate (6-chloropyridine-3- yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

3-morpholinobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

4,4-dimethylcyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridine in-3-yl)-1,4dihydropyride in-3-carboxylate (2-chloropyridine- 4-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

Tetrahydro-2H-pyran-4-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

4,4-difluorocyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridine-3-yl)-1,4-dihydropyride in-3-carboxylate

5-acetyl-M-benzyl-N,2,6-trimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxamide

Oxetan-3-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate

Isopropyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4- 14 040842 dihydropyridine-3-carboxylate

Cyclopropylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-(2,2,2trifluoroacetyl)benzo[b]thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate

2-phenylpropan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate

Methyl 2-amino-4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-amino-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Methyl 5-acetyl-2-amino-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Methyl 5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Cyclopentyl-5-acetyl-2-amino-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl 2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine 3,5-dicarboxylate

Cyclopentyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl 2,6-diamino-4-(benzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate

Cyclopropylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate

4,4-difluorocyclohexyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3-carboxylate

Methyl 2-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

4-fluorobenzyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Methyl 5-acetyl-2-amino-4-(5-fluorothie no[2,3-b]pyridine in-3-yl)-6-methyl-1,4dihydropyride in-3-carboxylate

Methyl 2-acetamido-5-acetyl-4-(5-fluorothieno[2,3-b]pyridin-3-yl)-6-methyl-1,4dihydropyridine in-3-carboxylate

Cyclopentylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl- 15 040842

1,4-dihydropyr idine-3,5-dicarboxylate

Dimethyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4dihydropyridine-3,5-dicarboxylate

3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6cyclopropyl-1,4-dihydropyride in-3,5-dicarboxylate

Dimethyl 2,6-diamino-4-(7-cyanobenzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5 dicarboxylate

5-(cyclopropylmethyl)-3-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6cyclopropyl-1,4-dihydropyride in-3,5-dicarboxylate

-(4-fluorobenzyl) 5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyride in-3,5-dicarboxylate

3-(4-fluorobenzyl) 5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl1,4-dihydropyridine-3,5-dicarboxylate

Cyclopropylmethyl-2-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine in-3-carboxylate

4-fluorobenzyl-2-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Cyclopropylmethyl-6-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2cyclopropyl-1,4-dihydropyride in-3-carboxylate

3-cyclopentyl-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate

Cyclopropylmethyl-5-acetyl-2-amino-4-(6-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

Cyclohexyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Cyclohexylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine in-3-carboxylate

Cyclopropylmethyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-5(cyclopropanecarbonyl)-6-methyl-1,4-dihydropyridine-3-carboxylate

3-fluorobenzyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

3-(cyclobutylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-

1,4-dihydropyr idine-3,5-dicarboxylate

3-((3,3-difluorocyclobutyl)methyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3yl)-6-methyl-1,4-dihydropyride in-3,5 - dicarboxylate

Cyclopropylmethyl-2-amino-5-carbamoyl-4-(7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3-carboxylate

3-((2,2-difluorocyclopropyl)methyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3yl)-6-methyl-1,4-dihydropyride in-3,5 - dicarboxylate

5-cyclopropyl-3-(cyclopropylmethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-16 040842 methyl-1,4-d ihydropyridine-3,5-dicarboxylate

3-((2,2-difluorocyclopropyl)methyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3yl)-6-cyclopropyl-1,4-dihydropyridine-3,5- dicarboxylate

3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyano-5-fluorobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3,5-dicarboxylate

3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyano-4-fluorobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3,5-dicarboxylate

3-isopropyl-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3,5-dicarboxylate

-((2,2-d iftoro-3,3-dimethylcyclopropyl)methyl)-5-methyl-2-amino-4-(7cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine -3,5-dicarboxylate

5-methyl-3-neopentyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyride in-3,5-dicarboxylate

3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanothieno[3,2-b]pyridin-3-yl)-6methyl-1,4-dihydropyridine-3,5-dicarboxylate

5-methyl-3-neopentyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4dihydropyride in-3,5-dicarboxylate

Bis(cyclopropylmethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate

3-(cyclopropylmethyl)-5-(prop-2-yn-1-yl)-2-amino-4-(7-cyanobenzo[b]thiophen-3yl)-6-methyl-1,4-d ihydropyride in- 3,5-dicarboxylate

3-(cyclopropylmethyl)-5-methyl-2-amino-4-(5,7-dicyanobenzo[b]thiophen-3-yl)-6methyl-1,4-d ihydropyridine-3,5-dicarboxylate

5-(but-2-yn-1-yl)-3-(cyclopropylmethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)6-methyl-1,4-dihydropyridine -3,5-dicarboxylate

5-methyl-3-(2,2,2-trifluoroethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-

1,4-d ihydropyridine-3,5-dicarboxylate

3-(cyclopropylmethyl)-5-(2,2,2-trifluoroethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3yl)-6-methyl-1,4-d ihydropyride in-3, 5-dicarboxylate

3-(cyclopropylmethyl)-5-methyl-2-amino-4-(6-chloro-7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-d ihydropyridine-3,5-dicarboxylate

3-(2-Fluoro-2-methylpropyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-d ihydropyridine-3,5 - dicarboxylate

-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyano-6-(trifluoromethyl)benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3,5- dicarboxylate

5-methyl-3-προπ-2-yn-1-yl 2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine

3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile

- 17 040842

4-(6-hydroxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarbonitrile

4-(6-Methoxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarbonitrile

2,6-d imethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridin-3,5-dicarbonitrile 4-(benzo[b]thiophen-3-yl)- 2-methyl-6-phenyl-1,4-dihydropyridine-3,5-dicarbonitrile

5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonitrile

Ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2,6-d-imethyl-1,4-dihydropyridine-3 carboxylate

Ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-methyl-6-phenyl-1,4-dihydropyridine-3-carboxylate

Ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-cyclopropyl-6-methyl-1,4dihydropyride in-3-carboxylate

Methyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-cyclopropyl-6-methyl-1,4d and hydropyride in-3-carboxylate

1,1'-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl)diethanone

1,1'-(4-(6-hydroxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5diyl)bis(ethan-1-one)

1,1'-(4-(6-Methoxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5diyl)diethanone

1,1'-(4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3,5diyl)diethanone

1,G-(4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5diyl)diethanone

1,D-(4-(5-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5diyl)diethanone

1,T-(4-(5-Fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5diyl)bis(ethan-1-one)

1,1'-(2,6-dimethyl-4-(5-morpholinobenzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5diyl)bis(ethan-1-one)

1,1'-(2,6-dimethyl-4-(5-(4-methylpiperazin-1-yl)benzo[b]thiophen-3-yl)-1,4dihydropyridine in-3, 5-d yl) bis(ethane-1-one)

1,1'-(4-(5-(benzylamino)benzo[b]thiophen-3-yl)-2,6-d imethyl-1,4-dihydropyridine-

3,5-d uyl)bis(ethane-1-one)

3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5carbonitrile

3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5carboxylic acid

- 18 040842

N-cyclopropyl-3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyride in-4yl)benzo[b]thiophene-5-carboxamide

N-(cyclopropylmethyl)-3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4yl)benzo[b]thiophene-5-carboxamide

1, Γ-(2,6-dimethyl-4-(5-(4-methylpiperazine-1-carbonyl)benzo[b]thiophen-3-yl)-1,4dihydropyridine in-3,5-d uyl)bis (ethane-1-one)

1, Γ-(2,6-dimethyl-4-(5-(morpholine-4-carbonyl)benzo[b]thiophen-3-yl)-1,4dihydropyrid in-3,5-d yl)bis(ethane -1 -on)

1,D-(2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridin-3,5diyl)bis(ethan-1-one)

Dimethyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine in-2,3-dicarboxylate

Dimethyl 5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine in2,3-dicarboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4d and hydropyride in-3-carboxylate

Dimethyl 4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate

Ethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyride in-3 carboxylate

Methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

1, G-(4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-d ihydro-pyridine-3,5diyl)diethanone

1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(methylsulfonyl)-1,4-dihydro-pyridin3-yl)ethanone

Methyl 5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

Methyl 5-acetyl-4-(5-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

Methyl 5-acetyl-4-(5-cyanobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

-(3-acetyl-5-(methoxycarbonyl)-2,6-dimethyl-1,4-dihydropyride in-4yl)benzo[b]thiophene-5-carboxylic acid

Methyl 5-acetyl-4-(5-(cyclopropylcarbamoyl)benzo[b]thiophen-3-yl)-2,6-dimethyl1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(5-((cyclopropylmethyl)carbamoyl)benzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2,6-dimethyl-4-(5-(4-methylpiperazin-1-carbonyl)benzo[b]thiophen3-yl)-1,4-dihydropyride in-3-carboxylate

- 19 040842

Methyl 5-acetyl-2,6-dimethyl-4-(5-(morpholine-4-carbonyl)benzo[b]thiophen-3-yl)1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-cyclopropyl-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl 2,6-dicyclopropyl-4-(5-fluorobenzo[b]thiophen-3-yl)-1,4-dihydropyridine in3,5-dicarboxylate

Methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Dimethyl 2,6-dicyclopropyl-4-(thieno[2,3-b]pyridine-3-yl)-1,4-dihydropyride in3,5-dicarboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine3-carboxylate

Methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl 4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine 3,5-dicarboxylate

Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine in-3-carboxylate

Methyl 5-acetyl-2-cyclopropyl-4-(7-(cyclopropylcarbamoyl)benzo[b]thiophen-3yl)-6-methyl-1,4-dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine 3,5-dicarboxylate

Methyl 5-acetyl-2-cyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-6methyl-1,4-d ihydropyridine-3-carboxylate

Dimethyl-2,6-dicyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-1,4d and hydropyride in-3,5-dicarboxylate

3-(3-acetyl-6-cyclopropyl-5-(methoxycarbonyl)-2-methyl-1,4-dihydropyridin-4yl)benzo[b]thiophene-7-carboxylic acid

Benzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine in-3-carboxylate

Bis(pyridin-4-ylmethyl)-2,6-dicyclopropyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3,5-dicarboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

- 20 040842

Pyridin-4-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-d ihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3yl)-1,4-d ihydropyridine-3-carboxylate

Benzyl-5-acetyl-2-cyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-6methyl-1,4-d ihydropyridine-3-carboxylate

Dibenzyl-2,6-dicyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3,5-dicarboxylate

Benzyl-5-acetyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Methyl-3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-7 carboxylate

3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-7carbonitrile

Pyridin-4-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-d ihydropyridine-3-carboxylate

4-fluorobenzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Bis(4-fluorobenzyl) 2,6-dicyclopropyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3,5-dicarboxylate

4-cyanobenzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(7-chlorobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4d ihydropyridine-3-carboxylate

Methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-(trifluoromethyl)benzo[b]thiophen-3yl)-1,4-d ihydropyridine-3-carboxylate

3-chlorobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4d ihydropyridine-3-carboxylate

2-phenylpropan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-d ihydropyridine-3-carboxylate

Cyclohexyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

2-phenylpropan-2-yl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3yl)-1,4-d ihydropyridine-3-carboxylate

1-(4-(7-bromobenzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2methyl-1,4-d-ihydropyridin-3-yl)ethan-1-one

3-chlorobenzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

- 21 040842

2-(4-fluorophenyl)propan-2-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)1,4-dihydropyridine-3-carboxylate

2-(4-fluorophenyl)propan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate

2-(4-fluorophenyl)propan-2-yl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3b]pyridin-3-yl)-1,4-dihydropyridine-3 -carboxylate

Methyl 5-acetyl-2-cyclopropyl-4-(7-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

Cyclopropylmethyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridine-3yl)-1,4-dihydropyridine-3-carboxylate

Cyclopentyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Cyclopropylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclobutyl-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4d and hydropyride in-3,5-dicarboxylate

Methyl 5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopentyl-6-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclohexyl-6-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4dihydropyride in-3-carboxylate

3-((4-methylpiperazin-1-yl)methyl)benzyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)2,6-d imethyl-1,4-dihydropyridine-3 -carboxylate

3-(cyclopropylmethyl)-5-methyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3,5-dicarboxylate

3-(cyclopropylmethyl)-5-methyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6d icyclopropyl-1,4-d ihydropyride in-3,5-dicarboxylate

Cyclopropylmethyl-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-d ihydropyridine-3-carboxylate

Dimethyl 2-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4d and hydropyride in-3,5-dicarboxylate

Dimethyl-2-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-

3,5-dicarboxylate

Methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine in-3-carboxylate

- 22 040842

Methyl-5-acetyl-2-((2-aminoethoxy)methyl)-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-

1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3-carboxylate

Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-formyl-1,4d and hydropyride in-3,5-dicarboxylate

Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-(hydroxymethyl)-1,4dihydropyridine-3,5-dicarboxylate

Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-formyl-6-methyl-1,4-dihydropyridine in3,5-dicarboxylate

Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-(hydroxymethyl)-6-methyl-1,4dihydropyridine in-3,5-dicarboxylate

Dimethyl-2-cyano-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3,5 dicarboxylate

Cyclopropylmethyl-5-acetyl-4-(6-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate

Cyclopropylmethyl-2,5-diacetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine in-3-carboxylate

Methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4d hydrochloride and in-3-carboxylate hydropyride

Methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3-carboxylate trifluoromethanesulfonate

4-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4 dihydropyridine-3-carboxylate

4-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

3-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

3-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

2-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

2-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

[3,4'-bipyridin]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)1,4-dihydropyridine-3-carboxylate

[3,3'-bipyridine]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

[2,4'-bipyridine]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

[2,3'-bipyridine]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-Dihydropyridine-3-carboxylate

[2,3'-bipyridine]-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-Dihydropyridine-3-carboxylate

[2,4'-bipyridine]-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-Dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-(pyridin-4-yl)benzo[b]thiophen-3-yl)1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-cyclopropyl-4-(7-cyclopropylbenzo[b]thiophen-3-yl)-6-methyl1,4-dihydropyridine-3-carboxylate

3-(pyridin-4-yl)benzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridine-

-yl)-1,4-dihydropyride in-3-carboxylate

1,D-(2,6-dimethyl-4-(5-(pyridin-3-yl)benzo[b]thiophen-3-yl)-1,4-dihydro-pyridine-

3,5-d uyl)diethanone

Methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-phenylbenzo[b]thiophen-3-yl)-1,4dihydropyridine-3-carboxylate

When the compounds of the present invention are combined with other therapeutic agents, said other therapeutic agents are selected from the group consisting of:

A - means of hormonal therapy, such as:

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- gonadoliberin receptor agonists or antagonists (GnRH);

- androgen receptor antagonists and CYP17 inhibitors;

B - blockers of oncogenic kinase signal transduction pathways, such as:

- vascular endothelial growth factor (VEGF) inhibitors,

- epidermal growth factor receptor (EGFR) inhibitors,

- inhibitors of phosphoinositide-3-kinase (PI3K),

- inhibitors of protein kinase B, also known as AKT,

- inhibitors of the target of rapamycin in mammalian cells (mTOR),

- inhibitors of c-Met, also referred to as MET or hepatocyte growth factor receptor (HGFR),

- inhibitors of Src (non-receptor tyrosine kinases),

- poly (ADP-ribose) polymerase (PARP),

- angiopoietin,

the anaplastic lymphoma kinase receptor, also known as ALK tyrosine kinase, and

- antibodies against insulin-like growth factors (IGF);

C - anticancer chemotherapeutic agents, such as:

- taxane anticancer drugs,

- topoisomerase II inhibitors,

- Antitumor antibiotics;

- inhibitors of HSP90 (heat shock protein 90);

D - agents that affect neuroendocrine differentiation, such as:

- Aurora kinase inhibitors;

E - agents that affect immune evasion, such as vaccines directed against prostate-specific antigen (PSA),

F - agents or natural extracts known to stimulate hair growth;

G - agents or natural extracts known to treat acne; And

H - agents or natural extracts known to treat hirsutism; And

I - agents known to treat conditions caused by elevated cortisol levels, such as:

- GR antagonists,

- Inhibitors of I-beta-HSD.

In an embodiment of the present invention, the other therapeutic agent is one or more immunotherapeutic agents selected from the group consisting of anti-CTLA4 antibodies, anti-PD1 antibodies, and anti-PDL1 antibodies. More preferably, the immunotherapeutic agent is selected from the group consisting of ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, AMP-224, MPDL3280A, MEDI4736 and MDX-1105.

Non-limiting examples of GnRH receptor agonists include leuprolide, goserelin, and buserelin. Non-limiting examples of GnRH receptor antagonists include, but are not limited to, degarelix and abarelix.

Non-limiting examples of androgen receptor antagonists include nilutamide, bicalutamide, flutamide, and enzalutamide.

Non-limiting examples of CYP17 inhibitors include abiraterone and gletherone.

Non-limiting examples of VEGF receptor inhibitors include bevacizumab, axitinib, and brivanib alaninate.

Non-limiting examples of EGFR inhibitors include gefitinib, afatinib, cetuximab, and panitumumab.

Non-limiting examples of PI3K inhibitors include pictilisib (also known as GDC 0941) and BKM120.

Non-limiting examples of mTOR inhibitors include temsirolimus, ridaphorolimus, and everolimus.

Non-limiting examples of dual PI3K and mTOR inhibitors include apitolisib (GDC0980), dactolisib (BEZ 235), and LY3023414.

Non-limiting examples of AKT inhibitors include A-443654, perifosin, and ipatasertib.

Non-limiting examples of c-Met inhibitors include tivantinib, JNJ-38877605, cabozantinib, and capmatinib.

Examples of Src blockers include dasatinib, saracatinib, bosutinib, and KX01, which are in clinical development.

Non-limiting examples of PARP inhibitors include olaparib and veliparib.

Non-limiting examples of ALK inhibitors include X-396, alectinib, ceritinib, lorlatinib, and crizotinib (a dual inhibitor of ALK and ROS-1).

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Non-limiting examples of anti-IGF antibodies include figitumumab, genitumab, and BI836845.

Non-limiting examples of taxane antineoplastic agents include cabazitaxel and larotaxel.

Non-limiting examples of topoisomerase II inhibitors include etoposide and teniposide.

Non-limiting examples of anticancer antibiotics include doxorubicin, bleomycin, daunorubicin, liposomal daunorubicin, mitoxantrone, epirubicin, idarubicin, and mitomycin C.

Non-limiting examples of HSP90 (heat shock protein 90) inhibitors include Debio 0932, MPC-3100, IPI-504, NVP-AUY922.

Non-limiting examples of Aurora kinase inhibitors include alisertib, tozasertib, danusertib, and barasertib.

Non-limiting examples of a PSA vaccine include ProstVac-VF.

Compounds of the present invention can be obtained by the methods described below. To facilitate the description of the methods, specific examples are used in some cases, however, they do not limit the scope of the present invention in any way.

If one of X ¹ , X ² , X ³ , X ⁴ and X ⁵ is C-B ¹ and the rest of X ¹ , X ² , X ³ , X ⁴ and X ⁵ are C-H, the compounds of formula (I) are benzothiophenes of formula (1-a3) as shown in Scheme 1-a and can be prepared by reaction of a thiophenol precursor (1-a1) wherein B ¹ is selected from halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl and aryl, with 2-bromo-1,1-diethoxyethane and potassium carbonate in acetone to give intermediates (1-a2) cyclized to benzothiophenes (1-a3) by heating with polyphosphoric acid in toluene.

Scheme 1-a

OEt

1-al 1-a2 1-a3

If one of X ¹ , X ² , X ³ , X ⁴ and X ⁵ is C-B ¹ and the rest of X ¹ , X ² , X ³ , X ⁴ and X ⁵ are C-H, the compounds of formula ( I) are benzothiophene intermediates of formula (III), as shown in scheme 1-b, they can be obtained from the halogen precursor (II), where the halogen (Hal) is selected from chlorine, iodine or, preferably, bromine.

Scheme 1-b

More specifically, if B ¹ represents -C(O)CF ₃ , one of the methods for the synthesis of benzothiophene derivatives of formula (III) is the reaction of the halogen precursor (II), in particular, bromoprecursor, with n-butyllithium and 2,2,2- trifluoro-1-morpholinoethan-1-one in diethyl ether at -60°C.

If B ¹ is -CN, the cyano group can be inserted by heating the halogen precursor (II), in particular the bromo precursor, with zinc cyanide and tetrakis(triphenylphosphine)palladium (0) in a sealed tube at 90°C. The cyano derivative (III) can be converted to the carboxylic acid by heating with potassium hydroxide in methanol and water at 80° C., which can then be converted to the methyl ester by refluxing in saturated HCl in methanol.

If B ¹ represents a mono- or dialkylamino group, one of the methods for the synthesis of benzothiophene derivatives of formula (III) is refluxing a halogen precursor (II), in particular a bromo precursor, with the corresponding amine, Pd ₂ (dba) ₃ , tricyclohexylphosphine and NaOtBu in dry toluene.

When B ¹ is mono- or dialkylaminocarbonyl, the benzothiophene intermediates of formula (V) can be prepared by reacting the precursor carboxylic acid (IV) with the appropriate amine, HOBT and DIPEA in DMF at room temperature as shown in Scheme 2.

Scheme 2

CO Λ/ζΏ· nUtiLUIrtnk

DMF, RT//

O(IV)(V)

The 3-formylbenzo[b]thiophenes of formula (VII) can be prepared by reacting the precursor (VI) with dichloro(methoxy)methane and titanium tetrachloride in dichloroethane at room temperature as shown in Reaction Scheme 3.

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Another way to insert a formyl group at position 3 of the bicyclic heterocycle (X), as shown in Reaction Scheme 4, is to heat the 3-bromo derivative (VIII) with copper(I) cyanide in NMP at 200°C and then reduce with DIBAL to toluene.

Scheme 4

Scheme 3

One method for the synthesis of dicarbonyl intermediates of formula (XI) and (XII) (used in the synthesis of compounds of formula (I) wherein R ² is -COOR ⁸ or -C(O)N(R ⁸ )R ⁹ ) is by heating commercially available 2,2,6-trimethyl-4H-1,3-dioxin-4-one and the corresponding alcohol or amine in toluene at 150°C as shown in the acetoacetylation reaction shown in Reaction Scheme 5.

Scheme 5

One method for the synthesis of dicarbonyl intermediates (XIV) (used in the synthesis of compounds of formula (I) where R ⁴ is alkyl, cycloalkyl, phenyl, or heteroaryl) is transesterification, in which the methyl ester (XIII) and the alcohol are refluxed in dry toluene using a Dean-Stark trap as shown in Scheme 6.

Scheme 6

In another transesterification method, dicarbonyl intermediates (XIV) are prepared by refluxing methyl ester (XIII) and alcohol in dry toluene in a sealed tube using 10 mole % bismuth(III) chloride and molecular sieves as shown in Scheme 7 .

Scheme 7

Dicarbonyl intermediates of formula (XIII) and (XVII) (used in the synthesis of compounds of formula (I) wherein R ² is -COR ⁸ or -COOR ⁸ ) can be synthesized via Claisen condensation by treating the methyl ketone derivative (XV) or acetone with tert-butoxide potassium in THF and reaction of the mixture with dimethyl carbonate or methyl or ethyl ester (XVI) as shown in Reaction Scheme 8.

Scheme 8

ίχνη

Ketoester intermediates of formula (XVIII) (used in the synthesis of compounds

- 26 040842 of formula (I), where R ² is -COOR ⁸ and R ⁴ is -CH2OR ⁶ or -CH2N(R ⁶ )R ⁷ ) can be synthesized by deprotonating the alcohol with sodium hydride in THF and treating the mixture with methyl-4 -chloro-3-oxobutanoate as shown in Reaction Scheme 9. Thus, the ketoester intermediates of formula (XIX) can be synthesized by heating methyl 4-chloro-3oxobutanoate with an amine in acetone and trimethylamine.

Scheme 9

The 1,3-ketoester intermediates of formula (XIV) can be converted to enamines (XX) by heating with ammonium acetate, acetic acid and molecular sieves in THF, or by reaction with ammonium bicarbonate in methanol as shown in Reaction Scheme 10. Thus, 1 ,3diketones (XXI) can be converted to a mixture of enamines (XXII) and (XXIII) in the manner described above, or alternatively by reaction in aqueous ammonia.

Scheme 10

NHjOAc, AcON Molen. sieves, THF or NH^HCO^ MeOH

NH ₄ OAc, AsOH mol. sieves, THF or NH^ H ₂ O

Knoevenagel reaction products of formula (XXIV)

and (XXVI) can be prepared by reacting aldehydes (X) (e.g. benzo[b]thiophene-3-carbaldehyde) and 1,3-dicarbonyl intermediates (XIV) or (XXV), respectively, with acetic acid, piperidine and molecular sieves in toluene in the microwave as described in Liu & Zhang, Angew. Chem. Int. Ed. 2009, 48, 6093-6 and shown in Reaction Scheme 11.

Scheme 11

The dihydropyridines of formula (XXVII) and (XXVIII) can be prepared by the 3-way Hantzsch synthesis by heating the Knoevenagel reaction products (XXVI) with 1,3-dicarbonyl compounds (XIV), (XXI) or (XXIX) and ammonia in alcohols such as such as isopropanol, ethanol, or 2,2,2-trifluoroethanol as shown in Reaction Scheme 12. Instead of ammonia, NH ₄ OAc in MeOH in microwave can be used to synthesize dihydropyridines of formula (XXVII), (XXVIII) and (XXX). pe chi.

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Scheme 12

Another way to obtain dihydropyridines (XXXI) and (XXXIII) is heating the products of the Knoevenagel reaction (XXVI) or (XXIV) with enamines (XXII) or (XXXII), respectively, in methanol in a microwave oven (Scheme 13).

Scheme 13

Dihydropyridines of formula (XXXIII) can also be prepared by heating the Knoevenagel reaction products (XXVI) and enamines (XX) in AcOH as shown in Reaction Scheme 14.

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Scheme 14

Dihydropyridines of formula (XXXV) (used as intermediates in the synthesis of compounds of formula (I) wherein R ⁴ is -NH 2 ) can be synthesized by heating the reaction product of Knoevenagel (XXVI) and amidine (XXXIV) with piperidine in isopropanol as shown in reaction scheme

15.

Scheme 15

The dihydropyridine backbone can be assembled without prior formation of a Knoevenagel reaction product. For example, compounds of formula (I) in which R ¹ and R ² are -CN can be synthesized by heating the aldehyde (X) and the enamines (XXXVIa) and (XXXVIb) with acetic acid in isopropanol as shown in Reaction Scheme 16. If R ³ is not the same as R ⁴ , mixtures of dihydropyridines (XXXVIIa), (XXXVIIb) and (XXXVIIc) are obtained, which must be separated, for example, by column chromatography.

Scheme 16

In a variant of the process described above, one of the enamines, eg (XXXVIb), can be replaced by a ketone, eg (XXXVIc), to obtain the same mixture of dihydropyridines (XXXVIIa), (XXXVIIb) and (XXXVIIc).

The reaction conditions given in Scheme 16 above (heating with acetic acid in alcohols such as, for example, isopropanol, optionally in the presence of substoichiometric amounts of piperidine) can be used on a larger scale for the synthesis of dihydropyridines of formula (I) in which R ¹ is -CHO, -COR ⁵ or -CN, and R ² is selected from -COR ⁸ , -S(O)nR ⁸ (where n is 1 or 2), -COOR ⁸ and -C(O)N(R ⁸ )R ⁹ , provided that the aldehyde (X) (for example, benzo[b]thiophene-3carbaldehyde) reacts with:

(a) two enamines, as non-limiting examples, compounds of formula (XX),

- 29 040842 (XXII), (XXIII), (XXXII) or (XXXVIa/b), or (b) one enamine, as non-limiting examples, compounds of formula (XX), (XXII), (XXIII), (XXXII) or (XXXVIa/b), and 1,3-dicarbonyl compound, as non-limiting examples, compounds of formula (XIV), (XXV) or (XXIX).

The enamines described above can also be prepared in situ, leading to yet another Hantzsch synthesis of the dihydropyridine backbone, in which compounds of formula (I) are prepared in a 4-component reaction by heating an aldehyde (e.g., benzo[b]thiophene-3-carbaldehyde), two 1,3-dicarbonyl compounds (eg compounds of formula (XIV), (XXV) or (XXIX)) and aqueous ammonia in alcohols (eg ethanol).

The methods described above for the synthesis of the 1,4-dihydropyridine backbone are variants of the well-described Hantzsch reaction, which is reviewed, for example, in Hantzsch reaction: Recent advances in Hantzsch 1,4-dihydropyridines, A. Saini et al., J Scient Indust Res 2008, 67, 95-111.

Dihydropyridines of formula (I) bearing halogen atoms such as -Br on the aromatic ring can be further derivatized by metal catalyzed coupling reactions in which the halogen atom is replaced by e.g. aryl, heteroaryl or small alkyl groups (Suzuki coupling reactions), amines (Buchwald-Hartwig coupling reactions) or cyano (coupling reactions using Zn).

For example, halogen-substituted benzyl esters of formula (XXXVIII) can be coupled with pyridinylboronic acid (or other heteroaryl-, phenyl- or alkylboronic acids) by heating both components with a palladium catalyst, for example tetrakis(triphenylphosphine)palladium, and a base, e.g. potassium carbonate, in a 3:1 mixture of DME and water to give dihydropyridine (XXXIX) as shown in Scheme 17.

Scheme 17

In another example, benzothiophenes of formula (XL) substituted with halogens as shown in Scheme 18 can be converted to compounds of formula (XLI) by a Suzuki coupling reaction with pyridylboronic acid using a catalyst (e.g., Pd(dppf)Cl ₂ *DCM) and aqueous Cs ₂ CO ₃ in dichloromethane at boiling point. In another example, coupling halogen-substituted benzothiophenes (XL) with stannanes like, for example, tributyl(phenyl)stannane using catalysts such as bis(triphenylphosphine)palladium(II) dichloride in hot toluene (2 ml) gives compounds of formula (XLII).

The bromine atom in the benzothiophenes (XL) shown in Scheme 18 can be replaced by a cyano group by heating with Zn(CN) ₂ and Pd(PPh ₃ ) ₄ in DMF to give the dihydropyridines of formula (XLIII).

Scheme 18

pharmacological activity.

Binding to the rat androgen receptor.

The assay was performed according to the instructions for the AR PolarScreen Competitive Assay Kit (Green) (Life Technologies, cat. no. A15880). Briefly, the test is based on the measurement of fluorescence polarization changes analyzed with Fluormone AL Green. Thus, when

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Fluormone binds to the receptor, fluorescence polarization is observed decreasing as the ligand competes for the receptor binding site and Fluormone is displaced.

The inhibition values for each of the compounds are measured in duplicate at 1 and 10 μM and the plate is incubated for 4 hours at RT. Fluorescence polarization is measured with a Tecan Infinite M1000 Pro plate reader spectrophotometer (X _ex =485 nm, X _em = 535 nm). To obtain a dose-response curve and calculate the power of inhibition (expressed as IC ₅₀ ) for AR, a 1:10 dilution series in 1-fold buffer from 10 μM to 0.1 nM was prepared for each compound.

Binding to the human androgen receptor.

Radioligand binding studies were performed on the endogenously expressed human androgen receptor using the LnCap prostate cancer cell line. The test is based on the measurement of the radiolabeled AR ligand [ ³ H]-methyltrienolone displaced by increasing concentrations of the test compound. The test is carried out in 96-well plates (Falcon, #353072). Positive and negative controls are also required on each assay plate to assess total and non-specific binding of the radioligand to the receptor. Cells (60,000 per well) were incubated for 24 h before the experiment at 37°C in an atmosphere of 5% CO ₂ . Medium was replaced with assay buffer (RPMI-640 (ATCC #30-2001) supplemented with 0.1% bovine serum albumin (Sigma #8806-56) and triamcinolone acetonide (Sigma #T6501)). Compounds at the desired concentrations and [ ³ H]methyltrienolone (Perkin Elmer #NET590) were added to the wells.

Table 1

Analysis conditions

Sample Non-specific binding General binding Analysis Buffer 80 µl 80 µl 90 µl Connection (10- multiple) 10 µl [ ³ H]methyltrienolone (20 nM) 10 µl 10 µl 10 µl Testosterone (200 µM) 10 µl

To obtain a dose-response curve and calculate the power of inhibition (expressed by IC ₅₀ ) for AR, a 1:10 dilution series in 1-fold buffer from 10 μM to 0.1 nM was prepared for each compound.

Cells were incubated for 2 h at 37°C in an atmosphere of 5% CO ₂ and then washed twice with ice-cold HBSS. The cells were then lysed with solubilizing buffer (Hanks' balanced salt solution (HBSS, Sigma # H6648), 0.5% sodium dodecyl sulfate 0.5% (SDS, Sigma #L7390-500G, lot # 078K0102) and 20% glycerol (Sigma Aldrich, # G2025) for 30 min at RT 75 µl aliquots were taken from each well, transferred to a 96-well flexible plate (Perkin Elmer, #1450-401) and mixed with 100 µl scintillation mix (OptiPhase SuperMix, PerkinElmer, #1200-439 The plates were shaken for 60 min and the radioactivity was measured with a beta scintillation counter (Microbeta Trilux, Perkin Elmer).

Competitive binding to the human glucocorticoid receptor IM-9 (GR IM-9).

Glucocorticoid receptor competition assays were performed in a polypropylene 96-well plate. Each well was incubated with 100 μg of cytosol from the IM9 cell line, 1.5 nM [ ³ I]-dexamethasone (71 Ci/mmol, 1 mCi/ml, Perkin Elmer NET1192001MC), test compounds and standard. Non-specific binding was determined in the presence of 10 μM triamcinolone (Sigma Aldrich T6376).

The reaction mixture (total volume: 200 μl/well) was incubated at 4°C for 6 h, 180 μl was transferred into a 96-well GF/B plate (Millipore, Madrid, Spain) pretreated with 0.5% PEI and treated with binder buffer (TES 10 mM, 10 mM sodium molybdate, EDTA 1 mM, pH 7.4, 20 mM 2-mercaptoethanol, 10% glycerol), then filtered and washed six times with 250 μl wash buffer (TES 10 mM, 10 mM sodium molybdate , EDTA 1 mM, pH 7.4, 20 mM 2-mercaptoethanol, 10% glycerol) before measurement with a beta-scintillation microplate counter (Microbeta Trilux, PerkinElmer, Madrid, Spain).

Functional analysis of the AR receptor.

MDA-MB-453 cells were cultured in DMEM (ATCC No. 30-2002), 10% FBS, 1% penicillin, 1% streptomycin, 75 μg/ml gentamicin.

The day before the assay, the cells were trypsinized and plated on a 384-well plate (Greiner, no. 781098) (8000 cells/well) in 50 μl of complete culture medium. Cells were stored at 37° C. under 5% CO ₂ overnight.

The medium was replaced with 50 μl of complete growth medium with 0.1% FBS. Compounds were dispensed with an Echo 550 (Labcyte) and incubated for 24 hours at 37° C. under 5% CO2. The antagonistic effect was measured in the presence of 1 nM DHT.

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After incubation, the assay medium was removed and 20 μl of 1x Promega lysis buffer was added to each well. The plate was incubated for 15 min at RT, quickly frozen until

-80°C and thawed to room temperature. 50 μl of luciferase substrate (E4550, Promega) was added to each well and luminescence was measured (integration time 1000 ms) using an EnSpire multichannel reader (Perkin Elmer).

Results.

The table shows the binding of some compounds of the present invention in different assays.

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C43 WITH V A C44 With V IN C45 With C46 V A IN C47 V A C48 With IN IN C52 IN V C53 A C56 IN A C57 V C58 A A V C60 V C61 WITH V C62 V C64 WITH V C65 WITH A V C66 IN A A C67 A A A C68 WITH C71 WITH A WITH C72 WITH A With C73 With A With C74 IN With C75 IN With C76 With A C77 IN C78 With IN C79 A With C80 WITH With C81 A C82 A C83 IN C84 A C85 WITH

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C86 IN C91 A C92 A C93 IN C94 A C95 A C96 IN C97 A C98 IN C99 IN C100 A C101 A C102 IN C103 A C104 A C105 IN C106 IN C107 A WITH C108 A WITH C109 A SPO A cm A C112 IN A C113 V A C114 WITH C115 WITH C116 IN C117 V A V C118 A A V C119 WITH A V C120 V A C121 With IN C122 IN A C123 A A

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Dl A IN With D2 C D3 A D5 A D6 V WITH D7 A WITH D8 A DIO A Dll A D12 A D13 A D14 WITH D15 IN D16 A D17 A D18 A D19 A D20 IN D21 A D22 C A D23 IN A D24 V A IN D25 With A D26 V IN D27 V A V D28 IN D29 V A D30 V A V D31 V A V D32 V A V D33 V A D34 V A D35 V IN D36 V A

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D37 V A IN D38 V A D39 V A IN D40 V A D41 V A A D42 V A D43 V A WITH D44 A D45 V A D46 With A WITH D47 V A WITH D48 A D49 A A D50 A D51 A D52 A D53 A D54 A D55 A D56 A El A A G1 A A G2 C G3 C G4 c Hl A H2 A H3 C H4 c H5 c H6 c H7 c H8 c H9 c

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NUDE WITH neither WITH H12 WITH H13 With H14 With H15 A V 12 V V L A J2 A J3 IN J6 WITH LO V L1 A L2 A LZ WITH L4 WITH L5 With L6 With L7 With L8 With L9 With J20 V J21 A A J22 A A A J23 A A IN WITH J24 WITH J25 IN J25-a V J26 A A IN J27 WITH WITH J28 A A J28-a IN A J29 IN J30 WITH

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J31 With A J32 With V J33 V V J34 V J36 WITH J38 V J40 With J41 A A V J42 IN A A J42-a IN J43 A IN K1 IN K2 WITH L1 With A V L2 With A V L3 A A V L4 A A V L5 A With L7 IN With L8 With L9 V L12 IN L13 IN L14 With ml With N1 With

Range:

A: IC ₅₀ <100 nM;

B: 100 nM<1C ₅₀ <1 μM;

C: IC ₅₀ >1 μM.

As can be seen from the results presented in Table. 1, the compounds of the present invention are nuclear receptor modulators selected from the androgen receptor and the glucocorticoid receptor.

The derivatives of the present invention can be used in the treatment or prevention of diseases known to be susceptible to amelioration by androgen receptor and glucocorticoid receptor modulator treatment, such as prostate cancer, castration-resistant prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, cancer stomach, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian cancer, and other solid tumors, melanoma, metastatic malignancies, benign prostatic hyperplasia, polycystic ovary syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism , muscle wasting disorders and cachexia, Cushing's syndrome, antipsychotic drug-induced weight gain, obesity, post-traumatic stress disorder, and alcoholism. Thus, the derivatives of the invention, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and/or salts thereof can be used in a method of treating human disorders, comprising administering to an individual in need of such treatment, an effective amount of a dihydropyridine derivative of the invention, or a pharmaceutically acceptable amount thereof. acceptable salt.

The present invention also relates to pharmaceutical compositions containing as active ingredient at least a dihydropyridine derivative of formula (I) or a pharmaceutically acceptable salt thereof, together with other therapeutic agents as defined above, and with a pharmaceutically acceptable excipient such as a carrier or diluent. . The active ingredient may comprise from 0.001 to 99% by weight, preferably from 0.01 to 90% by weight of the composition, depending on the nature of the composition and whether it needs to be further diluted prior to use. Preferably, the compositions are in a form suitable for oral, topical, nasal, rectal, transdermal or injection administration.

- 38 040842

The pharmaceutically acceptable excipients to be mixed with the active compound or salts of such a compound to form the compositions of the present invention are well known per se, and the specific excipients used will depend, among other things, on the intended mode of administration of the compositions.

The compositions of the present invention are preferably adapted for injection and oral administration. In this case, compositions for oral administration may be in the form of tablets, sustained release tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, inhalable dry powders or liquid preparations such as mixtures, elixirs, syrups or suspensions, all of which contain the compound according to the invention; such preparations can be obtained by methods well known in this field.

Diluents that can be used in preparing the compositions include liquid and solid diluents compatible with the active ingredient, if desired, together with colorants or flavors. Tablets or capsules may contain from 2 to 500 mg of the active ingredient, or an equivalent amount of its salt.

The liquid composition adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound together with, for example, sucrose to form a syrup. Suspensions may contain the insoluble active compound of the invention, or a pharmaceutically acceptable salt thereof, together with water, a suspending agent, or a flavoring agent.

Compositions for parenteral injection may be prepared from soluble salts which may or may not be lyophilized and may be dissolved in pyrogen-free aqueous media or other suitable parenteral injectable liquid.

Effective doses are generally in the range of 2-2000 mg of the active ingredient per day. The daily dose may be administered at one or more times, preferably 1 to 4 times per day.

The present invention will be further illustrated by the following examples. They are presented for illustrative purposes only and do not limit the scope of the invention in any way. The synthesis of the compounds of the invention is illustrated by the following examples, including the preparation of intermediates, which in no way limit the scope of the invention.

Examples

General information.

Reagents, solvents, and starting materials were purchased from commercial sources and used without further purification. All reactions were carried out in air and with anhydrous solvents, unless otherwise indicated. The term concentration refers to evaporation under vacuum using a Buchi Rotavapor. If indicated, the reaction products were purified by flash chromatography on silica gel (40-63 μm) using the indicated solvent system. Yields refer to isolated compounds estimated to be >95% pure as determined by 1H NMR. All dihydropyridines were obtained as racemic mixtures.

Mass spectrometry was carried out using a Varian MAT-711 spectrometer using EI and ESI methods. HPLC experiments were carried out with a LaChrom Elite L-2350 (Sunfire 5 µm silica gel column, 4.6 mm x 150 mm) equipped with an L2455 diode array detector. HPLC-MS analysis was performed using a Gilson instrument equipped with a Gilson 321 piston pump, a Gilson 864 vacuum degasser, a Gilson 189 injection module, a 1/1000 Gilson divider, a Gilson 307 pump, a Gilson 170 detector, and a Thermoquest Fennigan aQa detector.

1H and ^13C nuclear magnetic resonance experiments were carried out using Varian Inova 500 MHz or Varian Mercury 300 or 400 MHz NMR spectrometers. Recorded chemical shifts relative to the signal of the deuterated solvent or tetramethylsilane as an internal standard.

The coupling constants J are given in hertz (Hz), and the multiplicity was as follows: s=singlet, d=doublet, t=triplet, k=quartet, m=multiplet, or combinations thereof.

Obtaining Intermediates

General method aa.

Intermediate 1: 7-chlorobenzo[b]thiophene

(CH ₃ ) ₂ CO

To a solution of 2-chlorobenzenethiol (1.53 g, 10.58 mmol, 1.0 eq.) and 2-bromo-1,1-diethoxyethane (2.4 ml, 15.87 mmol, 1.5 eq.) in acetone (10 ml) was added potassium carbonate (3.65 g, 26.45 mmol, 2.5 eq.). The mixture was heated at reflux for 90 minutes and then 0.5 eq. 2-bromo-1,1 diethoxyethane. The mixture was heated at reflux for another 2 h, cooled to room temperature and concentrated. The resulting residue was purified by silica gel flash column chromatography using hexane/diethyl ether (2%) as eluent to give (2-chlorophenyl)(2,2-diethoxyethyl)sulfane as a light yellow oil (2. 71 g

97%).

To a solution of polyphosphoric acid (6.0 g, 51.97 mmol, 9 eq.) in toluene (15 ml) was added with vigorous stirring a solution of (2-chlorophenyl)(2,2-diethoxyethyl)sulfane (1.5 g, 5 .77 mmol, 1 eq.) in toluene (5 ml). The mixture was stirred at reflux for 5 hours and then poured into ice water (30 ml) and stirred for 10 minutes. The mixture was washed with toluene, saturated aqueous bicarbonate and brine, dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified by silica gel flash column chromatography using hexane as eluent (as described in WO 2009/008992 A2) to give 7-chlorobenzo[b]thiophene as a light yellow oil (0.68 g, 70%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.77-7.71 (m, 1H), 7.50 (d, J=5.4 Hz, 1H), 7 .41-7.30 (m, 3H).

Intermediate 2: 7-(trifluoromethyl)benzo[b]thiophene.

The title compound as a light yellow oil (0.44 g, 41%) was obtained by general method aa.

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 8.00 (d, J=7.9 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H) , 7.57 (d, J=5.5 Hz, 1H), 7.51-7.37 (m, 2H).

¹⁹ F-NMR (282 MHz, CDCl ₃ -d) δ (ppm): -63.13 (CF ₃ ).

Intermediate 3: 7-fluorobenzo[b]thiophene.

The title compound as a yellow oil (1.78 g, 52%) was obtained by general method aa.

1H-NMR (300 MHz, CDCl3-d) δ (ppm) δ 7.63 (d, J=8.0 Hz, 1H), 7.49 (d, J=5.3 Hz, 1H) , 7.41-7.30 (m, 2H), 7.07 (dd, J=9.8, 8.0 Hz, 1H).

¹⁹ F-NMR (282 MHz, CDCl ₃ -d) δ (ppm): -115.37 (CF).

Intermediate 4: 1-(benzo[b]thiophen-7-yl)-2,2,2-trifluoroethan-1-one

This compound was synthesized by a modified method from J. Med. Chem. 2002, 45, 4038-4046. 7-bromobenzo[b]thiophene (1.0 g, 4.69 mmol, 1.0 eq.) was dissolved in diethyl ether (25 ml) and cooled at -40°C. Then 1.6 M n-butyllithium (3.23 ml, 5.16 mmol, 1.1 eq.) was added dropwise and the solution was heated to 0°C in 1 h. The solution was cooled to -60°C and the solution was added in parts 2,2,2-trifluoro-1-morpholinoethan-1-one (0.86 g, 4.69 mmol, 1.0 eq.) in diethyl ether (5 ml). The resulting mixture was stirred at -60°C for 7 h and then warmed to room temperature. The solution was hydrolyzed with saturated NH ₄ Cl (5 ml), washed with NH ₄ Cl (3 times, 5 ml) and water (3 times, 5 ml), dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified by silica gel flash column chromatography using ethylhexane:ethyl acetate (10:1) as eluent to give a light yellow solid (0.98 g, 91%).

1H-NMR (300 MHz, CDCl3) δ=8.20 (ddd, J=7.9, 4.5, 1.4 Hz, 2H), 7.70 (d, J=5.5 Hz, 1H) , 7.58 (t, J=7.9 Hz, 1H), 7.49 (d, J=5.5 Hz, 1H).

¹⁹ F-NMR (282 MHz, CDC^) δ=-69.54 (s, CF3).

Intermediate 5: benzo[b]thiophene-5-carbonitrile.

Г PW _ [ JQ _Br AA dmf A''

Nitrogen gas was bubbled into a mixture of 5-bromobenzo[b]thiophene (510 mg, 2.34 mmol) and zinc cyanide (299 mg, 2.49 mmol) in dry DMF (3 mL) for 5 minutes. Tetrakis(triphenylphosphine)palladium (0) (153 mg, 0.13 mmol) was added, the tube was sealed and the mixture was stirred at 90° C. for 7 h. The reaction mixture was filtered through celite and the filtrate was extracted using AcOEt and NaHCO ₃ . The organic phase was concentrated and the residue was purified by column chromatography (yield: 82%).

1H-NMR (400 MHz, DMSO-d6) δ=7.58 (dd, 1H), 7.72 (m, 1H), 7.99 (d, 1H), 8.26 (m, 1H), 8 .43 (d, 1H).

Intermediate 6: benzo[b]thiophene-7-carbonitrile.

The title compound was synthesized as described above for benzo[b]thiophene-5carbonitrile.

1H-NMR (400 MHz, DMSO) δ=7.59 (dd, 1H), 7.65 (d, 1H), 7.96 (dd, 1H), 8.01 (d, 1H), 8.26 (dd, 1H).

Intermediate 7: benzo[b]thiophene-5-carboxylic acid.

+ con —- but

To a solution of benzo[b]thiophene-5-carbonitrile (400 mg, 2.51 mmol) in MeOH (40 ml), KOH (2.0 g, 35 mmol) and 10 ml of water were added in portions, and the mixture was stirred at 80°C for 36 hours. After acidification with 2N HCl (pH 4-5), the solid was filtered off and washed with pentane to give the title compound as an off-white solid (390 mg, 87%).

1H-NMR (400 MHz, DMSO-d6) δ=7.58 (dd, 1H), 7.72 (m, 1H), 8.01 (d, 1H), 8.29 (m, 1H), 8 .46 (d, 1H),

12.11 (s, 1H).

Intermediate 8: methyl benzo[b]thiophene-5-carboxylate.

Benzo[b]thiophene-5-carboxylic acid (390 mg, 2.19 mmol) was refluxed in saturated HCl in MeOH (30 mL) for 24 h. After evaporation of the solvent (340 mg, 76%), the methyl complex ether.

1H-NMR (400 MHz, DMSO-d6) δ=3.85 (s, 3H), 7.59 (dd, 1H), 7.73 (m, 1H), 7.98 (d, 1H), 8 .27 (m, 1H), 8.44 (d, 1H).

Intermediate 9: 5-fluorobenzo[b]thiophene-7-carbonitrile.

Synthesis of 7-bromo-5-fluorobenzo[b]thiophene.

By general method aa the title compound was obtained as a light yellow oil (1.02 g) which was used as such in the next step.

Synthesis of 5-fluorobenzo[b]thiophene-7-carbonitrile.

A solution of 7-bromo-5-fluorobenzo[b]thiophene (1.02 g, 4.41 mmol, 1.0 eq.) and copper cyanide (0.590 g, 6.62 mmol, 1.5 eq.) in N- methyl-2-pyrrolidone (12 ml) was stirred for 2 days in a sealed tube at 200°C. The mixture was cooled to room temperature, poured into saturated aqueous NaHCO ₃ (30 ml) and kept at 4°C for 60 min. The solid was filtered off and dissolved in a mixture of 40 ml NH4OH (28%)/NH ₄ Cl (saturated) (1:1) and ethyl acetate (60 ml) and stirred for 1 h. Then it was washed with ethyl acetate (3 times), dried ( Na ₂ SO ₄ ), concentrated and purified by silica gel flash column chromatography using hexane/diethyl ether (2%) as eluent to give 5-fluoro-3-formylbenzo[b]thiophene-7-carbonitrile as white solids (0.23 g, 29%).

1H-NMR (300 MHz, CDCl3) δ (ppm): 7.73 (dd, J=8.8, 2.3 Hz, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.47 (dd, J=8.1, 2.2 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H).

Intermediate 10: 4-fluorobenzo[b]thiophene-7-carbonitrile.

The title compound was obtained via a 2-step synthesis as described above for intermediate 9 as a white solid (0.33 g).

1H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.70 (dd, J=8.2, 4.5 Hz, 1H), 7.61 (d, J=5.5 Hz , 1H), 7.53 (d, J=5.5 Hz, 1H), 7.13 (t, J=8.8 Hz, 1H).

Intermediate 11: 5,7-dichlorobenzo[b]thiophene.

The title compound as a light yellow oil (1.57 g) was obtained by the general method aa.

1H-NMR (300 MHz, CDCl3) δ (ppm): 7.78 (dd, J=8.0, 0.8 Hz, 1H), 7.52 (s, 1H), 7.50 ( s, 1H), 7.46-7.42 (m, 1H).

Intermediate 12: 3-bromo-6-chlorobenzo[b]thiophene-7-carbonitrile. vgsn ₂ soon o η ⁵⁰⁰¹⁵ 9 ^m n ν,οη,ερη ₃ ^ _pH

N HjO.NijCOs 2) A1CI ₃ ^EUN

To a solution of 2-chloro-6-mercaptobenzonitrile (1.5 g, 8.84 mmol, 1.0 eq.) in ethanol (20 ml) was added sodium hydroxide solution (0.35 g, 8.84 mmol, 1.0 equiv.) in water (7 ml). Then a solution of 2-bromoacetic acid (1.35 g, 9.73 mmol, 1.1 eq.), sodium carbonate (0.51 g, 4.86 mmol, 0.5 eq.) in water (8 ml) was added, and stirred the mixture for 2 hours. Adjusted the pH of the mixture (~2) with HCl (2H) and extracted with ethyl acetate (2 times) and DCM (2 times). The organic phase was dried (Na2SO4) and concentrated to give 2-((3-chloro-2-cyanophenylthio)acetic acid as a yellow oil. The product was used in the next step without further purification.

1H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.51-7.44 (m, 2H), 7.42-7.35 (m, 1H), 3.79 (s, 2H), 2.83 (br. s, 1H).

Thionyl chloride (0.96 ml , 13.18 mmol, 1.5 eq.). The mixture was refluxed for 1 hour and then cooled to 0° C. while aluminum chloride (10.54 g, 79.06 mmol, 9 eq.) was added in portions. The mixture was stirred at RT overnight, cooled to 0° C. before adding water, and then extracted with ethyl acetate (3 times). The organic phase was dried (Na ₂ SO ₄ ), concentrated and purified by silica gel flash column chromatography using hexane/ethyl acetate (4:1) as eluent to give 6-chloro-3-oxo-2,3-dihydro-benzo[b]thiophene -7-carbonitrile (1.53 g, 83%).

1H-NMR (300 MHz, CDCI3) δ (ppm): 7.48 (d, J=8.5 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 3 .95 (s, 2H).

A solution of 6-chloro-3-oxo-2,3-dihydrobenzo[b]thiophene-7-carbonitrile (1.53 g, 7.79 mmol, 1.0 eq.) and sodium borohydride (0.32 g, 8. 57 mmol, 1.1 eq.) in ethanol (60 ml) was stirred for 1 h at RT, concentrated, redissolved in ethyl acetate and washed with water. The organic phase was dried over Na ₂ SO ₄ and concentrated to give 6-chloro-3-hydroxy-2,3-dihydro-benzo[b]thiophene-7carbonitrile, which was used in the next step without further purification.

Solution of 6-chloro-3-hydroxy-2,3-dihydrobenzo[b]thiophene-7-carbonitrile (7.79 mmol, 1.0 eq.) and rtoluenesulfonic acid (0.15 g, 78 mmol, 0.1 eq. .) in toluene (20 ml) was heated under reflux for 1 h, concentrated and purified by flash column chromatography on silica gel using hexane/ethyl acetate (6:1) as eluent to give 6chlorobenzo[b]thiophene-7- carbonitrile (1.26 g, 83%).

1H-NMR (300 MHz, CDC13) δ (ppm): 7.93 (d, J=8.6 Hz, 1H), 7.60 (d, J=5.4 Hz, 1H), 7 .47 (d, J=8.6 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H).

Solution of 6-chlorobenzo[b]thiophene-7-carbonitrile (1.26 g, 6.50 mmol, 1.0 eq.), N-bromosuccinimide (1.74 g, 9.76 mmol, 1.5 eq.) , acetic acid (0.04 ml, 0.64 mmol, 0.1 eq.) in Ν,N-dimethylformamide (10 ml) was heated at 130°C for 1 hour in a microwave reactor. Water was then added and the mixture was extracted with ethyl acetate (3 times). The organic phase was dried (Na ₂ SO ₄ ), concentrated and purified by silica gel flash column chromatography using hexane/ethyl acetate (8:1) as eluent to give 3-bromo-6-chlorobenzo[b]thiophene-7-carbonitrile (1.33 g, 75%).

Intermediate 13: 3-bromo-5-fluorothieno[2,3-b]pyridine.

Vg ₅

N-iodosuccinimide (1.99 g, 8.84 mmol , 1.0 eq.). The resulting mixture was stirred for 30 min at 90°C, then cooled to RT and concentrated. The residue was purified by silica gel flash column chromatography using hexane/ethyl acetate (2:1) as eluent to give 5-fluoro-3-iodopyridin-2-ol as a yellow solid (1.4 g, 65%).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 11.81 (s, 1H), 10.99 (br. s, 1H), 8.18 (dd, J=7, 2, 3.1 Hz, 1H), 7.65 (t, J=3.1 Hz, 1H).

A solution of 5-fluoro-3-iodopyridin-2-ol (0.5 g, 2.06 mmol, 1 eq.), palladium acetate (0.005 g, 0.02 mmol, 0.01 eq.), triphenylphosphine (0.011 g , 0.041 mmol, 0.02 eq.), copper iodide (0.008 g, 0.041 mmol, 0.02 eq.) in dry tetrahydrofuran (15 ml) was sparged with argon gas for 5 minutes. Trimethylsilylacetylene (0.43 ml, 3.10 mmol, 1.5 eq) and propylamine (0.34 ml, 4.13 mmol, 2 eq) were then added and the mixture was stirred at 38°C for 60 min, concentrated , taken up in ethyl acetate and washed with Rochelle's salt (2 times), 0.1 N hydrochloric acid (2 times) and saturated sodium bicarbonate (2 times). The organic phase was dried (Na2SO4), filtered, concentrated and purified by silica gel flash column chromatography using hexane/ethyl acetate (2:1) as eluent to give 5-fluoro-3-((trimethylsilyl)ethynyl)pyridine-2- ol as a light yellow oil (0.263 g, 61%).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 13.57 (br. s, 1H), 7.60 (dd, J=7.6, 3.1 Hz, 1H) , 7.39 (t, J=3.1 Hz, 1H), 0.26 (s, 9H).

Lawesson's reagent (0.0.25 ml, 0.63 mmol, 0.5 eq.). The mixture was stirred at 120°C for 60 min, concentrated and purified by silica gel flash column chromatography using ethylhexane:ethyl acetate (7:1) as eluent to give 5-fluoro-2(trimethylsilyl)thieno[2,3- b]pyridine as a yellow solid (0.22 g, 76%).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 3.68 (d, J=2.4 Hz, 1H), 2.95 (dd, J=9.0, 2, 4 Hz, 1H), 2.58 (s, 1H), -4.37 (s, 9H).

Potassium carbonate (0.332 g, 2 40 mmol, 2.5 eq.). The mixture was stirred at 65° C. for 60 minutes. The solid was then filtered off and washed with dichloromethane. The filtrate was concentrated, taken up in ethyl acetate, washed with water (2 times) and brine (2 times), dried (Na2SO4) and

- 42 040842 was concentrated and the residue was purified by silica gel flash column chromatography using hexane/ethyl acetate (20:1) as eluent to give 5-fluorothieno[2,3b]pyridine as a light yellow oil (0.111 g, 75 %).

1H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.47 (d, J=2.4 Hz, 1H), 7.75 (dd, J=8.9, 2.7 Hz , 1H), 7.63 (d, J=6.0 Hz, 1H), 7.24 (d, J=6.0 Hz, 1H).

To a solution of 5-fluorothieno[2,3-b]pyridine (0.78 g, 5.12 mmol, 1 eq.) in water (8 ml) was added hydrobromic acid (5.22 ml, 46.09 mmol, 9 eq. .) and bromine (0.39 g, 7.68 mmol, 1.5 eq.) and this mixture was stirred at 55°C for 20 h. The solid was filtered off and washed with saturated sodium bicarbonate, then taken up in ethyl acetate, washed with saturated sodium bicarbonate (2x), dried (Na ₂ SO ₄ ), concentrated and purified by silica gel flash column chromatography using hexane/ethyl acetate (20:1) as eluent to give 3-bromo-5fluorothieno[2,3- b]pyridine as a light yellow oil (0.73 g, 62%).

1H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.51 (s, 1H), 7.76 (dd, J=8.5, 2.5 Hz, 1H), 7.64 (s, 1H).

General method a.

Intermediate a1: N-cyclopropylbenzo[b]thiophene-5-carboxamide

To a solution of benzo[b]thiophene-5-carboxylic acid (700 mg, 3.93 mmol), EDC*HCl (1130 mg, 5.89 mmol), HOBT (601 mg, 3.93 mmol) in 15 ml DMF at 5°C was added cyclopropylamine (336 mg, 5.89 mmol) and DIPEA (1270 g, 9.89 mmol). The reaction mixture was stirred for 18 hours at room temperature. The solution was poured into saturated NaHCO ₃ and the precipitate was washed three times with cold water and once with pentane to give the desired amide derivative (700 mg, 82%).

1H-NMR (400 MHz, DMSO-d6) δ=0.60 (m, 2H), 0.71 (m, 2H), 2.93 (m, 1H), 7.56 (dd, 1H), 7 .67 (d, 1H), 7.93 (d, 1H), 8.22 (dd, 1H), 8.46 (d, 1H).

The following derivatives were synthesized in the general manner described above and used in the next step without further purification.

Intermediate a2: N-(cyclopropylmethyl)benzo[b]thiophene-5-carboxamide.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.20 (m, 2H), 0.47 (m, 2H), 1.05 (m, 1H), 3.14 (m, 2H), 7.49 (dd, 1H), 7.63 (d, 1H), 7.89 (d, 1H), 8.18 (dd, 1H), 8.30 (t, 1H), 8.42 (d , 1H).

Intermediate a3: benzo[b]thiophen-5-yl-(4-methylpiperazin-1-yl)methanone.

1H-NMR (400 MHz, DMSO-d6) δ=2.15 (s, 3H), 2.29 (m, 4H), 3.41 (m, 4H), 7.47 (dd, 1H), 7 .61 (d, 1H), 7.97 (d, 1H), 8.15 (dd, 1H), 8.50 (d, 1H).

Intermediate a4: benzo[b]thiophen-5-yl-(morpholino)methanone.

1H-NMR (400 MHz, DMSO-d6) δ=3.49 (m, 4H), 3.65 (m, 4H), 7.47 (dd, 1H), 7.61 (d, 1H), 7 .97 (d, 1H), 8.15 (dd, 1H), 8.50 (d, 1H).

Intermediate a5: N-cyclopropylbenzo[b]thiophene-7-carboxamide.

1H-NMR (400 MHz, DMSO) δ=0.62 (m, 2H), 0.74 (m, 2H), 2.91 (m, 1H), 7.47 (dd, 2H), 7.81 (d, 1H), 7.92 (d, 1H), 8.04 (dd, 1H), 8.69 (d, 1H).

Intermediate a6: benzo[b]thiophen-7-yl-(4-methylpiperazin-1-yl)methanone.

1H-NMR (400 MHz, DMSO) δ=2.19 (s, 3H), 2.28 (d, 4H), 3.42 (t, 4H), 7.37 (d, 1H), 7.46 (dd, 1H), 7.51 (d, 1H), 7.83 (d, 1H), 7.96 (dd, 1H).

General method b.

Intermediate b1: 4-(benzo[b]thiophen-5-yl)morpholine.

A solution of 5-bromobenzo[b]thiophene (600 mg, 2.82 mmol), morpholine (368 mg, 4.23 mmol), Pd ₂ (dba) ₃ (129 mg, 0.14 mmol), tricyclohexylphosphine (119 mg, 0.42 mmol) and NatButO (541 mg, 8.46 mmol) in dry toluene (20 ml) under N2 was heated at reflux for 24 h. After cooling, the mixture was poured into saturated aqueous NaHCO ₃ , extracted with AcOEt ( 3 times), dried over Na ₂ SO ₄ , filtered and concentrated. The product was isolated as a gray solid after flash column chromatography (230 mg, 37%).

1H-NMR (400 MHz, DMSO-d6) δ=3.45 (m, 4H), 3.23 (m, 4H), 6.94 (d, 1H), 7.42 (d, 1H), 7 .54 (dd, 1H), 7.66 (d, 1H), 7.71 (d, 1H).

The following derivatives were synthesized by the general method b above and used in the next step without further purification.

Intermediate b2: 1-(benzo[b]thiophen-5-yl)-4-methylpiperazine.

1H-NMR (400 MHz, DMSO-d6) δ=2.25 (s, 3H), 2.53 (m, 4H), 3.16 (m, 4H), 6.93 (d, 1H), 7 .39 (d, 1H), 7.61 (d, 1H), 7.51 (dd, 1H), 7.68 (d, 1H).

Intermediate b3: N-benzylbenzo[b]thiophene-5-amine.

- 43 040842

1H-NMR (400 MHz, DMSO-d6) δ=5.06 (d, 2H), 6.91 (d, 1H), 7.17 (m, 1H), 7.24 (m, 2H), 7 .27 (m, 2H),

7.32 (d, 1H), 7.49 (d, 1H), 7.51 (dd, 1H), 7.74 (t, 1H), 7.81 (d, 1H).

Intermediate b4: 1-(benzo[b]thiophen-7-yl)-4-methylpiperazine.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.27 (s, 3H), 2.54 (m, 4H), 3.14 (m, 4H), 6.97 (d, 1H), 7.33 (t, 1H), 7.43 (d, 1H), 7.55 (d, 1H), 7.71 (d, 1H).

Preparation of 3-formylbenzo[b]thiophene intermediates

General method with

Intermediate c1: 3-formylbenzo[b]thiophene-5-carbonitrile.

5-Cyanobenzo[b]thiophene (320 mg, 2 mmol) was dissolved in dry dichloroethane (4 ml) under nitrogen atmosphere. Dichloro(methoxy)methane (0.277 ml, 3 mmol) and titanium tetrachloride (0.33 ml) were added dropwise. The mixture was stirred at RT for 20 h, then poured into a mixture of NaHCO ₃ solution and ice and extracted with DCM. The organic phases were combined and concentrated and the residue was filtered off and washed with diethyl ether (yield: 32%).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=7.89 (dd, 1H), 8.39 (m, 1H), 8.86 (m, 1H), 9.16 (s, 1H), 10.16 (d, 1H).

The following derivatives were synthesized in the general manner described above and used in the next step without further purification:

Intermediate C2: 5-fluorobenzo[b]thiophene-3-carbaldehyde.

535 mg, 90%.

1H-NMR (400 MHz, DMSO-d6) δ=7.42 (m, 1H), 8.21 (m, 2H), 9.09 (s, 1H), 10.11 (s, 1H).

Intermediate c3: 5-morpholinobenzo[b]thiophene-3-carbaldehyde.

1H-NMR (400 MHz, DMSO-d6) δ=3.46 (m, 4H), 3.23 (m, 4H), 6.95 (d, 1H), 7.55 (dd, 1H), 7 .73 (d, 1H), 9.05 (s, 1H), 10.16 (s, 1H).

Intermediate C4: 5-(4-methylpiperazin-1-yl)benzo[b]thiophene-3-carbaldehyde.

1H-NMR (400 MHz, DMSO-d6) δ=2.19 (s, 3H), 2.49 (m, 4H), 3.25 (m, 4H), 7.23 (d, 1H), 7 .89 (d, 1H), 8.05 (d, 1H), 8.31 (s, 1H), 10.11 (s, 1H).

Intermediate C5: 5-(benzylamino)benzo[b]thiophene-3-carbaldehyde.

1H-NMR (400 MHz, DMSO-d6) δ=4.98 (d, 2H), 6.98 (d, 1H), 7.23 (dd, 1H), 7.17 (m, 1H), 7 .24 (m, 2H), 7.27 (m, 2H), 7.99 (d, 1H), 8.24 (t, 1H), 8.51 (s, 1H), 10.12 (s, 1H).

Intermediate c6: N-cyclopropyl-3-formylbenzo[b]thiophene-5-carboxamide.

1H-NMR (400 MHz, DMSO-d6) δ=0.60 (m, 2H), 0.71 (m, 2H), 2.93 (m, 1H), 7.68 (t, 1H), 7 .97 (d, 1H), 8.16 (d, 1H), 8.56 (dd, 1H), 9.09 (s, 1H), 10.15 (s, 1H).

Intermediate c7: N-(cyclopropylmethyl)-3-formylbenzo[b]thiophene-5-carboxamide.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.27 (m, 2H), 0.52 (m, 2H), 2.26 (m, 1H), 3.27 (m, 2H), 7.95 (d, 1H), 8.18 (dd, 1H), 8.48 (t, 1H), 8.53 (d, 1H), 9.04 (s, 1H), 10.12 (s , 1H).

Intermediate c8: 5-(4-methylpiperazine-1-carbonyl)benzo[b]thiophene-3-carbaldehyde.

1H-NMR (400 MHz, DMSO-d6) δ=2.16 (s, 3H), 2.29 (m, 4H), 3.41 (m, 4H), 7.97 (d, 1H), 8 .17 (d, 1H), 8.50 (d, 1H), 9.06 (s, 1H), 10.11 (s, 1H).

Intermediate C9: 5-(morpholine-4-carbonyl)benzo[b]thiophene-3-carbaldehyde.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=3.51 (m, 4H), 3.66 (m, 4H), 7.96 (d, 1H), 8.18 (d, 1H), 8.51 (d, 1H), 9.08 (s, 1H), 10.13 (s, 1H).

Intermediate c10: 3-formylbenzo[b]thiophene-7-carbonitrile.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=7.70 (t, 1H), 8.16 (d, 1H), 8.81 (d, 1H), 9.08 (s, 1H), 10.16 (s, 1H).

Intermediate c11: 7-(4-methylpiperazin-1-yl)benzo[b]thiophene-3-carbaldehyde.

1H-NMR (400 MHz, DMSO-d6) δ=2.91 (s, 4H), 3.30 (s, 6H), 3.49 (s, 9H), 7.16 (d, 1H), 7 .35 (t, 1H), 7.97 (d, 1H), 8.04 (d, 1H), 8.30 (d, 1H), 10.10 (s, 1H).

Intermediate C12: 7-(4-methylpiperazine-1-carbonyl)benzo[b]thiophene-3-carbaldehyde.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=3.41 (dd, 4H), 3.49 (dd, 4H), 3.90 (s, 3H), 7.66 (m, 1H), 8.23 (s, 2H), 9.08 (s, 1H), 10.15 (s, 1H).

Intermediate C13: N-cyclopropyl-3-formylbenzo[b]thiophene-7-carboxamide.

1H-NMR (400 MHz, DMSO-d6) δ=0.64 (dt, 2H), 0.75 (td, 2H), 2.93 (m, 1H), 7.64 (t, 1H), 8 .08 (dd, 1H), 8.72 (dd, 1H), 8.84 (d, 1H), 9.04 (s, 1H), 10.14 (s, 1H).

Intermediate C14: methyl 3-formylbenzo[b]thiophene-5-carboxylate.

The title compound was synthesized by the general method with and purified by homogenization with n-pentane to give a light brown solid (320 mg, 83%).

1H-NMR (400 MHz, DMSO-06) δ=3.97 (s, 3H), 7.73 (m, 1H), 8.20 (m, 1H), 8.85 (dd, 1H), 9 .08 (s, 1H), 10.15 (s, 1H).

The ester was hydrolyzed as follows.

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Intermediate C15: 3-formylbenzo[b]thiophene-5-carboxylic acid.

To a solution of methyl 3-formylbenzo[b]thiophene-5-carboxylate (320 mg, 1.45 mmol) in EtOH (15 mL) and water (5 mL) was added lithium hydroxide (230 mg, 9.6 mmol) at 0 °C. The mixture was stirred for 24 hours at room temperature. The product was isolated as a light yellow solid after acidification (pH 4-5) with 2 N HCl followed by filtration and washing with pentane (260 mg, 92% yield).

¹ H-NMR (400 MHz, DMSO-d6) δ=7.81 (m, 1H), 8.23 (m, 1H), 8.88 (dd, 1H), 9.08 (s, 1H), 10.15 (s, 1H), 12.45 (s, 1H).

Intermediate C16: 7-(2,2,2-trifluoroacetyl)benzo[b]thiophene-3-carbaldehyde.

The title compound was synthesized by the general method with and purified by flash column chromatography to give a yellow solid (0.31 g, 91%).

¹ H-NMR (300 MHz, CDCl3) δ=10.22 (s, 1H), 9.20 (s, 1H), 9.03 (d, J=8.0 Hz, 1H), 8.34 ( e, J=7.0 Hz, 1H), 7.88 (t, J=7.9 Hz, 1H).

¹⁹ F-NMR (282 MHz, CDCl3) δ=-68.92 (s, CF3).

Intermediate C17: 7-chlorobenzo[b]thiophene-3-carbaldehyde.

The title compound was synthesized by the general method with and purified by flash column chromatography to give a yellow solid (0.38 g, 48%).

¹ H-NMR (300 MHz, CDCl3-d) δ (ppm) δ 10.13 (s, 1H), 8.66-8.51 (m, 1H), 8.35 (s, 1H) , 7.53-7.41 (m, 2H).

Intermediate C18: 7-(trifluoromethyl)benzo[b]thiophene-3-carbaldehyde.

The title compound was synthesized by the general method with and purified by flash column chromatography to give a yellow solid (0.081 g, 16%).

¹ H-NMR (300 MHz, CDCl3-d) δ (ppm): 10.18 (s, 1H), 8.92 (d, J=8.0 Hz, 1H), 8.43 (s , 1H), 7.78 (d, J=7.5 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H).

¹⁹ F-NMR (282 MHz, CDCl ₃ -d) δ (ppm): -62.56 (CF ₃ ).

Intermediate C19: 7-fluorobenzo[b]thiophene-3-carbaldehyde.

The title compound was synthesized by the general method with and purified by flash column chromatography to give a yellow solid (0.27 g, 19%).

¹ H-NMR (300 MHz, CDCl3-d) δ (ppm): 10.15 (s, 1H), 8.45 (d, J=8.1 Hz, 1H), 8.34 (s , 1H), 7.48 (td, J=8.1, 5.1 Hz, 1H), 7.22-7.09 (m, 1H).

¹⁹ F-NMR (282 MHz, CDC^-d) δ (ppm): -115.33 (CF).

Intermediate C20: thieno[2,3-b]pyridine-3-carbaldehyde.

Step 1: 3-bromo-thieno[2,3-b]pyridine (500 mg, 2.35 mmol) and copper (I) cyanide (315 mg, 3.53 mmol) were suspended in NMP (10 ml) and stirred at 200°C for 20 h under N2 atmosphere. The solution was poured into saturated aqueous NaHCO ₃ , filtered and washed with water to give thieno[2,3b]pyridine-3-carbonitrile as a gray solid (376 mg, 95% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.65 (m, 1H), 8.39 (dd, 1H), 8.75 (m, 1H), 9.04 (d, 1H) .

Step 2: To a solution of diisobutylaluminum hydride (DIBAL) (25 wt% in toluene, 2.7 ml, 4.1 mmol) in toluene (45 ml) at -78° C. under N2 was added a solution of tueno[2, 3-b]pyridine-3carbonitrile (660 mg, 4.1 mmol) in toluene (4 ml). The temperature was allowed to rise to 0°C and the mixture was stirred until the reaction was complete. Then slowly added water (30 ml) and the product was extracted with AcOEt (3 times), dried over Na ₂ SO ₄ , filtered through silica gel and concentrated. The title compound was obtained as a brown solid and used in the next step without further purification (569 mg, 85% yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.60 (m, 1H), 8.68 (t, 1H), 8.80 (d, 1H), 9.08 (d, 1H) , 10.06 (s, 1H).

Intermediate C21: 5-fluoro-3-formylbenzo[b]thiophene-7-carbonitrile.

The title compound was obtained as a yellow solid (0.153 g, 58%) by the general method c.

¹ H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 10.14 (s, 1H), 8.68 (d, J=9.1 Hz, 1H), 8.53 ( s, 1H), 7.59 (d, J=9.1 Hz, 1H).

Intermediate C22: 4-fluoro-3-formylbenzo[b]thiophene-7-carbonitrile.

The title compound was obtained as a yellow solid (0.125 g, 33%) by the general method c.

¹ H-NMR (300 MHz, CDCl3-d) δ (ppm): 10.40 (s, 1H), 8.57 (s, 1H), 7.82 (dd, J=8.1, 4.4 Hz, 1H), 7.40-7.28 (m, 1H).

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Intermediate c23: 3-formylthieno[3,2-b]pyridine-7-carbonitrile.

This aldehyde was obtained in 4 stages using a different method.

First step: solution of 7-chlorothieno[3,2-b]pyridine (3.0 g, 17.68 mmol, 1.0 eq.), hydrobromic acid (30 ml, 265.28 mmol, 15 eq.) and bromine (2.28 ml, 44.20 mmol, 2.5 eq.) in water (40 ml) was stirred at 80° C. for 2 days. The mixture was cooled to room temperature and NaHCO ₃ was added until pH 8 was reached. The mixture was washed with ethyl acetate (3 times) and dichloromethane (2 times), dried over Na ₂ SO ₄ , concentrated and purified by silica gel flash column chromatography using hexane/ethyl acetate (15:1) as eluent to give 3-bromo-7-chlorothieno[3,2b]pyridine as a yellow solid (3.45 g, 79%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.74 (dd, J=5.0, 0.4 Hz, 1H), 7.84 (s, 1H), 7 .44-7.30 (m, 1H).

Second step: to a solution of 3-bromo-7-chlorothieno[3,2-b]pyridine (1.2 g, 4.82 mmol, 1.0 eq.), bis(triphenylphosphine)palladium (II) dichloride (0.338 g , 0.48 mmol, 0.1 eq.) and potassium carbonate (2.0 g, 14.48 mmol, 3 eq.) in a mixture of dimethyl ether and water (3:1) (32 ml) was added (E) styrylboronic acid (0.92 g, 6.28 mmol, 1.3 eq.). The resulting mixture was stirred at 110°C for 1 h. The mixture was cooled to RT, filtered through celite, washed with DCM, concentrated and purified by silica gel flash column chromatography using hexane/ethyl acetate (10:1) as eluent to obtain ( E)-7-Chloro-3-styrylthieno[3,2-b]pyridine as a yellow oil (0.870 g, 66%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.69 (d, J=5.6 Hz, 1H), 7.83 (s, 1H), 7.76 (d , J=16.4 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.53 (d, J=16.4 Hz, 1H), 7.42-7.33 (m, 3H), 7.29 (d, J=7.1 Hz, 1H).

Third stage: solution of (E)-7-chloro-3-styrylthieno[3,2-b]pyridine (0.870 g, 3.20 mmol, 1.0 eq.), zinc cyanide (0.75 g, 6.40 mmol, 2 eq.), tris(benzylideneacetone) dipalladium (0) (0.092 g, 0.16 mmol, 0.05 eq.), 1,1'-ferrocenedyl-bis-(diphenylphosphine) (0.234 g, 0.32 mmol, 0.1 eq.) and zinc (0.063 ml, 0.96 mmol, 0.3 eq.) in N,N-dimethylformamide (7 ml) were stirred at 160°C for 90 min. The mixture was cooled to RT, filtered through celite, washed with DCM, concentrated and purified by silica gel flash column chromatography using hexane/ethyl acetate (7:1) as eluent to give (E)-3-styrylthieno[3,2-b ]pyridine-7-carbonitrile as a light yellow solid (0.38 g, 47%).

Fourth step: a mixture of (E)-3-styrylthieno[3,2-b]pyridine-7-carbonitrile (0.370 g, 1.47 mmol, 1 eq.) and DCM (10 ml) at -78° C. N2 was bubbled into within 5 min. The mixture was then sparged with ozone for 15 minutes and dimethyl sulfide (1.1 ml, 14.78 mmol, 10 eq.) was added. The mixture was stirred at -78°C with nitrogen bubbling for 30 min, concentrated and purified by silica gel flash column chromatography using hexane/ethyl acetate (7:1) as eluent to give 3-formylthieno[3,2-b] pyridine-7-carbonitrile as a light yellow solid (0.125 g, 45%).

1H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 10.53 (s, 1H), 9.01 (d, J=4.7 Hz, 1H), 8.78 (s , 1H), 7.67 (d, J=4.7 Hz, 1H).

Intermediate c24: 3-formylbenzo[b]thiophene-5,7-dicarbonitrile.

This aldehyde was prepared starting from 5,7-dichlorobenzo[b]thiophene and following the 4-step synthesis described for intermediate c23, except that the cyanation reaction was carried out before the bromination step.

Yellow solid (0.22 g).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 10.18 (s, 1H), 9.28 (d, J=1.2 Hz, 1H), 8.60 (s , 1H), 8.04 (d, J=1.2 Hz, 1H).

Intermediate C25: 6-chloro-3-formylbenzo[b]thiophene-7-carbonitrile.

This aldehyde was prepared starting from 3-bromo-6-chlorobenzo[b]thiophene-7-carbonitrile and following steps 2 and 4 of the synthesis described for intermediate c23.

Yellow solid (0.29 g).

1H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 10.13 (s, 1H), 8.84 (d, J=8.8 Hz, 1H), 8.44 (s , 1H), 7.63 (d, J=8.8

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Hz, 1H).

Intermediate c26: 5-fluorothieno[2,3-b]pyridine-3-carbaldehyde.

A solution of 3-bromo-5-fluorothieno[2,3-b]pyridine (0.73 g, 3.14 mmol, 1.0 eq.) and copper cyanide (0.42 g, 4.72 mmol, 1.5 eq.) in N-methyl-2-pyrrolidone (18 ml) was stirred for 2 days in a sealed tube at 200°C, then cooled to RT and poured into saturated aqueous NaHCO ₃ (30 ml). This mixture was stirred at 4° C. for 60 minutes. The solid was filtered off and dissolved in a mixture of 40 ml NH4OH (28%)/NH ₄ Cl (sat.) (1:1) and ethyl acetate (60 ml), stirred for 1 h, and then extracted with ethyl acetate (3 times). The organic phase was dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel flash column chromatography using hexane/ethyl acetate (20:1) as eluent to give 5-fluorothieno[2,3-b]pyridine-3- carbonitrile as a white solid (0.32 g, 56%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.61 (d, J=2.4 Hz, 1H), 8.32 (s, 1H), 7.96 (dd , J=8.1, 2.7 Hz, 1H).

A solution of DIBAL-H (1.98 ml, 1.94 mmol, 1.1 eq.) in toluene. This mixture was stirred at -78°C for 5 minutes, then at -40°C for 6 hours and finally allowed to warm to RT. After adding water, the mixture was extracted with ethyl acetate (2 times), dried (Na ₂ SO ₄ ), concentrated and the residue was purified by flash silica gel column chromatography using hexane/ethyl acetate (10:1) as eluent to give 5-fluorothieno[2 ,3-b]pyridine3-carbaldehyde as a light yellow oil (0.149 g, 47%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 10.05 (s, 1H), 8.63 (dd, J=8.8, 2.6 Hz, 1H), 8 .56 (d, J=2.6 Hz, 1H), 8.50 (s, 1H).

Preparation of dicarbonyl intermediates

Dicarbonyl compounds were synthesized in accordance with the method described in the literature, as presented in the General methods below.

General method d (adapted from Haibin Mao et al., Chem. Int. Ed. 2013, 52, 6288-6291). O

Ao RXH--DD _R

X'O' \ Toluene, 160"C ^Λ

X=O,N; R= R ^fl , R ^s

To a solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (1 eq.) in toluene (5 M) at room temperature was added the corresponding alcohol or amine (1 eq.). The mixture was heated at 150°C for 6 h, then it was allowed to cool to room temperature and concentrated under vacuum. The residue was purified by silica gel flash column chromatography using ethyl acetate/hexane as eluent to give the dicarbonyl compound.

The following dicarbonyl compounds were synthesized by the general method d.

Intermediate d1: 2,2,2-trifluoroethyl-3-oxobutanoate.

Light brown oil (8.93 g, 70%).

1H-NMR (300 MHz, CDCl3) δ=4.53 (q, J=8.4 Hz, 1H), 3.57 (s, 1H), 2.28 (s, 1H).

¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=-73.92.

Intermediate d2: N,N-diethyl-3-oxobutanamide.

Yellow oil (1.5 g, 91%).

1H-NMR (300 MHz, CDCl ₃ ) δ=3.49 (s, 2H), 3.39 (q, J=7.1 Hz, 2H), 3.28 (q, J=7.2 Hz, 2H), 2.28 (s, 3H), 1.15 (dt, J=10.6, 7.1 Hz, 6H).

Intermediate d3: 1-(4-methylpiperazin-1-yl)butan-1,3-dione.

Yellow oil (1.8 g, 91%).

1H-NMR (300 MHz, CDCl ₃ ) δ=3.69-3.61 (m, 2H), 3.55 (s, 2H), 3.47-3.38 (m, 2H), 2.44 -2.33 (m, 4H), 2.30 (s, 3H), 2.27 (s, 3H).

Intermediate d4: 1-morpholinobutane-1,3-dione.

Dark yellow oil (1.6 g, 88%).

1H-NMR (300 MHz, CDCl ₃ ) δ=3.72-3.58 (m, 6H), 3.56 (s, 2H), 3.50-3.35 (m, 2H), 2.28 (s, 3H).

Intermediate d5: 2-methoxyethyl-3-oxobutanoate.

Yellow oil (1.5 g, 91%).

1 H-NMR (300 MHz, CDCl ₃ ) δ=4.34-4.24 (m, 2H), 3.65-3.55 (m, 2H), 3.49 (s, 2H), 3.38 (s, 3H), 2.27 (s, 3H).

Intermediate d6: 3-acetamidopropyl-3-oxobutanoate.

General method d using N-(3-hydroxypropyl)acetamide (obtained from K. Veejendra et al., J. Org. Chem. 2004, 69, 577-580) gave a light yellow oil (2.1 g, 92% ).

1H-NMR (300 MHz, CDCl ₃ ) δ=5.96 (br. s, 1H), 4.22 (t, J=6.0 Hz, 2H), 3.50 (s, 2H), 3, 33 (q, J=6.3 Hz, 2H), 2.28 (s, 3H), 1.98 (s, 3H), 1.93-1.80 (m, 2H).

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Intermediate d7: benzyl 3-oxobutanoate.

Light yellow oil (2 g, 98%).

1 H-NMR (300 MHz, CDCl ₃ ) δ=7.36 (s, 5H), 5.18 (s, 2H), 3.50 (s, 2H), 2.25 (s, 3H).

Intermediate d8: 2-morpholinoethyl-3-oxobutanoate.

Light yellow oil (2 g, 98%).

1H-NMR (300 MHz, CDCl ₃ ) δ=4.27 (t, J=5.8 Hz, 2H), 3.73-3.64 (m, 4H), 3.47 (s, 2H), 2.63 (t, J=5.8 Hz, 2H), 2.51-2.44 (m, 4H), 2.28 (s, 3H).

Intermediate d9: 2-(dimethylamino)ethyl-3-oxobutanoate.

Light yellow oil (2.1 g, 92%).

1H-NMR (300 MHz, CDCl3) δ=4.24 (t, J=5.7 Hz, 2H), 3.48 (s, 2H), 2.57 (t, J=5.7 Hz, 2H ), 2.27 (s, 9H).

Intermediate d10: 2-acetamidoethyl-3-oxobutanoate.

Yellow oil (1.1 g, 91%).

1H-NMR (300 MHz, CDCl3) δ=4.26 (t, J=4.6 Hz, 2H), 3.56-3.51 (m, 4H), 2.28 (s, 3H), 2 .00 (s, 3H).

Intermediate d11: cyclohexylmethyl-3-oxobutanoate.

Light yellow oil (1.4 g, 67%).

1H-NMR (300 MHz, CDCl ₃ ) δ=3.95 (d, J=6.4 Hz, 2H), 3.44 (s, 2H), 2.27 (s, 3H), 1.78- 1.56 (m, 6H), 1.331.09 (m, 3H), 1.06-0.83 (m, 2H).

Intermediate d12: pyridin-4-ylmethyl-3-oxobutanoate.

Yellow oil (1.2 g, 89%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.61 (d, J=5.6 Hz, 2H), 7.25 (d, J=4.1 Hz, 2H), 5.19 (s, 2H), 3.57 (s, 2H), 2.28 (s, 3H).

Intermediate d13: pyridin-2-ylmethyl-3-oxobutanoate.

Yellow oil (1.0 g, 74%).

1H-NMR (300 MHz, CDCl3) δ=8.58 (ddd, J=4.9, 1.8, 1.0 Hz, 1H), 7.71 (td, J=7.7, 1.8 Hz, 1H), 7.38 (ddt, J=7.8, 1.1, 0.6 Hz, 1H), 7.26-7.20 (m, 1H), 5.29 (s, 2H) , 3.57 (s, 2H), 2.28 (s, 3H).

Intermediate d14: 4-methoxybenzyl 3-oxobutanoate.

Light yellow oil (1.0 g, 43%).

1H-NMR (300 MHz, CDCl3) δ=7.29 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 5.10 (s, 2H ), 3.80 (s, 3H), 3.46 (s, 2H), 2.22 (s, 3H).

Intermediate d15: 2-((tert-butoxycarbonyl)oxy)ethyl 3-oxobutanoate.

Colorless oil (1.2 g, 46%).

1H-NMR (300 MHz, CDCl3) δ=4.32 (dd, J=19.8, 5.3 Hz, 4H), 3.47 (s, 2H), 2.27 (s, 2H), 1 .49 (s, 9H).

Intermediate d16: tert-Butyl 4-(((3-oxobutanoyl)oxy)methyl)piperidine-1carboxylate.

Yellow oil (0.46 g, 67%).

1H-NMR (300 MHz, CDCl ₃ ) δ=4.12 (d, J=14.5 Hz, 2H), 4.00 (d, J=6.5 Hz, 2H), 3.46 (s, 2H), 2.69 (t, J=12.5 Hz, 2H), 2.27 (s, 3H), 1.82 (s, 1H), 1.68 (d, J=13.6 Hz, 2H), 1.45 (s, 9H), 1.31-1.05 (m, 2H).

Intermediate d17: tetrahydro-2H-(pyran-4-yl)methyl-3-oxobutanoate.

Colorless oil (0.58 g, 83%).

1H-NMR (300 MHz, CDCl ₃ ) δ=4.05-3.92 (m, 4H), 3.47 (d, J=0.4 Hz, 2H), 3.39 (td, J=11 .9, 2.3 Hz, 2H), 2.27 (s, 3H), 2.03-1.83 (m, 1H), 1.63 (ddd, J=12.8, 3.9, 1 .9 Hz, 2H), 1.37 (dtd, J=13.3, 11.8, 4.5 Hz, 2H).

Intermediate d18: cyclohexyl-3-oxobutanoate.

Colorless oil (1.08 g, 84%).

1H-NMR (300 MHz, CDCl3) δ=4.81 (td, J=8.8, 3.8 Hz, 1H), 3.42 (s, 2H), 2.26 (s, 3H), 1 .91-1.80 (m, 2H), 1.77-1.66 (m, 2H), 1.61-1.49 (m, 2H), 1.47-1.29 (m, 4H) .

Intermediate d19: tetrahydro-2H-(pyran-4-yl)-3-oxobutanoate.

Colorless oil (0.6 g, 92%).

1H-NMR (300 MHz, CDCl3) δ=5.07-4.96 (m, 1H), 3.90 (dt, J=11.9, 4.6 Hz, 2H), 3.54 (ddd, J=11.9, 8.9, 3.0 Hz, 2H), 3.46 (s, 2H), 2.27 (s, 3H), 1.97-1.91 (m, 2H), 1 .70 (dtd, J=13.0, 8.9, 4.0 Hz, 2H).

Intermediate d20: cyclopropylmethyl-3-oxobutanoate.

Colorless oil (0.9 g, 82%).

1H-NMR (300 MHz, CDCl ₃ ) δ=3.97 (d, J=7.3 Hz, 2H), 3.46 (s, 2H), 2.28 (s, 3H), 1.23- 1.06 (m, 1H), 0.630.52 (m, 2H), 0.33-0.25 (m, 2H).

Intermediate d21: tert-butyl 4-(((3-oxobutanoyl)oxy)methyl)piperidine-1carboxylate.

Colorless oil (0.45 g, 71%).

1H-NMR (300 MHz, CDCl ₃ ) δ=4.13 (br. s, 2H), 4.00 (d, J=6.5 Hz, 2H), 3.46 (s, 2H), 2, 69 (t, J=12.7 Hz, 2H), 2.27 (s, 3H), 1.82 (tdd, J=15.2, 6.5, 3.5 Hz, 1H), 1.68 (d, J=12.7 Hz, 2H), 1.45 (s, 9H), 1.19 (dtd, J=12.7, 12.3, 5.7 Hz, 2H).

Intermediate d22: phenethyl 3-oxobutanoate.

Yellow oil (0.97 g, 58%).

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1H-NMR (300 MHz, CDCl ₃ ) δ=7.34-7.27 (m, 2H), 7.25-7.17 (m, 3H), 4.37 (t, J=7.0 Hz , 2H), 3.43 (s, 2H),

2.97 (t, J=7.0 Hz, 2H), 2.20 (s, 3H).

Intermediate d23: 1,3-dicyclopropylpropan-1,3-dione.

Colorless oil (1.3 g, 87%).

1H-NMR (300 MHz, CDCI3) δ=3.78 (s, 2H), 1.56 (td, J=8.0, 4.1 Hz, 2H), 1.15-1.03 (m, 4H), 0.98-0.85 (m, 4H).

Intermediate d24: methyl 3-cyclopropyl-3-oxopropanoate.

Light yellow oil (2.01 g, 79%).

1H-NMR (300 MHz, CDCl,) δ=3.74 (d, J=1.5 Hz, 3H), 3.58 (d, J=1.2 Hz, 2H), 2.17-1, 95 (m, 1H), 1.28-1.07 (m, 2H), 1.07-0.82 (m, 2H).

Intermediate d25: methyl 4-fluoro-3-oxobutanoate.

Light yellow oil (2.8 g, 78%).

1H-NMR (300 MHz, CDC13) δ=4.91 (d, J=47.5 Hz, 2H), 3.76 (s, 3H), 3.61 (d, J=3.7 Hz, 2H ).

%-NMR (282 MHz, CDC13) δ=123.96 (t, J=47.5 Hz).

Intermediate d26: methyl 4-(benzyloxy)-3-oxobutanoate.

Yellow oil (0.75 g, 51%).

1H-NMR (300 MHz, CDC13) δ=7.41-7.29 (m, 5H), 4.59 (s, 2H), 4.14 (s, 2H), 3.71 (s, 3H) , 3.56 (s, 2H).

Intermediate d27: methyl 3-oxo-4-phenoxybutanoate.

Yellow oil (47%).

1H-NMR (300 MHz, CDC13) δ=7.53-7.31 (m, 5H), 4.32 (s, 2H), 3.69 (s, 3H), 3.55 (s, 2H) .

Intermediate d28: 3-oxo-K-phenylbutanamide.

Yellow oil (0.98 g, 79%).

1H-NMR (300 MHz, CDC13) δ=9.08 (br. s, 1H), 7.54 (dt, J=8.8, 1.7 Hz, 2H), 7.38-7.28 ( m, 2H), 7.12 (tt, J=7.1, 1.1 Hz, 1H), 3.59 (s, 2H), 2.33 (s, 3H).

Intermediate d29: tert-butyl-4-((3-oxobutanoyl)oxy)piperidine-1-carboxylate.

Light yellow oil (1.3 g, 89%).

1H-NMR (300 MHz, CDCI3) δ=4.99 (tt, J=8.5, 3.6 Hz, 1H), 3.77-3.61 (m, 2H), 3.46 (s, 2H), 3.24 (ddd, J=13.3, 8.5, 3.6 Hz, 2H), 2.27 (s, 3H), 1.87 (ddt, J=12.9, 6, 5, 3.4 Hz, 2H), 1.63 (dp, J=12.9, 4.3 Hz, 2H), 1.46 (s, 9H).

Intermediate d30: cyclopentylmethyl-3-oxobutanoate.

Colorless oil (1.63 g, 84%).

1H-NMR (300 MHz, CDCI3) δ=4.03 (d, J=7.1 Hz, 2H), 3.45 (s, 2H), 2.27 (s, 3H), 2.24-2 .15 (m, 1H), 1.811.69 (m, 2H), 1.64-1.51 (m, 4H), 1.34-1.17 (m, 2H).

Intermediate d31: 1-methylpiperidin-4-yl-3-oxobutanoate.

Yellow oil (1.2 g, 57%).

1H-NMR (300 MHz, CDC13) δ=4.84 (tt, J=7.9, 3.8 Hz, 1H), 3.44 (s, 2H), 2.70-2.55 (m, 2H), 2.34-2.18 (m, 8H), 2.02-1.86 (m, 2H), 1.73 (dtd, J=12.7, 8.6, 3.8 Hz, 2H).

Intermediate d32: cyclopentyl 3-oxobutanoate.

Colorless oil (1.25 g, 70%).

1H-NMR (300 MHz, CDC13) δ=5.28-5.16 (m, 1H), 3.40 (s, 2H), 2.26 (s, 3H), 1.92-1.81 ( m, 2H), 1.76-1.66 (m, 4H), 1.63-1.54 (m, 2H).

Intermediate d33: 4,4-dimethylcyclohexyl-3-oxobutanoate.

Light yellow oil (0.42 g, 57%).

1H-NMR (300 MHz, CDC13) δ=4.80 (tt, J=8.8, 4.1 Hz, 1H), 3.42 (s, 2H), 2.27 (s, 3H), 1 .82-1.70 (m, 2H), 1.65-1.52 (m, 2H), 1.48-1.38 (m, 2H), 1.25 (ddd, J=14.0, 10.4, 4.1 Hz, 2H), 0.93 (s, 3H), 0.91 (s, 3H).

Intermediate d34: cyclobutyl 3-oxobutanoate.

Colorless oil (1.06 g, 51%).

1H-NMR (300 MHz, CDC13) δ=5.09-4.96 (m, 1H), 3.41 (s, 2H), 2.42-2.29 (m, 2H), 2.26 ( s, 3H), 2.14-2.00 (m, 2H), 1.86-1.54 (m, 2H).

Intermediate d35: 4-fluorobenzyl-3-oxobutanoate.

Colorless oil (1.32 g, 89%).

1H-NMR (300 MHz, CDCI3) δ=7.41-7.28 (m, 2H), 7.13-6.96 (m, 2H), 5.14 (s, 2H), 3.49 ( s, 2H), 2.24 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=-113.31.

Intermediate d36: pyridin-3-ylmethyl-3-oxobutanoate.

Light yellow oil (0.95 g, 70%).

1H-NMR (300 MHz, CDC13) δ=8.62 (d, J=2.2 Hz, 1H), 8.59 (dd, J=4.8, 1.6 Hz, 1H), 7.76 -7.65(m, 1H), 7.31(ddd, J=7.9, 4.8, 0.9Hz, 1H), 5.19(s, 2H), 3.51(s, 2H ), 2.25 (s, 3H).

Intermediate d37: tert-butyl 4-(((3-oxobutanoyl)oxy)methyl)benzoate.

Light yellow solid (0.59 g, 79%).

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1H-NMR (300 MHz, CDCl ₃ ) 6=7.96 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 5.15 (s, 2H), 1.93 (s, 2H),

1.93 (s, 3H), 1.59 (s, 9H).

Intermediate d38: 4-(cyclopropylcarbamoyl)benzyl 3-oxobutanoate.

A yellow oil (0.14 g, 76%) was obtained by general method d using N-cyclopropyl-4(hydroxymethyl)benzamide (J. Med. Chem., 2001, 44, 1491-1508).

1H-NMR (300 MHz, CDCl3) 6=7.73 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 6.23 (br.s , 1H), 5.20 (s, 2H), 3.52 (s, 2H), 2.90 (dc, J=7.2, 3.5 Hz, 1H), 2.25 (s, 3H) , 0.88 (k, J=6.5 Hz, 2H), 0.67-0.52 (m, 2H).

Intermediate d39: 4-bromobenzyl-3-oxobutanoate.

Yellow oil (0.5 g, 34%).

1H-NMR (300 MHz, CDCl,) δ=7.49 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 5.12 (s, 2H), 3.50 (s, 2H), 2.24 (s, 3H).

Intermediate d40: 3-bromobenzyl-3-oxobutanoate.

Yellow oil (1.5 g, 69%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.50 (d, J=1.8 Hz, 1H), 7.46 (dt, J=7.5, 1.8 Hz, 1H), 7, 29-7.21 (m, 2H), 5.13 (s, 2H), 3.51 (s, 2H), 2.25 (s, 3H).

Intermediate d41: 2-bromobenzyl-3-oxobutanoate.

Yellow oil (1.2 g, 83%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.56 (dd, J=7.8, 1.1 Hz, 1H), 7.41 (dd, J=7.5, 1.6 Hz, 1H ), 7.31 (td, J=7.5, 1.1 Hz, 1H), 7.18 (td, J=7.8, 1.6 Hz, 1H), 5.25 (s, 2H) , 3.52 (s, 2H), 2.26 (s, 3H).

Intermediate d42: (3-fluoropyridin-4-yl)methyl-3-oxobutanoate.

Yellow oil (0.305 g, 41%).

1H-NMR (300 MHz, CDCl3) δ=8.54-8.38 (m, 2H), 7.46-7.31 (m, 1H), 5.29 (s, 2H), 3.57 ( s, 2H), 2.29 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCl3) 6=-132.13 (s, CF).

Intermediate d43: pyrimidin-5-ylmethyl-3-oxobutanoate.

Yellow oil (0.65 g, 96%).

1H-NMR (300 MHz, CDCl3) 6=9.20 (s, 1H), 8.77 (s, 2H), 5.20 (s, 2H), 3.53 (s, 2H), 2.26 (s, 3H).

Intermediate d44: (5-bromopyrimidin-3-yl)methyl-3-oxobutanoate.

Yellow oil (0.5 g, 63%).

1H-NMR (300 MHz, CDCl3) 6=8.65 (d, J=2.0 Hz, 1H), 8.53 (s, 1H), 7.87 (s, 1H), 5.17 (s , 2H), 3.53 (s, 2H), 2.26 (s, 3H).

Intermediate d45: 3-cyanobenzyl-3-oxobutanoate.

Yellow oil (0.57 g, 75%).

1H-NMR (300 MHz, CDCl ₃ ) 6=7.68-7.57 (m, 3H), 7.53-7.45 (m, 1H), 5.20 (s, 2H), 3.54 (s, 2H), 2.27 (s, 3H).

Intermediate d46: 4-cyanobenzyl-3-oxobutanoate.

Yellow oil (0.62 g, 82%).

¹ H-NMR (300 MHz, CDCl3) 6=7.66 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 5.22 (s, 2H), 3.54 (s, 2H), 2.26 (s, 3H).

Intermediate d47: (6-chloropyridin-3-yl)methyl-3-oxobutanoate.

Yellow oil (0.69 g, 87%).

1H-NMR (300 MHz, CDCl ₃ ) 6=8.31 (s, 1H), 7.79-7.52 (m, 1H), 7.26 (d, J=8.2 Hz, 1H), 5.09 (s, 2H), 3.45 (s, 2H), 2.17 (s, 3H).

Intermediate d48: 3-morpholinobenzyl-3-oxobutanoate.

Yellow oil (0.71 g, 92%).

1H-NMR (300 MHz, CDCl3) 6=7.30 (d, J=7.9 Hz, 1H), 6.94-6.86 (m, 3H), 5.16 (s, 2H), 3 .90-3.86 (m, 4H), 3.51 (s, 2H), 3.21-3.17 (m, 4H), 2.27 (s, 3H).

Intermediate d49: (2-chloropyridin-4-yl)methyl-3-oxobutanoate.

Yellow oil (0.50 g, 63%).

1H-NMR (300 MHz, CDCl3) 6=8.41-8.33 (m, 1H), 7.32 (s, 1H), 7.19 (d, J=5.1 Hz, 1H), 5 .17 (s, 2H), 3.58 (s, 2H), 2.28 (s, 3H).

Intermediate d50: 4,4-difluorocyclohexyl-3-oxobutanoate.

Yellow oil (0.35 g, 91%).

1H-NMR (300 MHz, CDCl ₃ ) 6=4.93 (s, 1H), 4.53 (s, 2H), 2.04 (d, J=1.1 Hz, 3H), 1.89- 1.78 (m, 8H).

¹⁹ B-NMR (282 MHz, CDCl3) 6=-94.48 (d, J=252.2 Hz, CF), -100.51 (d, J=235.8 Hz, CF).

Intermediate d51: K-benzyl-K-methyl-3-oxobutanamide.

Yellow oil (2.50 g, 86%).

1H-NMR (300 MHz, CDCl ₃ ) 6=7.38-7.23 (m, 5H), 4.56 (d, J=32.5 Hz, 3H), 3.60 (d, J=12 .5 Hz, 2H), 2.89 (s, 2H), 2.29 (s, 3H).

Intermediate d52: 4-chlorobenzyl-3-oxobutanoate.

Yellow oil (0.5 g, 34%).

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1H-NMR (300 MHz, CDCl3) δ=7.49 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 5.12 (s, 2H ), 3.50 (s, 2H),

2.24 (s, 3H).

Intermediate d53: 3-chlorobenzyl-3-oxobutanoate.

Yellow oil (0.119 g, 75%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 7.35 (s, 1H), 7.33-7.27 (m, 2H), 7.25-7.19 (m , 1H), 5.14 (s, 2H), 3.52 (s, 2H), 2.26 (s, 3H).

Intermediate d54: 2-phenylpropan-2-yl-3-oxobutanoate.

The title compound as a yellow oil (2.46 g, 76%) was obtained by modified method d using 4-methylenexetan-2-one (1 eq.) and sodium acetate (0.1 eq.).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.41-7.27 (m, 5H), 3.42 (s, 2H), 2.25 (s, 3H), 1.80 (s, 6H ).

Intermediate d55: 2-(4-fluorophenyl)propan-2-yl-3-oxobutanoate.

The title compound as a yellow oil (0.52 g, 34%) was obtained by modified method d using 4-methylenexetan-2-one (1 eq.).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.40-7.31 (m, 2H), 7.05-6.95 (m, 2H), 3.41 ( s, 2H), 2.23 (s, 3H), 1.78 (s, 6H).

¹⁹ F-NMR (282 MHz, CDCl ₃ -d) δ (ppm): -115.79 (CF).

Intermediate d56: 2H-thiopyran-3,5-(4H,6H)-dione.

A yellow oil (2.1 g, 52%) was obtained by the synthesis method described in J. Org. Chem. 1977, 42, 11631169.

1 H-NMR (300 MHz, CDCl ₃ ) δ=3.57 (s, 2H), 3.39 (s, 4H).

Intermediate d57: 3-((4-methylpiperazin-1-yl)methyl)benzyl-3-oxobutanoate.

Step 1: Synthesis of 3-((4-methylpiperazin-1-yl)methyl)benzoate.

To a solution of 1-methylpiperazine (3.0 ml, 26.89 mmol, 3.08 eq.) in acetone (35 ml) was added potassium carbonate (2.41 g, 17.46 mmol, 2 eq.). The mixture was stirred for 10 minutes. Then methyl-3-bromobenzoate (2.0 g, 8.73 mmol, 1.0 eq.) was added and the mixture was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was concentrated and purified by silica gel flash column chromatography using dichloromethane/3% methanol as eluent to give methyl 3-((4-methylpiperazin-1-yl)methyl)benzoate as a yellow oil (2.1 g, 97%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.97 (s, 1H), 7.92 (dt, J=7.7, 1.4 Hz, 1H), 7 .53 (d, J=7.7 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 3.91 (s, 3H), 3.55 (s, 2H), 2 .48 (br. s, 8H), 2.29 (s, 3H).

Step 2: Synthesis of (3-((4-methylpiperazin-1-yl)methyl)phenyl)methanol.

Diisobutylaluminum hydride (18.73 ml, 18.73 mmol, 2.26 eq.). The mixture was stirred at room temperature for 5 hours. Then a solution of Rochelle's salt (105 ml) and dichloromethane (105 ml) were added. The mixture was stirred at room temperature for 60 minutes and then extracted with dichloromethane (3 times) and dried (Na ₂ SO ₄ ). The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography using dichloromethane/7% methanol as eluent to give (3-((4-methylpiperazin-1-yl)methyl)phenyl)methanol as a yellow oil (1 .75 g, 98%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.32-7.15 (m, 4H), 4.62 (s, 2H), 3.71 (t, J= 6.2 Hz, 1H), 3.45 (s, 2H), 2.37 (br. s, 8H), 2.20 (s, 3H).

Step 3: Synthesis of 3-((4-methylpiperazin-1-yl)methyl)benzyl-3-oxobutanoate.

The title compound as a yellow oil (0.55 g, 81%) was obtained by converting (3-((4methylpiperazin-1-yl)methyl)phenyl)methanol using general method d.

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 7.36-7.28 (m, 3H), 7.24-7.20 (m, 1H), 5.17 (s , 2H), 3.52 (s, 2H),

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3.50 (s, 2H), 2.53 (br.s, 8H), 2.34 (s, 3H), 2.25 (s, 3H).

Intermediate d58: cyclopropyl-3-oxobutanoate.

The title compound as a yellow oil (1.99 g, 81%) was obtained by modified method d using 4-methylenexetan-2-one (1 eq.) and sodium acetate (0.1 eq.).

1H-NMR (300 MHz, CDClj) δ=4.19-4.04 (m, 1H), 3.39 (s, 2H), 2.22 (s, 3H), 0.79-0.58 ( m, 4H).

Intermediate d59: prop-2-yn-1-yl-3-oxobutanoate.

The title compound as a yellow oil (2.5 g, 91%) was obtained by General method d.

1H-NMR (300 MHz, CDClj) δ=4.74 (d, J=2.5 Hz, 2H), 3.50 (s, 2H), 2.50 (t, J=2.5 Hz, 1H ), 2.28 (s, 3H).

Intermediate d60: but-2-yn-1-yl-3-oxobutanoate.

The title compound as a yellow oil (3.0 g, 92%) was obtained by general method d.

1H-NMR (300 MHz, CDClj) δ=4.65 (q, J=2.2 Hz, 2H), 3.44 (s, 2H), 2.22 (s, 3H), 1.80 (t , J=2.2 Hz, 3H).

Intermediate d61: 2,2,2-trifluoroethyl-3-oxobutanoate.

The title compound as a yellow oil (2.1 g, 81%) was obtained by General method d.

1H-NMR (300 MHz, CDClj) δ=4.53 (q, J=7.6, 6.9 Hz, 2H), 3.57 (s, 2H), 2.29 (s, 3H).

General method e.

Intermediate e1: oxetan-3-yl-3-cyclopropyl-3-oxopropanoate.

But

To a solution of methyl 3-cyclopropyl-3-oxopropanoate (1 g, 7.03 mmol, 1.2 eq.) in toluene (5 ml) was added oxetan-3-ol (0.37 ml, 5.87 mmol, 1 equiv.). The resulting mixture was refluxed using a Dean-Stark trap for 12 h, cooled to RT and concentrated. The resulting residue was purified by silica gel flash column chromatography using ethyl acetate/hexane (1:3) as eluent to give the title compound as a light yellow oil (0.52 g, 44%).

1H-NMR (300 MHz, CDCl ₃ ) δ=5.50 (n, J=5.8 Hz, 1H), 4.99-4.81 (m, 2H), 4.66 (dd, J=7 .8, 5.8 Hz, 2H), 3.63 (s, 2H), 2.02 (tt, J=7.8, 4.5 Hz, 1H), 1.17-1.08 (m, 2H), 1.05-0.93 (m, 2H).

Intermediate e2: isopropyl-3-cyclopropyl-3-oxopropanoate.

The title compound was obtained as a light yellow oil (0.9 g, 75%) by general method e.

1H-NMR (300 MHz, CDCl ₃ ) δ=5.06 (heptet, J=6.4 Hz, 1H), 3.52 (s, 2H), 2.14-1.93 (m, 1H), 1.26 (s, 3H), 1.24 (s, 3H), 1.15-1.06 (m, 2H), 1.00-0.90 (m, 2H).

Intermediate e3: benzyl 4,4,4-trifluoro-3-oxobutanoate.

The title compound as a red oil (1.8 g, 62%) was obtained by the general method e.

1H-NMR (300 MHz, CDCl3) δ=7.37 (s, 5H), 5.24 (s, 2H), 2.86 (s, 2H).

¹⁹ F-NMR (282 MHz, CDCf) δ=-87.15.

Intermediate e4: 2-phenylpropan-2-yl-3-cyclopropyl-3-oxopropanoate.

The title compound as a yellow oil (0.41 g, 29%) was obtained by general method e using 1 eq. DMAP.

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 7.40-7.31 (m, 4H), 7.23 (d, J=6.9 Hz, 1H), 3, 53 (s, 2H), 2.03-1.99 (m, 1H), 1.80 (s, 6H), 1.15-1.09 (m, 2H), 1.00-0.89 ( m, 2H).

Intermediate e5: cyclohexyl-3-cyclopropyl-3-oxopropanoate.

The title compound was obtained as a light yellow solid (1.2 g, 85%) by General Method e.

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 4.91-4.75 (m, 1H), 3.52 (s, 2H), 2.12-1.95 ( m, 1H), 1.93-1.79 (m, 2H), 1.78-1.60 (m, 2H), 1.53-1.23 (m, 6H), 1.18-1, 04 (m, 2H), 1.03-0.88 (m, 2H).

Intermediate e6: 3-chlorobenzyl-3-cyclopropyl-3-oxopropanoate.

The title compound as a yellow oil (0.69 g, 78%) was obtained by the general method e.

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.35 (s, 1H), 7.32-7.27 (m, 2H), 7.25-7.20 ( m, 1H), 5.15 (s, 2H), 3.63 (s, 2H), 2.09-1.92 (m, 1H), 1.20-1.05 (m, 2H), 1 .03-0.87 (m, 2H).

Intermediate e7: 2-(4-fluorophenyl)propan-2-yl-3-cyclopropyl-3-oxopropanoate.

The title compound as a yellow oil (0.52 g, 35%) was obtained by the general method e.

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 7.40-7.31 (m, 2H), 7.05-6.96 (m, 2H), 3.53 (s , 2H), 2.01 (tt, J=7.7, 4.4 Hz, 1H), 1.78 (s, 6H), 1.12 (pd, J=3.5, 1.4 Hz, 2H), 0.96 (dt, J=7.7, 3.5 Hz, 2H).

¹⁹ F-NMR (282 MHz, CDCf-d) δ (ppm): -115.92 (CF).

Intermediate e8: cyclopropylmethyl-3-cyclopropyl-3-oxopropanoate.

The title compound as a light yellow oil (2.2 g, 84%) was obtained by general method e using 1 eq. DMAP.

1 H-NMR (300 MHz, CDCl3-d) δ (ppm): 3.98 (d, J=7.3 Hz, 2H), 3.58 (s, 2H), 2.05 (tt, J=7.9, 4.6 Hz, 1H), 1.24-1.04 (m, 3H), 1.02-0.91 (m, 2H), 0.61-0.51 (m, 2H), 0.29 (dt, J=6.4, 4.6 Hz, 2H).

Intermediate e9: 3-bromobenzyl-3-cyclopropyl-3-oxopropanoate.

The title compound as a yellow oil (0.28 g, 27%) was obtained by the general method e.

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1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.51 (s, 1H), 7.45 (dt, J=7.5, 1.7 Hz, 1H), 7 .31-7.21 (m, 2H), 5.14 (s, 2H), 3.63 (s, 2H), 2.01 (tt, J=7.7, 4.5 Hz, 1H), 1.21-1.06 (m, 2H), 1.01-0.87 (m, 2H).

Intermediate e10: cyclopentyl-3-cyclopropyl-3-oxopropanoate.

The title compound as a light yellow oil (0.54 g, 79%) was obtained by the general method e.

1 H-NMR (300 MHz, CDCl3-d) δ (ppm): 5.22 (tt, J=6.0, 2.7 Hz, 1H), 3.51 (s, 2H), 2, 02 (tt, J=7.8, 4.5 Hz, 1H), 1.92-1.78 (m, 2H), 1.77-1.65 (m, 4H), 1.64-1, 53 (m, 2H), 1.16-1.04 (m, 2H), 0.95 (dt, J=7.8, 3.2 Hz, 2H).

Intermediate e11: cyclopentyl-2-cyanoacetate.

The title compound as a light yellow oil (2.34 g, 50%) was obtained by General Method e.

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 5.25 (td, J=5.8, 2.9 Hz, 1H), 3.41 (s, 2H), 1 .96-1.82 (m, 2H), 1.811.68 (m, 4H), 1.67-1.55 (m, 2H).

General method f.

Synthesis method adapted from Sabitha-G et al., Bismuth(III) Chloride-Catalyzed Highly Efficient Transeterification of β-Keto Esters, Helvetica Chimica Acta, Vol. 94; 2011.

Intermediate f1: pyridin-4-ylmethyl-3-cyclopropyl-3-oxopropanoate.

In a sealed flask, a mixture of 2.0 g molecular sieves, 500 mg (4.58 mmol) pyridin-4-ylmethanol, 0.83 ml (6.87 mmol) methyl 3-cyclopropyl-3-oxopropanoate and 10% (0. 45 mmol) of bismuth (III) chloride in 10 ml of dry toluene was stirred at reflux for 36 h. The reaction mixture was filtered and the filtrate was concentrated, the remaining solid was purified using silica gel column chromatography (cyclohexane/ethyl acetate) to obtain the desired β ketoester (455 mg, 45%).

1H-NMR (400 MHz, DMSO-d6) δ=0.94 (m, 4H), 2.12 (ddd, 1H), 3.86 (s, 2H), 5.20 (s, 2H), 7 .36 (d, 2H), 8.56 (d, 2H).

HPLC-MS: retention time 3.040; m/z 220.1 (MH ⁺ ).

The following intermediates were synthesized by the general method f.

Intermediate f2: 4-fluorobenzyl-3-cyclopropyl-3-oxopropanoate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.91 (m, 4H), 2.08 (m, 1H), 3.77 (s, 2H), 5.12 (s, 2H), 7.21 (t, 2H), 7.43 (dd, 2H).

Intermediate f3: 4-cyanobenzyl-3-cyclopropyl-3-oxopropanoate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.93 (m, 4H), 2.10 (ddd, 1H), 3.83 (s, 2H), 5.24 (s, 2H), 7.56 (d, 2H), 7.86 (d, 2H).

HPLC-MS: Rt 4.133; m/z 244.0 (MH ⁺ ).

General method g (adapted from M. A. Walker et al., Bioorg. Med. Chem. Lett. 2006, 16, 2920-2924).

The aromatic ketone (1 eq) was dissolved in THF (0.5 M) at room temperature and potassium tert-butoxide (3 eq) was added. The mixture was stirred for 5 minutes before dimethyl carbonate (10 eq.) was added. The reaction mixture was stirred at RT for 5 h, concentrated and quenched with water. The mixture was extracted with dichloromethane (3 times) and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica gel flash column chromatography using ethyl acetate/hexane as eluent to give the corresponding dicarbonyl compound.

The following intermediates were synthesized by the general method g.

Intermediate g1: methyl 3-oxo-3-phenylpropanoate.

Yellow oil (1.11 g, 66%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.95 (d, J=7.8 Hz, 2H), 7.65-7.41 (m, 3H), 4.01 (s, 2H), 3.76 (s, 3H).

Intermediate g2: methyl 3-oxo-3-(pyridin-3-yl)propanoate.

Yellow oil (1.22 g, 83%).

1H-NMR (300 MHz, CDCl ₃ ) δ=9.15 (dd, J=2.3, 1 Hz, 1H), 8.81 (dd, J=4.8, 1.7 Hz, 1H), 8.23 (ddd, J=8.0, 2.3, 1.7 Hz, 1H), 7.45 (ddd, J=8.0, 4.8, 0.9 Hz, 1H), 4, 02 (s, 2H), 3.76 (s, 3H).

Intermediate g3: 1-phenylpentan-2,4-dione.

Yellow oil (1.11 g, 66%).

1 H-NMR (300 MHz, CDCl ₃ ) δ=7.37-7.26 (m, 5H), 3.59 (s, 4H), 2.02 (s, 3H).

Intermediate g4: 1,3-dicyclopropylpropan-1,3-dione.

Light yellow oil (1.3 g, 87%).

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1H-NMR (300 MHz, CDCl ₃ ) δ=3.78 (s, 2H), 2.03 (td, J=7.9, 3.9 Hz, 2H), 1.14-1.04 (m , 8H).

Intermediate g5: tert-butyl-3-(3-methoxy-3-oxopropanoyl)azetidine-1-carboxylate.

Yellow oil (0.4 g, 63%).

1H-NMR (300 MHz, CDCl3) δ=4.11-3.98 (m, 4H), 3.73 (s, 3H), 3.66-3.53 (m, 1H), 3.47 ( s, 2H), 1.42 (s, 9H).

Intermediate g6: 1-(pyridin-3-yl)butan-1,3-dione.

Yellow oil (0.20 g, 30%).

1H-NMR (300 MHz, CDCl ₃ ) δ=15.95 (s, 1H), 9.05 (d, J=2.1 Hz, 1H), 8.71 (dd, J=4.8, 1 .6 Hz, 1H), 8.14 (dt, J=8.0, 2.0 Hz, 1H), 7.38 (ddd, J=8.0, 4.9, 0.9 Hz, 1H) , 6.17 (s, 1H), 2.21 (s, 3H).

Intermediate g7: methyl 3-cyclobutyl-3-oxopropanoate.

Colorless oil (1.97 g, 62%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 3.71 (s, 3H), 3.45-3.31 (m, 3H), 2.32-2.06 ( m, 4H), 2.05-1.74 (m, 2H).

Intermediate g8: methyl 3-cyclopentyl-3-oxopropanoate.

Colorless oil (0.51 g, 67%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 3.73 (s, 3H), 3.50 (s, 2H), 2.98 (n, J=7.9 Hz, 1H), 1.89-1.73 (m, 4H), 1.68-1.57 (m, 4H).

Intermediate g9: methyl 3-cyclohexyl-3-oxopropanoate.

Colorless oil (1.14 g, 78%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 3.71 (s, 3H), 3.48 (s, 2H), 2.44 (tt, J=11.1, 3 .4 Hz, 1H), 1.91-1.83 (m, 2H), 1.84-1.71 (m, 2H), 1.44-1.13 (m, 6H).

Intermediate g10: (Z)-3-amino-3-cyclopropylacrylonitrile. Colorless oil (1.3 g, 81%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 4.63 (br. s, 2H), 3.78 (s, 1H), 1.54-1.35 (m, 1H), 1.00-0.81 (m, 2H), 0.81-0.60 (m, 2H).

General method h (taken from S. Mitsuhashi et al., J. Am. Chem. Soc. 2008, 130, 4140).

Getting ketoesters:

OO OO

Alcohol (1.1 eq.) was added dropwise to a suspension of sodium hydride (2.2 eq.) in THF (0.5 M) at RT. The mixture was stirred for 5 minutes before methyl 4-chloro-3-oxobutanoate (1 eq.) was added dropwise. This mixture was stirred for 30 minutes and then concentrated in vacuo. Water was added and the pH was adjusted to 6-7 by adding an aqueous solution of 2 N HCl. The resulting mixture was extracted with dichloromethane (2 times) and ethyl acetate (2 times) and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography using ethyl acetate/hexane as eluent to give the corresponding dicarbonyl compound.

Getting Ketoamines:

Methyl 4-chloro-3-oxobutanoate (1 eq) was dissolved in acetone (0.5 M) at RT and amine (1.1 eq) was added. The mixture was stirred for 5 minutes before adding trimethylamine (2 eq.). This mixture was stirred at 100° C. for 3 hours and then concentrated in vacuo. The residue was taken up in water and extracted with dichloromethane (2 times) and ethyl acetate (2 times). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography using ethyl acetate/hexane as eluent to give the corresponding dicarbonyl compound.

The following intermediates were synthesized by the general method h.

Intermediate h1: methyl 4-methoxy-3-oxobutanoate.

Colorless oil (0.9 g, 93%).

1H-NMR (300 MHz, CDCl3) δ=4.10 (s, 2H), 3.75 (s, 3H), 3.50 (s, 2H), 3.40 (s, 3H).

Intermediate h2: methyl 4-(dimethylamino)-3-oxobutanoate.

Light yellow oil (0.37 g, 35%).

¹ H-NMR (300 MHz, CDCl3) δ=3.73 (s, 3H), 3.51 (s, 2H), 3.20 (s, 2H), 2.28 (s, 6H).

Intermediate h3: methyl 4-morpholino-3-oxobutanoate. Light yellow oil (0.5 g, 37%).

1H-NMR (300 MHz, CDCl3) δ=3.76-3.78 (m, 7H), 3.51 (s, 2H), 3.25 (s, 2H), 2.55-2.43 ( m, 4H).

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Preparation of enamine intermediates

General method i.

Intermediate i1: dimethyl-(2)-3-aminopent-2-enedioate.

O O O ic int O NH? ABOUT

Ammonium bicarbonate (1.13 g, 14.35 mmol, 2 .5 equiv.). The mixture was stirred at room temperature overnight and then concentrated. The resulting residue was purified by silica gel flash column chromatography using ethyl acetate/hexane (1:3) as eluent to give dimethyl (2)-3-aminopent-2-enedioate as a yellow oil (0.8 g, 81%) .

1H-NMR (300 MHz, CDCl3) δ=7.81 (br.s, 1H), 5.50 (br.s, 1H). 4.58 (s, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 3.15 (s, 2H).

The following intermediates were synthesized by the general method i.

Intermediate i2: cyclopropylmethyl-(2)-3-aminobut-2-enoate.

White solid (0.45 g, 53%).

1H-NMR (300 MHz, CDCl3) δ=7.91 (br. s, 2H), 4.56 (s, 1H), 3.88 (d, J=1.2 Hz, 2H), 1.90 (s, 3H), 1.191.07 (m, 1H), 0.58-0.50 (m, 2H), 0.32-0.23 (m, 2H).

Intermediate i3: methyl-(I)-3-amino-5-methoxypent-2-enoate.

Light yellow oil (0.93 g, 94%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.83 (br.s, 1H), 5.50 (br.s, 1H), 4.49 (s, 1H), 3.63 (s, 3H ), 3.59-3.54 (m, 2H), 3.36 (s, 3H), 2.37 (t, J=5.7 Hz, 2H).

Intermediate i4: methyl-(2)-3-amino-4-(benzyloxy)but-2-enoate.

Orange oil (0.55 g, 76%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.41-7.36 (m, 1H), 7.36-7.30 (m, 4H), 6.61 (br. s, 1H), 5 .27 (br. s, 1H), 4.58-4.54 (m, 1H), 4.52 (s, 2H), 4.07 (d, J=0.7 Hz, 2H), 3, 66 (s, 3H).

Intermediate i5: methyl-(2)-3-amino-4-phenoxybut-2-enoate.

Yellow solid (0.11 g, 65%).

1H-NMR (300 MHz, CDCl3) δ=7.35-7.27 (m, 2H), 7.05-6.87 (m, 3H), 5.86 (br. s, 2H), 4, 74-4.67 (m, 1H), 4.59 (d, J=0.8 Hz, 2H), 3.68 (s, 3H).

Intermediate i6: 5-amino-2H-thiopyran-3(6H)-one.

Brown solid (0.05 g, 35%).

1 H-NMR (300 MHz, CDCl ₃ ) δ=6.97 (br. s, 2H), 4.94 (s, 1H), 3.31 (s, 2H), 3.03 (s, 2H).

Intermediates i7 and i8: (2)-4-amino-1-methoxypent-3-en-2-one and (2)-4-amino-5-methoxypent-3-en-2-one.

A mixture of the title compounds, which was separated by flash chromatography, was obtained by the general method i.

i7: (2)-4-amino-1-methoxypent-3-en-2-one; light yellow oil, 0.703 g, 74%.

1H-NMR (300 MHz, CDCl3) δ=9.56 (br. s, 1H), 5.72 (br. s, 1H), 5.00 (s, 1H), 3.97 (s, 2H) , 3.38 (s, 3H), 2.05 (s, 3H).

i8: (2)-4-amino-5-methoxypent-3-en-2-one; light yellow oil, 0.25 g, 26%.

1H-NMR (300 MHz, CDCl3) δ=9.85 (br.s, 1H), 5.31 (s, 1H), 5.12 (br.s, 1H), 3.89 (s, 2H) , 3.41 (s, 3H), 1.97 (s, 3H).

Intermediate i9: methyl-(2)-3-amino-4-fluorobut-2-enoate.

Yellowish solid (0.22 g, 55%).

1H-NMR (300 MHz, CDCl ₃ ) δ=6.35 (br. s, 2H), 4.89 (d, J=46.9 Hz, 2H), 4.59 (s, 1H), 3, 67 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=122.24 (t, J=46.9 Hz).

Intermediate i10: cyclohexylmethyl-(2)-3-aminobut-2-enoate.

Yellowish oil (0.8 g, 73%).

1H-NMR (300 MHz, CDCl3) δ=7.88 (s, 2H), 4.53 (s, 1H), 3.86 (d, J=6.6 Hz, 2H), 1.90 (s , 3H), 1.87-1.47 (m, 6H), 1.38-1.12 (m, 3H), 1.08-0.76 (m, 2H).

Intermediate i11: cyclopentylmethyl-(2)-3-aminobut-2-enoate.

Yellowish oil (0.3 g, 55%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.92 (s, 2H), 4.54 (s, 1H), 3.93 (d, J=7.1 Hz, 2H), 2.20 ( n, J=7.5 Hz, 1H), 1.90 (s, 3H), 1.74 (dtdd, J=13.6, 7.5, 5.2, 3.4 Hz, 2H), 1 .67-1.46 (m, 4H), 1.34-1.18 (m, 2H).

Intermediate i12: cyclohexyl-(2)-3-aminobut-2-enoate.

Yellowish oil (0.75 g, 63%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.90 (s, 2H), 4.73 (tt, J=8.8, 4.3 Hz, 1H), 4.52 (s, 1H), 2.27 (s, 3H), 1.72 (d, J=10.3 Hz, 4H), 1.61-1.49 (m, 4H), 1.49-1.35 (m, 2H) .

Intermediate i13: cyclopentyl-(2)-3-aminobut-2-enoate.

Yellowish oil (0.17 g, 24%).

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1H-NMR (300 MHz, CDCl ₃ ) δ=7.90 (s, 2H), 4.73 (tt, J=8.8, 4.3 Hz, 1H), 4.52 (s, 1H), 2.27 (s, 3H), 1.72 (d, J=10.3 Hz, 2H), 1.61-1.49 (m, 4H), 1.49-1.35 (m, 2H) .

Intermediate i14: benzyl-(Z)-3-aminobut-2-enoate.

Yellowish oil (0.203 g, 68%).

1H-NMR (300 MHz, CDCl3) δ=7.91 (s, 2H), 7.36-7.28 (m, 5H), 5.12 (s, 2H), 4.61 (s, 1H) , 1.91 (s, 3H).

Intermediate i15: (tetrahydro-2H-pyran-4-yl)methyl (Z)-3-aminobut-2-enoate.

Yellowish oil (0.23 g, 77%).

1H-NMR (300 MHz, CDCl3) δ=7.85 (s, 2H), 4.51 (s, 1H), 4.05-3.85 (m, 4H), 3.37 (td, J= 11.8, 2.2 Hz, 2H), 1.96-1.86 (m, 4H), 1.62 (ddt, J=10.8, 4.3, 2.2 Hz, 2H), 1 .35 (dtd, J=13.3, 11.8, 4.5 Hz, 2H).

Intermediate i16: (tetrahydro-2H-pyran-4-yl)methyl (Z)-3-aminobut-2-enoate.

Yellowish oil (0.23 g, 77%).

1H-NMR (300 MHz, CDCl3) δ=7.85 (s, 2H), 4.51 (s, 1H), 4.05-3.85 (m, 4H), 3.37 (td, J= 11.8, 2.2 Hz, 2H), 1.96-1.86 (m, 4H), 1.62 (ddt, J=10.8, 4.3, 2.2 Hz, 2H), 1 .35 (dtd, J=13.3, 11.8, 4.5 Hz, 2H).

Intermediate i17: pyridin-4-ylmethyl-(Z)-3-aminobut-2-enoate.

Yellow oil (0.19 g, 69%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.71-8.39 (m, 2H), 7.89 (s, 2H), 7.29-7.23 (m, 2H), 5.13 (s, 2H), 4.64 (s, 1H), 1.94 (s, 3H).

Intermediate i18: 4-fluorobenzyl-(Z)-3-aminobut-2-enoate.

Yellow oil (0.72 g, 96%).

¹ H-NMR (300 MHz, CDCl3) δ=7.96 (s, 2H), 7.40-7.30 (m, 2H), 7.11-6.89 (m, 2H), 5.07 (s, 2H), 4.58 (s, 1H), 1.97-1.81 (m, 3H).

Intermediate i19: tert-butyl-(Z)-4-(((3-aminobut-2-enoyl)oxy)methyl)benzoate.

Yellow oil (0.40 g, 89%).

¹ H-NMR (300 MHz, CDCl3) δ=7.98-7.92 (m, 2H), 7.42-7.33 (m, 2H), 5.15 (s, 2H), 4.61 (s, 1H), 1.92 (s, 3H), 1.58 (s, 9H) 1.28 (s, 2H).

Intermediate i20: pyridin-3-ylmethyl-(Z)-3-aminobut-2-enoate.

Yellowish oil (0.50 g, 71%).

1H-NMR (300 MHz, CDCl3) δ=8.62 (d, J=1.7 Hz, 1H), 8.54 (dd, J=4.8, 1.6 Hz, 1H), 7.94 (s, 2H), 7.70 (dt, J=7.8, 1.9 Hz, 1H), 7.31-7.27 (m, 1H), 5.12 (s, 2H), 4, 58 (s, 1H), 1.92 (s, 3H).

Intermediate i21: 4-bromobenzyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.48 g, 95%).

¹ H-NMR (300 MHz, CDCl3) δ=7.85 (s, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 5.05 (s, 2H), 4.58 (s, 1H), 1.91 (s, 3H).

Intermediate i22: 3-bromobenzyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.2 g, 69%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.92 (s, 2H), 7.51 (s, 1H), 7.44 (m, 2H), 7.24-7.18 (m, 1H ), 5.07 (s, 2H), 3.52 (s, 1H), 1.92 (s, 3H).

Intermediate i23: 2-bromobenzyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.45 g, 90%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.95 (br. s, 2H), 7.61-7.44 (m, 1H), 7.41 (d, J=7.6 Hz, 1H ), 7.33-7.22 (m, 1H), 7.22-7.06 (m, 1H), 5.19 (s, 2H), 4.64 (s, 1H), 1.93 ( s, 3H).

Intermediate i24: (3-fluoropyridin-4-yl)methyl (Z)-3-aminobut-2-enoate.

Light yellow oil (0.207 g, 69%).

¹ H-NMR (300 MHz, CDCl3) δ=8.55-8.30 (m, 2H), 7.92 (br. s, 2H), 7.35 (t, J=5.6 Hz, 1H ), 5.22 (s, 2H), 4.64 (s, 1H), 1.95 (s, 3H).

¹⁹ B-NMR (282 MHz, CDCl3) δ=-132.71 (s, F).

Intermediate i25: pyrimidin-5-ylmethyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.415 g, 64%).

1H-NMR (300 MHz, CDCl3) δ=9.16 (s, 1H), 8.77 (d, J=4.8 Hz, 2H), 7.94 (br. s, 2H), 5.12 (s, 2H), 3.53 (s, 1H), 1.93 (s, 3H).

Intermediate i26: (5-bromopyrimidin-3-yl)methyl (Z)-3-aminobut-2-enoate.

Light yellow oil (0.364 g, 73%).

1H-NMR (300 MHz, CDCl ₃ ) δ=9.16 (d, J=4.8 Hz, 1H), 8.77 (d, J=4.8 Hz, 1H), 7.94 (s, 3H), 5.12 (s, 2H), 3.53 (s, 1H), 1.93 (s, 3H).

Intermediate i27: 2-phenylpropan-2-yl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.20 g, 69%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.74 (br. s, 1H), 7.41-7.29 (m, 5H), 4.61 (s, 1H), 4.34 (br. .s, 2H), 1.88 (s, 3H), 1.76 (s, 6H).

Intermediate i28: 3-cyanobenzyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.52 g, 93%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.92 (br. s, 2H), 7.66 (s, 1H), 7.57 (d, J=7.9 Hz, 2H), 7, 51-7.36 (m, 1H),

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5.12 (s, 2H), 4.60 (s, 1H), 1.93 (s, 3H).

Intermediate i29: 4-cyanobenzyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.56 g, 90%).

1H-NMR (300 MHz, CDCI3) δ=7.92 (br. s, 2H), 7.67-7.61 (m, 2H), 7.44 (d, J=7.9 Hz, 2H) , 5.15 (s, 2H), 4.61 (s, 1H), 1.93 (s, 3H).

Intermediate i30: 4-cyanobenzyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.22 g, 75%).

1H-NMR (300 MHz, CDCl ,) δ=8.37 (s, 1H), 7.90 (s, 2H), 7.65 (dd, J=8.2, 2.4 Hz, 1H) , 7.30 (dd, J=12.8, 8.2 Hz, 1H), 5.07 (s, 2H), 4.54 (s, 1H), 1.90 (s, 3H).

Intermediate i31: 3-morpholinobenzyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.69 g, 97%).

1H-NMR (300 MHz, CDC13) δ=7.92 (s, 2H), 7.31-7.20 (m, 1H), 6.88 (dd, J=16.4, 8.5 Hz, 3H), 5.07 (s, 2H), 4.60 (s, 1H), 3.86 (t, J=4.8 Hz, 4H), 3.16 (t, J=4.8 Hz, 4H), 1.91 (s, 3H).

Intermediate i32: 4,4-dimethylcyclohexyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.55 g, 81%).

1H-NMR (300 MHz, CDC13) δ=7.85 (br. s, 2H), 4.71 (tt, J=8.9, 4.2 Hz, 1H), 4.52 (s, 1H) , 1.90 (s, 3H), 1.82-1.70 (m, 2H), 1.58 (dt, J=9.3, 5.8 Hz, 2H), 1.49-1.39 (m, 2H), 1.26 (ddd, J=13.7, 10.8, 4.1 Hz, 2H), 0.93 (s, 3H), 0.91 (s, 3H).

Intermediate i33: (2-chloropyridin-4-yl)methyl (Z)-3-aminobut-2-enoate.

Light yellow oil (0.25 g, 83%).

1H-NMR (300 MHz, CDCI3) δ=8.33 (d, J=5.4 Hz, 1H), 7.92 (br. s, 2H), 7.30 (s, 1H), 7.17 (d, J=5.4 Hz, 1H), 5.10 (s, 2H), 4.64 (s, 1H), 1.95 (s, 3H).

Intermediate i34: 4,4-difluorocyclohexyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.30 g, 94%).

1H-NMR (300 MHz, CDCI3) δ=7.86 (br. s, 2H), 5.16-4.75 (m, 1H), 4.53 (s, 1H), 2.16-1, 98 (m, 3H), 2-1.78 (m, 8H).

%-NMR (282 MHz, CDCI3) δ=-94.48 (d, J=252.2 Hz), -100.51 (d, J=235.8 Hz).

Intermediate i35: (Z)-3-amino-N-benzyl-N-methylbut-2-enamide.

Light yellow oil (0.70 g, 71%).

1H-NMR (300 MHz, CDCI3) δ=7.54-6.96 (m, 7H), 4.72 (s, 1H), 4.56 (m, 2H), 2.92 (s, 3H) , 1.90 (s, 3H).

Intermediate i36: oxetan-3-yl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.04 g, 17%).

1H-NMR (300 MHz, CDC13) δ=6.33 (s, 2H), 5.42 (tt, J=6.4, 5.6 Hz, 1H), 4.87 (td, J=6, 8, 1.0 Hz, 2H), 4.66 (ddd, J=6.9, 5.6, 1.0 Hz, 2H), 4.50 (s, 1H), 1.48-1.38 (m, 1H), 0.98-0.83 (m, 2H), 0.83-0.70 (m, 2H).

Intermediate i37: 3-chlorobenzyl-(Z)-3-aminobut-2-enoate.

Light yellow oil (0.198 g, 99%).

1H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.93 (br. s, 1H), 7.36 (s, 1H), 7.33-7.26 (m, 1H), 7.24 (s, 2H), 5.08 (s, 2H), 4.89-4.39 (m, 2H), 1.93 (s, 3H).

Intermediate i38: 2-phenylpropan-2-yl-(Z)-3-amino-3-cyclopropylacrylate.

Light yellow solid (0.38 g, 93%).

1H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.40-7.31 (m, 4H), 7.24-7.17 (m, 1H), 6.19 ( s, 2H), 4.56 (s, 1H), 1.76 (s, 6H), 1.47-1.31 (m, 1H), 0.87-0.79 (m, 2H), 0 .78-0.70 (m, 2H).

Intermediate i39: cyclohexyl-(Z)-3-amino-3-cyclopropylacrylate.

Light yellow solid (0.22 g, 43%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 6.22 (br. s, 2H), 4.80-4.58 (m, 1H), 4.46 (s, 1H ), 1.97-1.77 (m, 2H), 1.80-1.61 (m, 2H), 1.56-1.18 (m, 7H), 0.90-0.78 (m , 2H), 0.78-0.68 (m, 2H).

Intermediate i40: (Z)-3-amino-1,3-dicyclopropylprop-2-en-1-one.

Light yellow solid (0.22 g, 44%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 9.82 (br. s, 1H), 5.12 (s, 1H), 4.83 (br. s, 1H), 1.75-1.59 (m, 1H), 1.49-1.32 (m, 1H), 1.01-0.84 (m, 4H), 0.84-0.76 (m, 2H ), 0.76-0.63 (m, 2H).

Intermediate i41: 3-chlorobenzyl-(Z)-3-amino-3-cyclopropylacrylate.

Light yellow solid (0.14 g, 70%).

1H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.37-7.29 (m, 1H), 7.23-7.17 (m, 3H), 6.25 ( br.s, 2H), 5.03 (s, 1H), 4.65 (s, 2H), 1.19-1.03 (m, 1H), 0.92-0.75 (m, 2H) , 0.78-0.63 (m, 2H).

Intermediate i42: 2-(4-fluorophenyl)propan-2-yl-(Z)-3-aminobut-2-enoate.

Light yellow solid (0.20 g, 80%).

1H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.77 (br. s, 1H), 7.39-7.27 (m, 2H), 7.08-6, 93 (m, 2H), 4.58 (s, 1H), 4.36 (br. s, 1H), 1.88 (s, 3H), 1.74 (s, 6H).

¹⁹ F-NMR (282 MHz, CDCl3-d) δ (ppm): -117.11 (CF).

Intermediate i43: 2-(4-fluorophenyl)propan-2-yl-(Z)-3-amino-3-cyclopropylacrylate.

Yellow solid (0.43 g, 96%).

- 57 040842

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 7.41-7.28 (m, 2H), 7.09-6.89 (m, 2H), 6.11 (br .s, 2H), 4.54 (s,

1H), 1.73 (s, 6H), 1.40 (qt, J=8.1, 5.0 Hz, 1H), 0.89-0.81 (m, 2H), 0.73 (dt , J=8.1, 5.0 Hz, 2H).

¹⁹ F-NMR (282 MHz, CDC^-d) δ (ppm): -117.14 (CF).

Intermediate i44: 3-bromobenzyl-(2)-3-amino-3-cyclopropylacrylate.

Light yellow solid (0.15 g, 54%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.57-7.48 (m, 1H), 7.46-7.37 (m, 1H), 7.33- 7.24 (m, 1H), 7.25-7.18 (m, 1H), 6.10 (br. s, 2H), 5.06 (s, 1H), 3.75 (s, 2H) , 2.10-1.93 (m, 1H), 1.18-1.03 (m, 2H), 1.03-0.92 (m, 2H).

Intermediate i45: methyl-(2)-3-amino-3-cyclobutyl acrylate.

Light yellow solid (0.35 g, 70%).

'11-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 6.98 (br. s, 2H), 4.53 (s, 1H), 3.64 (s, 3H), 3.05 (n, J=8.4 Hz, 1H), 2.22-1.95 (m, 4H), 1.94-1.57 (m, 2H).

Intermediate i46: methyl-(7)-3-amino-3-cyclopentyl acrylate.

Light yellow solid (0.42 g, 83%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.52 (br. s, 2H), 4.59 (s, 1H), 3.63 (s, 3H), 2 .49 (n, J=8.5 Hz, 1H), 2.07-1.85 (m, 2H), 1.85-1.40 (m, 6H).

Intermediate i47: methyl-(2)-3-amino-3-cyclohexyl acrylate.

Light yellow solid (0.45 g, 92%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 17.57 (br. s, 2H), 4.54 (s, 1H), 3.63 (s, 3H), 1, 98-1.60 (m, 6H), 1.35-1.13 (m, 5H).

Intermediate i48: 3-((4-methylpiperazin-1-yl)methyl)benzyl-(7)-3-aminobut-2-enoate.

Yellow solid (0.54 g, 98%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.91 (s, 2H), 7.29 (s, 4H), 5.09 (s, 2H), 4.60 (s, 1H), 3.51 (s, 2H), 2.52 (br. s, 8H), 2.33 (s, 3H), 1.91 (s, 3H).

Other ways to obtain enamines.

The following enamines were obtained by alternative methods.

Intermediate i49: 2,2,2-trifluoroethyl-(2)-3-aminobut-2-enoate.

O O NH ₄ OAc NH ₂ o

JL Jk AcOH L 1 _Λ

-------------- -~~'c) sez

Molek. sieve ^J

THF

2,2,2-Trifluoroethyl-3-oxobutanoate (1 g, 5.43 mmol, 1 eq) was dissolved in THF (1.2 M) at RT and molecular sieves (2 g), ammonium acetate (0.83 g, 10.87 mmol, 2 eq.) and acetic acid (0.310 ml, 5.43 mmol, 1 eq.). The reaction mixture was heated at 110° C. for 6 h and then allowed to cool RT. Water was added and the mixture was extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel flash column chromatography using ethyl acetate/hexane (1:3) as eluent to give 2,2,2-trifluoroethyl-(2)-3-aminobut-2-enoate (0.5 g, 56 %).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.89 (br. s, 1H), 4.84 (br. s, 1H), 4.59 (s, 1H), 4.44 (q, J = 8.7 Hz, 2H), 1.93 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ=-73.40 (t, J=8.6 Hz, 3F).

Intermediate i50: methyl-(2)-3-amino-3-(pyridin-3-yl)acrylate.

The method described for 2,2,2-trifluoroethyl-(2)-3-aminobut-2-enoate (see above) was used to obtain the title compound (0.7 g, 72%).

1H-NMR (300 MHz, CDCl3) δ=8.80 (s, 1H), 8.66 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.40-7 .30 (m, 1H), 4.96 (s, 1H), 3.72 (s, 3H).

Intermediate i51: mixture of (2)-4-amino-5-phenylpent-3-en-2-one and (2)-4-amino-1-phenylpent-3-en-2-one.

To obtain a mixture of (7)-4-amino-5-phenylpent-3-en-2-one and (2)-4-amino-1-phenylpent-3-en-2-one as a yellow oil (0.5 g, 79%), used in this form in the next stage, used the method described for 2,2,2-trifluoroethyl-(2)-3-aminobut-2-enoate (see above).

Intermediate i52: (2)-4-aminopent-3-en-2-one.

Received by the method described in US patent No. 8030302 (3.7 g, 74%).

1H-NMR (300 MHz, CDCl3) δ=9.70 (br. s, 1H), 5.04 (br. s, 1H), 4.92 (s, 1H), 2.03 (s, 3H) , 1.91 (s, 3H).

Intermediate i53: 5-amino-2H-pyran-3(6H)-one.

The title compound as a dark orange solid (0.35 g, 90%) was obtained by the method described in Synth. Comm. 2004, 34, 557-565.

1H-NMR (300 MHz, CDCl ₃ ) δ=7.03 (br. s, 2H), 5.01 (s, 1H), 4.18 (s, 2H), 3.80 (s, 2H).

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Preparation of amidine intermediates

The general way

Intermediate y1: cyclopentyl 3-amino-3-iminopropanoate hydrochloride.

Step 1: Synthesis of cyclopentyl 3-imino-3-phenoxypropanoate hydrochloride.

A mixture of cyclopentyl-2-cyanoacetate (2.81 g, 18.34 mmol, 1.15 eq.) and phenol (1.50 g, 15.95 mmol, 1.3 eq.) was stirred at -20°C when gaseous HCl was bubbled into the mixture for 90 minutes. The mixture was then left at 4°C for two days without stirring. Cold ether was added and the mixture was stirred at 0°C. The resulting solid was filtered off and washed with cold ether to give cyclopentyl 3-imino-3-phenoxypropanoate hydrochloride as a white solid (2.76 g, 61%).

1H-NMR (300 MHz, DMSO-d6) δ (ppm): 7.55-7.41 (m, 1H), 7.20-7.09 (m, 2H), 6.80-6 .70 (m, 2H), 5.105.01 (m, 1H), 3.95 (s, 4H), 1.94-1.69 (m, 2H), 1.68-1.47 (m, 6H ).

Step 2: Synthesis of cyclopentyl 3-imino-3-phenoxypropanoate.

A solution of potassium carbonate (0.73 g, 5.30 mmol , 1.5 eq.) in water (11 ml) at 0°C. The resulting mixture was stirred until the solid dissolved and then washed with ether, dried (Na ₂ SO ₄ ) and concentrated to give cyclopentyl 3-imino-3-phenoxypropanoate as a light yellow oil (0.86 g, 99%).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 7.66 (br. s, 2H), 7.51-7.39 (m, 2H), 7.35-7, 23 (m, 1H), 7.20-7.10 (m, 2H), 4.97 (dc, J=5.1, 3.1 Hz, 1H), 3.46 (s, 1H), 1 .89-1.65 (m, 2H), 1.64-1.25 (m, 6H).

Step 3: Synthesis of cyclopentyl 3-amino-3-iminopropanoate hydrochloride.

nh ₄ ci

methanol

HCl _NH about

Ό'

Ammonium chloride (0.21 g, 3.84 mmol, 1 1 equivalent). The mixture was stirred at room temperature overnight and concentrated. The remaining solid was homogenized with diethyl ether and filtered to give cyclopentyl 3-amino-3-iminopropanoate hydrochloride as a white solid (0.61 g, 84%).

1H-NMR (300 MHz, DMSO-d6) δ (ppm): 9.12 (br. s, 2H), 8.82 (br. s, 2H), 5.12 (tt, J=4 .9, 2.2 Hz, 1H), 3.55 (s, 2H), 1.81 (t, J=7.5 Hz, 2H), 1.76-1.47 (m, 6H).

The cyclopentyl-2-cyanoacetate precursor used in step 1 of the synthesis of intermediate y1 was purchased from commercial suppliers. Other alkyl-2-cyanoacetates were synthesized using the following ester preparation (step 0) as shown for 3-fluorobenzyl-2-cyanoacetate, precursor of intermediate y2.

Step 0: Synthesis of 3-fluorobenzyl-2-cyanoacetate.

To a solution of 2-cyanoacetic acid (4.45 g, 52.32 mmol, 1.0 eq.) in DCM (34 ml) was added (3fluorophenyl)methanol (5.67 ml, 52.32 mmol, 1.0 eq. ) and cooled at 0°C. A solution of N,N-dicyclohexylcarbodiimide (10.79 g, 52.32 mmol, 1.0 eq.) and dimethylaminopyridine (0.32 g, 2.62 mmol, 0.05 eq.) in DCM (16 ml) and the mixture was stirred at RT overnight. The solid was filtered off and washed with DCM. The filtrate was concentrated and purified by silica gel flash column chromatography using ethyl acetate/hexane (1:3) as eluent to give 3-fluorobenzyl-2-cyanoacetate as a light yellow oil (7.2 g, 66%).

1H-NMR (300 MHz, DMSO-d6) δ (ppm): 7.45-7.27 (m, 1H), 7.20-7.01 (m, 3H), 5.22 (s , 2H), 3.51 (s, 2H).

The following amidine intermediates were prepared by the general method (steps 0-3).

Intermediate y2: 3-fluorobenzyl-3,3-diaminoacrylate hydrochloride.

White solid (0.550 g).

1H-NMR (300 MHz, DMSO-d6) δ (ppm): 9.36 (br. s, 2H), 9.05 (br. s, 2H), 7.64-7.43 (m , 4H), 5.21 (s, 2H), 3.78 (s, 2H).

Intermediate y3: cyclobutylmethyl-3,3-diaminoacrylate hydrochloride.

White solid (0.542 g).

1H-NMR (300 MHz, DMSO-d6) δ (ppm): 9.27 (br. s, 2H), 8.99 (br. s, 2H), 4.19-3.85 (m , 2H), 3.67 (s, 2H),

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2.67-2.53 (m, 1H), 2.11-1.54 (m, 6H).

Intermediate y4: 3,3-(difluorocyclobutyl)methyl-3,3-diaminoacrylate.

White solid (0.450 g).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.33 (br. s, 2H), 9.01 (br. s, 2H), 4.17 (d, J= 5.1 Hz, 2H), 3.71 (s, 2H), 2.79-2.53 (m, 3H), 2.44-2.29 (m, 2H).

Intermediate y5: 2,2-(difluorocyclopropyl)methyl-3,3-diaminoacrylate hydrochloride.

White solid (0.36 g).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.33 (br. s, 2H), 9.05 (br. s, 2H), 4.42-4.21 ( m, 1H), 4.14-3.90 (m, 1H), 3.73 (s, 2H), 2.20-2.00 (m, 1H), 1.82-1.61 (m, 1H), 1.61-1.36 (m, 1H).

Intermediate y6: isopropyl 3,3-diaminoacrylate hydrochloride.

White solid (0.47 g).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.28 (br.s, 2H), 9.00 (br.s, 2H), 4.95 (pd, J= 6.3, 1.5 Hz, 1H), 3.62 (s, 2H), 1.22 (d, J=6.3 Hz, 6H).

Intermediate y7: (2,2-Difluoro-3,3-dimethylcyclopropyl)methyl-3,3diaminoacrylate hydrochloride.

White solid (0.132 g).

1 H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.31 (s, 2H), 9.03 (s, 2H), 4.21 (d, J=8.8 Hz , 2H), 3.70 (s, 2H), 1.82-1.56 (m, 1H), 1.34-0.94 (m, 6H).

Intermediate y8: neopentyl 3,3-diaminoacrylate hydrochloride.

White solid (0.791 g).

1 H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.25 (s, 2H), 8.97 (s, 2H), 3.79 (s, 2H), 3.66 (s, 2H), 0.89 (s, 9H).

Intermediate y9: 2,2,2-trifluoroethyl-(E)-3-amino-3-(2,2,2-trifluoroethoxy)acrylate.

The title compound was prepared by following step 0 of the general method y and a slightly modified version of steps 1 and 2 as described below.

Stage 1

„ F HOGH, CF,, HC1 {gas} FM

Ό γ F _a C O O ^F Stage 5: CHO _R1 ether

Step 1: mixture of 2,2,2-trifluoroethyl 2-cyanoacetate (3.5 g, 20.94 mmol, 1.15 eq.) and 2,2,2-trifluoroethyl-1-ol (1.32 ml, 18.21 mmol, 1 eq.), which was stirred at -20°C, sparged with gaseous HCl for 60 min. The mixture was then left at 4°C for two days without stirring. The mixture was then stirred again and cold ether was added at 0°C. The solid was filtered off and washed with cold ether to give 2,2,2-trifluoroethyl-(E)-3-amino-3-(2,2,2-trifluoroethoxy)acrylate hydrochloride as a white solid (2.5 g, 40% ).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 7.70 (s, 1H), 5.83 (s, 2H), 4.73 (ddc, J=37.4, 18.4, 9.0 Hz, 4H), 3.89 (s, 1H).

Step 2: To a mixture of 2,2,2-trifluoroethyl-(E)-3-amino-3-(2,2,2-trifluoroethoxy)acrylate hydrochloride (0.13 g, 0.43 mmol, 1.0 eq. ) and ether (5 ml) was added a solution of potassium carbonate (0.088 g, 0.64 mmol, 1.5 eq.) in water (1.5 ml) at 0°C. The resulting mixture was stirred until the solid dissolved. The mixture was extracted with ether and the organic phase was dried (Na ₂ SO ₄ ) and concentrated to give 2,2,2-trifluoroethyl-(E)-3-amino-3-(2,2,2-trifluoroethoxy)acrylate as a colorless oil (0.12 g, 98%), which was used as such in the next step.

Intermediate y10: 2-fluoro-2-methylpropyl-3-amino-3-iminopropanoate hydrochloride.

The title compound as a white solid (0.28 g) was obtained by the general method y (steps 0-3).

1 H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.33 (s, 2H), 9.04 (s, 2H), 4.19 (d, J=21.1 Hz , 2H), 3.76 (s, 2H), 1.41-1.34 (m, 6H).

Intermediate y11: cyclopropylmethyl-3,3-diaminoacrylate hydrochloride.

The title compound as a white solid (0.48 g) was obtained by the general method y (steps 0-3).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.13 (br. s, 3H), 8.83 (br. s, 2H), 5.13 (t, J= 6.0 Hz, 1H), 3.57 (s, 2H), 1.86-1.80 (m, 1H), 1.68-1.58 (m, 4H).

Intermediate y12: 4,4-difluorocyclohexyl-3-amino-3-iminopropanoate hydrochloride.

The title compound as a white solid (0.098 g) was obtained by the general method y (steps 0-3).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): δ 9.32 (s, 2H), 9.02 (s, 2H), 4.96-4.66 (m, 1H ), 3.41 (s, 2H), 2.101.76 (m, 8H).

Intermediate y13: 4-fluorobenzyl-3-amino-3-iminopropanoate hydrochloride.

The title compound as a white solid (0.45 g) was obtained by the general method y (steps 0-3).

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.30 (br.s, 2H), 9.01 (br.s, 2H), 7.49-7.43 ( m, 2H), 7.26-7.17

- 60 040842 (m, 2H), 5.17 (s, 2H), 3.73 (s, 2H).

Intermediate y14: cyclopentylmethyl-3-amino-3-iminopropanoate hydrochloride.

The title compound as a white solid (0.22 g) was obtained by the general method y (steps 0-3).

1H-NMR (300 MHz, DMSO-d6) δ (ppm): 9.31 (br. s, 2H), 9.03 (br. s, 2H), 3.96 (d, 2H), 3.76 (s, 2H), 2.22.1 (m, 1H), 1.8-1.6 (m, 2H), 1.6-1.4 (m, 4H), 1.4- 1.1 (m, 2H).

Obtaining intermediate compounds-products of the Knoevenagel reaction

General method i (taken from Lu Liu et al., Chem. Int. Ed. 2009, 48, 6093-6096).

Intermediate j 1: 3-(benzo[b]thiophen-3-ylmethylene)pentan-2,4-dione.

Benzo[b]thiophene-3-carbaldehyde (1 g, 6.16 mmol, 1 eq.) was dissolved in toluene (0.5 M) at RT and acetic acid (0.176 ml, 3.08 mmol, 0.5 eq. .), piperidine (0.061 ml, 0.61 mmol, 0.1 eq.), molecular sieves (6 g) and 2,4-pentanedione (0.95 ml, 9.24 mmol, 1.5 eq.). The reaction mixture was heated in a microwave oven at 111°C until the disappearance of the starting material (4 h). The mixture was allowed to cool to RT and then concentrated. The resulting residue was purified by silica gel flash column chromatography using ethyl acetate/hexane (1:6) as eluent to give the Knoevenagel reaction product as a yellow solid (1.8 g, 60%).

1H-NMR (300 MHz, CDCI3) δ=7.89 (t, J=7.5 Hz, 2H), 7.76 (s, 1H), 7.72 (s, 1H), 7.48 (n , J=7.4 Hz, 2H), 2.49 (s, 3H), 2.30 (s, 3H).

The following intermediates were synthesized by the general method j.

Intermediate j2: (E)-2-(benzo[b]thiophen-3-ylmethylene)-1-(pyridin-3-yl)butan-1,3dione.

Yellow solid (0.25 g, 33%).

1H-NMR (300 MHz, CDCI3) δ=9.03 (s, 1H), 8.72 (d, J=3.6 Hz, 1H), 8.20 (ddd, J= 8.0, 2, 3, 1.7 Hz, 1H), 8.14 (d, J=0.9 Hz, 1H), 7.96 (dt, J=8.1, 1.0 Hz, 1H), 7.83 ( ddd, J=7.9, 1.2, 0.7 Hz, 1H), 7.53 (s, 1H), 7.52-7.32 (m, 3H), 2.52 (s, 3H) .

Intermediate j3: methyl-(Z)-2-(benzo[b]thiophen-3-ylmethylene)-4-chloro-3-oxobutanoate.

Yellow solid (0.4 g, 32%).

1H-NMR (300 MHz, CDCI3) δ=8.16 (s, 1H), 8.03-7.86 (m, 2H), 7.82 (s, 1H), 7.60-7.39 ( m, 2H), 4.34 (s, 2H), 3.90 (s, 3H).

Intermediate j4: (E)-2-(benzo[b]thiophen-3-ylmethylene)-1-cyclopropylbutane-1,3-dione.

Yellow oil (0.4 g, 63%).

1H-NMR (300 MHz, CDC13) δ=7.96-7.84 (m, 3H), 7.75 (d, J=1.1 Hz, 1H), 7.56-7.38 (m, 2H), 2.45 (s, 3H), 2.03 (dt, J=7.9, 3.6 Hz, 1H), 1.28-1.08 (m, 2H), 1.04-0 .83 (m, 2H).

Intermediate j5: tetrahydro-2H-pyran-4-yl-(Z)-3-oxo-2-(thieno[2,3-b]pyridin-3ylmethylene)butanoate.

Yellow oil (0.04 g, 25%).

1H-NMR (300 MHz, CDCI3) δ=8.63 (d, J=4.6 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.94 (s, 1H ), 7.76 (s, 1H), 7.40 (dd, J=8.1, 4.6Hz, 1H), 5.16 (tt, J=8.6, 4.1Hz, 1H) , 3.81 (dt, J=11.8, 4.6 Hz, 2H), 3.49 (ddd, J=11.8, 8.8, 3.0 Hz, 2H), 2.46 (s , 3H), 1.91 (dp, J=8.5, 4.1 Hz, 2H), 1.63 (dtd, J=13.0, 8.5, 4.1 Hz, 2H).

Intermediate j6: isopropyl-(Z)-3-(7-bromobenzo[b]thiophen-3-yl)-2(cyclopropanecarbonyl)acrylate.

Yellow oil (0.13 g, 32%).

1H-NMR (300 MHz, CDCI3) δ=7.88 (s, 2H), 7.85 (s, 1H), 7.57-7.53 (m, 1H), 7.38-7.31 ( m, 1H), 5.19 (n, J=6.3 Hz, 1H), 2.08 (tt, J=7.8, 4.6 Hz, 1H), 1.35 (s, 3H), 1.32 (s, 3H), 1.21-1.11 (m, 2H), 1.02-0.91 (m, 2H).

Intermediate j7: methyl-(Z)-2-((7-bromobenzo[b]thiophen-3-yl)methylene)-4,4,4-trifluoro-3oxobutanoate.

Yellow solid (0.040 g, 10%).

1H-NMR (300 MHz, CDC13) δ=8.22 (d, J=1.0 Hz, 1H), 7.87 (t, J=1.3 Hz, 1H), 7.78-7.75 (m, 1H), 7.69 (d, J=5.0 Hz, 1H), 7.38-7.34 (m, 1H), 3.92 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCI3) δ=-75.69 (s, CF3).

Intermediate j8: cyclopropylmethyl-(2)-3-(7-bromobenzo[b]thiophen-3-yl)-2(cyclopropanecarbonyl)acrylate.

Yellow solid (0.25 g, 59%).

1H-NMR (300 MHz, CDCI3) δ=7.96-7.84 (m, 3H), 7.58 (d, J=7.6 Hz, 1H), 7.40-7.33 (m, 1H), 4.13 (d, J=7.5 Hz, 2H), 2.10 (tt, J=7.5, 4.6 Hz, 1H), 1.25-1.18 (m, 3H ), 0.99 (dt, J=7.9, 3.5 Hz, 2H), 0.71-0.46 (m, 2H), 0.410.23 (m, 2H).

Intermediate j9: cyclopropylmethyl-(2)-3-(7-bromobenzo[b]thiophen-3-yl)-2-(cyclopropanecarbonyl)acrylate.

Yellow solid (0.13 g, 50%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.33-8.24 (m, 2H), 7.93 (s, 1H), 7.78 (s, 1H), 7.72 (t, J =7.8 Hz, 1H), 2.50 (s, 3H), 2.30 (s, 3H).

%-NMR (282 MHz, CDCl3) δ=-69.81 (s, CF3).

Intermediate j 10: 3-((7-chlorobenzo[b]thiophen-3-yl)methylene)pentan-2,4-dione.

Yellow solid (0.158 g, 56%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 7.77 (d, J=7.1 Hz, 2H), 7.69 (s, 1H), 7.45 (d , J=5.0 Hz, 2H), 2.48 (s, 3H), 2.29 (s, 3H).

Intermediate j11: 3-((7-(trifluoromethyl)benzo[b]thiophen-3-yl)methylene)pentan-2,4dione.

Yellow solid (0.052 g, 50%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 8.06 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.80-7, 73 (m, 2H), 7.61 (t, J=8.0 Hz, 1H), 2.50 (s, 3H), 2.30 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCl3-d) δ (ppm): -62.87 (CF3).

Intermediate j 12: 3-(2-acetyl-3-oxobut-1-en-1-yl)benzo[b]thiophene-7-carbonitrile.

Dark yellow solid (0.132 g, 68%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.10 (d, J=8.1 Hz, 1H), 7.85 (s, 1H), 7.81 (d , J=7.5 Hz, 1H), 7.69 (s, 1H), 7.60 (td, J=8.1, 7.4, 1.0 Hz, 1H), 2.49 (s, 3H), 2.31 (s, 3H).

Intermediate j13: cyclopropylmethyl-(Z)-2-(cyclopropanecarbonyl)-3-(thieno[2,3b]pyridin-3-yl)acrylate.

Yellow solid (0.146 g, 61%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.63 (d, J=4.6 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H ), 7.91 (s, 1H), 7.90 (s, 1H), 7.40 (ddd, J=8.4, 4.6, 0.8 Hz, 1H), 4.12 (d, J=7.2Hz, 2H), 2.21-2.04(m, 1H), 1.29-1.13(m, 3H), 1.110.93(m, 2H), 0.67-0 .54 (m, 2H), 0.43-0.27 (m, 2H).

Intermediate j14: cyclopentyl-(Z)-2-(cyclopropanecarbonyl)-3-(thieno[2,3b]pyridin-3-yl)acrylate.

Light yellow solid (0.21 g, 90%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 8.63 (dd, J=4.6, 1.4 Hz, 1H), 8.19 (dd, J=8.2 , 1.4 Hz, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.40 (dd, J=8.2, 4.6 Hz, 1H), 5.36 (tt, J=5.7, 2.5 Hz, 1H), 2.10 (tt, J=8.0, 4.6 Hz, 1H), 1.981.86 (m, 2H), 1.86- 1.70 (m, 4H), 1.69-1.57 (m, 2H), 1.19 (dt, J=6.9, 3.5 Hz, 2H), 0.99 (dt, J= 8.0, 3.5 Hz, 2H).

Intermediate j15: cyclopropylmethyl-(Z)-3-(7-cyanobenzo[b]thiophen-3-yl)-2(cyclopropanecarbonyl)acrylate.

Yellow solid (0.23 g, 69%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.19-8.09 (m, 1H), 7.95 (s, 1H), 7.92 (s, 1H) , 7.81-7.74 (m, 1H), 7.62-7.53 (m, 1H), 4.13 (d, J=7.2 Hz, 2H), 2.12 (tt, J =7.8, 4.6 Hz, 1H), 1.29-1.13 (m, 3H), 1.07-0.93 (m, 2H), 0.67-0.55 (m, 2H ), 0.35 (dt, J=6.2, 4.6 Hz, 2H).

Intermediate j16: methyl-(Z)-3-(7-cyanobenzo[b]thiophen-3-yl)-2(cyclopropanecarbonyl)acrylate.

Yellow solid (0.21 g, 80%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 8.13 (t, J=9.1 Hz, 1H), 8.02-7.86 (m, 2H), 7. 79 (d, J=7.7 Hz, 1H), 7.57 (td, J=7.7, 2.7 Hz, 1H), 3.89 (s, 3H), 2.13-2.01 (m, 1H), 1.28-1.16 (m, 2H), 1.14-0.93 (m, 2H).

Intermediate j17: methyl-(Z)-2-((7-cyanobenzo[b]thiophen-3-yl)methylene)-3oxobutanoate.

Yellow solid (0.11 g, 60%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 8.11 (d, J=8.2 Hz, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.80 (d, J=7.4 Hz, 1H), 7.62-7.54 (m, 1H), 3.87 (s, 3H), 2.47 (s, 3H).

Intermediate j18: (E)-2-((7-cyanobenzo[b]thiophen-3-yl)methylene)-3-oxobutanamide.

Yellow solid (0.17 g, 58%).

1H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.35 (s, 1H), 8.14-8.07 (m, 1H), 7.88-7.73 ( m, 2H), 7.63-7.54 (m, 1H), 6.08 (br. s, 1H), 5.87 (br. s, 1H), 2.55 (s, 3H).

Intermediate j19: cyclopropyl-(E)-2-((7-cyanobenzo[b]thiophen-3-yl)methylene)-3oxobutanoate.

Yellow solid (0.104 g, 30%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.09 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.80 (d , J=7.3 Hz, 2H), 7.637.51 (m, 1H), 4.43-4.31 (m, 1H), 2.46 (s, 3H), 0.85-0.74 ( m, 2H), 0.73-0.61 (m, 2H).

Intermediate j20: methyl-(E)-2-((7-cyano-5-fluorobenzo[b]thiophen-3-yl)methylene)-3oxobutanoate.

Yellow solid (0.136 g, 60%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 8.07 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 7.56 (d, J=7.7 Hz, 1H), 3.87 (s, 3H), 2.47 (s, 3H).

- 62 040842

Intermediate j21: methyl-(E)-2-((7-cyano-4-fluorobenzo[b]thiophen-3-yl)methylene)-3oxobutanoate.

Yellow solid (0.116 g, 63%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.11 (s, 1H), 7.85 (s, 1H), 7.76 (dd, J=8.2, 4.3 Hz, 1H), 7.24-7.16 (m, 1H), 3.89 (s, 3H), 2.35 (s, 3H).

Intermediate j22: methyl-(E)-2-((7-cyanothieno[3,2-b]pyridin-3-yl)methylene)-3oxobutanoate.

Yellow solid (0.77 g, 40%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.91 (d, J=4.7 Hz, 1H), 8.32 (s, 1H), 8.15 (s , 1H), 7.63 (d, J=4.7 Hz, 1H), 3.90 (s, 3H), 2.53 (s, 3H).

Intermediate j23: cyclopropylmethyl-(E)-2-((7-cyanobenzo[b]thiophen-3-yl)methylene)3-oxobutanoate.

Yellow solid (0.45 g, 52%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.11 (dd, J=8.2, 0.9 Hz, 1H), 8.06 (s, 1H), 7 .83 (d, J=0.9 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.57 (dd, J=8.2, 7.5 Hz, 1H) , 4.13 (d, J=7.4 Hz, 2H), 2.48 (s, 3H), 1.26-1.04 (m, 1H), 0.66-0.51 (m, 2H ), 0.38-0.21 (m, 2H).

Intermediate j24: prop-2-yn-1-yl-(E)-2-((7-cyanobenzo[b]thiophen-3-yl)methylene)-3oxobutanoate.

Yellow solid (0.7 g, 85%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 8.13 (dd, J=8.2, 0.9 Hz, 1H), 7.99 (s, 1H), 7. 96 (s, 1H), 7.80 (d, J=7.1 Hz, 1H), 7.62-7.55 (m, 1H), 4.89 (d, J=2.5 Hz, 2H ), 2.55 (t, J=2.5 Hz, 1H), 2.40 (s, 3H).

Intermediate j25: methyl-(E)-2-((5,7-dicyanobenzo[b]thiophen-3-yl)methylene)-3oxobutanoate.

Yellow solid (0.135 g, 59%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.31 (d, J=1.4 Hz, 1H), 7.96-7.87 (m, 2H), 7 .49 (s, 1H), 4.13 (d, J=1.0 Hz, 3H), 2.04 (d, J=1.0 Hz, 3H).

Intermediate j26: But-2-yn-1-yl-(E)-2-((7-cyanobenzo[b]thiophen-3-yl)methylene)-3oxobutanoate.

Yellow solid (0.125 g, 36%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 8.11 (td, J=4.4, 0.8 Hz, 2H), 7.86 (d, J=0.8 Hz, 1H), 7.80 (d, J=7.4 Hz, 1H), 7.58 (dd, J=8.2, 7.4 Hz, 1H), 4.86 (k, J=2 .3 Hz, 2H), 2.48 (s, 3H), 1.89 (t, J=2.3 Hz, 3H).

Intermediate j27: (2,2,2-trifluoroethyl)-2-((7-cyanobenzo[b]thiophen-3-yl)methylene)-3oxobutanoate.

Yellow solid (0.079 g, 38%).

1H-NMR (300 MHz, CDCl3-d) δ (ppm): 8.15-7.98 (m, 2H), 7.95-7.88 (m, 1H), 7.86-7 .72 (m, 2H), 4.66 (dc, J=11.7, 8.3 Hz, 2H), 2.53-2.40 (m, 3H).

Intermediate j28: methyl-(E)-2-((6-chloro-7-cyanobenzo[b]thiophen-3-yl)methylene)-3oxobutanoate.

Yellow solid (0.24 g, 56%).

1 H-NMR (300 MHz, CDCl ₃ -d) δ (ppm): 8.01 (d, J=8.7 Hz, 1H), 7.91 (d, J=0.9 Hz, 1H ), 7.84 (d, J=0.9 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 3.90 (s, 3H), 2.36 (s, 3H ).

Intermediate j29: (E)-3-(2-cyano-3-oxobut-1-en-1-yl)benzo[b]thiophene-7-carbonitrile.

The title compound was obtained as a yellow solid (0.23 g, 69%) by general method j using 3-oxobutanenitrile.

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.07 (s, 1H), 8.47 (s, 1H), 8.22 (d, J=8.2 Hz , 1H), 7.85 (d, J=7.4 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 2.63 (s, 3H).

Intermediate j30: 3-((5-fluorothieno[2,3-b]pyridin-3-yl)methylene)pentan-2,4-dione.

The title compound as a yellow solid (0.132 g, 61%) was obtained by general method j.

1H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 8.56 (d, J=2.4 Hz, 1H), 7.90 (s, 1H), 7.83 (dd , J=8.7, 2.4 Hz, 1H), 7.55 (s, 1H), 2.48 (s, 3H), 2.32 (s, 3H).

Examples Preparation of dihydropyridines

Method A (Rampa, A et al., Forsch. 1992, 42, 1284).

Example A1: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

A mixture of 3-(benzo[b]thiophen-3-ylmethylene)pentan-2,4-dione (0.24 g, 0.98 mmol, 1 eq.), methyl 3-63 040842 oxobutanoate (0.158 ml, 1 47 mmol, 1.5 eq.) and 30% aqueous ammonia solution (0.62 ml, 9.8 mmol, 10 eq.) in u-PrOH (2 ml) were heated at reflux temperature for 12 h. The solvent was removed at reduced pressure. The residue was taken up in water and extracted with dichloromethane and ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated and the crude product was purified by silica gel flash column chromatography using CH ₂ Cl ₂ /MeOH (1%) as eluent to give the title compound as yellow solid (114 mg, 25%).

1H-NMR (300 MHz, CDCl ,) δ=8.10 (d, J=8.0 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.34 (dt , J=24.0, 7.1 Hz, 2H), 7.13 (s, 1H), 6.27 (br.s, 1H), 5.47 (s, 1H), 3.64 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H), 2.14 (s, 3H).

HRMS (IE) m/z calculated C ₁₉ H ₁₉ NO ₃ S [M ⁺ ]: 341.1086, found: 341.1069.

Example A1 is a racemic mixture of two stereoisomers which were separated by semi-preparative chiral HPLC (column: ChiralPak IA, 5 µm, 4.6x250 mm, eluent: nhexane/n-PrOH 95:5) to give example A2 (enantiomer 1, Tr= 22.54 min, 95.60% ee; 96.46% purity; and Example A3 (enantiomer 2, Tr=18.10 min, 99.88% ee; 92.87% purity). Purity was determined using an RP-C18 analytical column (Gemini-NX C18 5 µm, 4.6 x 150 mm; eluents: ACN/water/100 mM ammonium acetate, pH 7). Absolute stereochemistry was not determined.

Example A4: 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxamide. The title compound as a yellow solid (73 mg, 22%) was obtained by method A.

1H-NMR (300 MHz, CDCI3) δ=8.05 (d, J=7.7 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.29 (dt, J =15.0, 7.0 Hz, 2H), 7.09 (s, 1H), 6.76 (s, 1H), 5.65 (br.s, 2H), 5.34 (s, 1H) , 2.25 (s, 3H), 2.08 (s, 6H).

HRMS (IE) m/z calculated C ₁₈ H ₁₈ N ₂ O ₂ S: 326.0910, found: 326.1011.

Example A5: 1-(4-(benzo[b]thiophen-3-yl)-5-benzoyl-2,6-dimethyl-1,4-dihydropyridin-3-yl)ethan-1-one. The title compound was obtained as a dark yellow solid (63 mg, 16%) by method A. 1H-NMR (300 MHz, CDCI3) δ=7.79-7.70 (m, 1H), 7.65-7. 56 (m, 1H), 7.53-7.31 (m, 5H), 7.25-7.18 (m, 2H), 7.06 (s, 1H), 5.72 (br.s, 1H), 5.56 (s, 1H), 2.48 (s, 3H), 2.07 (s, 3H), 1.77 (s, 3H).

HRMS (IE): m/z calculated C ₂₄ H ₂₁ NO ₂ S [M ⁺ ]: 387.1293, found: 387.1286.

Example A6: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-phenyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a dark yellow solid (15 mg, 5%) was obtained by method A using MeOH.

1H-NMR (300 MHz, CDC13) δ=8.21 (d, J=8.2 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.45-7.31 (m, 5H), 7.30-7.24 (m, 3H), 6.02 (br. s, 1H), 5.59 (s, 1H), 3.38 (s, 3H), 2, 41 (s, 3H), 2.17 (s, 3H).

HRMS (IE): m/z calculated C ₂₄ H ₂₁ nO ₃ S [M ⁺ ]: 403.1242, found: 403.1252.

In the Hantzsch synthesis of the following examples, preformed enamines were used instead of mixtures of 1,3-dicarbonyl compounds and ammonia.

Example A8: 1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-nicotinoyl-1,4-dihydropyridin-3-yl)ethan1-one.

The title compound as a dark yellow solid (60 mg, 19%) was obtained by method A using (E)-4-aminopent-3-en-2-one in EtOH.

1H-NMR (300 MHz, CDC13) δ=8.64 (d, J=11.7 Hz, 2H), 7.84-7.60 (m, 3H), 7.35-7.21 (m, 3H), 7.08 (s, 1H), 5.97 (br. s, 1H), 5.56 (s, 1H), 2.45 (s, 3H), 2.10 (s, 3H), 1.77 (s, 3H).

HRMS (IE): m/z calculated C ₂₃ H ₂₀ N ₂ O ₂ S [M ⁺ ]: 388.1245, found: 388.1229.

Example A9: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydro-[2,3'-bipyridine]-3-carboxylate.

The title compound as a yellow solid (31 mg, 16%) was obtained by method A using methyl-(Z)-3-amino-3-(pyridin-3-yl)acrylate in acetic acid.

1H-NMR (300 MHz, CDCI3) δ=8.49 (s, 1H), 8.42 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.83 (d , J=8.0 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.41 (t, J=7.5 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.26-7.16 (m, 2H), 6.68 (br. s, 1H), 5.59 (s, 1H), 3.37 (s, 3H) , 2.41 (s, 3H), 2.15 (s, 3H).

HRMS (IE) m/z calculated C ₂₃ H ₂₀ N ₂ O ₃ S [M ⁺ ]: 404.1195, found: 404.1179.

Example A10: 2,2,2-trifluoroethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (190 mg, 58%) was obtained by method A using 2,2,2-trifluoroethyl-(E)-3-aminobut-2-enoate in 2,2,2-trifluoroethanol.

1H-NMR (300 MHz, CDC13) δ=8.08 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.35 (dt, J =21.4, 7.1 Hz, 2H), 7.17 (s, 1H), 6.10 (br.s, 1H), 5.47 (s, 1H), 4.58-4.27 ( m, 2H), 2.37 (s, 3H), 2.31 (s, 3H), 2.16 (s, 2H).

%-NMR (300 MHz, CDC13) δ=-73.39 (t, J=8.1 Hz).

HRMS (IE) m/z calculated C ₂₀ H ₁₈ F ₃ NO ₃ S [M ⁺ ]: 409.0960, found: 409.0943.

Example A10 was hydrolyzed to give the carboxylic acid of Example A11.

Example A11: 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid

- 64 040842 slots.

2,2,2-Trifluoroethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate (0.05 g, 0.14 mmol, 1 eq.) was dissolved in dioxane (3 ml) at room temperature. Sodium hydroxide (0.42 ml, 0.84 mmol, 6 eq.) was added and the reaction mixture was heated at 130° C. for 4 h. The solvent was removed under reduced pressure and water and 2 N HCl (pH 6-7) were added. The mixture was extracted with dichloromethane and ethyl acetate and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica gel flash column chromatography using CH ₂ Cl ₂ /MeOH (4%) as eluent to give the title compound (15 mg, 38%).

1H-NMR (300 MHz, CDCl ₃ ) δ=11.82 (s, 1H), 8.95 (s, 1H), 8.14 (dd, J=6.9, 1.3 Hz, 1H), 7.89 (dd, J=1.0, 1.6 Hz, 1H), 7.32 (td, J=1.6, 1.5 Hz, 2H), 7.18 (s, 1H), 5 .40 (s, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 2.10 (s, 3H).

HRMS (IE) m/z calculated C ₁₈ H ₁₇ NO ₃ S [M ⁺ ]: 327.0929, found: 327.0937.

Method B (taken from WO 2006047537).

Example B1: 1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(4-methylpiperazin-1-carbonyl)-1,4-dihydropyridin-3-yl)ethan-1 - He.

A mixture of 3-(benzo[b]thiophen-3-ylmethylene)pentan-2,4-dione (0.12 g, 0.49 mmol, 1 eq.), 1-(4methylpiperazin-1-yl)butan-1, 3-dione (0.1 g, 0.54 mmol, 1.1 eq.), ammonium acetate (0.06 g, 0.73 mmol, 1.5 eq.) in MeOH (2 ml) was heated in a microwave reactor at 130°C for 15 min. The reaction mixture was allowed to cool to RT and then concentrated. The residue was purified by silica gel flash column chromatography using CH ₂ Cl ₂ /MeOH (5%) as eluent to give the title compound as a yellow solid (30 mg, 16%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.87 (d, J=7.6 Hz, 1H), 7.80 (d, J=7.3 Hz, 1H), 7.34 (dt, J=14.8, 6.7 Hz, 2H), 7.09 (s, 1H), 5.91 (br. s, 1H), 5.38 (s, 1H), 3.90 (d, J =11.6 Hz, 1H), 3.11-2.92 (m, 1H), 2.91-2.73 (m, 1H), 2.68-2.55 (m, 1H), 2, 37 (s, 3H), 2.33-2.19 (m, 2H), 1.90 (s, 3H), 1.85 (s, 3H), 1.69 (s, 3H), 1.55 -1.36 (m, 1H), 0.40-0.17 (m, 1H).

HRMS (IE): m/z calculated C ₂₃ H ₂₇ N ₃ O ₂ S [M ⁺ ]: 409.1824, found: 409.1834.

Example B2: 5-acetyl-4-(benzo[b]thiophen-3-yl)-N,N-diethyl-2,6-dimethyl-1,4-dihydropyridine-3-carboxamide.

The title compound was obtained as a yellow solid (30 mg, 16%) by Method B.

1H-NMR (300 MHz, CDCl ₃ ) δ=7.86 (d, J=7.3 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.35-7, 28 (m, 2H), 7.11 (s, 1H), 5.68 (br. s, 1H), 5.37 (s, 1H), 3.50-3.28 (m, 1H), 3 .23-2.94 (m, 1H), 2.86-2.75 (m, 1H), 2.70-2.45 (m, 1H), 2.37 (s, 3H), 1.93 (s, 3H), 1.71 (s, 3H), 0.94 (t, J=6.0 Hz, 3H), 0.20 (s, 3H).

HRMS (IE) m/z calculated C ₂₂ H ₂₆ N ₂ O ₂ S [M ⁺ ]: 382.1715, found: 382.1724.

Example B3: 1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(morpholine-4-carbonyl)-1,4-dihydropyridin-3-yl)ethan-1-one.

The title compound was obtained as a yellow solid (18 mg, 12%) by Method B.

1H-NMR (300 MHz, CDCl3) δ=7.89 (d, J=7.3 Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.45-7.28 (m, 2H), 7.11 (s, 1H), 5.66 (br. s, 1H), 5.39 (s, 1H), 3.84 (d, J=11.8 Hz, 1H) , 3.54-3.36 (m, 2H), 3.14-2.97 (m, 2H), 2.90-2.79 (m, 2H), 2.66-2.45 (m, 1H), 2.38 (s, 3H), 1.93 (s, 3H), 1.70 (s, 3H).

HRMS (IE): m/z calculated C ₂₂ H ₂₄ N ₂ O ₃ S [M ⁺ ]: 396.1508, found: 396.1494.

Example B4: 2-methoxyethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (30 mg, 16%) by Method B.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.13 (d, J=8.0 Hz, 1H), 7.80 (d, J=1.9 Hz, 1H), 7.45-7, 29 (m, 2H), 7.17 (s, 1H), 5.90 (br. s, 1H), 5.49 (s, 1H), 4.20 (t, J=4.8 Hz, 2H ), 3.57-3.50 (m, 2H), 3.33 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H), 2.14 (s, 3H) .

HRMS (IE): m/z calculated C2iH2 ₃ NO4S [M ⁺ ]: 385.1348, found: 385.1335.

Example B5: 3-acetamidon-propyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (22 mg, 11%) by Method B.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.14 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.347.25 (m, 1H), 7.14 (s, 1H), 5.56 (br. s, 1H), 5.46 (s, 1H), 4, 24-3.95 (m, 2H), 3.06-2.71 (m, 2H), 2.32 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H) , 2.04-1.94 (m, 1H), 1.85 (s, 3H), 1.81-1.43 (m, 2H).

HRMS (IE): m/z calculated C ₂₃ H ₂₆ N ₂ O ₄ S [M ⁺ ]: 426.1613, found: 426.1603.

Example B6: benzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

- 65 040842

The title compound was obtained as a yellow solid (19 mg, 10%) by Method B.

1H-NMR (300 MHz, CDC13) δ=8.01 (d, J=8.7 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.41-7.26 (m, 5H), 7.26-7.19 (m, 2H), 7.09 (s, 1H), 5.87 (br. s, 1H), 5.49 (s, 1H), 5, 19-5.01 (m, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H).

HRMS (IE): m/z calculated C ₂₅ H ₂₃ nO ₃ S [M ⁺ ]: 417.1399, found: 417.1399.

Example B7: 2-morpholinoethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate.

The title compound was obtained as a yellow solid (30 mg, 11%) by Method B.

1H-NMR (300 MHz, CDCI3) δ=8.11 (d, J=9.1 Hz, 1H), 7.79 (d, J=7.1 Hz, 1H), 7.42-7.25 (m, 2H), 7.15 (s, 1H), 6.07 (br. s, 1H), 5.49 (s, 1H), 4.29-4.07 (m, 2H), 3, 59 (t, J=4.6 Hz, 4H), 2.51 (t, J=5.7 Hz, 2H), 2.38-2.33 (m, 7H), 2.31 (s, 3H ), 2.16 (s, 3H).

HRMS (IE) m/z calculated C ₂₄ H ₂₈ N ₂ O ₄ S [M ⁺ ]: 440.1770, found: 440.1783.

Example B8: 2-(dimethylamino)ethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (15 mg, 7%) by Method B.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.12 (d, J=8.0 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.43-7, 23 (m, 2H), 7.15 (s, 1H), 5.97 (br. s, 1H), 5.48 (s, 1H), 4.19 (heptet, J=5.8 Hz, 2H ), 2.59 (c, J=6.2 Hz, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 2.23 (s, 6H), 2.15 (s , 3H).

HRMS (IE): m/z calculated C ₂₂ H ₂₆ N ₂ O ₃ S [M ⁺ ]: 398.1664, found: 398.1663.

Example B9: 2-acetamidoethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (34 mg, 14%) by method B.

1H-NMR (300 MHz, CDCl ,) δ=8.19 (d, J=8.0 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.43 (t , J=7.4 Hz, 1H), 7.34 (t, J=7.4 Hz, 1H), 7.20 (s, 1H), 5.84 (br.s, 1H), 5.47 (s, 1H), 4.86 (br.s, 1H), 4.25-4.09 (m, 1H), 4.07-3.86 (m, 1H), 3.60-3.38 (m, 1H), 3.24-3.08 (m, 1H), 2.37 (s, 3H), 2.34 (s, 3H), 2.20 (s, 3H), 1.61 ( s, 3H).

HRMS (IE): m/z calculated C ₂₂ H ₂₄ N ₂ O ₄ S [M ⁺ ]: 412.1457, found: 412.1458.

Example B10: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(methoxymethyl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a light yellow solid (25 mg, 14%) by Method B.

1H-NMR (300 MHz, CDC13) δ=8.10 (d, J=8.0 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.42-7.27 (m, 3H), 7.15 (s, 1H), 5.46 (s, 1H), 4.59 (dd, J=26.8 Hz, 2H), 3.63 (s, 3H), 3 .47 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H).

HRMS (IE): m/z calculated C ₂₀ H ₂₁ NO ₄ S [M ⁺ ]: 371.1191, found: 371.1176.

Example B11: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-((dimethylamino)methyl)-6-methyl-1,4dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (25 mg, 11%) by Method B.

1H-NMR (300 MHz, CDC13) δ=8.18 (s, 1H), 8.10 (d, J=8.2 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H ), 7.43-7.28 (m, 2H), 7.14 (s, 1H), 5.47 (s, 1H), 3.73-3.50 (m, 5H), 2.42 ( s, 3H), 2.29 (s, 6H), 2.14 (s, 3H).

HRMS (IE) m/z calculated C ₂₁ H ₂₄ N ₂ O ₃ S [M ⁺ ]: 384.1508, found: 384.1506.

Example B12: pyridin-4-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (25 mg, 13%) by Method B.

1H-NMR (300 MHz, CDC13) δ=8.49-8.34 (m, 2H), 8.03 (d, J=6.8 Hz, 1H), 7.80 (d, J=8, 5 Hz, 1H), 7.35-7.20 (m, 2H), 7.14 (s, 1H), 6.93 (s, 1H), 6.91 (s, 1H), 6.33 ( s, 1H), 5.52 (s, 1H), 5.08 (k, J=13.7 Hz, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 2, 16 (s, 3H).

HRMS (IE): m/z calculated C ₂₄ H ₂₂ N ₂ O ₃ S [M ⁺ ]: 418.1351, found: 418.1360.

Example B13: 4-methoxybenzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate.

The title compound was obtained as a yellow solid (28 mg, 13%) by Method B.

1H-NMR (300 MHz, CDCI3) δ=8.00 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.32-7.20 (m, 2H), 7.16 (d, J=8.5 Hz, 2H), 7.08 (s, 1H), 6.83 (d, J=8.6 Hz, 2H), 5.93 (s, 1H), 5.47 (s, 1H), 5.02 (d, J=2.8 Hz, 2H), 3.81 (s, 3H), 2.35 (s, 3H), 2 .28 (s, 3H), 2.11 (s, 3H).

HRMS (IE): m/z calculated C ₂₆ H ₂₅ NO ₄ S [M ⁺ ]: 447.1504, found: 447.1506.

Example B15: Pyridin-2-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (35 mg, 14%) by Method B.

1H-NMR (300 MHz, CDCI3) δ=8.53 (d, J=4.0 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.78 (d, J =8.5Hz, 1H), 7.52-7.43(m, 1H), 7.31-7.21(m, 2H), 7.15(d, J=5.4Hz, 2H) , 6.91 (d, J=7.8 Hz, 1H), 6.22 (s, 1H), 5.55 (s, 1H), 5.22 (d, J=3.8 Hz, 2H) , 2.34 (s, 3H), 2.31 (s, 3H), 2.14 (s, 3H).

HRMS (IQ) m/z calculated C ₂₄ H ₂₃ N ₂ O ₃ S [M+ ¹ ]: 419.1429, found: 419.1436.

Example B16: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(morpholino-methyl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (25 mg, 10%) by Method B.

- 66 040842

1H-NMR (300 MHz, CDCl ₃ ) δ=8.16-7.97 (m, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.42-7.17 (m , 2H), 7.11 (s, 1H),

5.47 (s, 1H), 3.82-3.69 (m, 5H), 3.64 (s, 4H), 2.52 (t, J=4.6 Hz, 4H), 2.42 (s, 3H), 2.13 (s, 3H).

HRMS (IE) m/z calculated C ₂₃ H ₂₆ N ₂ O ₄ S [M ⁺ ]: 426.1613, found: 426.1604.

Example B16-a: dimethyl 4-(benzo[b]thiophen-3-yl)-2,6-bis(morpholinomethyl)-1,4-dihydropyridine 3,5-dicarboxylate.

1H-NMR (300 MHz, CDC13) δ=9.52 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H ), 7.47-7.14 (m, 2H), 7.05 (s, 1H), 5.48 (s, 1H), 3.80 (d, J=4.6 Hz, 12H), 3 .55 (d, J=1.7 Hz, 6H), 2.56 (tk, J=11.7, 5.9, 4.9 Hz, 8H).

HRMS (IE) m/z calculated C ₂₇ H ₃₃ N ₃ O ₆ S [M ⁺ ]: 527.2090, found: 527.2064.

Example B17: 2-hydroxyethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydroiiridine-3-carboxylate.

The title compound was obtained as a yellow solid (25 mg, 10%) by Method B.

1H-NMR (300 MHz, CDC13) δ=8.14 (d, J=8.1 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.35 (dt, J =25.8, 7.3 Hz, 2H), 7.17(s, 1H), 6.07(s, 1H), 5.48(s, 1H), 4.25-4.05(m, 2H), 3.68 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.83 (br. s, 1H).

HRMS (IE): m/z calculated C ₂₀ H ₂₁ NO ₄ S [M ⁺ ]: 371.1191, found: 371.1190.

Example B18: 1-(4-(benzo[b]thiophen-3-yl)-5-(cycloyroyancarbonyl)-6-cycloiroyyl-2-methyl-1,4dihydroyridin-3-yl)ethan-1-one.

The title compound as a yellow solid (15 mg, 10%) was irradiated with syosobe B.

1H-NMR (300 MHz, CDCI3) δ=8.07 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.45-7.26 (m, 2H), 7.04 (s, 1H), 5.78 (s, 1H), 5.57 (s, 1H), 2.39 (s, 3H), 2.37-2.23 ( m, 1H), 2.13 (s, 4H), 1.27 (s, 1H), 1.11 (tdd, J=5.6, 4.3, 2.7 Hz, 1H), 1.05 -0.88 (m, 3H), 0.86-0.75 (m, 1H), 0.70 (d, J=5.5 Hz, 2H).

HRMS (IE) m/z calculated C ₂₃ H ₂₃ NO ₂ S [M ⁺ ]: 377.1424, found: 377.1428.

Example B19: methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(1-(tert-butoxycarbonyl)azetidin-3-yl)6-methyl-1,4-dihydroiiridin-3 -carboxylate.

The title compound as a light yellow solid (0.065 mg, 19%) was irradiated with syosobe B.

1H-NMR (300 MHz, CDC13) δ=8.06 (d, J=8.1 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.50-7.22 (m, 2H), 7.14 (s, 1H), 6.69 (s, 1H), 5.48 (s, 1H), 4.68 (tt, J=8.8, 4.6 Hz, 1H), 4.22 (td, J=8.9, 3.6 Hz, 2H), 3.82 (ddd, J=14.7, 9.0, 5.0 Hz, 2H), 3.63 (s, 3H), 2.45 (s, 3H), 2.14 (s, 3H), 1.46 (s, 9H).

HRMS (IE): m/z calculated C ₂₆ H ₃₀ N ₂ O ₅ S [M ⁺ ]: 482.1875, found: 482.1874.

Example B20: (1-(tert-butoxycarbonyl)iieridin-4-yl)methyl-5-acetyl-4-(benzo[b]thiophen-3-yl)2,6-dimethyl-1,4-dihydroiiridin-3- carboxylate.

The title compound as a yellow solid (0.06 mg, 26%) was irradiated with syosobe B.

1H-NMR (300 MHz, CDCI3) δ=8.12 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.32 (ddd, J =23.7, 11.3, 4.4 Hz, 2H), 7.12(s, 1H), 6.23(s, 1H), 5.47(s, 1H), 4.11-3, 79 (m, 4H), 2.72-2.44 (m, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H), 1.71 -1.58 (m, 1H), 1.44 (s, 10H), 1.38-1.21 (m, 1H), 0.99 (td, J=11.8, 4.2 Hz, 2H ).

HRMS (IE) m/z calculated C ₂₉ H ₃₆ N ₂ O ₅ S [M ⁺ ]: 524.2345, found: 524.2349.

Example B21: cyclohexylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydro-iiridine-3-carboxylate.

The title compound was a light yellow solid (35 mg, 17%) and was irradiated with syosobe B.

1H-NMR (300 MHz, CDC13) δ=8.13 (d, J=7.9 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.43-7.19 (m, 2H), 7.12 (s, 1H), 5.96 (s, 1H), 5.49 (s, 1H), 3.87 (d, J=6.2 Hz, 2H), 2 .36 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H), 1.70-1.46 (m, 6H), 1.27-1.01 (m, 4H ), 1.01-0.75 (m, 1H).

HRMS (IE) m/z calculated C ₂₅ H ₂₉ NO ₃ S [M ⁺ ]: 423.1868, found: 423.1876.

Example B22: methyl 4-(benzo[b]thiophen-3-yl)-5-(cycloyroyancarbonyl)-2,6-dicycloiroyyl-1,4dihydroyridine-3-carboxylate.

The title compound was a light yellow solid (0.030 g, 11%) and was irradiated with syosobe B.

1H-NMR (300 MHz, CDC13) δ=8.09 (ddd, J=8.1, 1.1, 0.7 Hz, 1H), 7.78 (ddd, J=7.8, 1.1 , 0.7 Hz, 1H), 7.457.27 (m, 2H), 7.03 (s, 1H), 5.66 (br.s, 1H), 5.59 (s, 1H), 3.64 (s, 3H), 2.73 (tg, J=8.5, 5.5 Hz, 1H), 2.37 (tt, J=8.5, 5.5 Hz, 1H), 2.22 ( tt, J=7.8, 4.6 Hz, 1H), 1.13-0.86 (m, 6H), 0.80-0.52 (m, 6H).

HRMS (IE) m/z calculated C ₂₅ H ₂₅ NO ₃ S [M ⁺ ]: 419.1555, found: 419.1543.

HPLC (98.4%): retention time 11.68 min.

Example B23: 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-M-phenyl-1,4-dihydroiiridine-3-carboxamide.

The title compound as a yellow solid (0.04 g, 23%) was irradiated with syosobe B.

1H-NMR (300 MHz, CDC13) δ=8.11-8.04 (m, 1H), 7.89-7.81 (m, 1H), 7.41-7.27 (m, 3H), 7.25-6.98 (m, 6H), 5.66 (br. s, 1H), 5.44 (s, 1H), 2.38 (s, 3H), 2.22 (s, 3H) , 2.16 (s, 3H).

HRMS (IE) m/z calculated C ₂₄ H ₂₂ N ₂ O ₂ S [M ⁺ ]: 402.1402, found: 402.1403.

HPLC (96.5%): retention time 24.12 min.

- 67 040842

Method C.

Example C1: tetrahydro-2H-n-piran-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate.

n

A mixture of tetrahydro-2H-n-piran-4-yl-(Z)-2-(benzo[b]thiophen-3-ylmethylene)-3-oxobutanoate (0.056 g, 0.17 mmol) and (E)-4-aminopent- 3-en-2-one (0.017 g, 0.17 mmol) in methanol (1 ml) was heated in a microwave reactor at 130°C for 60 min. The mixture was allowed to cool to RT and the solvent was removed under reduced pressure. The residue was purified by column chromatography (2:1 hexane: ethyl acetate) to give a light yellow solid (0.07 g, 43%).

1H-NMR (300 MHz, CDCl3) δ=8.13 (d, J=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.42-7.26 (m, 2H), 7.13 (s, 1H), 5.77 (br.s, 1H), 5.49 (s, 1H), 4.94 (tg, J=8.9, 4.5 Hz, 1H), 3.84 (ddd, J=15.8, 12.0, 4.5 Hz, 2H), 3.46 (ddd, J=12.0, 8.9, 6.2, 3 .0 Hz, 2H), 2.38 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.96-1.56 (m, 4H).

HRMS (IE) m/z calculated C23H25NO4S [M ⁺ ]: 411.1504, found: 411.1503.

HPLC (99.4%): retention time 22.96 min.

The following examples were prepared by method C.

Example C2: (tetrahydro-2H-pyran-4-yl)methyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate.

Light yellow solid (0.018 g, 28%).

1H-NMR (300 MHz, CDCls) δ=8.12 (d, J=8.1 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.44-7.23 (m, 2H), 7.13 (s, 1H), 5.87 (br. s, 1H), 5.48 (s, 1H), 4.09-3.57 (m, 4H), 3, 53-3.08 (m, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.88-1.52 (m, 1H) , 1.52-1.08 (m, 4H).

HRMS (IE) m/z calculated C ₂ 4H ₂₇ NO ₄ S [M ⁺ ]: 425.1661, found: 425.1661.

HPLC (98.8%): retention time 17.86 min.

Example C3: cyclohexyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

Light yellow solid (0.07 g, 36%).

1H-NMR (300 MHz, CDCl3) δ=8.19-8.11 (m, 1H), 7.85-7.72 (m, 1H), 7.40-7.28 (m, 2H), 7.12 (s, 1H), 5.77 (br.s, 1H), 5.49 (s, 1H), 4.77 (dt, J=9.2, 5.0 Hz, 1H), 2 .38 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H), 1.92-1.61 (m, 4H), 1.47-1.13 (m, 6H ).

HRMS (IE) m/z calculated C ₂₄ H ₂₇ NO ₃ S [M ⁺ ]: 409.1712, found: 409.1714.

HPLC (98.4%): retention time 20.63 min.

Example C4: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(2-methoxy-2-oxoethyl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

Light yellow solid (0.148 g, 45%).

1H-NMR (300 MHz, CDCl3) δ=8.08 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.42-7.26 (m, 2H), 7.21 (s, 1H), 6.96 (br. s, 1H), 5.50 (s, 1H), 4.02-3.76 (m, 2H), 3, 73 (s, 3H), 3.63 (s, 3H), 2.39 (s, 3H), 2.15 (s, 3H).

HRMS (IE) m/z calculated C ₂₁ H ₂₁ NO ₅ S [M+]: 399.1140, found: 399.1148.

HPLC (95.2%): retention time 20.91 min.

Example C5: Methyl 5-acetyl-2,6-dimethyl-4-(2-methylbenzo[b]thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate.

Light yellow solid (0.065 g, 25%).

1H-NMR (300 MHz, CDCl ₃ ) δ=7.83 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.35-7, 14 (m, 2H), 5.63 (br. s, 1H), 5.59 (s, 1H), 3.49 (s, 3H), 2.50 (s, 3H), 2.29 (s , 3H), 2.25 (s, 3H), 2.07 (s, 3H).

HRMS (IE) m/z calculated C ₂₀ H ₂₁ NO ₃ S [M ⁺ ]: 355.1242, found: 355.1241.

HPLC (98.43%): retention time 18.11 min.

Example C6: cyclopropylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate.

Light yellow solid (0.065 g, 25%).

1H-NMR (300 MHz, CDCl3) δ=8.15 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.34 (dt, J =13.l, 7.4 Hz, 2H), 7.16 (s, 1H), 5.78 (br.s, 1H), 5.51 (s, 1H), 3.88 (dd, J= 7.6, 3.9 Hz, 2H), 2.39 (s, 3H), 2.32 (s, 3H), 2.15 (s, 3H), 1.08 (ddt, J=10.9 , 7.6, 3.9 Hz, 1H), 0.51 (d, J=7.6 Hz, 2H), 0.20 (d, J=4.9 Hz, 2H).

HRMS (IE) m/z calculated C22H23NO3S [M ⁺ ]: 381.1399, found: 381.1399.

HPLC (98.9%): retention time 17.72 min.

Example C7: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(2-methoxyethyl)-6-methyl-1,4dihydropyridine-3-carboxylate.

Light yellow solid (0.16 g, 64%).

1H-NMR (300 MHz, CDCl3) δ=8.09 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.43-7.27 (m, 2H), 7.21

- 68 040842 (br. s, 1H), 7.16 (s, 1H), 5.49 (s, 1H), 3.63 (s, 3H), 3.61 (d, J=5.1 Hz , 2H), 3.40 (s, 3H), 3.26-3.11 (m, 1H), 3.102.97 (m, 1H), 2.36 (s, 3H), 2.15 (s, 3H).

HRmS (IE) m/z calculated C ₂₁ H ₂₃ NO ₄ S [M ⁺ ]: 385.1348, found: 385.1347.

HPLC (99.7%): retention time 19.65 min.

Example C8: methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-((benzyloxy)methyl)-6-methyl-1,4dihydropyridine-3-carboxylate.

Yellow solid (0.18 g, 64%).

1H-NMR (300 MHz, CDC1 ₃ ) δ=8.09 (d, J=8.0 Hz, 1H), 7.85-7.76 (m, 1H), 7.45-7.24 (m , 8H), 7.13 (s, 1H), 5.45 (s, 1H), 4.85-4.66 (m, 2H), 4.62 (s, 2H), 3.61 (s, 3H), 2.37 (s, 3H), 2.13 (s, 3H).

HRMS (IE) m/z calculated C ₂₆ H ₂₅ nO ₄ S [M ⁺ ]: 447.1504, found: 447.1490.

HPLC (95.6%): retention time 11.55 min.

Example C9: methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(phenoxymethyl)-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.11 g, 52%).

1H-NMR (300 MHz, CDC13) δ=8.15-8.07 (m, 1H), 7.86-7.76 (m, 1H), 7.43-7.27 (m, 4H), 7.17 (s, 1H), 7.14 (br.s, 1H), 7.07-6.93 (m, 3H), 5.50 (s, 1H), 5.36-5.12 ( m, 2H), 3.67 (d, J=0.6 Hz, 3H), 2.40 (s, 3H), 2.15 (d, 3H).

HRMS (IE) m/z calculated C ₂₅ H ₂₃ NO ₄ S [M ⁺ ]: 433.1348, found: 433.1346.

HPLC (96.0%): retention time 10.20 min.

Example C10: phenethyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.075 g, 21%).

1H-NMR (300 MHz, CDCI3) δ=7.98-7.89 (m, 1H), 7.81-7.75 (m, 1H), 7.35-7.26 (m, 3H), 7.24-7.13 (m, 4H), 7.00 (s, 1H), 5.75 (br.s, 1H), 5.40 (s, 1H), 4.38 (dt, J= 10.9, 6.6 Hz, 1H), 4.21 (dt, J=10.9, 7.2 Hz, 1H), 2.88 (t, J=6.6 Hz, 2H), 2, 37 (s, 3H), 2.23 (s, 3H), 2.10 (s, 3H).

HRMS (IE) m/z calculated C ₂₆ H ₂₅ NO ₃ S [M ⁺ ]: 431.1555, found: 431.1549.

HPLC (97.6%): retention time 17.80 min.

Example C11: methyl 4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2-methyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.080 g, 40%).

1H-NMR (300 MHz, CDC13) δ=8.53 (s, 1H), 8.09-7.91 (m, 1H), 7.91-7.79 (m, 1H), 7.37- 7.16 (m, 2H), 7.03 (s, 1H), 5.28 (s, 1H), 3.51 (s, 3H), 2.47-2.39 (m, 1H), 2 .28 (s, 3H), 2.28-2.20 (m, 1H), 1.00-0.59 (m, 8H).

HrMS (lE) m/z calculated C ₂₃ H ₂₃ NO ₃ S [M ⁺ ]: 393.1399, found: 393.1403.

HPLC (98.3%): retention time 16.05 min.

Example C14: methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.012 g, 6%).

1H-NMR (300 MHz, CDCl ,) δ=8.00 (ddd, J=8.1, 1.3, 0.7 Hz, 1H), 7.83 (ddd, J=7.8, 1 .3, 0.7 Hz, 1H), 7.467.30 (m, 2H), 7.17 (s, 1H), 6.22 (br. s, 1H), 5.51 (s, 1H), 3 .65 (s, 3H), 2.43 (s, 3H), 2.11 (s, 3H).

¹⁹ F-NMR (300 MHz, CDCI3) δ=-63.89 (3F).

HRMS (lE) m/z calculated C ₁₉ H ₁₆ F ₃ NO ₃ S [M ⁺ ]: 395.0803, found: 395.0792.

HPLC (99.5%): retention time 12.57 min.

Example C15 and Example C16: methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-benzyl-2-methyl-1,4dihydropyridine-3-carboxylate and methyl 4-(benzo[b ]thiophen-3-yl)-2,6-dimethyl-5-(2-phenylacetyl)-1,4-dihydropyridine-3-carboxylate.

Method C gave examples C15 and C16, which were separated by column chromatography.

Example C15: yellow solid (0.02 g, 6%).

1H-NMR (500 MHz, CDCI3) δ=8.07 (d, J=8.2 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.41-7.26 (m, 7H), 7.14 (s, 1H), 5.70 (br. s, 1H), 5.53 (s, 1H), 4.35 (d, J=16.1 Hz, 1H) , 4.11 (d, J=16.1 Hz, 1H), 3.64 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H).

HRMS (IE) m/z calculated C ₂₅ H ₂₃ NO ₃ S [M ⁺ ]: 417.1399, found: 417.1400.

HPLC (98.6%): retention time 12.86 min.

Example C16: yellow solid (0.078 g, 24%).

1H-NMR (500 MHz, CDC13) δ=8.13 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.40 (ddd, J =8.2, 7.0, 1.3Hz, 1H), 7.33(ddd, J=8.2, 7.0, 1.3Hz, 1H), 7.26-7.20(m , 2H), 7.20-7.15 (m, 2H), 7.00 (s, 1H), 6.99 (s, 1H), 5.82 (br. s, 1H), 5.60 ( s, 1H), 3.91 (d, J=15.9 Hz, 1H), 3.67 (s, 3H), 3.58 (d, J=15.9 Hz, 1H), 2.40 ( s, 3H), 2.29 (s, 3H).

HRMS (IE) m/z calculated C ₂₅ H ₂₃ NO ₃ S [M ⁺ ]: 417.1399, found: 417.1396.

HPLC (95.4%): retention time 15.69 min.

Example C18: methyl 4-(benzo[b]thiophen-3-yl)-5-(2-methoxyacetyl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate.

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Yellow solid (0.03 g, 23%).

1H-NMR (300 MHz, CDC13) δ=8.10 (d, J=8.7 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.41 (t, J =7.6Hz, 1H), 7.33(t, J=7.6Hz, 1H), 7.16(s, 1H), 5.96(s, 1H), 5.44(s, 1H ), 4.32 (d, J=16.1 Hz, 1H), 3.92 (d, J=16.6 Hz, 1H), 3.66 (s, 3H), 3.28 (s, 3H ), 2.43 (s, 3H), 2.31 (s, 3H).

HrMS (lE) m/z calculated C ₂₀ H ₂₁ NO ₄ S [M ⁺ ]: 371.1191, found: 371.1183.

HPLC (97.4%): retention time 22.72 min.

Example C19: methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-(methoxymethyl)-2-methyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.062 g, 36%).

1H-NMR (300 MHz, CDC1 ₃ ) δ=8.08 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.42-7, 36 (m, 2H), 7.31 (t, J=7.5 Hz, 1H), 7.17 (s, 1H), 5.47 (s, 1H), 4.71 (s, 2H), 3.65 (s, 3H), 3.52 (s, 3H), 2.32 (s, 3H), 2.07 (s, 3H).

HRMS (IE) m/z calculated C ₂₀ H ₂₁ NO ₄ S [M ⁺ ]: 371.1191, found: 371.1187.

HPLC (96.0%): retention time 26.61 min.

Example C20: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(fluoromethyl)-6-methyl-1,4-dihydropyridine3-carboxylate.

Yellow solid (0.015 g, 7%).

1H-NMR (300 MHz, CDC13) δ=8.09 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.36 (dt, J =24.7, 7.3 Hz, 2H), 7.18 (s, 1H), 6.72 (d, J=6.5 Hz, 1H), 5.65 (dd, J=47.7, 16.3 Hz, 2H), 5.44 (s, 1H), 3.63 (s, 3H), 2.43 (s, 3H), 2.14 (s, 3H).

¹⁹ B-NMR (282 MHz, CDCI3) δ=122.68 (td, J=47.7, 6.5 Hz).

HRMS (lE) m/z calculated C ₁₉ H ₁₈ FNO ₃ S [M ⁺ ]: 359.0991, found: 359.0977.

HPLC (96.8%): retention time 13.25 min.

Example C21: cyclopropylmethyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.055 g, 52%).

1H-NMR (300 MHz, CDCl ,) δ=7.82 (dd, J=10.5, 2.3 Hz, 1H), 7.70 (dd, J=8.7, 5.0 Hz, 1H), 7.24 (s, 1H), 7.06 (td, J=8.7, 2.3 Hz, 1H), 5.95 (s, 1H), 5.43 (s, 1H), 3.97-3.80 (m, 2H), 2.37 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.19-1.02 (m, 1H), 0.62-0.43 (m, 2H), 0.28-0.15 (m, 2H).

¹⁹ B-NMR (282 MHz, CDCI3) δ=-118.91 (s).

HRMS (IE) m/z calculated C ₂₂ H22FNO ₃ S [M ⁺ ]: 399.1304, found: 399.1318.

HPLC (98.9%): retention time 17.97 min.

Example C22: 1-(t-butoxycarbonyl)piperidin-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (0.085 g, 21%) using method C using ammonium acetate (1.5 eq.) in methanol.

1H-NMR (300 MHz, CDCI3) δ=8.12 (d, J=7.8 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.34 (dt, J =12.9, 7.2 Hz, 2H), 7.12 (s, 1H), 5.80 (s, 1H), 5.48 (s, 1H), 4.91 (dt, J=8, 6, 4.4 Hz, 1H), 3.67 (dd, J=15.3, 7.8 Hz, 2H), 3.07 (dt, J=10.2, 5.2 Hz, 2H), 2.38 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H), 1.62-1.52 (m, 4H), 1.45 (s, 9H).

HRMS (IE) m/z calculated C2 ₈ H ₃₄ N ₂ O ₅ S [M ⁺ ]: 510.2188, found: 510.2182.

HPLC (99.0%): retention time 21.85 min.

Example C23: cyclopentylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (0.035 g, 14%) using method C using ammonium acetate (1.5 eq.) in methanol.

1H-NMR (300 MHz, CDC13) δ=8.13 (d, J=7.9 Hz, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.43-7.29 (m, 2H), 7.13 (s, 1H), 5.84 (br. s, 1H), 5.50 (s, 1H), 3.95 (d, J=7.3 Hz, 2H) , 2.38 (s, 3H), 2.31 (s, 3H), 2.22-2.09 (m, 4H), 1.771.45 (m, 6H), 1.18-1.11 (m , 2H).

HRmS (IE) m/z calculated C ₂₄ H ₂₇ NO ₃ S [M ⁺ ]: 409.1712, found: 409.1712.

HPLC (99.4%): retention time 16.93 min.

Example C24: cyclopropylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.035 g, 43%).

1H-NMR (300 MHz, CDCI3) δ=8.53-8.46 (m, 2H), 7.30 (dd, J=7.9, 4.6 Hz, 1H), 7.23 (s,

1H), 6.53 (s, 1H), 5.47 (s, 1H), 3.95-3.73 (m, 2H), 2.37 (s, 3H), 2.32 (s, 3H ), 2.17 (s, 3H), 1.03 (ddd, J=12.7, 8.0, 5.0 Hz, 1H), 0.48 (d, J=8.0 Hz, 2H) , 0.17 (d, J=4.4 Hz, 2H).

HRMS (IE) m/z calculated C ₂₁ H22N ₂ O ₃ S [M ⁺ ]: 382.1351, found: 382.1346.

HPLC (97.9%): retention time 25.95 min.

Example C25: 1-methylpiperidin-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.025 g, 10%) was obtained by method C using ammonium acetate (1.5 eq.) in methanol.

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1H-NMR (300 MHz, CDCl ₃ ) δ=8.13 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.34 (dt, J=15.9, 7.3 Hz,

2H), 7.11 (s, 1H), 6.03 (s, 1H), 5.49 (s, 1H), 4.78 (tt, J=8.5, 4.1 Hz, 1H), 2.67-2.50 (d, J=17.6 Hz, 2H), 2.35 (s,

3H), 2.30 (s, 3H), 2.27 (d, J=2.3 Hz, 1H), 2.20 (s, 3H), 2.16 (s, 3H), 2.12 ( br.s, 1H), 1.96-1.83 (m, 2H), 1.801.59 (m, 2H).

HRmS (IE) m/z calculated C ₂₄ H ₂₈ N ₂ O ₃ S [M ⁺ ]: 424.1821, found: 424.1827.

HPLC (96.8%): retention time 33.18 min.

Example C26: cyclopentyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.04 g, 17%) was obtained by method C using ammonium acetate (1.5 eq.) in methanol.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.14 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.42-7, 28 (m, 2H), 7.11 (s, 1H), 5.81 (s, 1H), 5.48 (s, 1H), 5.27-5.11 (m, 1H), 2.38 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H), 1.90-1.47 (m, 8H).

HRMS (IE) m/z calculated C ₂₃ H ₂₅ NO ₃ S [M ⁺ ]: 395.1555, found: 395.1558.

HPLC (97.1%): retention time 17.56 min.

Example C27: 4,4-dimethylcyclohexyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a light yellow solid (0.03 g, 11%) using method C using ammonium acetate (1.5 eq.) in methanol.

1H-NMR (300 MHz, CDCl3) δ=8.15 (ddd, J=8.1, 1.3, 0.7 Hz, 1H), 7.79 (ddd, J=7.8, 1.3 , 0.7 Hz, 1H), 7.407.28 (m, 2H), 7.13 (s, 1H), 5.78 (br.s, 1H), 5.50 (s, 1H), 4.74 (tt, J=8.8, 4.2 Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H), 1.80-1, 66 (m, 1H), 1.66-1.50 (m, 3H), 1.46-1.27 (m, 3H), 1.27-1.16 (m, 1H), 0.88 ( s, 3H), 0.88 (s, 3H).

HRMS (IE) m/z calculated C ₂₆ H ₃₁ NO ₃ S [M ⁺ ]: 437.2025, found: 437.2028.

HPLC (98.3%): retention time 16.78 min.

Example C28: cyclobutyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a light yellow solid (0.02 g, 9%) using method C using ammonium acetate (1.5 eq.) in methanol.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.14 (d, J=7.9 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.35-7, 31 (m, 2H), 7.13 (s, 1H), 6.09 (s, 1H), 5.47 (s, 1H), 5.00-4.89 (m, 1H), 2.36 (s, 3H), 2.32-2.23 (m, 5H), 2.15 (s, 3H), 2.12-1.99 (m, 1H), 1.99-1.85 (m , 1H), 1.82-1.66 (m, 1H), 1.66-1.51 (m, 1H).

HRMS (lE) m/z calculated C ₂₂ H ₂₃ NO ₃ S [M ⁺ ]: 381.1399, found: 381.1408.

HPLC (99.0%): retention time 17.42 min.

Example C29: Methyl 5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.035 g, 37%) was obtained by method C using trifluoroacetic acid (1.5 eq.) in methanol.

1H-NMR (300 MHz, CDCl ₃ ) δ=7.71 (dd, J=9.6, 3.6 Hz, 2H), 7.24 (s, 1H), 7.11 (td, J=8 .7, 2.4 Hz, 1H), 6.30 (s, 1H), 5.43 (s, 1H), 3.69 (s, 3H), 2.43 (s, 3H), 2.13 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCl3) δ=-63.84 (s, CF ₃ ), -118.19 (td, J=9.6, 4.9 Hz, F).

HRMS (IE) m/z calculated C ₁₉ H ₁₅ NO ₃ SF4 [M ⁺ ]: 413.0709, found: 413.0702.

HPLC (99.1%): retention time 13.51 min.

Example C30: Methyl 5-acetyl-2,6-dimethyl-4-(thieno[3,2-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.015 g, 24%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.66 (dd, J=4.5, 1.5 Hz, 1H), 8.07 (dd, J=8.2, 1.5 Hz, 1H ), 7.29 (s, 1H), 7.18 (dd, J=8.2, 4.5 Hz, 1H), 5.97 (s, 1H), 5.72 (s, 1H), 3 .63 (s, 3H), 2.45 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H).

HRMS (IE) m/z calculated C ₁₈ H ₁₈ N ₂ O ₃ S [M ⁺ ]: 342.1038, found: 342.1034.

HPLC (98.8%): retention time 22.75 min.

Example C31: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-methyl-6-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.035 g, 24%) was obtained by method C using trifluoroacetic acid (1.5 eq.) in methanol.

1H-NMR (300 MHz, CDCl ₃ ) δ=7.97-7.91 (m, 1H), 7.83 (ddd, J=7.7, 1.4, 0.7 Hz, 1H), 7 .44-7.30(m, 2H), 7.24(s, 1H), 5.94(s, 1H), 5.40(s, 1H), 3.58(s, 3H), 2, 39 (s, 3H), 1.99 (q, J=0.7 Hz, 3H).

¹⁹ F-NMR (282 MHz, CDCl3) δ=-63.65. (c, CF3).

HRMS (IE) m/z calculated C ₁₉ H ₁₆ NO ₃ SF ₃ [M ⁺ ]: 395.0803, found: 395.0810.

HPLC (98.5%): retention time 10.44 min.

Example C32: cyclopropylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.075 g, 50%).

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1H-NMR (300 MHz, CDCl ₃ ) δ=8.12 (d, J=2.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.28 (d, J=2.5Hz, 1H), 7.21(s, 1H), 5.78(s, 1H), 5.44(s, 1H), 3.90(d, J=7.3Hz, 2H), 2.39 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.29-1.13 (m,

1H), 0.59-0.46 (m, 2H), 0.21 (dd, J=4.8, 1.8 Hz, 2H).

HRMS (IE) m/z calculated C ₂₂ H ₂₂ NO ₃ SC1 [M ⁺ ]: 415.1009, found: 415.0997.

HPLC (99.6%): retention time 18.43 min.

Example C33: cyclohexylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.080 g, 61%).

1H-NMR (300 MHz, CDCl3) δ=8.10 (br. s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.31-7.21 (m, 1H) , 7.17 (s, 1H), 6.05 (br.s, 1H), 5.42 (s, 1H), 3.90 (ddd, J=27.5, 10.8, 6.6 Hz , 2H), 2.36 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H), 1.851.43 (m, 6H), 1.32-1.01 (m, 3H), 1.01-0.78 (m, 2H).

HRmS (IE) m/z calculated C ₂₅ H2 ₈ nO ₃ SC1 [M+]: 457.1478, found: 457.1477.

HPLC (99.1%): retention time 18.16 min.

Example C34: cyclohexylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.075 g, 58%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.57-8.44 (m, 2H), 7.32 (dd, J=8.2, 4.6 Hz, 1H), 7.20 (s , 1H), 6.40 (s, 1H), 5.46 (s, 1H), 3.86 (dd, J=6.1, 3.5 Hz, 2H), 2.37 (s, 3H) , 2.33 (s, 3H), 2.18 (s, 3H), 1.70-1.44 (m, 6H), 1.16 (d, J=40.3 Hz, 3H), 0, 91-0.74 (m, 2H).

HRMS (IE) m/z calculated C ₂ 4H2 ₈ N ₂ O ₃ S [M ⁺ ]: 424.1821, found: 424.1833.

HPLC (98.9%): retention time 25.30 min.

Example C35: cyclopentylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.095 g, 75%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.49 (d, J=8.2 Hz, 2H), 7.31 (dd, J=8.1, 4.6 Hz, 1H), 7, 20 (s, 1H), 6.44 (s, 1H), 5.46 (s, 1H), 4.01-3.86 (m, 2H), 2.37 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.14-2.02 (m, 1H), 1.67-1.44 (m, 6H), 1.21-1.05 (m , 2H).

HRMS (IE) m/z calculated C2 ₃ H2 ₆ N ₂ O ₃ S [M ⁺ ]: 410.1664, found: 410.1665.

HPLC (98.4%): retention time 25.14 min.

Example C3 6: cyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine3-carboxylate.

Yellow solid (0.028 g, 48%).

1H-NMR (300 MHz, CDCl3) δ=8.59-8.40 (m, 2H), 7.31 (dd, J=8.2, 4.6 Hz, 1H), 7.19 (s, 1H), 6.47 (s, 1H), 5.46 (s, 1H), 4.75 (tt, J=8.8, 3.9 Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H), 1.87-1.74 (m, 1H), 1.75-1.55 (m, 3H), 1.56-1, 45 (m, 1H), 1.45-1.13 (m, 5H).

HRMS (IE) m/z calculated C ₂₃ H2 ₆ N ₂ O ₃ S [M ⁺ ]: 410.1664, found: 410.1665.

HPLC (98.2%): retention time 24.87 min.

Example C37: cyclopentyl 5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.034 g, 59%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.53-8.42 (m, 2H), 7.31 (dd, J=8.2, 4.6 Hz, 1H), 7.17 (s , 1H), 5.85 (s, 1H), 5.44 (s, 1H), 5.16 (dc, J=6.1, 3.0 Hz, 1H), 2.38 (s, 3H) , 2.31 (s, 3H), 2.17 (s, 3H), 1.80 (td, J=15.9, 14.5, 6.1 Hz, 2H), 1.67-1.46 (m, 6H).

HRMS (IE) m/z calculated C ₂ 2H24N ₂ O ₃ S [M ⁺ ]: 396.1508, found: 396.1505.

HPLC (98.9%): retention time 25.70 min.

Example C38: Methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.022 g, 51%) was obtained by method C using trifluoroacetic acid (1.5 eq.) in methanol.

1H-NMR (300 MHz, CDCl ,) δ=8.00 (d, J=1.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.31 (dd , J=8.6, 1.6 Hz, 1H), 7.20 (s, 1H), 6.29 (s, 1H), 5.45 (s, 1H), 3.71 (s, 3H) , 2.44 (s, 3H), 2.13 (s, 3H).

%-NMR (282 MHz, CDCl·,) δ=-63.85 (s, CF3).

HRMS (lE) m/z calculated C ₁₉ H ₁₅ NO ₃ SF ₃ Cl [M ⁺ ]: 429.0413, found: 429.0413.

HPLC (95.7%): retention time 13.94 min.

Example C39: benzyl 5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.070 g, 69%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.50-8.44 (m, 1H), 8.26 (dd, J=8.2, 1.5 Hz, 1H), 7.34-7 .24 (m, 2H), 7.26 (d, J=0.8 Hz, 1H), 7.20-7.16 (m, 2H), 7.16-7.10 (m, 2H), 5.95 (s, 1H), 5.44 (s, 1H), 5.07 (s, 2H), 2.37 (s, 3H), 2.33 (s, 3H), 2.13 (s , 3H).

HRMS (lE) m/z calculated C ₂ 4H22N ₂ O ₃ S [M ⁺ ]: 418.1351, found: 418.1358.

- 72 040842

HPLC (99.4%): retention time 26.38 min.

Example C40: (tetrahydro-2H-pyran-4-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3yl)-1,4-dihydropyridin-3 - carboxylate.

Yellow solid (0.029 g, 45%).

1H-NMR (300 MHz, CDCl ,) δ=8.55-8.43 (m, 2H), 7.32 (dd, J=8.1, 4.6 Hz, 1H), 7.19 ( s, 1H), 6.18 (s, 1H), 5.45 (s, 1H), 3.99-3.77 (m, 4H), 3.24 (dtd, J=20.2, 11, 6, 2.5 Hz, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.18 (s, 3H), 1.47-1.15 (m, 5H).

HRMS (IE) m/z calculated C ₂₃ H ₂₆ N ₂ O ₄ S [M ⁺ ]: 426.1613, found: 426.1600.

HPLC (99.5%): retention time 32.56 min.

Example C41: benzyl 5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.018 g, 11%).

1H-NMR (300 MHz, CDC13) δ=7.75-7.63 (m, 2H), 7.33-7.17 (m, 5H), 7.16 (s, 1H), 7.04 ( td, J=8.9, 8.5, 2.0 Hz, 1H), 5.92 (s, 1H), 5.42 (s, 1H), 5.10 (k, J=12.3 Hz , 2H), 2.35 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H).

¹⁹ F-NMR (282 MHz, CDC13) δ=-118.53 (s, CF).

HRMS (IE) m/z calculated C25H ₂₂ NO ₃ Sf [M ⁺ ]: 435.1304, found: 435.1307.

HPLC (97.1%): retention time 18.43 min.

Example C42: benzyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.065 g, 60%).

1H-NMR (300 MHz, CDCI3) δ=8.06 (d, J=1.7 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.39-7.18 (m, 6H), 7.13 (s, 1H), 6.00 (s, 1H), 5.44 (s, 1H), 5.27-4.96 (m, 2H), 2.35 ( s, 3H), 2.30 (s, 3H), 2.13 (s, 3H).

HRMS (IE) m/z calculated C25H ₂₂ NO ₃ SC1 [M+]: 451.1011, found: 451.1011.

HPLC (97.4%): retention time 18.38 min.

Example C43: (tetrahydro-2H-pyran-4-yl)methyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.076 g, 46%).

1H-NMR (300 MHz, CDC13) δ=8.10 (d, J=1.8 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.27-7.24 (m, 1H), 7.18 (s, 1H), 6.15 (br. s, 1H), 5.39 (s, 1H), 3.93-3.82 (m, 4H), 3, 50-3.19(m, 2H), 2.35(s, 3H), 2.17(s, 3H), 2.03(s, 3H), 1.89-1.63(m, 2H) , 1.51-1.47 (m, 1H), 1.35-1.17 (m, 2H).

HRMS (IE) m/z calculated C ₂ 4H ₂₆ NO ₄ SC1 [M ⁺ ]: 459.1271, found: 459.1272.

HPLC (99.4%): retention time 24.50 min.

Example C44: (tetrahydro-2H-pyran-4-yl)methyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.097 g, 57%).

1H-NMR (300 MHz, CDCI3) δ=7.79 (d, J=9.7 Hz, 1H), 7.70 (dd, J=8.3, 5.1 Hz, 1H), 7.21 (s, 1H), 7.06 (t, J=8.3 Hz, 1H), 6.02 (s, 1H), 5.40 (s, 1H), 3.99-3.73 (m, 4H), 3.28 (dt, J=25.5, 12.5 Hz, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 1.81 (s, 1H), 1.54-1.13 (m, 4H).

¹⁹ F-NMR (282 MHz, CDCI3) δ=-118.74 (s, CF).

HRMS (lE) m/z calculated C ₂ 4H ₂₆ NO ₄ Sf [M ⁺ ]: 443.1567, found: 443.1574.

HPLC (99.6%): retention time 24.69 min.

Example C45: benzyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.015 g, 27%) was obtained by method C using trifluoroacetic acid (1.5 eq.) in methanol.

1H-NMR (300 MHz, CDC13) δ=7.97-7.90 (m, 1H), 7.85-7.77 (m, 1H), 7.35-7.29 (m, 2H), 7.29-7.22 (m, 3H), 7.16-7.07 (m, 3H), 6.18 (s, 1H), 5.53 (s, 1H), 5.07 (q, J=12.2 Hz, 2H), 2.42 (s, 3H), 2.10 (s, 3H).

^-NMR (282 MHz, CDCI3) δ=-63.64 (s, CF3).

HRMS (IE) m/z calculated C ₂ 5H ₂₀ NO ₃ SF ₃ [M ⁺ ]: 471.1116, found: 471.1117.

HPLC (99.3%): retention time 12.46 min.

Example C46: pyridin-4-ylmethyl-5-acetyl-4-(5-fluoro-benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.091 g, 55%).

1H-NMR (300 MHz, CDCI3) δ=8.50-8.42 (m, 2H), 7.76-7.63 (m, 2H), 7.21 (s, 1H), 7.04 ( td, J=8.7, 2.5 Hz, 1H), 6.96 (d, J=5.2 Hz, 2H), 6.13 (s, 1H), 5.45 (s, 1H), 5.11 (q, J=13.7 Hz, 2H), 2.36 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCI3) δ=-118.54 (s, CF).

HRMS (lE) m/z calculated C2 ₄ H ₂₁ N ₂ O ₃ SF [M ⁺ ]: 436.1257, found: 436.1255.

HPLC (99.5%): retention time 26.10 min.

Example C47: 4-fluorobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

- 73 040842

Yellow solid (0.050 g, 43%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.49 (d, J=4.5 Hz, 1H), 8.28 (dd, J=8.2, 1.6 Hz, 1H), 7, 21-7.07 (m, 4H), 6.95 (t, J=8.6 Hz, 2H), 6.06 (s, 1H), 5.43 (s, 1H), 5.11-4 .93 (m, 2H), 2.37 (s, 3H), 2.33 (s, 3H), 2.14 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCl3) 6=-113.87 (s, CF).

HRMS (IE) m/z calculated C ₂₄ H ₂₁ N ₂ O ₃ SF [M ⁺ ]: 436.1257, found: 436.1259.

HPLC (98.5%): retention time 20.40 min.

Example C48: pyridin-3-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.025 g, 15%) was obtained by method C using ammonium acetate (1.5 eq.) in methanol.

1H-NMR (300 MHz, CDCl3) 6=8.50 (d, J=11.7 Hz, 2H), 8.01-7.96 (m, 1H), 7.85-7.66 (m, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.32-7.21 (m, 2H), 7.17 (t, J=6.5 Hz, 1H), 7, 10 (s, 1H), 6.14 (s, 1H), 5.46 (s, 1H), 5.08 (d, J=3.1 Hz, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H).

HRMS (IE) m/z calculated C ₂₄ H ₂₂ N ₂ O ₃ S [M ⁺ ]: 418.1351, found: 418.1346.

HPLC (98.0%): retention time 24.79 min.

Example C51: 1,1'-(4-(Benzo[b]thiophen-3-yl)-2-benzyl-6-methyl-1,4-dihydropyridin-3,5diyl)bis(ethan-1-one).

Yield: 8% (18 mg, yellow solid).

1H-NMR (300 MHz, CDCl3) 6=8.12 (d, J=7.8 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.45-7.28 (m, 5H), 7.32-7.19 (m, 2H), 7.09 (s, 1H), 5.85 (s, 1H), 5.66 (s, 1H), 4.15 ( dd, J=16.5 Hz, J=41.8 Hz, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 2.17 (s, 3H).

HRMS (IE) m/z calculated C ₂₅ H ₂₃ NO ₂ S [M ⁺ ]: 401.1450, found: 401.1442.

Example C52: 1-(5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3-yl)-2-phenylethan-1-one.

Light yellow solid (35 mg, 15%).

1H-NMR (300 MHz, CDCl3) 6=8.12 (d, J=8.1 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.47-7.25 (m, 5H), 7.22 (d, J=8.3 Hz, 2H), 7.09 (s, 1H), 5.85 (s, 1H), 5.66 (s, 1H), 4 .15 (dd, J=94.6, 16.2 Hz, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 2.17 (s, 3H).

HRMS (IE) m/z calculated C ₂₅ H ₂₃ NO ₂ S [M ⁺ ]: 401.1450, found: 401.1437.

Example C53: Methyl 5-acetyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-2-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate.

The title compound as a yellow solid (30 mg, 26%) was obtained by method C using 1.5 eq. TFA.

1H-NMR (300 MHz, CDCl3) 6=8.56 (br. s, 1H), 8.36 (dd, J=8.2, 1.3 Hz, 1H), 7.36 (dd, J= 8.2, 4.5 Hz, 1H), 7.23 (s, 1H), 6.52 (br. s, 1H), 5.49 (s, 1H), 3.66 (s, 3H), 2.44 (s, 3H), 2.16 (s, 3H).

^-NMR (282 MHz, CDCl3) 6=-63.72 (CF3).

HRMS (lE) m/z calculated C ₁₈ H ₁₅ N ₂ O ₃ SF ₃ [M ⁺ ]: 396.0755, found: 396.0768.

Example C54: 1-(2-methyl-5-(piperidine-1-carbonyl)-4-(thieno[2,3-b]pyridin-3-yl)-6(trifluoromethyl)-1,4-dihydropyridine-3 -yl)ethane-1-one.

The title compound as a yellow solid (10 mg, 15%) was obtained by method C using 1.5 eq. TFA.

1H-NMR (300 MHz, CDCl3) 6=8.60 (dd, J=4.6, 1.6 Hz, 1H), 8.13 (dd, J=8.2, 1.6 Hz, 1H) , 7.42-7.31(m, 2H), 5.65(s, 1H), 5.47(s, 1H), 3.35-3.14(m, 2H), 2.80-2 .65 (m, 1H), 2.41 (s, 3H), 2.26-2.12 (m, 1H), 1.93 (s, 3H), 1.39-1.22 (m, 2H ), 1.23-1.04 (m, 2H), 1.06-0.82 (m, 2H).

¹⁹ F-NMR (282 MHz, CDCl3) 6=-67.14 (CF3).

HRMS (IE) m/z calculated C ₂₂ H ₂₂ N ₃ O ₂ SF ₃ [M+]: 449.1385, found: 449.1378.

Example C55: 4-(((5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3carbonyl)oxy)methyl)benzoic acid.

4-(tert-butoxycarbonyl)benzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate (yellow solid, 30 mg, 66% ) was obtained by method C.

1H-NMR (300 MHz, CDCl3) 6=8.00 (d, J=8.1 Hz, 1H), 7.88 (d, J=8.6 Hz, 2H), 7.79 (d, J = 8.1 Hz, 1H), 7.32-7.22 (m, 3H), 7.19 (d, J=7.9 Hz, 2H), 5.86 (s, 1H), 5.49 (s, 1H), 5.11 (s, 2H), 2.37 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H), 1.60 (s, 9H) .

Ester hydrolysis: 4-(tert-butoxycarbonyl)benzyl-5-acetyl-4-(benzo[b]thiophen-3yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate mixture (0.05 g , 0.09 mmol) in dichloromethane (3 ml) was stirred at 0°C. Trifluoroacetic acid (0.5 ml) in dichloromethane (2 ml) was added dropwise at the same temperature over 60 minutes. The mixture was allowed to warm to RT and the solvent was removed under reduced pressure. The residue was purified by column chromatography (5% DCM in methanol) to give a yellow solid (0.012 g, 27%).

1H-NMR (300 MHz, CDCl ₃ ) 6=17.14 (s, 1H), 9.14 (s, 1H), 8.02 (dd, J=4.8, 3.0 Hz, 1H), 7.89 (dd, J=6.2, 3.0 Hz, 1H), 7.81 (d, J=7.9 Hz, 2H), 7.30-7.24 (m, 2H), 7 .20 (s, 1H), 7.12 (d, J=7.9 Hz, 2H), 5.46 (s, 1H), 5.05

- 74 040842 (s, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 2.11 (s, 3H).

HRMS (lE) m/z calculated C ₂₆ H ₂₃ NO ₅ SNa [M ^+Na ]: 484.1189, found: 484.1188.

Example C56: benzyl-5-acetyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate.

Method C using 1.5 eq. TFA in dioxane gave the title compound as a yellow solid (35 mg, 12%).

1H-NMR (300 MHz, CDCI3) δ=8.51 (s, 1H), 8.23 (d, J=8.1 Hz, 1H), 7.32-7.07 (m, 7H), 6 .45 (s, 1H), 5.49 (s, 1H), 5.09 (d, J=2.6 Hz, 2H), 2.43 (s, 3H), 2.14 (s, 3H) .

1^-NMR (282 MHz, CDCl·,) δ=-63.44 (CF ₃ ).

HRMS (IE) m/z calculated C ₂₄ H ₁₉ N ₂ O ₃ SF ₃ [M ⁺ ]: 472.1068, found: 472.1067.

Example C57: Pyridin-3-ylmethyl-5-acetyl-4-(5-fluoro-benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (60 mg, 50%) by Method C.

1H-NMR (300 MHz, CDC13) δ=8.52 (d, J=4.3 Hz, 1H), 8.48 (s, 1H), 7.72-7.63 (m, 2H), 7 .46 (d, J=7.8 Hz, 1H), 7.24-7.18 (m, 1H), 7.17 (s, 1H), 7.04 (td, J=8.7, 2 .5 Hz, 1H), 6.27 (s, 1H), 5.39 (s, 1H), 5.11 (s, 2H), 2.34 (s, 3H), 2.30 (s, 3H ), 2.14 (s, 3H).

¹⁹ F-NMR (282 MHz, CDC13) δ=-118.51 (q, J=9.2 Hz, CF).

HRMS (IE) m/z calculated C ₂₄ H ₂₁ N ₂ O ₃ SF [M ⁺ ]: 436.1257, found: 436.1252.

Example C58: pyridin-3-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (68 mg, 49%) by Method C.

1H-NMR (300 MHz, CDCI3) δ=8.52 (s, 2H), 7.98 (d, J=7.9 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H ), 7.36 (d, J=7.1 Hz, 1H), 7.23-7.10 (m, 3H), 5.93 (s, 1H), 5.41 (s, 1H), 5 .08 (k, J=12.8 Hz, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.13 (s, 3H).

HRMS (IE) m/z calculated C ₂₄ H ₂₁ N ₂ O ₃ SBr [M ⁺ ]: 496.0456, found: 496.0462.

Example C59: Pyridin-3-ylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (30 mg, 31%) by Method C.

1H-NMR (300 MHz, CDC13) δ=8.52 (d, J=15.9 Hz, 2H), 8.29 (d, J=8.2 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.43-7.29 (m, 2H), 7.25-7.14 (m, 2H), 6.00 (s, 1H), 5.48 (s, 1H), 5.07 (q, J=13.7, 13.0 Hz, 2H), 2.38 (s, 3H), 2.36 (s, 3H), 2.15 (s, 3H).

HRMS (lE) m/z calculated C ₂₅ H ₂₁ N ₃ O ₃ S [M ⁺ ]: 443.1304, found: 443.1288.

Example C60: Pyridin-3-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (68 mg, 35%) by Method C.

1H-NMR (300 MHz, CDCI3) δ=8.52 (s, 2H), 8.04 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.49 (d , J=7.8 Hz, 1H), 7.29-7.19 (m, 2H), 7.15 (s, 1H), 6.00 (s, 1H), 5.41 (s, 1H) , 5.13 (s, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.14 (s, 3H).

HRMS (IE) m/z calculated C ₂₄ H ₂₁ N ₂ O ₃ SCl [M ⁺ ]: 452.0961, found: 452.0959.

Example C61: pyridin-3-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (35 mg, 34%) by Method C.

1H-NMR (300 MHz, CDCI3) δ=8.62-8.40 (m, 3H), 8.29 (d, J=8.0 Hz, 1H), 7.40 (d, J=8, 0 Hz, 1H), 7.23-7.14 (m, 3H), 6.05 (s, 1H), 5.43 (s, 1H), 5.09 (k, J=12.6 Hz, 2H), 2.38 (s, 3H), 2.35 (s, 3H), 2.15 (s, 3H).

HRMS (IE) m/z calculated C ₂₃ H ₂₁ N ₃ O ₃ S [M ⁺ ]: 419.1304, found: 419.1306.

Example C62: pyridin-4-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (35 mg, 48%) by Method C.

1H-NMR (300 MHz, CDC13) δ=8.46 (d, J=4.7 Hz, 2H), 8.04 (s, 1H), 7.70 (d, J=8.5 Hz, 1H ), 7.23-7.16 (m, 2H), 6.99 (d, J=5.0 Hz, 2H), 6.00 (s, 1H), 5.46 (s, 1H), 5 .22-5.03 (m, 2H), 2.38 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H).

HRMS (IE) m/z calculated C ₂₄ H ₂₁ N ₂ O ₃ SCl [M ⁺ ]: 452.0961, found: 452.0954.

Example C63: 4-(cyclopropylcarbamoyl)benzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (30 mg, 13%) by method C.

1H-NMR (300 MHz, CDCI3) δ=8.00 (dd, J=6.9, 2.4 Hz, 1H), 7.84-7.75 (m, 1H), 7.61 (d, J=8.2Hz, 2H), 7.34-7.24(m, 1H), 7.28-7.20(m, 1H), 7.18(d, J=8.2Hz, 2H ), 7.10 (s, 1H), 6.18 (br.s, 1H), 5.87 (br.s, 1H), 5.49 (s, 1H), 5.10 (s, 2H) , 2.90 (dt, J=6.9, 3.6 Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H), 0, 93-0.82 (m, 2H), 0.67-0.57 (m, 2H).

HRMS (IE) m/z calculated C ₂₉ H ₂₉ N ₂ O ₄ S [M ⁺¹ ]: 501.1843, found: 501.1841.

Example C64: pyridin-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

- 75 040842

The title compound was obtained as a yellow solid (28 mg, 40%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.51-8.41 (m, 3H), 8.37 (dd, J=8.2, 1.6 Hz, 1H), 7.22-7 .15 (m, 2H), 6.96 (d, J=5.5 Hz, 2H), 5.49 (s, 1H), 5.28 (s, 1H), 5.04 (q, J= 15.0 Hz, 2H), 2.35 (s, 6H), 2.18 (s, 3H).

HRMS (IE) m/z calculated C ₂₃ H ₂₁ N ₃ O ₃ S [M ⁺ ]: 419.1304, found: 419.1304.

Example C65: 4-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (131 mg, 72%) by Method C.

1H-NMR (300 MHz, CDCl,) δ=8.50 (d, J=4.7 Hz, 1H), 8.34 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.18 (s, 2H), 6.99 (d, J=8.0 Hz, 2H), 6.00 (s, 1H), 5.43 (s, 1H), 4.99 ( k, J=12.5 Hz, 2H), 2.39 (s, 3H), 2.36 (s, 3H), 2.16 (s, 3H).

HRMS (IE) m/z calculated C ₂₄ H ₂₁ N ₂ O ₃ SBr [M ⁺ ]: 496.0456, found: 496.0441.

Example C66: 3-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (115 mg, 54%) by Method C.

1H-NMR (300 MHz, CDC13) δ=8.50 (dd, J=4.6, 1.5 Hz, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.48 -7.37(m, 1H), 7.33(t, J=1.5Hz, 1H), 7.23-7.01(m, 4H), 5.97(s, 1H), 5, 44 (s, 1H), 5.02 (q, J=12 Hz, 2H), 2.38 (s, 3), 2.36 (s, 3H), 2.15 (s, 3H).

HRMS (IE) m/z calculated C ₂₄ H ₂₁ N ₂ O ₃ SBr [M ⁺ ]: 496.0456, found: 496.0456.

Example C67: 2-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (127 mg, 74%) by Method C.

1H-NMR (300 MHz, CDC13) δ=8.46 (dd, J=4.7, 1.6 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 7.57 -7.48 (m, 1H), 7.23-7.05 (m, 5H), 6.04 (s, 1H), 5.47 (s, 1H), 5.14 (q, J=15 Hz, 2H), 2.39 (s, 3H), 2.38 (s, 3H), 2.16 (s, 3H).

HRMS (IE) m/z calculated C ₂₄ H ₂₁ N ₂ O ₃ SBr [M ⁺ ]: 496.0456, found: 496.0446.

Example C68: (3-fluoropyridin-4-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (30 mg, 47%) by Method C.

1H-NMR (300 MHz, CDC13) δ=8.50 (d, J=4.6 Hz, 1H), 8.44-8.30 (m, 2H), 8.23 (s, 1H), 7 .20 (c, J=4.9 Hz, 2H), 6.88 (t, J=5.4 Hz, 1H), 6.18 (s, 1H), 5.47 (s, 1H), 5 .24-5.09 (m, 2H), 2.38 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H).

%-NMR (282 MHz, CDC13) δ=-132.30 (s, CF).

HRMS (IE) m/z calculated C ₂₃ H ₂₀ N ₃ O ₃ SF [M ⁺ ]: 437.1209, found: 437.1215.

Example C69: pyrimidin-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (35 mg, 58%) by Method C.

1H-NMR (300 MHz, CDC13) δ=9.13 (s, 1H), 8.56 (s, 2H), 8.50 (dd, J=4.6, 1.6 Hz, 1H), 8 .33 (dd, J=8.2, 1.6 Hz, 1H), 7.23 (dd, J=8.3, 4.6 Hz, 1H), 7.18 (s, 1H), 6, 51 (s, 1H), 5.42 (s, 1H), 5.08 (q, J=12 Hz, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2, 16 (s, 3H).

HRMS (IE) m/z calculated C ₂₂ H ₂₀ N ₄ O ₃ S [M ⁺ ]: 420.1256, found: 420.1262.

Example C70: (5-bromopyrimdin-3-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)1,4-dihydropyridine-3-carboxylate .

The title compound was obtained as a yellow solid (84 mg, 63%) by Method C.

1H-NMR (300 MHz, CDC13) δ=8.58 (s, 1H), 8.50 (d, J=4.3 Hz, 1H), 8.38 (s, 1H), 8.32 (d , J=7.8 Hz, 1H), 7.54 (s, 1H), 7.22 (dd, J=4.3, 7.8 Hz, 1H), 7.18 (s, 1H), 6.32 (br. s, 1H), 5.43 (s, 1H), 5.04 (q, J=13 Hz, 2H), 2.37 (s, 3H), 2.35 (s, 3H ), 2.16 (s, 3H).

HRMS (IE) m/z calculated C ₂₃ H ₂₀ N ₃ O ₃ SBr [M ⁺ ]: 497.0409, found: 497.0412.

Example C71: 2-phenylpropan-2-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (17 mg, 27%) by Method C.

1H-NMR (300 MHz, CDCI3) δ=8.60-8.47 (m, 1H), 8.36 (dd, J=8.2, 1.6 Hz, 1H), 7.23-7, 09 (m, 5H), 7.086.99 (m, 2H), 6.02 (s, 1H), 5.49 (s, 1H), 2.38 (s, 3H), 2.31 (s, 3H ), 2.15 (s, 3H), 1.70 (s, 3H), 1.64 (s, 3H).

HRmS (IE) m/z calculated C ₂₆ H ₂₇ N ₂ O ₃ S [M ⁺¹ ]: 447.1737, found: 447.1736.

Example C72: 3-cyanobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (38 mg, 58%) by Method C.

1H-NMR (300 MHz, CDCI3) δ=8.55-8.45 (m, 1H), 8.34 (dd, J=8.2, 1.5 Hz, 1H), 7.54 (dt, J=7.4, 1.5 Hz, 1H), 7.45 (s, 1H), 7.37-7.27 (m, 2H), 7.24-7.20 (m, 1H), 7 .19 (s, 1H), 6.40 (s, 1H), 5.45 (s, 1H), 5.06 (q, J=12 Hz, 2H), 2.37 (s, 3H), 2 .35 (s, 3H), 2.17 (s, 3H).

HRMS (IE) m/z calculated C ₂₅ H ₂₁ N ₃ O ₃ S [M ⁺ ]: 443.1304, found: 443.1310.

Example C73: 4-cyanobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

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The title compound was obtained as a yellow solid (25 mg, 40%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.55-8.45 (m, 1H), 8.34 (dd, J=8.2, 1.5 Hz, 1H), 7.54 (dt , J=7.4, 1.5 Hz, 1H), 7.45 (s, 1H), 7.37-7.27 (m, 2H), 7.24-7.20 (m, 1H), 7.19 (s, 1H), 6.40 (s, 1H), 5.45 (s, 1H), 5.19-4.93 (q, J=12 Hz, 2H), 2.37 (s , 3H), 2.35 (s, 3H), 2.17 (s, 3H).

HRMS (IE) m/z calculated C ₂₅ H ₂₁ N ₃ O ₃ S [M ⁺ ]: 443.1304, found: 443.1306.

Example C74: (6-chloropyridin-3-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (80 mg, 54%) by Method C.

1H-NMR (300 MHz, CDCl3) δ=8.57-8.46 (m, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.26 (d, J=2, 4 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.22 (d, J=4.6 Hz, 1H), 7.20-7.12 (m, 2H) , 6.16 (s, 1H), 5.41 (s, 1H), 5.13-4.93 (q, J=12 Hz, 2H), 2.38 (s, 3H), 2.36 ( s, 3H), 2.17 (s, 3H).

HRMS (IE) m/z calculated C ₂₃ H ₂₀ N ₃ O ₃ SCl [M ⁺ ]: 453.0914, found: 453.0894.

Example C75: 3-morpholinobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (50 mg, 69%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.51-8.45 (m, 1H), 8.32 (d, J=8.1 Hz, 1H), 7.24-7.11 (m , 3H), 6.89 (d, J=8.1 Hz, 1H), 6.74 (d, J=6.9 Hz, 2H), 5.92 (s, 1H), 5.45 (s , 1H), 5.04 (d, J=3.0 Hz, 2H), 3.88 (d, J=4.8 Hz, 4H), 3.09 (t, J=4.8 Hz, 4H ), 2.39 (s, 3H), 2.35 (s, 3H), 2.14 (s, 3H).

HRMS (IE) m/z calculated C ₂₈ H ₂₉ N ₃ O ₄ S [M ⁺ ]: 503.1879, found: 503.1878.

Example C76: 4,4-dimethylcyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (45 mg, 73%) by Method C.

1H-NMR (300 MHz, CDCl3) δ=8.57-8.45 (m, 2H), 7.31 (dd, J=8.1, 4.7 Hz, 1H), 7.20 (s, 1H), 6.90 (s, 1H), 5.46 (s, 1H), 4.71 (tt, J=8.8, 4.1 Hz, 1H), 2.35 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H), 1.70-1.49 (m, 3H), 1.35-1.17 (m, 5H), 0.86 (s, 3H), 0.83 (s, 3H).

HRMS (IE) m/z calculated C ₂₅ H ₃₀ N ₂ O ₃ S [M ⁺ ]: 438.1977, found: 438.1967.

Example C77: (2-chloropyridin-4-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (117 mg, 75%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.53 (s, 1H), 8.41 (d, J=8.2 Hz, 1H), 8.22 (d, J=5.1 Hz, 1H), 7.22 (s, 2H), 7.01 (d, J=7.4 Hz, 1H), 6.85 (d, J=5.1 Hz, 1H), 6.14 (s, 1H), 5.49 (s, 1H), 5.13-4.96 (q, J=12 Hz, 2H), 2.40 (s, 6H), 2.19 (s, 3H).

HRMS (IE) m/z calculated C ₂ 3H ₂₀ N3O ₃ SCl [M ⁺ ]: 453.0914, found: 453.0927.

Example C78: tetrahydro-2H-pyran-4-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (25 mg, 51%) by Method C.

1H-NMR (300 MHz, CDCl3) δ=8.50 (d, J=8.1 Hz, 2H), 7.33 (dd, J=8.1, 4.7 Hz, 1H), 7.24 -7.17 (m, 1H), 6.70 (s, 1H), 5.46 (s, 1H), 4.92 (tt, J=8.9, 4.2 Hz, 1H), 3, 81 (ddt, J=16.6, 11.5, 4.2 Hz, 2H), 3.46 (ddt, J=12.0, 5.3, 2.9 Hz, 2H), 2.36 ( s, 3H), 2.33 (s, 3H), 2.18 (s, 3H), 1.92-1.83 (m, 1H), 1.80-1.71 (m, 1H), 1 .69-1.57 (m, 1H), 1.53-1.40 (m, 1H).

HRMS (IE) m/z calculated C ₂₂ H ₂₄ N ₂ O ₄ S [M ⁺ ]: 412.1457, found: 412.1457.

Example C79: 4,4-difluorocyclohexyl-5-α-cetyl-2,6-dimethyl-4-(mueno[2,3-b]nirudin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (45 mg, 83%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.57-8.48 (m, 2H), 7.33 (dd, J=7.9, 4.8 Hz, 1H), 7.20 (s , 1H), 6.96 (s, 1H), 5.46 (s, 1H), 4.90 (s, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 2 .19 (s, 3H), 1.96-1.58 (m, 8H).

^-NMR (282 MHz, CDCl ₃ ) δ=-95.77 (d, J=247.3 Hz CF).

HRMS (IE) m/z calculated C ₂₃ H ₂₄ N ₂ O ₃ SF ₂ [M ⁺ ]: 446.1476, found: 446.1475.

Example C80: 5-acetyl-N-benzyl-N,2,6-trimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine3-carboxamide.

The title compound was obtained as a yellow solid (37 mg, 67%) by Method C.

1H-NMR (300 MHz, CDCl3) δ=8.51 (d, J=4.6 Hz, 1H), 8.16-8.06 (m, 1H), 7.25-7.15 (m, 5H), 7.08-6.98 (m, 2H), 6.12 (s, 1H), 5.37 (s, 1H), 4.65 (d, J=14.1 Hz, 1H), 4.07 (d, J=14.1 Hz, 1H), 2.36 (s, 3H), 2.13 (s, 3H), 1.98 (s, 3H), 1.68 (s, 3H ).

HRMS (IE) m/z calculated C ₂₅ H ₂₅ N ₃ O ₂ S [M ⁺ ]: 431.1667, found: 431.1675.

Example C81: oxetan-3-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (5.2 mg, 6%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.12 (d, J=8.0 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.30 (d, J=7.9Hz, 1H), 7.18(s, 1H), 5.73(s, 1H), 5.45(s, 1H), 5.40(k, J=5.9Hz, 1H), 4.89-4.80 (m, 2H), 4.61-4.49 (m, 2H), 2.55 (tt, J=8.6, 5.7 Hz, 1H), 2 .36 (s, 3H), 2.16 (s, 3H), 1.01 (ddp, J=18.2, 8.6, 4.6 Hz, 2H), 0.69 (dc, J=7 .4, 4.6, 4.0 Hz, 2H).

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HRMS (IE) m/z calculated C ₂₃ H ₂₂ NO ₄ SBr [M ⁺ ]: 487.0453, found: 487.0439.

Example C82: isopropyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (21 mg, 14%) by Method C.

1H-NMR (300 MHz, CDCI3) δ=8.14 (d, J=8.1 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.30 (s, 1H ), 7.24 (s, 1H), 7.15 (s, 1H), 5.68 (s, 1H), 5.44 (s, 1H), 5.03 (n, J=6.2 Hz , 1H), 2.53 (ddd, J=8.8, 5.7, 3.4 Hz, 1H), 2.36 (s, 3H), 2.14 (s, 3H), 1.21 ( d, J=6.2 Hz, 3H), 1.12 (d, J=6.2 Hz, 3H), 1.01-0.88 (m, 2H), 0.67 (dkvd, J=11 .1, 5.7, 3.4 Hz, 2H).

HRMS (IE) m/z calculated C ₂₃ H ₂₄ NO ₃ SBr [M ⁺ ]: 473.0660, found: 473.0677.

Example C83: methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (8 mg, 18%) was obtained by method C using 1.5 eq. TFA to MeOH.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.00 (d, J=8.1 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.35-7, 28 (m, 1H), 7.24 (s, 1H), 6.20 (br. s, 1H), 5.47 (s, 1H), 3.65 (s, 3H), 2.44 (s , 3H), 2.12 (s, 3H).

^-NMR (282 MHz, CDCI3) δ=63.85 (s, CF ₃ ).

HRMS (IE) m/z calculated C ₁₉ H ₁₅ NO ₃ SF ₃ Br [M ⁺ ]: 472.9908, found: 472.9915.

Example C84: cyclopropylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (20 mg, 13%) was obtained by method C using dioxane.

1H-NMR (300 MHz, CDCI3) δ=8.15 (d, J=8.1 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.29-7.23 (m, 1H), 7.17 (s, 1H), 5.70 (br. s, 1H), 5.47 (br. s, 1H), 3.95-3.86 (m, 2H), 2.59 (tt, J=8.7, 5.7 Hz, 1H), 2.36 (s, 3H), 2.14 (s, 3H), 1.12-0.87 (m, 3H) , 0.73-0.59 (m, 2H), 0.57-0.44 (m, 2H), 0.26-0.14 (m, 2H).

HRMS (IE) m/z calculated C ₂₄ H ₂₄ NO ₃ SBr [M ⁺ ]: 485.0660, found: 485.0676.

Example C85: methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-(2,2,2-trifluoroacetyl)benzo[b]thiophen-3yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (42 mg, 44%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.64 (d, J=8.1 Hz, 1H), 8.17 (d, J=7.4 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.32 (s, 1H), 5.89 (br. s, 1H), 5.54 (s, 1H), 3.64 (s, 3H), 2, 59 (tt, J=8.7, 5.6 Hz, 1H), 2.36 (s, 3H), 2.14 (s, 3H), 1.060.85 (m, 2H), 0.81-0 .58 (m, 2H).

HRmS (IE) m/z calculated C ₂₃ H ₂₀ NO ₄ SF ₃ [M ⁺ ]: 463.1065, found: 463.1054.

Example C86: 2-phenylpropan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (18 mg, 18%) by Method C.

1H-NMR (300 MHz, CDCI3) δ=8.06 (d, J=8.1 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.21-7.10 (m, 5H), 7.07-6.98 (m, 2H), 5.87 (br. s, 1H), 5.49 (s, 1H), 2.36 (s, 3H), 2, 28 (s, 3H), 2.14 (s, 3H), 1.72 (s, 3H), 1.64 (s, 3H).

HRMS (ESI) m/z calculated C ₂₇ H ₂₆ NO ₃ SBr [M ⁺ ]: 546.0709, found: 546.0711.

HPLC (98.2%): retention time 18.30 min.

Example C87: Methyl 5-acetyl-4-(7-chlorobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (80 mg, 69%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.07-7.99 (m, 1H), 7.39-7.28 (m, 2H), 7.15 (d, J=1.7 Hz , 1H), 5.67 (s, 1H), 5.45 (s, 1H), 3.66 (s, 3H), 2.59 (tt, J=8.4, 5.7 Hz, 1H) , 2.35 (s, 3H), 2.13 (s, 3H), 1.04-0.90 (m, 2H), 0.66 (dtt, J=9.0, 5.7, 3, 4 Hz, 2H).

HRMS (IE) m/z calculated C ₂₁ H ₂₀ NO ₃ SCl [M ⁺ ]: 401.0852, found: 401.0855.

HPLC (99.1%): retention time 18.66 min.

Example C88: methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-(trifluoromethyl)benzo[b]thiophen-3-yl)1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (55 mg, 80%) by Method C.

1H-NMR (300 MHz, CDCI3) δ=8.35 (d, J=8.2 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.49 (t, J =7.9 Hz, 1H), 7.20 (s, 1H), 5.66 (br.s, 1H), 5.51 (s, 1H), 3.65 (s, 3H), 2.59 (heptet, J=6.9, 6.2 Hz, 1H), 2.36 (s, 3H), 2.13 (s, 3H), 1.09-0.84 (m, 2H), 0, 7509-0.57 (m, 2H).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): -62.96 (s, CF ₃ ).

HRMS (lE) m/z calculated C ₂₂ H ₂₀ No ₃ SF ₃ [M ⁺ ]: 435.1116, found: 435.1129.

HPLC (99.4%): retention time 19.68 min.

Example C89: 3-chlorobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (78 mg, 53%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.49 (dd, J=4.6, 1.6 Hz, 1H), 8.29 (dd, J=8.2, 1.6 Hz, 1H ), 7.28-7.23 (m, 1H), 7.22-7.13 (m, 4H), 7.01 (dt, J=7.6, 1.6 Hz, 1H), 6, 26 (s, 1H), 5.44 (s, 1H), 5.09-4.97 (m, 2H), 2.37 (s, 3H),

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2.34 (s, 6H), 2.15 (s, 3H).

HRMS (IE) m/z calculated C ₂₄ H ₂₁ N ₂ O ₃ SCl [M ⁺ ]: 452.0961, found: 452.0966.

HPLC (98.6%): retention time 19.83 min.

Example C90: 2-phenylpropan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (20 mg, 17%) by Method C.

1H-NMR (300 MHz, CDQ3) δ=8.05 (d, J=8.0 Hz, 1H), 7.52-7.40 (m, 1H), 7.22-7.13 (m, 4H), 7.12 (s, 1H), 7.10-7.04 (m, 2H), 5.67 (br.s, 1H), 5.50 (s, 1H), 2.63-2 .47 (m, 1H), 2.35 (s, 3H), 2.13 (s, 3H), 1.72 (s, 3H), 1.67 (s, 3H), 1.03-0, 77 (m, 2H), 0.76-0.57 (m, 2H).

HRMS (ESI) m/z calculated C ₂₉ H ₂₈ NO ₃ SBrNa [M ^+Na ]: 572.0865, found: 572.0865.

HPLC (98.82%): retention time Rt 17.16 min.

Example C91: cyclohexyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (70 mg, 79%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.52 (s, 1H), 8.46 (d, J=8.1 Hz, 1H), 7.31 (dd, J=8.1, 4 .7 Hz, 1H), 7.13 (s, 1H), 5.69 (br. s, 1H), 5.47 (s, 1H), 4.83-4.71 (m, 1H), 2 .64-2.47 (m, 1H), 2.36 (s, 3H), 2.16 (s, 3H), 1.90-1.70 (m, 2H), 1.68-1.50 (m, 4H), 1.35-1.19 (m, 4H), 1.08-0.87 (m, 2H), 0.78-0.58 (m, 2H).

HRMS (IE) m/z calculated C ₂₅ H ₂₈ N ₂ O ₃ S [M ⁺ ]: 436.1821, found: 436.1841.

HPLC (99.3%): retention time 18.47 min.

Example C92: 2-phenylpropan-2-yl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (15 mg, 16%) by Method C.

1H-NMR (300 MHz, CDCl3) δ=8.50 (dd, J=4.6, 1.6 Hz, 1H), 8.33 (dd, J=8.2, 1.6 Hz, 1H) , 7.23-7.12(m, 4H), 7.11(s, 1H), 7.12-7.02(m, 2H), 5.71(s, 1H), 5.49(s , 1H), 2.65-2.49 (m, 1H), 2.36 (s, 3H), 2.13 (s, 3H), 1.70 (s, 3H), 1.67 (s, 3H), 1.03-0.83 (m, 2H), 0.76-0.58 (m, 2H).

HRMS (ESI) m/z calculated C ₂₈ H ₂₉ N ₂ O ₃ S [M ⁺¹ ]: 473.1893, found: 473.1891.

HPLC (95.7%): retention time 25.13 min.

Example C93: 1-(4-(7-bromobenzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2-methyl1,4-dihydropyridin-3-yl)ethan-1-one.

The title compound was obtained as a yellow solid (80 mg, 56%) by Method C.

1H-NMR (300 MHz, CDCl3) δ=8.09 (d, J=8.1 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.28 (d, J =8.1 Hz, 1H), 7.10 (s, 1H), 5.84 (br.s, 1H), 5.50 (s, 1H), 2.41 (s, 3H), 2.38 -2.27(m, 1H), 2.20-2.01(m, 4H), 1.41-1.22(m, 1H), 1.20-1.06(m, 1H), 1 .07-0.90 (m, 3H), 0.84-0.65 (m, 3H).

HRMS (IE) m/z calculated C ₂₃ H ₂₂ NO ₂ SBr [M ⁺ ]: 455.0555, found: 455.0540.

HPLC (99.1%): retention time 22.48 min.

Example C94: 3-chlorobenzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (16 mg, 13%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.53 (d, J=4.6 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 7.32-7, 28 (m, 1H), 7.25-7.18 (m, 3H), 7.16 (s, 1H), 7.07 (d, J=7.4 Hz, 1H), 5.79 (br .s, 1H), 5.50 (s, 1H), 5.16-5.04 (m, 2H), 2.73-2.51 (m, 1H), 2.39 (s, 3H), 2.19 (s, 3H), 1.08-0.87 (m, 2H), 0.83-0.61 (m, 2H).

HRMS (IE) m/z calculated C ₂₆ H ₂₃ N ₂ O ₃ SCl [M ⁺ ]: 478.1118, found: 478.1118.

HPLC (96.7%): retention time 19.79 min.

Example C95: 2-(4-fluorophenyl)propan-2-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridin-3- carboxylate.

The title compound was obtained as a yellow solid (10 mg, 7%) by Method C.

1H-NMR (300 MHz, CDCl3) δ (ppm): 8.52 (d, J=3.9 Hz, 1H), 8.35 (dd, J=8.3, 1.6 Hz, 1H), 7.21 (dd, J=8.2, 4.6 Hz, 1H), 7.16 (s, 1H), 7.00-6.91 (m, 2H), 6.87-6 .75 (m, 2H), 5.90 (s, 1H), 5.48 (s, 1H), 2.38 (s, 3H), 2.30 (s, 3H), 2.15 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCl3) δ (ppm): -116.44 (CF).

HRMS (lE) m/z calculated C ₂₆ H ₂₅ N ₂ O ₃ SF [M ⁺ ]: 464.1570, found: 464.1570.

HPLC (98.2%): retention time 19.52 min.

Example C96: 2-(4-fluorophenyl)propan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl6-methyl-1,4-dihydropyridine-3 - carboxylate.

The title compound was obtained as a yellow solid (30 mg, 17%) by Method C.

1H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.03 (d, J=8.1 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.17 (t, J=7.9 Hz, 1H), 7.12 (s, 1H), 6.98 (dd, J=8.7, 5.4 Hz, 2H), 6.80 (t , J=8.7 Hz, 2H), 5.61 (s, 1H), 5.48 (s, 1H), 2.62-2.45 (m, 1H), 2.35 (s, 3H) , 2.13 (s, 3H), 1.69 (s, 3H), 1.65 (s, 3H), 1.04-0.82 (m, 2H), 0.76-0.59 (m , 2H).

¹⁹ F-NMR (282 MHz, CDCl3) δ (ppm): -116.65 (CF).

HRMS (IE) m/z calculated C ₂₉ H ₂₇ N ₂ O ₃ SBrFNa [M ^+Na ]: 590.0771, found: 590.0772.

HPLC (98.0%): retention time 18.52 min.

- 79 040842

Example C97: 2-(4-fluorophenyl)propan-2-yl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3b]pyridin-3-yl)-1,4-dihydropyridine- 3-carboxylate.

The title compound was obtained as a yellow solid (38 mg, 24%) by Method C.

1H-NMR (300 MHz, CDCl ,) δ (ppm): 8.55-8.44 (m, 1H), 8.33 (dd, J=8.2, 1.3 Hz, 1H ), 7.19 (dd, J=8.2, 4.6 Hz, 1H), 7.10 (s, 1H), 7.03-6.93 (m, 2H), 6.79 (t, J=8.7 Hz, 2H), 5.97 (br. s, 1H), 5.46 (s, 1H), 2.60-2.43 (m, 1H), 2.34 (s, 3H ), 2.12 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H), 1.00-0.80 (m, 2H), 0.78-0.56 ( m, 2H).

¹⁹ B-NMR (282 MHz, CDC13) δ (ppm): -116.53 (CF).

HRMS (IE) m/z calculated C ₂₈ H ₂₈ N ₂ O ₃ SF [M ⁺ ]: 491.1799, found: 491.1800.

HPLC (98.9%): retention time 19.26 min.

Example C98: Methyl 5-acetyl-2-cyclopropyl-4-(7-fluoro-benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (94 mg, 71%) by Method C.

1H-NMR (300 MHz, CDC13) δ (ppm): 7.89 (d, J=8.2 Hz, 1H), 7.35 (td, J=8.0, 5.2 Hz, 1H), 7.13 (s, 1H), 7.01 (dd, J=9.7, 8.0 Hz, 1H), 5.63 (br.s, 1H), 5.47 (s, 1H ), 3.67 (s, 3H), 2.60 (tt, J=8.7, 5.7 Hz, 1H), 2.36 (s, 3H), 2.14 (s, 3H), 1 .08-0.85 (m, 2H), 0.74-0.56 (m, 2H).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): -116.08 (CF).

HRMS (IE) m/z calculated C ₂₁ H ₂₀ NO ₃ SF [M ⁺ ]: 385.1148, found: 385.1132.

HPLC (99.3%): retention time 22.58 min.

Example C99: cyclopropylmethyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (12 mg, 26%) was obtained by method C using dioxane.

1H-NMR (300 MHz, CDCI3) δ (ppm): 8.53-8.50 (m, 1H), 8.46 (dd, J=8.2, 1.6 Hz, 1H), 7.29 (dd, J=8.2, 4.6 Hz, 1H), 7.17 (s, 1H), 5.71 (br.s, 1H), 5.48 (s, 1H), 3 .90 (dd, J=7.3, 2.7 Hz, 2H), 2.60 (tt, J=8.6, 5.7 Hz, 1H), 2.37 (s, 3H), 2, 16 (s, 3H), 1.05-0.91 (m, 3H), 0.72-0.61 (m, 2H), 0.55-0.43 (m, 2H), 0.27- 0.12 (m, 2H).

HRMS (IE) m/z calculated C ₂₃ H ₂₄ N ₂ O ₃ S [M ⁺ ]: 408.1508, found: 408.1509.

HPLC (99.7%): retention time 30.16 min.

Example C100: cyclopentyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (27 mg, 14%) was obtained by method C using dioxane.

1H-NMR (300 MHz, CDC13) δ (ppm): 8.52 (dd, J=4.6, 1.5 Hz, 1H), 8.46 (dd, J=8.2, 1 .5 Hz, 1H), 7.30 (dd, J=8.2, 4.6 Hz, 1H), 7.12 (s, 1H), 5.71 (br.s, 1H), 5.45 (s, 1H), 5.24-5.11 (m, 1H), 2.62-2.45 (m, 1H), 2.36 (s, 3H), 2.16 (s, 3H), 1.92-1.72 (m, 2H), 1.64-1.44 (m, 6H), 1.07-0.85 (m, 2H), 0.76-0.56 (m, 2H ).

HRMS (IE) m/z calculated C ₂₄ H ₂₆ N ₂ O ₃ S [M ⁺ ]: 422.1664, found: 422.1662.

HPLC (99.7%): retention time 30.24 min.

Example C101: cyclopropylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (9 mg, 26%) was obtained by method C using dioxane.

1H-NMR (300 MHz, CDC13) δ (ppm): 8.56-8.41 (m, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.46 ( t, J=7.5 Hz, 1H), 7.24 (s, 1H), 5.71 (br.s, 1H), 5.53 (s, 1H), 3.98-3.77 (m , 2H), 2.70-2.52 (m, 1H), 2.37 (s, 3H), 2.16 (s, 3H), 1.09-0.92 (m, 3H), 0, 77-0.58 (m, 2H), 0.53-0.39 (m, 2H), 0.27-0.10 (m, 2H).

HRMS (IE) m/z calculated C ₂₅ H ₂₄ N ₂ O ₃ S [M ⁺ ]: 432.1508, found: 432.1516.

HPLC (97.8%): retention time 22.16 min.

Example C102: Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclobutyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (41 mg, 29%) by Method C.

1H-NMR (300 MHz, CDCI3) δ (ppm): 8.09 (d, J=8.8 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7 .29 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 6.10 (br.s, 1H), 5.41 (s, 1H), 3.63 (s, 3H), 2.42 (s, 3H), 2.33-2.17 (m, 2H), 2.14 (s, 3H), 2.061.78 (m, 5H).

HRmS (IE) m/z calculated C ₂₂ H ₂₂ NO ₃ SBr [M ⁺ ]: 459.0504, found: 459.0505.

HPLC (95.2%): retention time 18.21 min.

Example C103: Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound was obtained as a yellow solid (80 mg, 65%) by Method C.

1H-NMR (300 MHz, CDC13) δ (ppm): 8.36 (d, J=9.2 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H), 7 .46 (dd, J=9.2, 7.3 Hz, 1H), 7.24 (s, 1H), 5.64 (br.s, 1H), 5.47 (s, 1H), 3, 56 (s, 3H), 3.54 (s, 3H), 2.77-2.67 (m, 1H), 2.34 (s, 3H), 1.07-0.96 (m, 2H) , 0.77-0.65 (m, 2H).

HRMS (IE) m/z calculated C ₂₂ H ₂₀ N ₂ O ₄ S [M ⁺ ]: 408.1144, found: 408.1153.

HPLC (99.2%): retention time 12.64 min.

- 80 040842

Example C104: Methyl 5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (40 mg, 48%) by Method C.

1H-NMR (300 MHz, CDCl ,) δ (ppm): 8.24 (d, J=9.1 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H) , 7.56-7.44 (m, 1H), 7.23 (s, 1H), 5.73 (br.s, 1H), 5.14 (s, 1H), 3.55 (s, 3H ), 2.87-2.71 (m, 1H), 2.09 (s, 3H), 1.13-0.99 (m, 2H), 0.82-0.65 (m, 2H).

HRMS (IE) m/z calculated C ₂₁ H ₁₇ N ₃ O ₂ S [M ⁺ ]: 375.1041, found: 375.1046.

HPLC (99.0%): retention time 21.27 min.

Example C105: Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopentyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (59 mg, 40%) by Method C.

1H-NMR (300 MHz, CDC13) δ (ppm): 8.06 (d, J=8.0 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 7 .29 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 5.88 (br.s, 1H), 5.45 (s, 1H), 4.26-4, 02 (m, 1H), 3.63 (s, 3H), 2.38 (s, 3H), 2.15 (s, 3H), 2.041.90 (m, 2H), 1.78-1.69 (m, 4H), 1.53-1.38 (m, 2H).

HRMS (IE) m/z calculated C ₂₃ H ₂₁ NO ₃ SBr [M ⁺ ]: 473.0660, found: 473.0647.

HPLC (97.4%): retention time 12.81 min.

Example C106: Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclohexyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (89 mg, 59%) by Method C.

1H-NMR (300 MHz, CDC13) δ (ppm): 8.05 (d, J=8.8 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7 .28 (d, J=7.5 Hz, 1H), 7.18 (s, 1H), 6.00 (br.s, 1H), 5.44 (s, 1H), 3.80-3, 66 (m, 1H), 3.62 (s, 3H), 2.38 (s, 3H), 2.15 (s, 3H), 1.921.69 (m, 5H), 1.44-1.20 (m, 5H).

HRMS (IE) m/z calculated C ₂₄ H ₂₆ NO ₃ SBr [M ⁺ ]: 487.0817, found: 487.0801.

HPLC (96.7%): retention time 11.94 min.

Example C107: Methyl 5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3-carboxylate.

The title compound was obtained as a yellow solid (15 mg, 13%) by Method C.

1H-NMR (300 MHz, CDC13) δ (ppm): 8.25 (dd, J=8.2, 0.9 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 7.55-7.45 (m, 1H), 7.20 (s, 1H), 5.57 (br.s, 1H), 5.14 (s, 1H), 3.56 (s , 3H), 2.87-2.70 (m, 1H), 1.93-1.78 (m, 1H), 1.16-0.83 (m, 5H), 0.80-0.63 (m, 3H).

HRMS (IE) m/z calculated C ₂₃ H ₁₉ N ₃ O ₂ S [M ⁺ ]: 401.1198, found: 401.1199.

HPLC (96.5%): retention time 15.42 min.

Example C108: 3-((4-methylpiperazin-1-yl)methyl)benzyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)2,6-dimethyl-1,4-dihydropyridin- 3-carboxylate.

The title compound was obtained as a yellow solid (33 mg, 18%) by Method C.

1H-NMR (300 MHz, CDCI3) δ (ppm): 7.98 (d, J=8.2 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7 .27-7.04 (m, 6H), 5.80 (br. s, 1H), 5.44 (s, 1H), 5.07 (s, 2H), 3.44 (s, 2H), 2.48-2.41 (m, 4H), 2.37 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H), 1 .73-1.60 (m, 4H).

HRMS (IE) m/z calculated C ₃₁ H ₃₄ N ₃ O ₃ SBr [M ⁺ ]: 607.1504, found: 607.1491.

HPLC (98.4%): retention time 9.94 min.

Example C109: 3-(cyclopropylmethyl)-5-methyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound was prepared using method variant C by heating in dioxane in a sealed tube at 130° C. overnight to give a yellow solid (35 mg, 28%).

1H-NMR (300 MHz, CDC13) δ (ppm): 8.40 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7 .44 (t, J=7.7 Hz, 1H), 7.26 (s, 1H), 5.61 (br.s, 1H), 5.49 (s, 1H), 3.84-3, 73 (m, 2H), 3.55 (s, 3H), 2.81-2.65 (m, 1H), 2.34 (s, 3H), 1.02 (dd, J=8.9, 5.5 Hz, 2H), 0.95-0.80 (m, 1H), 0.72 (d, J=6.1 Hz, 2H), 0.38 (t, J=9.7 Hz, 2H), 0.06 (s, 2H).

HRMS (IE) m/z calculated C ₂₅ H ₂₄ N ₂ NaO ₄ S [M ⁺ ]: 471.1349, found: 471.1347.

Example C110: 3-(cyclopropylmethyl)-5-methyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl1,4-dihydropyridine-3,5-dicarboxylate.

The title compound was prepared using method variant C by heating in dioxane in a sealed tube at 130° C. overnight to give a yellow solid (20 mg, 15%).

1H-NMR (300 MHz, CDC13) δ (ppm): 8.41 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.4 Hz, 1H), 7 .44 (t, J=7.8 Hz, 1H), 7.23 (s, 1H), 5.56 (br.s, 1H), 5.51 (s, 1H), 3.79 (d, J=7.3Hz, 2H), 3.57(s, 3H), 2.85-2.61(m, 2H), 1.090.84(m, 5H), 0.75-0.55(m , 4H), 0.47-0.29 (m, 2H), 0.15-0.02 (m, 2H).

HRMS (IE) m/z calculated C ₂₇ H ₂₆ N ₂ NaO ₄ S [M ^+Na ]: 497.1505, found: 497.1503.

Example C111: cyclopropylmethyl-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was prepared using method variant C by heating the reaction mixture in MeOH in a sealed tube at 130° C. for 7 hours to give a yellow solid (8 mg, 7%).

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.24 (d, J=8.3 Hz, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.27 (s, 1H), 5.73 (br.s, 1H), 5.19 (s, 1H), 3.75 (d , J=7.3 Hz, 2H), 2.92-2.70 (m, 1H), 2.09 (s, 3H), 1.140.97 (m, 2H), 0.88-0.66 ( m, 3H), 0.40-0.12 (m, 2H), 0.08-0.17 (m, 2H).

HRMS (IE) m/z calculated C ₂₄ H ₂₁ N ₃ NaO ₂ S [M ^+Na ]: 438.1247, found: 438.1245.

Example C112: Dimethyl 2-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound was prepared using the three steps of Y. Satoh et al., Chem. Pharm. Bull. 1991, 39, 3189-3201.

In the first step, dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-(dimethoxymethyl)1,4-dihydropyridine-3,5-dicarboxylate was obtained using a variant of method C by heating the reaction mixture in methanol in a sealed tube at 130° C. for 90 min to give a yellow solid (130 mg, 48%).

In the second step, dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-(dimethoxymethyl)-1,4dihydropyridine-3,5-dicarboxylate (0.100 g, 0.21 mmol) was stirred in acetone (4 ml) and 4 N hydrochloric acid (0.53 ml, 2.13 mmol) at room temperature for 60 minutes. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and washed with toluene, saturated bicarbonate and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate, which was used in the next step without further purification.

In the third stage, a mixture of dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-formyl-1,4dihydropyridine-3,5-dicarboxylate, sodium acetate (0.026 g, 0.32 mmol ) and hydroxylamine hydrochloride (0.018 g, 0.25 mmol) in acetic acid (1 ml) were stirred at room temperature for 60 minutes. Acetic anhydride (0.142 ml, 1.48 mmol) was added and stirred at room temperature for 60 minutes and then at 95°C for 120 minutes. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and washed with toluene, saturated bicarbonate and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated and the residue was purified by column chromatography (4:1 hexane:ethyl acetate) to give the title compound dimethyl-2-cyano-4-(7-cyanobenzo[b]thiophene-3- yl)-6-cyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate as a yellow solid (0.030 g, 34%).

1H-NMR (300 MHz, CDCl3) δ (ppm): 8.33 (d, J=8.3 Hz, 1H), 7.72 (d, J=7.3 Hz, 1H), 7 .58-7.49 (m, 1H), 7.35 (s, 1H), 6.73 (br. s, 1H), 5.52 (s, 1H), 3.69 (s, 3H), 3.64 (s, 1H), 3.55 (s, 3H), 3.03-2.86 (m, 2H), 2.21-2.07 (m, 2H).

HRMS (IE) m/z calculated C22H18N3O4S [M ⁺¹ ]: 420.1013, found: 420.1012.

Example C113: Dimethyl 2-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.046 g, 41%) was obtained following the 3-step procedure described above for the synthesis of Example C112.

1H-NMR (300 MHz, CDCl3) δ (ppm): 8.35 (d, J=8.3 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 7 .58-7.47 (m, 1H), 7.36 (s, 1H), 6.70 (br. s, 1H), 5.52 (s, 1H), 3.69 (s, 3H), 3.56 (s, 3H), 2.42 (s, 3H).

- 82 040842

HRMS (IE) m/z calculated C ₂₀ H ₁₄ N ₃ O ₄ S [M ⁺¹ ]: 392.0700, found: 392.0698.

Example C114: methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

At the first stage, methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-((2-(1,3-dioxoisoindolin2-yl)ethoxy)methyl)-6-methyl-1, 4-dihydropyridine-3-carboxylate using method variant C by heating in methanol in a sealed tube at 130° C. for 7 hours to give a yellow solid (120 mg, 60%).

Deprotection: in the second step, methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-((2-(1,3dioxoisoindolin-2-yl)ethoxy)methyl)-6-methyl -1,4-dihydropyridine-3-carboxylate (0.060 g, 0.11 mmol) and hydrazine monohydrate (0.018 g, 0.56 mmol) were heated in ethanol (3 ml) at 78°C for 5 min. The mixture was allowed to cool to RT and after addition of hydrazine monohydrate (0.018 g, 0.56 mmol) was stirred at room temperature overnight. The mixture was filtered, concentrated and the residue was purified by column chromatography (dichloromethane: methanol 10%) to give a yellow solid (0.020 g, 44%).

1 H-NMR (300 MHz, CDCl ,) δ (ppm): 8.15-8.01 (m, 2H), 7.80 (d, J=7.6 Hz, 1H), 7, 34 (dt, J=24.5, 6.8 Hz, 2H), 7.15 (br.s, 1H), 5.45 (br.s, 1H), 4.85-4.49 (m, 2H), 3.62 (s, 3H), 3.57 (t, J=5.0 Hz, 2H), 2.97 (br.s, 2H), 2.42 (s, 3H), 2, 13 (s, 3H), 1.78 (br.s, 3H).

Example C115: methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl 1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.030 g, 33%) was obtained following the 2-step method described above for the synthesis of Example C114.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.10 (d, J=7.5 Hz, 2H), 7.46 (d, J=7.3 Hz, 1H), 7.31-7.25(m, 1H), 7.22(s, 1H), 5.40(s, 1H), 4.85-4.56(m, 2H), 3.60(s, 5H), 2.99 (s, 2H), 2.42 (s, 5H), 2.13 (s, 3H).

Example C116: methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl 1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.035 g, 51%) was obtained following the 2-step method described above for the synthesis of Example C114.

1H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.41 (d, J=8.2 Hz, 1H), 8.27 (br. s, 1H), 7.66 (d , J=7.2Hz, 1H), 7.47(t, J=7.8Hz, 1H), 7.27(s, 1H), 5.47(s, 1H), 4.85-4 .56 (m, 2H), 3.59 (s, 5H), 2.98 (s, 2H), 2.42 (s, 3H), 2.15 (s, 3H), 1.83 (s, 2H).

HRMS (IE) m/z calculated C ₂₂ H ₂₄ N ₃ O ₄ S [M ⁺¹ ]: 426.1482, found: 426.1480.

Examples C117 and C118 were prepared by the following 3-step synthesis.

Example C117: Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate.

In the first step, dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-(dimethoxymethyl)1,4-dihydropyridine-3,5-dicarboxylate was prepared using Process Variant C by heating in methanol in a sealed tube at 130° C. for 1.5 h to give a yellow solid (0.130 g, 48%).

1H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.36 (d, J=8.3 Hz, 1H), 7.67 (d, J=7.4 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (s, 1H), 6.80 (s, 1H), 5.98 (s, 1H), 5.52 (s, 1H ), 3.59 (s, 3H), 3.58 (s, 3H), 3.44 (s, 3H), 3.43 (s, 3H), 2.89-2.79 (m, 1H) , 1.11-0.89 (m, 2H), 0.91-0.58 (m, 2H).

Deprotection: In the second step, a mixture of dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2cyclopropyl-6-(dimethoxymethyl)-1,4-dihydropyridine-3,5-dicarboxylate (0.100 g, 0 .21 mmol) and 4 N hydrochloric acid (0.53 ml, 2.13 mmol) in acetone (4 ml) were stirred at room temperature for 60 minutes. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with toluene, saturated bicarbonate and brine, then dried (Na ₂ SO ₄ ) and concentrated to give the title compound, which was used without further purification.

1H-NMR (300 MHz, CDCI3) δ (ppm): 10.50 (s, 1H), 8.33 (d, J=8.3 Hz, 1H), 7.71 (d, J= 7.0Hz, 1H), 7.51(t, J=7.8Hz, 1H), 7.32(s, 1H), 7.26(s, 1H), 5.59(s, 1H) , 3.68 (s, 3H), 3.62 (d, J=6.2 Hz, 1H), 3.57 (s, 3H), 2.98 (t, J=7.6 Hz, 2H) , 2.17-2.05 (m, 2H).

HRMS (APCI) m/z calculated C ₂₂ H ₁₉ N ₂ O ₅ S [M ⁺¹ ]: 423.1009, found: 423.1007.

Example C118: Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-(hydroxymethyl)-1,4-dihydropyridine-3,5-dicarboxylate.

Recovery: In the third step, sodium borohydride (0.005 g, 0.13 mmol) was added to a mixture of dimethyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-formyl-1,4-dihydropyridine -3,5 dicarboxylate (0.047 g, 0.11 mmol) in ethanol (3 ml) at 0° C., which was stirred at the same temperature for 1 hour. Water was then added and the mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na ₂ SO ₄ ), filtered and concentrated and the resulting residue was purified by column chromatography (2:1 hexane:ethyl acetate) to give the title compound as a yellow solid (0.026 g, 56%).

- 83 040842

1H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.33 (d, J=7.9 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.52-7.45 (m, 2H),

7.30 (s, 1H), 5.46 (s, 1H), 4.82 (br.s, 2H), 3.61 (t, J=6.2 Hz, 2H), 3.54 (s , 3H), 3.53 (s, 3H), 2.93 (t, J=7.4 Hz,

2H), 2.86 (br. s, 1H), 2.17-2.05 (m, 2H).

Example C119: Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-formyl-6-methyl-1,4-dihydropyridine 3,5-dicarboxylate.

The title compound was prepared following the synthesis described for Example C117 to give a solid which was used without further purification.

1H-NMR (300 MHz, CDCI3) δ (ppm): 10.50 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 7.70 (d, J= 7.3 Hz, 1H), 7.557.46 (m, 1H), 7.33 (s, 1H), 7.10 (br.s, 1H), 5.58 (s, 1H), 3.67 ( s, 3H), 3.57 (s, 3H), 2.45 (s, 3H).

HRMS (APCI) m/z calculated C ₂₀ H ₁₇ N ₂ O ₅ S [M ⁺¹ ]: 397.0853, found: 397.0853.

Example C120: Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-(hydroxymethyl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate.

The title compound was prepared following the synthesis described for Example C118 to give a yellow solid (0.007 g, 16%).

1H-NMR (300 MHz, CDCI3) δ (ppm): 8.35 (d, J=8.5 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7 .47 (t, J=7.7 Hz, 1H), 7.30 (s, 1H), 7.24 (br.s, 1H), 5.45 (s, 1H), 4.83 (d, J=2.1 Hz, 2H), 3.54 (s, 3H), 3.53 (s, 3H), 2.41 (s, 3H), 1.61 (s, 1H).

HRMS (APCI) m/z calculated C ₂₀ H ₁₉ N ₂ O ₅ S [M ⁺¹ ]: 399.1009, found: 399.1010.

Example C121: Dimethyl 2-cyano-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound was prepared from methyl-(2)-4,4-dimethoxy-3-oxo-2-(thieno[2,3-b]pyridin-3ylmethylene)butanoate after the 3-step synthesis described for Examples C117 and C118 to give yellow solid (0.025 g).

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.33 (d, J=8.3 Hz, 1H), 7.72 (d, J=7.3 Hz, 1H), 7.58-7.49 (m, 1H), 7.35 (s, 1H), 6.73 (br.s, 1H), 5.52 (s, 1H), 3.69 (s, 3H) , 3.64 (s, 1H), 3.55 (s, 3H), 3.03-2.86 (m, 2H), 2.21-2.07 (m, 2H).

HRMS (APCI) m/z calculated C ₂₂ H ₁₈ N ₃ O ₄ S [M ⁺¹ ]: 420.1013, found: 420.1012.

Example C122: cyclopropylmethyl-5-acetyl-4-(6-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate.

The title compound was prepared using method variant C by heating in dioxane in a sealed tube at 130° C. for 2 hours to give a yellow solid (0.010 g, 10%).

1H-NMR (300 MHz, CDCI3) δ (ppm): 8.30 (d, J=9.1 Hz, 1H), 8.11 (s, 1H), 7.59 (d, J= 9.1 Hz, 1H), 7.36 (s, 1H), 5.71 (br.s, 1H), 5.54 (s, 1H), 3.88 (dd, J=7.3, 2 .1 Hz, 2H), 2.68-2.54 (m, 1H), 2.36 (s, 3H), 2.15 (s, 3H), 1.08-0.93 (m, 3H) , 0.74-0.64 (m, 2H), 0.54-0.42 (m, 2H), 0.22-0.12 (m, 2H).

HRMS (APCI) m/z calculated C ₂₅ H ₂₅ N ₂ O ₃ S [M ⁺¹ ]: 433.1580, found: 433.1581.

Example C123: cyclopropylmethyl-2,5-diacetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate.

The title compound was prepared using method variant C by heating in dioxane in a sealed tube at 130° C. for 2 hours to give a yellow solid (0.006 g, 11%).

1H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.47 (d, J=8.2 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.29 (s, 1H), 5.86 (br.s, 1H), 5.52 (s, 1H), 3.91-3 .78 (m, 2H), 2.40 (s, 3H), 2.35 (s, 3H), 2.16 (s, 3H), 0.260.07 (m, 1H), 1.09-0, 95 (m, 2H), 0.57-0.38 (m, 2H).

Method D

Example D1: Methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

A mixture of 3-(benzo[b]thiophen-3-ylmethylene)pentan-2,4-dione (0.15 g, 0.61 mmol, 1 eq.), methyl-3-amino3-iminopropanoate (0.093 g, 0. 61 mmol, 1 eq.) and piperidine (0.073 g, 0.74 mmol, 1.2 eq.) in n-PrOH (5 ml) were stirred at reflux temperature for 4 h. The reaction mixture was concentrated in vacuo and the resulting precipitate was filtered off. , washed with methanol, dichloromethane and ether and dried to give the title compound as a yellow solid (65 mg, 31%).

1H-NMR (300 MHz, CDCI3) δ=8.00 (s, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H ), 6.63-6.43 (m, 2H), 6.40 (s, 1H), 5.80 (s, 2H), 4.46 (s, 1H), 2.66 (s, 3H) , 1.46 (s, 3H), 1.24 (s, 3H).

HRMS (IE) m/z calculated C ₁₈ H ₁₈ N ₂ O ₃ S [M ⁺ ]: 342.1038, found: 342.1044.

Example D2: methyl 2-amino-4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a light yellow solid (40 mg, 48%) was obtained by method D.

1H-NMR (300 MHz, CDCl ,) δ=8.02 (d, J=7.7 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.40-7 .19 (m, 3H), 7.10 (s,

1H), 6.23 (s, 2H), 5.51 (s, 1H), 3.61 (s, 3H), 2.23-1.97 (m, 4H), 0.96 (dc, J =6.9, 2.1 Hz, 1H), 0.82 (td, J=1.2, 6.3,

3.5 Hz, 2H), 0.68 (dt, J=8.6, 4.2 Hz, 1H).

HRMS (IE) m/z calculated C ₂₀ H ₂₀ N ₂ O ₃ S [M ⁺ ]: 368.1195, found: 368.1183.

Example D3: Methyl 5-acetyl-2-amino-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine3-carboxylate.

The title compound as a yellow solid (0.075 g, 44%) was obtained by method D.

1H-NMR (300 MHz, CDCI3) 6=7.75-7.67 (m, 2H), 7.48 (s, 1H), 7.19 (s, 1H), 7.05 (t, J= 7.7 Hz, 1H), 6.27 (s, 2H), 5.29 (s, 1H), 3.66 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCI3) 6=-119.10 1(s).

HRMS (IE) m/z calculated C ₁₈ H ₁₇ FN ₂ O ₃ S [M ⁺ ]: 360.0944, found: 360.0943.

Example D4: Methyl 5-acetyl-2-amino-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine3-carboxylate.

The title compound as a yellow solid (0.031 g, 24%) was obtained by method D using methanol.

1H-NMR (300 MHz, CDC13) 6=8.82 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H ), 7.39-7.27 (m, 2H), 6.61 (br. s, 2H), 5.22 (s, 1H), 3.45 (s, 3H), 2.27 (s, 3H), 2.05 (s, 3H).

HRMS (IE) m/z calculated C ₁₈ H ₁₇ N ₂ O ₃ SBr [M ⁺ ]: 420.0143, found: 420.0130.

HPLC (98.4%): retention time 16.46 min.

Example D5: Methyl 5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine3-carboxylate.

The title compound as a yellow solid (0.075 g, 64%) was obtained by method D using methanol.

1H-NMR (300 MHz, CDCI3) 6 (ppm): 8.35 (d, J=8.2 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H), 7 .46 (t, J=7.8 Hz, 1H), 7.27 (s, 1H), 6.33 (br.s, 1H), 6.03 (br.s, 2H), 5.39 ( s, 1H), 3.61 (s, 3H), 2.35 (s, 3H), 2.14 (s, 3H).

HRMS (IE) m/z calculated C ₁₉ H ₁₈ N ₃ O ₃ S [M ⁺ ]: 368.1063, found: 368.1064.

HPLC (98.4%): retention time 20.05 min.

Example D6: cyclopentyl 5-acetyl-2-amino-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.070 g, 46%) was obtained by method D using methanol.

1H-NMR (300 MHz, DMSO) 6 (ppm): 8.83 (br. s, 1H), 8.11-8.01 (m, 1H), 7.55 (d, J=7 .5 Hz, 1H), 7.397.26 (m, 2H), 6.65 (br. s, 2H), 5.21 (s, 1H), 5.03-4.89 (m, 1H), 2 .26 (s, 3H), 2.11 (s, 3H), 1.86-1.71 (m, 1H), 1.69-1.52 (m, 3H), 1.54-1.33 (m, 3H), 1.33-1.19 (m, 1H).

HRMS (IE) m/z calculated C ₂₂ H ₂₃ N ₂ O ₃ SBr [M ⁺ ]: 474.0613, found: 474.0605.

HPLC (95.5%): retention time 13.81 min.

Example D7: Dimethyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.045 g, 34%) was obtained by method D using methanol.

1H-NMR (300 MHz, DMSO) 6 (ppm): 8.33 (d, J=8.0 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7 .43 (t, J=8.0 Hz, 1H), 7.27 (s, 1H), 6.91 (br.s, 1H), 6.20 (br.s, 2H), 5.37 ( s, 1H), 3.53 (s, 3H), 3.51 (s, 3H), 2.27 (s, 3H).

HRMS (IE) m/z calculated C ₁₉ H ₁₇ N ₃ O ₄ S [M ⁺ ]: 383.0940, found: 383.0947.

HPLC (97.5%): retention time 14.58 min.

Example D8: cyclopentyl 5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.048 g, 31%) was obtained by method D using methanol.

1H-NMR (300 MHz, DMSO) 6 (ppm): 8.35-8.20 (m, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.35 ( t, J=7.8 Hz, 1H), 7.18 (br.s, 2H), 6.16 (br.s, 2H), 5.30 (s, 1H), 5.11-4.95 (m, 1H), 2.17 (s, 3H), 2.12 (s, 3H), 1.86-1.73 (m, 1H), 1.71-1.51 (m, 3H), 1.52-1.36 (m, 3H), 1.35-1.24 (m, 1H).

HRMS (IE) m/z calculated C ₂₃ H ₂₃ N ₃ O ₃ S [M ⁺ ]: 421.1460, found: 421.1453.

HPLC (98.4%): retention time 17.10 min.

Example D9: Dimethyl 2,6-diamino-4-(benzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound was obtained as a yellow solid (0.115 g, 53%) using method D using benzo[b]thiophene-3-carbaldehyde and methyl 3-amino-3-iminopropanoate (2 eq.).

1H-NMR (300 MHz, CDC13) 6=8.13-7.90 (m, 2H), 7.86 (d, J=8.0 Hz, 1H), 7.58-7.34 (m, 3H), 7.19 (s, 1H), 6.98 (s, 1H), 6.54 (s, 1H), 4.74 (s, 1H), 3.72 (s, 3H), 3, 60 (s, 1H), 3.37 (s, 3H).

Example D10: cyclopropylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.038 g, 51%) was obtained by method D using morpholine (1.2 eq.) in isopropanol.

1H-NMR (300 MHz, CDCI3) δ=8.43 (d, J=8.3 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.43 (t, J =7.8 Hz, 1H), 7.30 (s, 1H), 6.51 (br.s, 1H), 6.08 (br.s, 2H), 5.43 (s, 1H), 3 .83 (d, J=7.3 Hz, 2H), 2.33 (s, 3H), 2.17 (s, 3H), 1.100.95 (m, 1H), 0.60-0.40 ( m, 2H), 0.27-0.03 (m, 2H).

Example D11: 4,4-difluorocyclohexyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.053 g, 30%) was obtained by method D using morpholine (1.2 eq.) in isopropanol.

1H-NMR (300 MHz, CDC13) δ=8.35 (d, J=8.2 Hz, 1H), 7.67 (d, J=7.3 Hz, 1H), 7.45 (t, J =7.8 Hz, 1H), 7.28 (s, 1H), 6.05 (br.s, 2H), 5.42 (s, 1H), 4.82 (br.s, 1H), 2 .32 (s, 3H), 2.20 (s, 3H), 2.02-1.80 (m, 3H), 1.76-1.58 (m, 5H), 1.53-1.38 (m, 1H).

^-NMR (282 MHz, CDC1 ₃ ) δ (ppm): -97.60 (CF), -98.46 (CF).

Example D12: Methyl 2-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.022 g, 15%) was obtained by method D using morpholine (1.2 eq.) in isopropanol.

1H-NMR (300 MHz, CDC13) δ=8.24-8.16 (m, 1H), 7.74-7.67 (m, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.31 (s, 1H), 6.89 (br. s, 1H), 6.26 (br. s, 2H), 5.03 (s, 1H), 3.49 (s, 3H ), 2.04 (s, 3H).

Example D13: 4-fluorobenzyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.074 g, 43%) was obtained by method D using morpholine (1.2 eq.) in isopropanol.

1H-NMR (300 MHz, CDCl ,) δ=8.14 (d, J=7.9 Hz, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.20 (s , 2H), 7.13-7.02 (m, 2H), 6.95 (t, J=8.2 Hz, 2H), 6.48 (br.s, 1H), 6.12 (br. s, 2H), 5.37 (s, 1H), 4.98 (s, 2H), 2.31 (s, 3H), 2.12 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): -113.91 (CF).

Example D14: Methyl 5-acetyl-2-amino-4-(5-fluorothieno[2,3-b]pyridin-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.012 g, 67%) was obtained by method D using methanol.

1H-NMR (300 MHz, CDC13) δ=8.90 (s, 1H), 8.55 (d, J=2.6 Hz, 1H), 8.16 (dd, J=10.5, 2, 6 Hz, 1H), 7.48 (s, 1H), 6.65 (br. s, 2H), 5.20 (s, 1H), 3.48 (s, 3H), 2.30 (s, 3H), 2.11 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): -129.28 (d, J=10.4 Hz).

Example D14 was further modified to give example D15.

Example D15: Methyl 2-acetamido-5-acetyl-4-(5-fluorothieno[2,3-b]pyridin-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

Methyl 5-acetyl-2-amino-4-(5-fluorothieno[2,3-b]pyridin-3-yl)-6-methyl-1,4-dihydropyridine3-carboxylate mixture (0.025 g, 0.07 mmol ) and acetyl chloride (0.005 ml, 0.07 mmol) in pyridine (1 ml) was stirred at 75° C. for 3 h. The mixture was allowed to cool to RT and the solvent was removed under reduced pressure. The residue was purified by column chromatography (DCM:MeOH 2%) to give a yellow solid (0.017 g, 61%).

1H-NMR (300 MHz, CDC13) δ=11.71 (br. s, 1H), 10.50 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.02 (dd, J=9.8, 2.7 Hz, 1H), 7.34 (s, 1H), 5.33 (s, 1H), 3.66 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H).

¹⁹ F-NMR (282 MHz, CDC13) δ (ppm): -133.66 (d, J=9.5 Hz).

Example D16: cyclopentylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.066 g, 51%) was obtained by method D using morpholine (1.2 eq.) in isopropanol.

1H-NMR (300 MHz, CDC13) δ=8.36 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.43 (t, J =7.8 Hz, 1H), 7.26 (s, 1H), 6.25 (br.s, 1H), 6.02 (br.s, 2H), 5.42 (s, 1H), 3 .90 (dd, J=1.2, 1.8 Hz, 2H), 2.32 (s, 3H), 2.18 (s, 3H), 1.58 (d, J=34.3 Hz, 7H), 1.28-1.04 (m, 2H).

Example D17: 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.070 g, 47%) was obtained by method D using morpholine (1.2 eq.) in isopropanol.

1H-NMR (300 MHz, CDCI3) δ=8.36 (d, J=8.7 Hz, 1H), 7.64 (d, J=7.1 Hz, 1H), 7.47-7.37 (m, 1H), 7.32 (s, 1H), 5.99 (br. s, 2H), 5.87 (br. s, 1H), 5.41 (s, 1H), 3.71 ( d, J=7.2 Hz, 2H), 3.52 (s, 3H), 2.35 (s, 3H), 0.91-0.75 (m, 1H), 0.44-0.24 (m, 2H), 0.13-0.10 (m, 2H).

Example D18: dimethyl 2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.054 g, 41%) was obtained by method D using methanol.

1H-NMR (300 MHz, CDCl ,) δ=8.32 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.44 (t , J=7.8 Hz, 1H), 7.24 (s, 1H), 6.18 (br.s, 2H), 6.15 (br.s, 1H), 5.39 (s, 1H) , 3.56 (s, 3H), 3.52 (s, 3H), 2.81-2.64 (m, 1H), 1.01-0.84 (m, 2H), 0.83-0 .60 (m, 2H).

Example D19: 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.017 g, 12%) was obtained by method D.

1H-NMR (300 MHz, CDCI3) δ=8.37 (d, J=8.2 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.42 (t, J =7.8 Hz, 1H), 7.28 (s, 1H), 6.15 (br.s, 2H), 6.02 (br.s, 1H), 5.42 (s, 1H), 3 .72 (d, J=7.2 Hz, 2H), 3.55 (s, 3H), 2.78-2.62 (m, 1H), 1.01-0.77 (m, 3H), 0.79-0.62 (m, 2H), 0.47-0.24 (m, 2H), 0.12-0.09 (m, 2H).

Example D20: Dimethyl 2,6-diamino-4-(7-cyanobenzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.135 g, 66%) was obtained by method D using methanol.

1H-NMR (300 MHz, CDC13) δ=8.14 (d, J=1.9 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.69 (t, J =7.9 Hz, 1H), 7.47 (br.s, 1H), 7.21 (s, 1H), 7.16 (br.s, 1H), 6.60 (br.s, 2H) , 4.74 (s, 1H), 3.70 (s, 3H), 3.56 (s, 1H), 3.35 (s, 3H).

Example D21: 5-(cyclopropylmethyl)-3-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.040 g, 31%) was obtained by method D using morpholine in isopropanol.

1H-NMR (300 MHz, CDCI3) δ=8.35 (d, J=8.2 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.42 (t, J =7.7 Hz, 1H), 7.26 (s, 1H), 6.26 (br.s, 3H), 5.41 (s, 1H), 3.77 (d, J=7.2 Hz , 2H), 3.52 (s, 3H), 2.84-2.66 (m, 1H), 0.97-0.80 (m, 3H), 0.81-0.61 (m, 2H ), 0.48-0.25 (m, 2H), 0.15-0.08 (m, 2H).

Example D22: 3-(4-fluorobenzyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.035 g, 25%) was obtained by method D using morpholine in isopropanol.

1H-NMR (300 MHz, CDC13) δ=8.11 (d, J=8.3 Hz, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.30-7.15 (m, 2H), 6.97-6.77 (m, 4H), 6.68 (s, 1H), 6.22 (br. s, 2H), 5.34 (s, 1H), 5, 04-4.75 (m, 2H), 3.50 (s, 3H), 2.26 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): -114.23 (CF).

Example D23: 3-(4-fluorobenzyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl 1,4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.035 g, 25%) was obtained by method D using morpholine in isopropanol.

1H-NMR (300 MHz, CDCI3) δ=8.10 (d, J=8.2 Hz, 1H), 7.60 (d, J=7.3 Hz, 1H), 7.25-7.13 (m, 2H), 6.87 (q, J=8.7, 7.6 Hz, 4H), 6.29 (s, 2H), 6.20 (s, 1H), 5.36 (s, 1H), 5.00-4.77 (m, 2H), 3.52 (s, 3H), 2.83-2.53 (m, 1H), 0.99-0.82 (m, 2H) , 0.79-0.62 (m, 2H).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): -114.26 (CF).

Example D24: cyclopropylmethyl-2-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.035 g, 23%) was obtained by method D using piperidine in dioxane.

1H-NMR (300 MHz, CDC13) δ=8.20 (d, J=8.3 Hz, 1H), 7.69 (d, J=7.4 Hz, 1H), 7.45 (t, J =7.8 Hz, 1H), 7.35 (s, 1H), 7.04 (br.s, 1H), 6.27 (br.s, 2H), 5.08 (s, 1H), 3 .69 (dt, J=1.2, 3.8 Hz, 2H), 2.02 (s, 3H), 0.83-0.64 (m, 1H), 0.35-0.11 (m , 2H), 0.06-0.29 (m, 2H).

HRMS (APCI) m/z calculated C ₂₁ H ₁₉ N ₄ O ₂ S [M+ ¹ ]: 391.1223, found: 391.1223.

Example D25: 4-fluorobenzyl-2-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.010 g, 8%) was obtained by method D using morpholine in dioxane.

1H-NMR (300 MHz, CDCI3) δ=8.08 (d, J=8.2 Hz, 1H), 7.69 (d, J=7.1 Hz, 1H), 7.38 (t, J =7.8 Hz, 1H), 7.28 (s, 1H), 6.79 (s, 2H), 6.77 (s, 2H), 6.46 (br.s, 1H), 6.28 (s, 2H), 5.05 (s, 1H), 4.98-4.75 (m, 2H), 2.09 (s, 3H).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): -114.12 (CF).

HRMS (APCI) m/z calculated C ₂₄ H ₁₈ N ₄ O ₂ S [M ⁺ ]: 445.1129, found: 445.1126.

Example D26: cyclopropylmethyl-6-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl 1,4-dihydropyridine-3-carboxylate.

Method D was carried out at room temperature overnight to give the title compound as a yellow solid (0.060 g, 51%).

1H-NMR (300 MHz, DMSO4) δ=8.20 (d, J=8.3 Hz, 1H), 7.95 (d, J=7.3 Hz, 1H), 7.76 (br.s , 1H), 7.61 (t,

- 87 040842

J=7.8 Hz, 1H), 6.77 (s, 1H), 5.51 (br.s, 2H), 5.21 (s, 1H), 4.60-4.35 (m, 1H ), 3.56 (d, J=7.2 Hz, 2H), 1.23-1.10 (m, 1H), 0.81-0.64 (m, 1H), 0.64-0, 47 (m, 1H), 0.39-0.29 (m, 2H), 0.27-0.12 (m, 2H), 0.04-0.20 (m, 2H).

HRMS (APCI) m/z calculated C ₂₃ H ₂₁ N ₄ O ₂ S [M ⁺¹ ]: 417.1380, found: 417.1382.

Example D27: 3-Cycloentyl-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.082 g, 51%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCL3) δ=8.30 (d, J=8.7 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.43 (t, J =7.8Hz, 1H), 7.30(s, 1H), 6.07(s, 2H), 6.03(s, 1H), 5.32(s, 1H), 5.07-4 .92 (m, 1H), 3.54 (s, 3H), 2.32 (s, 3H), 1.87-1.74 (m, 1H), 1.71-1.57 (m, 2H ), 1.54-1.40 (m, 3H), 1.39-1.29 (m, 1H), 1.24-1.11 (m, 1H).

HRMS (APCI) m/z calculated C ₂₃ H ₂₄ N ₃ O ₄ S [M ⁺¹ ]: 438.1482, found: 438.1481.

Example D28: cyclopropylmethyl-5-acetyl-2-amino-4-(6-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.062 g, 45%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCl ,) δ=8.93 (br. s, 1H), 8.53 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 7 .75 (d, J=8.4 Hz, 1H), 7.59 (s, 1H), 6.69 (br.s, 2H), 5.32 (s, 1H), 3.79-3, 62 (m, 2H), 2.30 (s, 3H), 2.09 (s, 3H), 1.06-0.87 (m, 1H), 0.40 (d, J=8.0 Hz , 2H), 0.20-0.02 (m, 2H).

HRMS (APCI) m/z calculated C ₂₂ H ₂₂ N ₃ O ₃ S [M ⁺¹ ]: 408.1376, found: 408.1378.

Example D29: cyclohexyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.066 g, 43%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.37 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.1 Hz, 1H), 7.43 (t, J =7.8 Hz, 1H), 7.27 (s, 1H), 6.25 (br.s, 1H), 6.03 (br.s, 2H), 5.40 (s, 1H), 4 .77-4.56(m, 1H), 2.32(s, 3H), 2.17(s, 3H), 1.99-1.86(m, 1H), 1.78-1.67 (m, 1H), 1.63-1.49 (m, 3H), 1.39-1.07 (m, 5H).

HRMS (APCI) m/z calculated C ₂₄ H ₂₆ N ₃ O ₃ S [M ⁺¹ ]: 436.1689, found: 436.1690.

Example D30: cyclohexylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.077 g, 46%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.37 (d, J=8.1 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.45 (t, J =7.8 Hz, 1H), 7.28 (s, 1H), 6.38 (br.s, 1H), 6.06 (br.s, 2H), 5.41 (s, 1H), 3 .81 (d, J=6.6 Hz, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 1.691.53 (m, 4H), 1.51-1.37 ( m, 2H), 1.16-0.96 (m, 3H), 0.87-0.73 (m, 2H).

HRmS (APCI) m/z calculated C ₂₅ H ₂₈ N ₃ O ₃ S [M ⁺¹ ]: 450.1846, found: 450.1849.

Example D31: cyclopropylmethyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-5(cyclopropanecarbonyl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.120 g, 40%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.38 (d, J=8.2 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.42 (t, J =7.8 Hz, 1H), 7.32 (s, 1H), 6.54 (br.s, 1H), 6.14 (br.s, 2H), 5.56 (s, 1H), 3 .82 (d, J=7.3 Hz, 2H), 2.25 (s, 3H), 2.13-1.98 (m, 1H), 1.04-0.94 (m, 2H), 0.91-0.69 (m, 3H), 0.50-0.38 (m, 2H), 0.21-0.05 (m, 2H).

HRMS (APCI) m/z calculated C ₂₄ H ₂₄ N ₃ O ₃ S [M ⁺¹ ]: 434.1533, found: 421.1537.

Example D32: 3-fluorobenzyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.058 g, 34%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.17 (d, J=8.5 Hz, 1H), 7.60 (d, J=7.3 Hz, 1H), 7.23 (s, 3H ), 6.96 (t, J=8.5 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H), 6.74 (d, J=11.4 Hz, 1H), 6.41 (br. s, 1H), 6.12 (br. s, 2H), 5.39 (s, 1H), 5.064.92 (m, 2H), 2.32 (s, 3H), 2 .13 (s, 3H).

¹⁹ F-NMR (282 MHz, CDC13) δ (ppm): -112.76 (s, CF).

HRMS (APCI) m/z calculated C ₂₅ H ₂₁ N ₃ O ₃ SF [M ⁺¹ ]: 462.1282, found: 462.1278.

Example D33: 3-(cyclobutylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.040 g, 33%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.31 (d, J=8.1 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.44 (t, J =7.8 Hz, 1H), 7.29 (s, 1H), 6.82 (s, 1H), 6.22 (br.s, 2H), 5.35 (s, 1H), 3.89 (t, J=7.2 Hz, 2H), 3.54 (s, 3H), 2.41-2.29 (m, 1H), 2.26 (s, 3H), 1.93-1, 63 (m, 4H), 1.58-1.27 (m, 2H).

HRMS (APCI) m/z calculated C ₂₃ H ₂₄ N ₃ O ₄ S [M ⁺ ]: 438.1482, found: 438.1483.

Example D34: 3-((3,3-difluorocyclobutyl)methyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-88 040842 methyl-1,4- dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.035 g, 22%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCl ,) δ=8.28 (d, J=8.2 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.46 (t , J=7.8 Hz, 1H), 7.31 (s, 1H), 6.19 (s, 1H), 6.14 (br. s, 2H), 5.35 (s, 1H), 4 .00-3.81 (m, 2H), 3.55 (s, 3H), 2.35 (m, 1H), 2.32 (s, 3H), 2.26-1.93 (m, 4H ).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): -83.87 (d, J=193.0 Hz), -93.31 (d, J=193.0 Hz).

HRMS (APCI) m/z calculated C2 ₃ H22N ₃ O ₄ SF ₂ [M ⁺ ]: 474.1294, found: 474.1295.

Example D35: cyclopropylmethyl-2-amino-5-carbamoyl-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl1,4-dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.011 g, 11%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.28 (d, J=8.2 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.46-7.33 (m, 2H), 6.93 (br.s, 1H), 6.28 (br.s, 2H), 5.37 (br.s, 2H), 5.21 (s, 1H), 3. 76 (d, J=7.2 Hz, 2H), 2.16 (s, 3H), 0.95-0.85 (m, 1H), 0.53-0.27 (m, 2H), 0 .23-0.06 (m, 2H).

HRMS (APCI) m/z calculated C21H21N4O3S [M ⁺¹ ]: 409.1329, found: 409.1324.

Example D36: 3-((2,2-difluorocyclopropyl)methyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)6-methyl-1,4-dihydropyridine-3 ,5-dicarboxylate.

The title compound as a yellow solid (0.065 g, 40%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCI3) δ=8.31 (dd, J=7.7, 2.8 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.52 -7.38 (m, 1H), 7.31 (d, J=3.3 Hz, 1H), 6.07 (br. s, 3H), 5.37 (s, 1H), 4.16- 3.95 (m, 1H), 3.91-3.71 (m, 1H), 3.52 (s, 3H), 2.35 (s, 3H), 1.71-1.60 (m, 1H), 1.29-1.16 (m, 1H), 0.90 (s, 1H).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): -129.21 (ddt, J=160.2, 70.2, 10.9 Hz), -143.62 (ddd, J= 160.2, 51.3, 10.9 Hz).

HRMS (APCI) m/z calculated C ₂ 2H2 ₀ N ₃ O4SF ₂ [M ⁺ ]: 460.1137, found: 460.1137.

Example D37: 5-cyclopropyl-3-(cyclopropylmethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.008 g, 5%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.32 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.47-7.36 (m, 1H), 7.28 (s, 1H), 6.35 (br. s, 1H), 6.11 (br. s, 2H), 5.31 (s, 1H), 4.03- 3.89 (m, 1H), 3.71 (d, J=7.2 Hz, 2H), 2.33 (s, 3H), 1.25 (s, 1H), 1.00-0.69 (m, 2H), 0.60-0.28 (m, 4H), 0.22-0.03 (m, 2H).

HRMS (APCI) m/z calculated C24H24N3O4S [M ⁺¹ ]: 450.1482, found: 450.1481.

Example D38: 3-((2,2-difluorocyclopropyl)methyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)6-cyclopropyl-1,4-dihydropyridine-3 ,5-dicarboxylate.

The title compound as a yellow solid (0.004 g, 26%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCI3) δ=8.32 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.44 (t, J =7.8 Hz, 1H), 7.27 (s, 1H), 6.30 (br.s, 3H), 5.38 (s, 1H), 4.15-3.95 (m, 1H) , 3.91-3.73(m, 1H), 3.55(s, 3H), 2.77-2.62(m, 1H), 1.84-1.40(m, 1H), 1 .28-1.17 (m, 2H), 1.03-0.52 (m, 4H).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): -129.11 (ddt, J=160.0, 62.6, 11.7 Hz), -143.52 (ddd, J= 160.0, 35.4, 11.7 Hz).

HRMS (APCI) m/z calculated C24H22N ₃ O ₄ SF ₂ [M ⁺¹ ]: 486.1294, found: 486.1292.

Example D39: 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyano-5-fluorobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3,5-dicarboxylate .

The title compound as a yellow solid (0.020 g, 28%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.05 (dd, J=10.0, 2.3 Hz, 1H), 7.46-7.36 (m, 2H), 6.14 (s, 1H), 6.08 (br. s, 2H), 5.32 (s, 1H), 3.73 (d, J=7.3 Hz, 2H), 3.55 (s, 3H), 2, 35 (s, 3H), 0.94-0.78 (m, 1H), 0.53-0.25 (m, 2H), 0.170.11 (m, 2H).

¹⁹ F-NMR (282 MHz, CDC13) δ (ppm): -117.83 (d, J=7.7 Hz).

HRMS (APCI) m/z calculated C22H21N ₃ O ₄ SF [M ⁺¹ ]: 442.1231, found: 442.1231.

Example D40: 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyano-4-fluorobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3,5-dicarboxylate .

The title compound as a yellow solid (0.015 g, 16%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=7.62 (dd, J=8.2, 4.0 Hz, 1H), 7.33 (s, 1H), 7.09 (dd, J=11, 0, 8.2 Hz, 1H), 6.15-6.01 (m, 3H), 5.66 (d, J=4.0 Hz, 1H), 3.76-3.57 (m, 2H ), 3.48 (s, 3H), 2.32 (s, 3H), 0.91-0.59 (m, 1H), 0.390.02 (m, 2H), 0.02-0.25 ( m, 2H).

¹⁹ F-NMR (282 MHz, CDC13) δ (ppm): -104.35 (d, J=11.0 Hz).

- 89 040842

HRMS (APCI) m/z calculated C ₂₂ H ₂₁ N ₃ O ₄ SF [M ⁺¹ ]: 442.1231, found: 442.1229.

Example D41: 3-isopropyl-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.045 g, 26%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCI3) δ=8.34 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.43 (t, J =7.8 Hz, 1H), 7.29 (s, 1H), 6.91 (br.s, 1H), 6.25 (br.s, 2H), 5.34 (s, 1H), 4 .95-4.76 (m, 1H), 3.53 (s, 3H), 2.26 (s, 3H), 1.18 (d, J=6.1 Hz, 3H), 0.70 ( e, J=6.1 Hz, 3H).

HRMS (APCI) m/z calculated C ₂₁ H ₂₂ N ₃ O ₄ S [M ⁺¹ ]: 412.1326, found: 412.1335.

Example D42: 3-((2,2-difluoro-3,3-dimethylcyclopropyl)methyl)-5-methyl-2-amino-4-(7cyanobenzo[b]thiophen-3-yl)-6-methyl-1, 4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.052 g, 31%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.32 (ddd, J=8.3, 5.3, 1.0 Hz, 1H), 7.65 (d, J=7.4 Hz, 1H ), 7.50-7.39 (m, 1H), 7.31 (s, 1H), 6.12 (d, J=3.4 Hz, 1H), 6.08 (d, J=2, 2 Hz, 2H), 5.37 (s, 1H), 4.16-4.02 (m, 1H), 3.97-3.81 (m, 1H), 3.55 (d, J=1 .5 Hz, 3H), 2.33 (d, J=2.9 Hz, 3H), 1.40-1.21 (m, 1H), 1.15 (dd, J=2.4, 1, 5 Hz, 2H), 1.01-0.92 (m, 3H), 0.90 (dd, J=2.9, 1.4 Hz, 1H).

¹⁹ F-NMR (282 MHz, CDCl ,) δ (ppm): -137.08 (ddd, J=156.1, 65.1, 13.6 Hz), -148.04 (dd, J=155.7, 19.2 Hz).

HRMS (APCI) m/z calculated C ₂₄ H ₂₄ N ₃ O ₄ SF ₂ [M ⁺¹ ]: 488.1450, found: 488.1468.

Example D43: 5-methyl-3-neopentyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.061 g, 40%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.34 (d, J=8.2 Hz, 1H), 7.63 (d, J=7.1 Hz, 1H), 7.45-7, 36 (m, 1H), 7.32 (s, 1H), 6.10 (br. s, 3H), 5.44 (s, 1H), 3.80-3.53 (m, 5H), 2 .30 (s, 3H), 0.74 (s, 9H).

HRMS (APCI) m/z calculated C ₂₃ H ₂₆ N ₃ O ₄ S [M ⁺¹ ]: 440.1639, found: 440.1638.

Example D44: 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanothieno[3,2-b]pyridin-3-yl)-6methyl-1,4-dihydroyridine-3,5-dicarboxylate .

The title compound as a yellow solid (0.048 g, 42%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCl ,) δ=8.77 (d, J=4.7 Hz, 1H), 7.64 (s, 1H), 7.42 (d, J=4.7 Hz , 1H), 6.34 (s, 1H), 6.13 (s, 2H), 5.54 (s, 1H), 3.83-3.62 (m, 2H), 3.56 (s, 3H), 2.26 (s, 3H), 0.92-0.75 (m, 1H), 0.39-0.17 (m, 2H), 0.10-0.13 (m, 2H) .

HRMS (APCI) m/z calculated C ₂₁ H ₂₁ N ₄ O ₄ S [M ⁺¹ ]: 425.1278, found: 425.1280.

Example D45: 5-methyl-3-neopentyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.063 g, 35%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.33 (dd, J=8.3, 1.0 Hz, 1H), 7.64 (dd, J=7.6, 0.8 Hz, 1H ), 7.41 (dd, J=8.3, 7.4 Hz, 1H), 7.28 (s, 1H), 6.13 (br.s, 2H), 5.91 (br.s, 1H), 5.46 (s, 1H), 3.75-3.56 (m, 5H), 2.68-2.51 (m, 1H), 0.94-0.84 (m, 2H) , 0.75 (s, 9H), 0.72-0.64 (m, 2H).

HRMS (APCI) m/z calculated C ₂₅ H ₂₈ N ₃ O ₄ S [M ⁺¹ ]: 466.1795, found: 466.1798.

Example D46: bis(cyclopropylmethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.120 g, 56%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCI3) δ=8.40 (d, J=7.3 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.39 (dd, J = 8.2, 7.4 Hz, 1H), 7.34 (s, 1H), 6.02 (br.s, 3H), 5.44 (s, 1H), 3.83-3.64 ( m, 4H), 2.36 (s, 3H), 0.97-0.75 (m, 2H), 0.51-0.23 (m, 4H), 0.16-0.07 (m, 4H).

HRMS (APCI) m/z calculated C ₂₅ H ₂₆ N ₃ O ₄ S [M ⁺¹ ]: 464.1639, found: 464.11638.

Example D47: 3-(cyclopropylmethyl)-5-(prop-2-yn-1-yl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine- 3,5-dicarboxylate.

The title compound as a yellow solid (0.112 g, 52%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.39 (dd, J=8.3, 1.0 Hz, 1H), 7.64 (dd, J=7.1, 1.2 Hz, 1H ), 7.41 (dd, J=8.2, 7.4 Hz, 1H), 7.34 (s, 1H), 6.02 (br.s, 3H), 5.44 (s, 1H) , 4.63-4.42 (m, 2H), 3.71 (d, J=7.3 Hz, 2H), 2.46-2.26 (m, 4H), 0.91-0.73 (m, 1H), 0.49-0.20 (m, 2H), 0.12-0.14 (m, 2H).

HRMS (APCI) m/z calculated C ₂₄ H ₂₂ N ₃ O ₄ S [M ⁺¹ ]: 448.1326, found: 448.1327.

Example D48: 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(5,7-dicyanobenzo[b]thiophen-3-yl)-6-methyl1,4-dihydropyridine-3,5-dicarboxylate.

- 90 040842

The title compound as a yellow solid (0.005 g, 8%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCl ,) δ=8.64 (s, 1H), 7.85 (s, 1H), 7.49 (s, 1H), 6.07 (br. s, 2H) , 5.97 (br. s, 1H),

5.40 (s, 1H), 3.72 (d, J=7.3 Hz, 2H), 3.55 (s, 3H), 2.37 (s, 3H), 0.87-0.82 (m, 1H), 0.58-0.29 (m, 2H), 0.16-0.11 (m, 2H).

HRMS (APCI) m/z calculated C ₂₃ H ₂ iN ₄ O ₄ S [M ⁺¹ ]: 449.1278, found: 449.1277.

Example D49: 5-(but-2-yn-1-yl) 3-(cyclopropylmethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine- 3,5-dicarboxylate.

The title compound as a yellow solid (0.007 g, 4%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.39 (dd, J=8.3, 1.0 Hz, 1H), 7.64 (dd, J=7.1, 1.2 Hz, 1H) , 7.41 (dd, J=8.2, 7.4 Hz, 1H), 7.34 (s, 1H), 6.02 (br.s, 3H), 5.44 (s, 1H), 4.63-4.42 (m, 2H), 3.71 (d, J=7.3 Hz, 2H), 2.46-2.26 (m, 4H), 0.91-0.73 ( m, 1H), 0.49-0.20 (m, 2H), 0.12-0.14 (m, 2H).

HRMS (APCI) m/z calculated C25H24N3O4S [M ⁺¹ ]: 462.1482, found: 462.1480.

Example D50: 5-methyl-3-(2,2,2-trifluoroethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5 -dicarboxylate.

The title compound was prepared using method variant D: a mixture of methyl-(Z)-2-((7-cyanobenzo[b]thiophen-3-yl)methylene)-3-oxobutanoate (0.123 g, 0.43 mmol), 2.2, 2-trifluoroethyl-3-amino-3-iminopropanoate (0.115 g, 0.43 mmol), ammonium acetate (0.033 g, 0.43 mmol) in trifluoroethanol (3 ml) was stirred at room temperature overnight and then concentrated. The residue was purified by column chromatography (1:1 hexane:ethyl acetate) to give a yellow solid (0.019 g, 10%).

1H-NMR (300 MHz, CDC13) δ=8.30 (d, J=8.3 Hz, 1H), 7.68 (d, J=7.2 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.34 (s, 1H), 6.55 (br.s, 1H), 6.24 (br.s, 2H), 5.41 (s, 1H), 4 .54-4.38 (m, 1H), 4.23-4.07 (m, 1H), 3.57 (s, 3H), 2.35 (s, 3H).

%-NMR (282 MHz, CDC13) δ (ppm): -73.93 (t, J=9.8 Hz).

HRMS (APCI) m/z calculated C2 ₀ H ₁₇ N ₃ O ₄ SF ₃ [M ⁺¹ ]: 452.0886, found: 452.0885.

Example D51: 3-(cyclopropylmethyl)-5-(2,2,2-trifluoroethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3yl)-6-methyl-1,4-dihydropyridine-3 ,5-dicarboxylate.

The title compound as a yellow solid (0.0065 g, 7%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCI3) δ=8.34 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.44-7.38 (m, 1H), 7.34 (s, 1H), 6.16 (br.s, 1H), 6.04 (br.s, 2H), 5.42 (s, 1H), 4.41 ( dk, J=12.7, 8.5 Hz, 1H), 4.20 (dt, J=12.7, 8.5 Hz, 1H), 3.73 (d, J=7.3 Hz, 2H ), 2.38 (s, 3H), 0.90-0.82 (m, 1H), 0.47-0.29 (m, 2H), 0.10-0.04 (m, 2H).

%-NMR (282 MHz, CDCI3) δ (ppm): -73.88 (t, J=9.1 Hz).

HRMS (APCI) m/z calculated C23H21N3O4SF3 [M ⁺¹ ]: 492.1199, found: 492.1197.

Example D52: 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(6-chloro-7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3,5-dicarboxylate .

The title compound as a yellow solid (0.060 g, 39%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.27 (d, J=8.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.29 (s, 1H ), 6.14-5.94 (m, 3H), 5.35 (s, 1H), 3.76-3.67 (m, 2H), 3.54 (s, 3H), 2.34 ( s, 3H), 0.93-0.75 (m, 1H), 0.48-0.24 (m, 2H), 0.12-0.09 (m, 2H)

HRMS (APCI) m/z calculated C22H21N3O4SC1 [M ⁺¹ ]: 458.0936, found: 458.0938.

Example D53: 3-(2-fluoro-2-methylpropyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl1,4-dihydropyridine-3,5 -dicarboxylate.

The title compound as a yellow solid (0.060 g, 39%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCI3) δ=8.34 (d, J=9.0 Hz, 1H), 7.64 (d, J=7.4 Hz, 1H), 7.47-7.37 (m, 1H), 7.32 (s, 1H), 6.63 (br.s, 1H), 6.20 (br.s, 2H), 5.43 (s, 1H), 4.12- 3.79 (m, 2H), 3.56 (s, 3H), 2.30 (s, 3H), 1.27-1.03 (m, 6H).

¹⁹ F-NMR (282 MHz, CDCI3) δ (ppm): (-142.28)-(-148.26) (m, CF).

HRMS (APCI) m/z calculated C22H23N3O4SF [M ⁺¹ ]: 444.1388, found: 444.1388.

Example D54: 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyano-6-(trifluoromethyl)benzo[b]thiophen3-yl)-6-methyl-1,4-dihydropyridine-3, 5-dicarboxylate.

The title compound as a yellow solid (0.003 g, 3%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.09 (d, J=8.4 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.35 (s, 1H ), 6.03-5.91 (m, 3H), 5.24 (s, 1H), 3.84 (d, J=7.0 Hz, 2H), 3.58 (s, 3H), 2 .22 (s, 3H), 0.88-0.77 (m, 1H), 0.50-0.22 (m, 2H), 0.140.10 (m, 2H).

Example D55: 5-methyl-3-prop-2-yn-1-yl 2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4- 91 040842 dihydropyridine- 3,5-dicarboxylate.

The title compound as a yellow solid (0.005 g, 4%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDC13) δ=8.34 (d, 1H), 7.63 (d, 1H), 7.49 (t, 1H), 7.31 (s, 1H), 6.1 (br. s, 3H), 5.44 (s, 1H), 4.44-4.26 (m, 2H), 3.59 (s, 3H), 2.42-2.24 (m, 4H ).

Example D56: 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate.

The title compound as a yellow solid (0.007 g, 5%) was obtained by method D using morpholine at room temperature overnight.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.33 (d, 1H), 7.65 (d, 1H), 7.44-7.35 (m, 1H), 7.31 (s, 1H ), 6.09 (br. s, 2H), 5.96 (br. s, 1H), 5.48 (s, 1H), 3.76 (d, 2H), 2.38 (s, 3H) , 0.98-0.81 (m, 1H), 0.46-0.26 (m, 2H), 0.14-0.11 (m, 2H).

Method E.

Example E1: 4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile.

A mixture of thionapthene-3-carboxaldehyde (0.5 g, 3.08 mmol), 3-aminocrotonitrile (0.554 ml, 6.74 mmol) and acetic acid (0.076 ml, 3.08 mmol) in isopropyl alcohol (10 ml) was stirred at 100° C. for 18 hours. The mixtures were allowed to cool to RT and concentrated. The residue was made basic with aqueous sodium bicarbonate, the resulting solid was filtered off and washed with cold water and ethyl ether. The desired product was obtained as a light yellow solid (0.738 g, 82%).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.06 (s, 6H), 5.00 (s, 1H), 7.36-7.46 (m, 1H), 7.65 (s , 1H), 7.89 (d, 1H), 8.03 (d, 1H), 9.67 (s, 1H).

HPLC-MS: retention time 3.878 min, m/z 292.0 (MH ⁺ ).

The following examples were synthesized by method E.

Example E2: 4-(6-Hydroxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.05 (s, 6H), 4.80 (s, 1H), 6.86 (dd, 1H), 7.13 (s, 1H), 7.24 (d, 1H), 7.61 (d, 1H), 9.64 (s, 2H).

HPLC-MS: retention time 3.285 min, m/z 308.0 (MH ⁺ ).

Example E3: 4-(6-methoxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.06 (s, 6H), 3.81 (s, 3H), 4.84 (s, 1H), 7.00 (d, 1H), 7.20 (s, 1H), 7.50 (d, 1H), 7.71 (d, 1H), 9.69 (s, 1H).

HPLC-MS: retention time 3.962 min, m/z 322.0 (MH ⁺ ).

Example E4: 2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarbonitrile.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=8.90 (s, 1H), 8.47 (s, 1H), 7.78 (s, 1H), 7.72 (d, 1H), 6.91 (t, 1H), 6.17 (s, 1H), 2.65 (s, 6H).

HPLC-MS: retention time 2.735; m/z 229.9 (MH ⁺ ).

Method F.

Example F1: 4-(benzo[b]thiophen-3-yl)-2-methyl-6-phenyl-1,4-dihydropyridine-3,5-dicarbonitrile.

A mixture of thionapthene-3-carboxaldehyde (0.104 g, 0.64 mmol), 3-aminocrotonitrile (0.052 g, 0.64 mmol), benzoylacetonitrile (0.0897 g, 0.62 mmol) and acetic acid (0.035 ml, 0. 64 mmol) in isopropyl alcohol (3.5 ml) was heated to 100° C. and left to stir for 16 h. The mixture was allowed to cool to RT and concentrated. The residue was basified with aqueous sodium bicarbonate and the resulting solid was filtered and purified by column chromatography (3:1 hexane:ethyl acetate) to give a light yellow solid (0.0162 g, 7%).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.12 (s, 3H), 5.17 (s, 1H), 7.39-7.49 (m, 2H), 7.50-7 .59 (m, 5H), 7.78 (s, 1H), 8.01 (dd, 1H), 8.06 (dd, 1H), 9.92 (s, 1H).

HPLC-MS: retention time 4.329 min, m/z 354.1 (MH ⁺ ).

The following examples were synthesized by method F.

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Example F2: 4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3,5-dicarbonitrile.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.95 (s, 4H), 2.06 (s, 3H), 4.98 (s, 1H), 7.41 (s, 2H), 7.64 (s, 1H), 7.84 (s, 1H), 8.03 (s, 1H), 8.82 (s, 1H).

HPLC-MS: retention time 4.138 min, m/z 318.0 (MH ⁺ ).

Example F3: 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonitrile.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.00 (s, 6H), 2.31 (s, 3H), 5.16 (s, 1H), 7.30-7.48 (m , 3H), 7.97 (d, 1H), 8.04 (d, 1H), 9.30 (s, 1H).

HPLC-MS: retention time 3.816 min, m/z 175.1 (MH+-134).

Example F4: Ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.90 (t, 3H), 2.02 (s, 3H), 2.30 (s, 3H), 3.85 (dd, 2H), 5.02 (s, 1H), 7.31-7.45 (m, 3H), 7.91 (d, 1H), 7.96 (d, 1H), 9.30 (s, 1H).

HPLC-MS: retention time 4.418 min, m/z 205.1 (MH+-134).

Example F5: ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-methyl-6-phenyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.98 (t, 3H), 2.37 (s, 3H), 3.92 (q, 2H), 5.17 (s, 1H), 7.41 (ddd, 2H), 7.49 (d, 5H), 8.00 (t, 2H), 9.60 (s, 1H).

HPLC-MS: retention time 4.946 min, m/z 267.1 (MH+-134).

Example F6: ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxyl.

1H-NMR (400 MHz, DMSO-d6) δ=0.80-0.98 (m, 6H), 0.96-1.06 (m, 1H), 2.03 (s, 3H), 2, 73-2.84 (m, 1H), 3.82-3.95 (m, 2H), 5.02 (s, 1H), 7.32 (s, 1H), 7.33-7.44 ( m, 2H), 7.90 (d, 1H), 7.96 (d, 1H), 8.23 (s, 1H).

HPLC-MS: retention time 4.693 min, m/z 231.1 (MH+-134).

Example F7: methyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.79-0.95 (m, 3H), 1.02 (ddd, 1H), 2.03 (s, 3H), 2.78 (dc, 1H), 3.45 (s, 3H), 5.01 (s, 1H), 7.30 (s, 1H), 7.39 (dt, 2H), 7.90 (d, 1H), 7, 96 (dd, 1H), 8.28 (s, 1H).

HPLC-MS: retention time 4.438 min, m/z 217.1 (MH+-134).

Way G.

Example G1: 1,1'-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5-diyl)diethanone.

A mixture of thionapthene-3-carboxaldehyde (0.2 g, 1.23 mmol), acetylacetone (0.25 ml, 2.47 mmol) and aqueous ammonium hydroxide solution (38-40%, 0.12 ml) in ethanol (1 ml) was heated to 90° C. and allowed to stir for 16 hours. The mixture was allowed to cool to RT and then poured into 10 ml of cold water. The resulting precipitate was filtered off, dried and washed with cold diethyl ether. The desired product was obtained as a bright yellow solid (0.193 g, 48%).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.17 (s, 6H), 2.29 (s, 6H), 5.52 (s, 1H), 7.23 (s, 1H), 7.33 (dt, 2H), 7.88 (d, 1H), 8.12 (d, 1H), 9.08 (s, 1H).

HPLC-MS: retention time 3.668 min, m/z 192.1 (MH+-134).

The following examples were synthesized by method G.

Example G2: 1,1'-(4-(6-Hydroxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5diyl)bis(ethan-1-one).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.28 (s, 12H), 5.29 (s, 1H), 6.76 (d, 2H), 7.10 (s, 1H), 7.45 (d, 1H), 9.10 (s, 1H), 9.40 (s, 1H).

HPLC-MS: retention time 2.950 min, m/z 192.1 (MH ⁺ -150).

Example G3: 1,1'-(4-(6-Methoxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5diyl)diethanone.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.29 (d, 12H), 3.75 (s, 3H), 5.32 (s, 1H), 6.86 (d, 1H), 6.89 (dd, 1H), 7.36 (d, 1H), 7.55 (d, 1H), 9.12 (s, 1H).

HPLC-MS: retention time 3.676 min, m/z 192 (MH+-164).

Example G4: 1,1'-(4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridin-3,5diyl)diethanone.

1H-NMR (400 MHz, DMSO-d6) δ=0.69 (dd, 2H), 0.74 (dd, 4H), 0.78-0.84 (m, 2H), 2.18-2, 25 (m, 2H), 2.27 (s, 6H), 5.69 (s, 1H), 7.21 (s, 1H), 7.26-7.36 (m, 2H), 7.89 (d, 1H), 7.97 (d, 1H), 83.99 (s, 1H).

Method N.

Example H1: 1,1'-(4-(5-Chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5diyl)diethanone.

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A mixture of 5-chlorobenzo[b]thiophene-3-carbaldehyde (0.05 g, 0.26 mmol), 4-amino-3-penten-2-one (0.60 g, 0.52 mmol) and acetic acid ( 0.015 ml) in isopropanol (1.5 ml) was heated to 100° C. and allowed to stir for 16 h. The mixture was allowed to cool to RT and then treated with saturated aqueous sodium bicarbonate (10 ml). The solid was filtered off, washed with water, dried and purified by column chromatography (3:1 hexane:ethyl acetate) to give a fine yellow solid (8.8 mg, 9.5%).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.17 (s, 6H), 2.31 (s, 6H), 5.44 (s, 1H), 7.33 (d, 2H), 7.92 (d, 1H), 8.23 (s, 1H), 9.15 (s, 1H).

HPLC-MS: retention time 4.072 min, m/z 192.1 (MH+-168).

The following examples were synthesized by the method of H.

Example H2: 1,1'-(4-(5-Bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5diyl)diethanone.

1H-NMR (400 MHz, DMSO-d6) δ=2.17 (s, 6H), 2.31 (s, 6H), 5.44 (s, 1H), 7.30 (d, 1H), 7 .44 (d, 1H), 7.86 (d, 1H), 8.38 (s, 1H), 9.16 (s, 1H).

Example H3: 1,1'-(4-(5-Fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5diyl)bis(ethan-1-one).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=9.15 (s, 1H), 7.92 (dd, J=8.1, 4.2 Hz, 2H), 7.34 (s, 1H ), 7.20 (td, J=8.8, 2.3 Hz, 1H), 5.44 (s, 1H), 2.32 (s, 6H), 2.18 (s, 6H).

Example H4: 1,1'-(2,6-dimethyl-4-(5-morpholinobenzo[b]thiophen-3-yl)-1,4-dihydropyridin-3,5diyl)bis(ethan-1-one).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=9.11 (s, 1H), 7.70 (d, 1H), 7.49 (d, 1H), 7.20 (s, 1H), 7.09 (dd, 1H), 5.48 (s, 1H), 3.80 (t, 4H), 3.12 (t, 4H), 2.27 (s, 6H), 2.19 (s , 6H).

Example H5: 1,1'-(2,6-dimethyl-4-(5-(4-methylpiperazin-1-yl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3,5-diyl) bis(ethane-1-one).

1H-NMR (400 MHz, DMSO-d6) δ=9.12 (s, 1H), 7.67 (d, 1H), 7.48 (d, 1H), 7.19 (s, 1H), 5 .48 (s, 1H), 3.80 (t, 4H), 3.12 (t, 4H), 2.27 (s, 6H), 2.19 (s, 6H).

Example H6: 1,1'-(4-(5-(benzylamino)benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5diyl)bis(ethane-1- He).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=8.98 (s, 1H), 7.50 (d, 1H), 7.43 (d, 2H), 7.32 (t, 2H), 7.23 (t, 1H), 7.14 (d, 1H), 7.08 (s, 1H), 6.77 (dd, 1H), 6.21 (t, 1H), 5.33 (s , 1H), 4.30 (d, 2H), 2.22 (s, 6H), 2.09 (s, 6H).

Example H7: 3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5-carbonitrile.

1H-NMR (400 MHz, DMSO-d6) δ=2.17 (s, 6H), 2.33 (s, 6H), 5.49 (s, 1H), 7.43 (s, 1H), 7 .67 (dd, 1H), 8.13 (d, 1H), 8.66 (s, 1H), 9.20 (s, 1H).

HPLC-MS: retention time 3.563; m/z 351.1 (MH ⁺ ).

Example H8: 3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5-carboxylic acid

1H-NMR (400 MHz, DMSO-d ₆ ) δ=9.13 (s, 1H), 8.82 (s, 1H), 7.96 (d, 1H), 7.85 (d, 1H), 7.33 (s, 1H), 5.54 (s, 1H), 2.30 (s, 6H), 2.18 (s, 6H).

Example H9: N-cyclopropyl-3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4yl)benzo[b]thiophene-5-carboxamide.

1H-NMR (400 MHz, DMSO-d6) δ=9.13 (s, 1H), 8.64 (s, 1H), 8.42 (d, 1H), 7.93 (d, 1H), 7 .72 (d, 1H), 7.32 (s, 1H), 5.53 (s, 1H), 2.89 (m, 1H), 2.29 (s, 6H), 2.18 (s, 6H), 0.73 (m, 2H), 0.61 (m, 2H).

Example H10: N-(cyclopropylmethyl)-3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4yl)benzo[b]thiophene-5-carboxamide.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=9.12 (s, 1H), 8.68 (s, 1H), 8.50 (d, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.32 (s, 1H), 5.53 (s, 1H), 3.26 (t, 2H), 2.29 (s, 6H), 2.18 (s , 6H), 1.08 (m, 1H), 0.45 (m, 2H), 0.28 (m, 2H).

Example H11: 1,1'-(2,6-dimethyl-4-(5-(4-methylpiperazin-1-carbonyl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3,5-diyl) bis(ethane-1-one).

1H-NMR (400 MHz, CDC13) δ=8.21 (s, 1H), 7.82 (d, 1H), 7.42 (d, 1H), 7.21 (d, 1H), 6.17 (s, 1H), 5.61 (s, 1H), 3.77 (d, 4H), 2.54 (m, 4H), 2.38 (s, 3H), 2.34 (s, 3H) , 2.22 (s, 3H), 2.08 (s, 3H).

Example H12: 1,1'-(2,6-dimethyl-4-(5-(morpholine-4-carbonyl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3,5-diyl)bis( ethane-1-one).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=9.15 (s, 1H), 8.21 (s, 1H), 7.97 (d, 1H), 7.35 (dd, 1H), 7.32 (s, 1H), 5.50 (s, 1H), 3.67 (m, 8H), 2.31 (s, 6H), 2.16 (s, 6H).

Example H13: 1,1'-(2,6-dimethyl-4-(thieno[3,2-c]pyridin-3-yl)-1,4-dihydropyridine-3,5-94040842 diyl)bis(ethane -1 -on).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=9.35 (s, 1H), 9.18 (s, 1H), 8.36 (d, 1H), 7.95 (d, 1H), 7.34 (s, 1H), 5.58 (s, 1H), 2.31 (s, 6H), 2.19 (s, 6H).

Example H14: 1,1'-(2,6-dimethyl-4-(thieno[2,3-c]pyridin-3-yl)-1,4-dihydropyridine-3,5 diyl)bis(ethane-1- He).

1H-NMR (400 MHz, DMSO-d ₆ ) 5=9.17 (s, 1H), 9.13 (d, 1H), 8.44 (d, 1H), 8.05 (dd, 1H), 7.57 (s, 1H), 5.51 (s, 1H), 2.31 (s, 6H), 2.17 (s, 6H).

Example H15: 1,1'-(2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridin-3,5diyl)bis(ethan-1-one ).

1H-NMR (400 MHz, DMSO-d ₆ ) 5=9.15 (s, 1H), 8.49 (d, 2H), 7.43 (s, 1H), 7.33 (s, 1H), 5.47 (s, 1H), 2.32 (s, 6H), 2.18 (s, 6H).

Method I

Example II: dimethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-2,3-dicarboxylate.

A mixture of benzo[b]thiophene-3-carbaldehyde (0.20 g, 1.23 mmol), pentane-2,4-dione (0.123 g, 1.23 mmol), dimethyl-but-2-enedioate (0.182 ml, 1.48 mmol), ammonium acetate (0.143 g, 1.85 mmol), iodine (0.094 g, 0.37 mmol) and two drops of acetic acid were stirred in methanol (3 ml) at 60°C for 12 h. solvent under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed twice with saturated NaS ₂ O ₃ and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by column chromatography (2:1 hexane:ethyl acetate) to give a yellow solid (0.028 g, 6%).

1H-NMR (300 MHz, CDC13) 5=7.94-7.80 (m, 2H), 7.46-7.29 (m, 2H), 7.19 (s, 1H), 6.38 ( br.s, 1H), 5.38 (s, 1H), 3.81 (s, 3H), 3.52 (s, 3H), 2.43 (s, 3H), 2.04 (s, 3H ).

HRMS (APCI) m/z calculated C ₂₀ H ₂₀ NO ₅ S [M ⁺¹ ]: 386.1056, found: 386.1058.

Example 12: Dimethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-2,3-dicarboxylate.

The title compound was prepared by method I to give a yellow solid (0.04 g, 2%).

1H-NMR (300 MHz, CDC13) 5=8.24 (d, J=1.9 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.50 (t, J =7.9 Hz, 1H), 7.34 (s, 1H), 6.43 (br.s, 1H), 5.41 (s, 1H), 3.84 (s, 3H), 3.55 (s, 3H), 2.44 (s, 3H), 2.11 (s, 3H).

HRMS (APCI) m/z calculated C ₂₁ H ₁₉ N ₂ O ₅ S [M ⁺¹ ]: 411.1009, found: 411.1006.

Way J.

Example J1: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine3-carboxylate.

A mixture of thionapthene-3-carboxaldehyde (0.106 g, 0.65 mmol), methyl 3-cyclopropyl-3-oxopropanoate (0.071 g, 0.72 mmol) and 4-amino-3-penten-2-one (0.088 g, 0. 61 mmol) and acetic acid (0.035 ml) in isopropyl alcohol (1.5 ml) was heated to 100°C and left to stir for 19 h. The mixture was allowed to cool to RT and then treated with saturated aqueous sodium bicarbonate (10 ml) . The solid was filtered off, washed with water, dried and purified by column chromatography (4:1 hexane:ethyl acetate) to give a fine yellow solid (0.075 g, 44%).

1H-NMR (400 MHz, DMSO-d ₆ ) 5=0.76 (s, 2H), 0.96 (d, 2H), 2.12 (s, 3H), 2.33 (s, 3H), 2.69 (s, 1H), 3.58 (s, 3H), 5.43 (s, 1H), 7.15 (s, 1H), 7.31 (s, 1H), 7.38 (s , 1H), 7.90 (s, 2H), 8.05 (d, 1H).

HPLC-MS: retention time 4.302 min, m/z 234.1 (MH+-133).

The product of the second reaction was isolated by column chromatography.

Example L-a: dimethyl 4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate.

1 H-NMR (400 MHz, DMSO-d ₆ ) 5=0.56 (s, 2H), 0.82 (s, 2H), 0.90 (d, 2H), 1.04 (s, 2H), 2.56 (m, 2H), 3.55 (s, 5H), 5.37 (s, 1H), 7.05 (s, 1H), 7.11 (s, 1H), 7.32 (t , 1H), 7.39 (t, 1H), 7.90 (d, 1H), 7.98 (s, 1H).

HPLC-MS: retention time 4.935; m/z 276.1 (MH ⁺ ).

The following examples were synthesized by the method of J.

- 95 040842

Example J2: Ethyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=1.1 (t, 3H), 2.11 (s, 3H), 2.25 (s, 3H), 2.31 (s, 3H), 3.99 (d, 2H), 5.40 (s, 1H), 7.23 (s, 1H), 7.31 (t, 1H), 7.37 (m, 1H), 7.89 (d , 1H), 8.08 (d, 1H), 9.02 (s, 1H).

HPLC-MS: retention time 4.284 min, m/z 222.1 (MH+-134).

Example J3: Methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydroiiridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=2.13 (s, 3H), 2.25 (s, 3H), 2.33 (s, 3H), 3.54 (s, 3H), 5 .33 (s, 1H), 7.33 (s, 1H), 7.93 (d, 1H), 8.11 (d, 1H), 8.52 (s, 1H), 9.11 (s, 1H).

HPLC-MS: retention time 4.431 min, m/z 208.1 (MH+-168).

Example J6: 1,1'-(4-(benzo[b]thiophen-3-yl)-2-cycloiroyl-6-methyl-1,4-dihydroiiridin-3,5diyl)diethanone.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.72 (m, 2H), 0.80 (m, 2H), 2.16 (s, 3H), 2.26 (d, 1H), 2.33 (s, 6H), 5.60 (s, 1H), 7.21 (s, 1H), 7.32 (dd, 2H), 7.89 (d, 1H), 8.04 (d , 1H), 9.02 (s, 1H).

HPLC-MS: retention time 4.692; m/z 352.0 (MH ⁺ ).

Example J10: 1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(methylsulfonyl)-1,4-dihydro-yridin-3-yl)-ethanone.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.16 (s, 3H), 2.29 (d, 6H), 2.47 (s, 3H), 5.47 (s, 1H), 7.33 (t, 1H), 7.437.37 (m, 2H), 7.93 (d, 1H), 8.07 (d, 1H), 9.26 (s, 1H).

HPLC-MS: retention time 3.395 min, m/z 228.0 (MH+-134).

Example J11: Methyl 5-acetyl-4-(5-fluoro-benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydroiiridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=9.10 (s, 1H), 7.93 (dd, J=8.8, 5.2 Hz, 1H), 7.81 (dd, J= 11.0, 2.5 Hz, 1H), 7.35 (s, 1H), 7.20 (td, J=8.8, 2.6 Hz, 1H), 5.33 (s, 1H), 3.54 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H).

HPLC-MS: retention time 4.345; m/z 360.0 (MH ⁺ ).

Example J12: Methyl 5-acetyl-4-(5-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydroiiridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=9.11 (s, 1H), 8.26 (d, 1H), 7.88 (d, 1H), 7.45 (d, 1H), 7 .31 (s, 1H), 5.34 (s, 1H), 3.58 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 2.16 (s, 3H).

Example J13: Methyl 5-acetyl-4-(5-cyanobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydroiiridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=9.16 (s, 1H), 8.53 (s, 1H), 8.15 (d, 1H), 7.67 (d, 1H), 7.46 (s, 1H), 5.40 (s, 1H), 3.55 (s, 3H), 2.35 (s, 3H), 2.27 (s, 3H), 2.17 (s , 3H).

Example J14: 3-(3-Acetyl-5-(methoxycarbonyl)-2,6-dimethyl-1,4-dihydroyridin-4yl)benzo[b]thiophene-5-carboxylic acid.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=12.94 (s, 1H), 9.12 (s, 1H), 8.77 (s, 1H), 8.00 (d, 1H), 7.85 (d, 1H), 7.32 (s, 1H), 5.52 (s, 1H), 3.56 (s, 3H), 2.35 (s, 3H), 2.24 (s , 3H), 2.12 (s, 3H).

Example J15: Methyl 5-acetyl-4-(5-(cycloiroyylcarbamoyl)benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydroyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=9.06 (s, 1H), 8.59 (s, 1H), 8.45 (d, 1H), 7.91 (d, 1H), 7 .72 (dd, 1H), 7.26 (s, 1H), 5.39 (s, 1H), 3.53 (s, 3H), 2.85 (m, 1H), 2.37 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H), 0.69 (m, 2H), 0.58 (m, 2H).

Example J16: Methyl 5-acetyl-4-(5-((cycloyroyylmethyl)carbamoyl)benzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydro-yridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=9.10 (s, 1H), 8.66 (s, 1H), 8.60 (d, 1H), 7.97 (d, 1H), 7 .81 (d, 1H), 7.30 (s, 1H), 5.43 (s, 1H), 3.57 (s, 3H), 3.20 (m, 2H), 2.85 (m, 1H), 2.34 (s, 3H), 2.22 (s, 3H), 2.10 (s, 3H), 0.45 (m, 2H), 0.26 (m, 2H).

Example J17: Methyl 5-acetyl-2,6-dimethyl-4-(5-(4-methyliiierazine-1-carbonyl)benzo[b]thiophen-3yl)-1,4-dihydroiiridine-3-carboxylate.

1H-NMR (400 MHz, CDC13) δ=8.22 (s, 1H), 7.82 (d, 1H), 7.36 (dd, 1H), 7.22 (d, 1H), 5.94 (s, 1H), 5.46 (s, 1H), 3.77 (d, 4H), 3.65 (s, 3H), 2.53 (m, 4H), 2.38 (s, 3H) , 2.36 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H).

Example J18: Methyl 5-acetyl-2,6-dimethyl-4-(5-(morpholine-4-carbonyl)benzo[b]thiophen-3-yl)-1,4dihydro-iiridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=9.11 (s, 1H), 8.13 (s, 1H), 7.97 (d, 1H), 7.35 (d, 1H), 7.32 (s, 1H), 5.39 (s, 1H), 3.64 (m, 8H), 3.36 (s, 3H), 2.32 (s, 3H), 2.25 (s , 3H), 2.12 (s, 3H).

Example J19: Methyl 5-acetyl-2,6-dimethyl-4-(thieno[3,2-c]iiridin-3-yl)-1,4-dihydroiiridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=9.27 (d, 1H), 9.13 (s, 1H), 8.36 (d, 1H), 7.97 (dd, 1H), 7 .35 (s, 1H), 5.48 (s, 1H), 3.52 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H), 2.14 (s, 3H).

Example J20: Methyl 5-acetyl-2,6-dimethyl-4-(thieno[2,3-c]iiridin-3-yl)-1,4-dihydroiiridine-3carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=9.15 (s, 1H), 9.12 (s, 1H), 8.46 (d, 1H), 7.97 (dd, 1H), 7 .59 (s, 1H), 5.41

- 96 040842 (s, 1H), 3.52 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H), 2.12 (s, 3H).

Example J21: Methyl 5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=9.10 (s, 1H), 8.50 (dd, 1H), 8.40 (dd, 1H), 7.45 (dd, 1H), 7 .35 (s, 1H), 5.36 (s, 1H), 3.52 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H).

Example J22: Methyl 5-acetyl-2-cyclopropyl-4-(5-fluoro-benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.76 (m, 1H), 0.87 (m, 2H), 1.05 (m, 1H), 2.14 (s, 3H), 2 .33 (s, 3H), 2.70 (m, 1H), 3.57 (s, 3H), 5.34 (s, 1H), 7.21 (t, 1H), 7.27 (s, 1H), 7.80 (s, 1H), 7.93 (dd, 1H), 7.96 (s, 1H).

HPLC-MS: retention time 4.645 m/z 234.1 (MH ⁺ ).

The product of the second reaction was isolated by column chromatography.

Example J22-a: Dimethyl 2,6-dicyclopropyl-4-(5-fluorobenzo[b]thiophen-3-yl)-1,4-dihydropyridine 3,5-dicarboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.60 (m, 2H), 0.68 (m, 2H), 1.00 (m, 4H), 2.76 (m, 2H), 3.61 (s, 6H), 5.42 (s, 1H), 5.54 (s, 1H), 7.05 (t, 1H), 7.14 (s, 1H), 7.71 (m , 1H).

HPLC-MS: retention time 5.256; m/z 428.1 (MH ⁺ ).

Example J23: Methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=8.51 (dd, 1H), 8.39 (dd, 1H), 7.95 (s, 1H), 7.44 (dd, 1H), 7 .27 (s, 1H), 5.38 (s, 1H), 3.56 (s, 3H), 2.71 (dd, 1H), 2.34 (s, 3H), 2.14 (s, 3H), 0.84 (t, 4H).

The product of the second reaction was isolated by column chromatography.

Example J23-a: Dimethyl 2,6-dicyclopropyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.57 (q, 2H), 0.83 (m, 2H), 0.91 (t, 2H), 1.04 (q, 2H), 2 .57 (td, 2H), 3.54 (s, 6H), 5.31 (s, 1H), 7.09 (s, 1H), 7.26 (s, 1H), 7.45 (dd, 1H), 8.30 (dd, 1H), 8.52 (m, 1H).

HPLC-MS: retention time 4.848; m/z 411.0 (MH ⁺ ).

Example J24: Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.81 (m, 7H), 1.07 (dt, 1H), 2.14 (m, 1H), 2.28 (s, 3H), 2.74 (m, 1H), 3.57 (s, 3H), 5.49 (s, 1H), 7.14 (s, 1H), 7.31 (t, 1H), 7.36 (t , 1H), 7.90 (m, 2H), 7.98 (d, 1H).

HPLC-MS: retention time 4.670; m/z 260.1 (MH ⁺ ).

Example J25: Methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.84 (m, 3H), 1.05 (m, 1H), 2.15 (s, 3H), 2.34 (s, 3H), 2.70 (ddd, 1H), 3.58 (s, 3H), 5.35 (s, 1H), 7.26 (s, 1H), 7.35 (dd, 1H), 7.94 (d , 1H), 7.97 (s, 1H), 8.08 (d, 1H).

HPLC-MS: retention time 5.312; m/z 402.9 (MH ⁺ ).

The product of the second reaction was isolated by column chromatography.

Example J25-a: Dimethyl 4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=2.28 (s, 6H), 3.50 (s, 6H), 5.26 (s, 1H), 7.33 (s, 2H), 7 .93 (d, 1H), 8.00 (s, 1H), 9.10 (s, 1H).

HPLC-MS: retention time 4.773; m/z 224.1 (MH ⁺ ).

Example J26: Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.82 (m, 3H), 1.05 (dc, 1H), 2.13 (s, 3H), 2.33 (s, 3H), 2.69 (m, 1H), 3.56 (s, 3H), 5.38 (s, 1H), 7.28 (s, 1H), 7.37 (t, 1H), 7.57 (d, 1H ), 7.93 (s, 1H), 8.10 (d, 1H).

HPLC-MS: retention time 5.355; m/z 448.8 (MH ⁺ ).

Example J27: Methyl 5-acetyl-2-cyclopropyl-4-(7-(cyclopropylcarbamoyl)benzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.59 (m, 2H), 0.71 (m, 2H), 0.84 (dd, 4H), 2.10 (s, 3H), 2.33 (s, 3H), 2.68 (m, 1H), 2.88 (m, 1H), 3.55 (s, 3H), 5.40 (s, 1H), 7.21 (s , 1H), 7.47 (m, 1H), 7.86 (d, 1H), 7.89 (s, 1H), 8.23 (d, 1H), 8.63 (d, 1H).

HPLC-MS: retention time 4.354; m/z 451.0 (MH ⁺ ).

Example J28: Methyl 5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.85 (m, 3H), 1.06 (m, 1H), 2.14 (s, 2H), 2.34 (s, 3H), 2 .70 (t, 1H), 3.54 (s, 3H), 5.42 (d, 1H), 7.60 (dd, 1H), 7.38 (s, 1H), 7.91 (d, 1H), 7.98 (s, 1H), 8.42 (dd, 1H).

HPLC-MS: retention time 4.848; m/z 393.0 (MH ⁺ ).

Example J28-a: Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine 3,5-dicarboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.58 (td, 2H), 0.88 (m, 4H), 1.03 (q, 2H), 2.56 (m, 2H), 3.53 (s, 6H),

- 97 040842

5.36 (s, 1H), 7.10 (s, 1H), 7.38 (s, 1H), 7.62 (m, 1H), 7.92 (d, 1H), 8.32 (d , 1H).

HPLC-MS: retention time 5.493; m/z 435.0 (MH ⁺ ).

Example J29: Methyl 5-acetyl-2-cyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-6-methyl1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.76 (m, 1H), 0.87 (m, 2H), 1.06 (dt, 1H), 2.12 (s, 3H), 2 .34 (s, 3H), 2.69 (m, 1H), 3.55 (s, 3H), 3.93 (s, 3H), 5.43 (s, 1H), 7.28 (s, 1H), 7.57 (t, 1H), 7.92 (s, 1H), 8.04 (d, 1H), 8.39 (d, 1H).

HPLC-MS: retention time 4.875; m/z 426.1 (MH ⁺ ).

The product of the second reaction was isolated by column chromatography.

Example J29-a: Dimethyl-2,6-dicyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3,5-dicarboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.56 (td, 2H), 0.87 (m, 4H), 1.05 (td, 2H), 2.57 (m, 2H), 3.53 (s, 6H), 3.93 (s, 3H), 5.38 (s, 1H), 7.06 (s, 1H), 7.27 (s, 1H), 7.58 (t , 1H), 8.05 (d, 1H), 8.30 (d, 1H).

HPLC-MS: retention time 5.520; m/z 468.1 (MH ⁺ ).

Ester functionality on the benzothiophene ring of methyl 5-acetyl-2-cycloiroyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydro-yridine-3-carboxylate (Example J29) hydrolyzed as follows.

Example J30: 3-(3-acetyl-6-cyclopropyl-5-(methoxycarbonyl)-2-methyl-1,4-dihydropyridin-4yl)benzo[b]thiophene-7-carboxylic acid.

A mixture of methyl 5-acetyl-2-cyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate (0.004 g, 0.094 mmol) and 1 M NaOH (0.47 ml, 0.470 mmol) in 1 ml THF was stirred at 40° C. over the weekend. The reaction mixture was diluted with 0.1 M NaOH and washed with DCM. The aqueous layer was cooled to 0° C. and 4 M HCl was added until a solid began to precipitate. Then 1 M HCl was added dropwise until a pH of 2-3 was reached. The precipitate was filtered off, washed with water and purified by column chromatography (DCM/MeOH) to give the title compound (0.0116 g, 30%).

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.83 (m, 2H), 1.06 (m, 2H), 2.12 (s, 3H), 2.34 (s, 3H), 2.69 (m, 1H), 3.56 (s, 3H), 5.43 (s, 1H), 7.24 (s, 1H), 7.54 (t, 1H), 7.91 (s , 1H), 8.01 (d, 1H), 8.34 (d, 1H), 13.46 (s, 1H).

HPLC-MS: retention time 3.039; m/z 410.0 (MH ⁺ ).

Example J31: benzyl 5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

The title compound was prepared by method J.

1H-NMR (400 MHz, DMSO-d6) δ=0.81 (m, 3H), 1.08 (m, 1H), 2.15 (s, 3H), 2.34 (s, 3H), 2 .72 (dt, 1H), 5.06 (d, 2H), 5.41 (s, 1H), 7.17 (dd, 2H), 7.24 (s, 1H), 7.27 (m, 2H), 7.30 (dd, 2H), 8.00 (s, 1H), 8.31 (d, 1H), 8.47 (d, 1H).

HPLC-MS: retention time 4.976; m/z 445.1 (MH ⁺ ).

Example J32: Pyridin-4-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.83 (m, 3H), 1.09 (m, 1H), 2.16 (s, 3H), 2.33 (s, 3H), 2.73 (m, 1H), 5.11 (q, 2H), 5.51 (s, 1H), 7.08 (d, 2H), 7.18 (s, 1H), 7.28 (m , 2H), 7.90 (d, 1H), 8.02 (d, 2H), 8.41 (d, 2H).

HPLC-MS: retention time 4.673; m/z 445.1 (MH ⁺ ).

The product of the second reaction was isolated by column chromatography.

Example J32-a: bis(pyridin-4-ylmethyl)-2,6-dicyclopropyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.62 (m, 2H), 0.86 (dd, 4H) 1.06 (dt, 2H), 2.57 (m, 2H), 5, 08 (m, 4H), 5.42 (s, 1H), 7.06 (d, 4H), 7.19 (dd, 1H), 7.28 (s, 1H), 7.33 (s, 1H ), 8.15 (dd, 1H), 8.40 (d, 4H), 8.46 (dd, 1H).

HPLC-MS: retention time 4.445; m/z 565.2 (MH ⁺ ).

Example J33: Pyridin-4-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=2.15 (s, 3H), 2.31 (d, 6H), 5.06 (dd, 2H), 5.43 (s, 1H), 7 .00 (d, 2H), 7.24 (t, 1H), 7.39 (s, 1H), 7.53 (d, 1H), 8.08 (d, 1H), 8.38 (d, 2H), 9.18 (s, 1H).

HPLC-MS: retention time 4.799; m/z 497.0 (MH ⁺ ).

Example J34: Pyridin-4-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.86 (m, 3H), 1.09 (dd, 1H), 2.18 (s, 3H), 2.34 (s, 3H), 2.75 (ddd, 1H), 5.11 (d, 2H), 5.44 (s, 1H), 7.05 (d, 2H), 7.30 (s, 1H), 7.32 (dd , 1H), 7.94 (d, 1H), 8.07 (s, 1H), 8.10 (d, 1H), 8.40 (d, 2H).

HPLC-MS: retention time 5.002; m/z 479.0 (MH ⁺ ).

Example J35: Pyridin-4-ylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.86 (m, 3H), 1.10 (m, 1H), 2.18 (s, 3H), 2.35 (s, 3H), 2 .75 (t, 1H), 5.08

- 98 040842 (dd, 2H), 5.50 (s, 1H), 7.03 (d, 2H), 7.42 (s, 1H), 7.46 (t, 1H), 7.87 (d , 1H), 8.08 (s, 1H), 8.39 (dd, 3H).

HPLC-MS: retention time 4.603; m/z 470.1 (MH ⁺ ).

Example J36: iiridin-4-ylmethyl-5-acetyl-2-cycloiroyl-6-methyl-4-(thieno[2,3-b]iiridin-3-yl)1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.85 (dt, 3H), 1.10 (m, 1H), 2.18 (s, 2H), 2.34 (s, 2H), 2 .75 (dd, 1H), 5.10 (dd, 2H), 5.45 (s, 1H), 7.06 (d, 2H), 7.32 (m, 2H), 8.06 (s, 1H), 8.36 (d, 1H), 8.40 (d, 2H), 8.48 (d, 1H).

HPLC-MS: retention time 3.943; m/z 446.1 (MH ⁺ ).

Example J37: benzyl 5-acetyl-2-cycloiroyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-6-methyl 1,4-dihydropyridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.80 (dd, 3H), 1.08 (d, 1H), 2.13 (s, 3H), 2.34 (s, 3H), 2 .71 (t, 1H), 3.93 (s, 3H), 5.05 (s, 2H), 5.47 (s, 1H), 7.18 (d, 2H), 7.26 (s, 4H), 7.42 (t, 1H), 8.00 (m, 2H), 8.32 (d, 1H).

HPLC-MS: retention time 5.546; m/z 502.2 (MH ⁺ ).

The product of the second reaction was isolated by column chromatography.

Example J37-a: Dibenzyl-2,6-dicycloiroyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3,5-dicarboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.55 (dd, 2H), 0.82 (dd, 4H), 1.05 (m, 2H), 2.57 (m, 2H), 3.93 (s, 3H), 5.01 (q, 4H), 5.44 (s, 1H), 7.15 (d, 4H), 7.26 (m, 8H), 7.99 (d , 1H), 8.12 (d, 1H).

HPLC-MS: retention time 6.574; m/z 621.3 (MH ⁺ ).

Example J38: benzyl 5-acetyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydro-yridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=2.11 (s, 3H), 2.28 (s, 3H), 2.32 (s, 3H), 3.92 (s, 3H), 5 .00 (s, 2H), 5.44 (s, 1H), 7.14 (d, 2H), 7.24 (d, 3H), 7.33 (s, 1H), 7.41 (dd, 1H), 8.00 (d, 1H), 8.33 (d, 1H), 9.12 (s, 1H).

HPLC-MS: retention time 5.546; m/z 502.2 (MH ⁺ ).

Example J39: methyl 3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydro-iiridin-4-yl)benzo[b]thiophene-7carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=2.16 (s, 6H), 2.31 (s, 6H), 3.92 (s, 3H), 5.52 (s, 1H), 7 .34 (s, 1H), 7.55 (t, 1H), 8.03 (d, 1H), 8.50 (d, 1H), 9.13 (s, 1H).

HPLC-MS: retention time 4.224; m/z 384.1 (MH ⁺ ).

Example J40: 3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydro-iiridin-4-yl)benzo[b]thiophene-7-carbonitrile.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=2.17 (s, 5H), 2.32 (s, 5H), 5.52 (s, 1H), 7.43 (s, 1H), 7.59 (m, 1H), 7.90 (d, 1H), 8.54 (d, 1H), 9.19 (s, 1H).

HPLC-MS: retention time 4.212; m/z 351.1 (MH ⁺ ).

Example J41: iiridin-4-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cycloiroyl-6-methyl1,4-dihydro-iiridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.85 (m, 3H), 1.09 (t, 1H), 2.16 (s, 3H), 2.34 (s, 3H), 2 .73 (m, 1H), 5.10 (d, 2H), 5.45 (s, 1H), 7.05 (d, 2H), 7.24 (m, 1H), 7.31 (s, 1H), 7.54 (d, 1H), 8.06 (m, 2H), 8.40 (d, 2H).

HPLC-MS: retention time 5.143; m/z 523.1 (MH ⁺ ).

Example J42: 4-fluorobenzyl-5-acetyl-2-cycloiroyl-6-methyl-4-(thieno[2,3-b]iiridin-3-yl)-1,4dihydroiiridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.80 (m, 8H), 1.05 (d, 3H), 2.15 (s, 7H), 2.33 (s, 8H), 5 .04 (q, 5H), 5.39 (d, 2H), 7.08 (t, 4H), 7.24 (m, 7H), 7.30 (dd, 3H), 7.99 (s, 2H), 8.29 (dd, 2H), 8.48 (dd, 2H).

HPLC-MS: retention time 5.056; m/z 463.1 (MH ⁺ ).

The product of the second reaction was isolated by column chromatography.

Example J42-a: bis(4-fluorobenzyl)-2,6-dicycloiroyl-4-(thieno[2,3-b]iiridin-3-yl)-1,4dihydroiridin-3,5-dicarboxylate.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=0.57 (dd, 2H), 0.82 (m, 6H), 1.02 (d, 2H), 5.01 (d, 4H), 5.34 (d, 1H), 7.19 (m, 8H), 8.05 (dd, 2H), 8.46 (m, 2H).

HPLC-MS: retention time 6.223; m/z 599.2 (MH ⁺ ).

Example J43: 4-cyanobenzyl-5-acetyl-2-cycloiroyl-6-methyl-4-(thieno[2,3-b]iiridin-3-yl)-1,4dihydroiiridine-3-carboxylate.

1H-NMR (400 MHz, DMSO-d6) δ=0.83 (m, 3H), 1.09 (m, 1H), 2.16 (s, 3H), 2.34 (s, 3H), 2 .73 (m, 1H), 5.14 (dd, 2H), 5.41 (s, 1H), 7.31 (m, 4H), 7.70 (d, 2H), 8.03 (s, 1H), 8.32 (d, 1H), 8.47 (d, 1H).

HPLC-MS: retention time 4.766; m/z 470.1 (MH ⁺ ).

Way K.

Example K1: Methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydro-iridine-3-carboxylate hydrochloride.

- 99 040842

To a mixture of methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate (0.07 g, 0.20 mmol) in DCM /MeOH (1:1, 2 ml), 2 M HCl in ether (0.21 ml, 0.40 mmol) was added dropwise at 0°C. The mixture was allowed to warm to RT and stirred at RT overnight. The solvent was removed under reduced pressure and the remaining solid was washed with ether and dichloromethane to give a white solid (0.055 g, 71%). Calculated C ₁₈ H ₁₉ ClN ₂ O ₃ S (378.08): C, 57.06; H, 5.06; N, 7.39; S, 8.46. Found: C, 56.14; H,5.25; N7.05; S,8,22.

1H-NMR (300 MHz, DMSO-d ₆ ) δ=12.36 (s, 1H), 10.27 (s, 1H), 9.60 (s, 1H), 8.06 (d, J=8 .0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.63-7.40 (m, 2H), 7.40-7.14 (m, 1H), 4 .98 (s, 1H), 4.34 (s, 1H), 3.81 (s, 3H), 2.44 (s, 3H), 2.17 (s, 3H).

Example K2: Methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate trifluoromethanesulfonate.

The title compound as a white solid (0.091 g, 89%) was obtained by method K. Calcd C ₁₉ H ₁₉ F ₃ N ₂ O ₆ S ₂ (492.06): C, 46.34; H, 3.89; N, 5.69; S, 13.02. Found: C 46.28; H, 4.21; N, 5.53; S, 13.15.

1H-NMR (300 MHz, DMSO-d ₆ ) δ=11.67 (s, 1H), 10.04 (s, 1H), 9.34 (s, 1H), 8.06 (d, J=8 .0 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.65-7.46 (m, 2H), 7.41-7.17 (m, 1H), 4 .99 (s, 1H), 4.24 (s, 1H), 3.81 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H).

Method L.

Example L1: 4-(pyrudin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate.

Mixture of 4-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate (0.030 g, 0.06 mmol) , pyridin-4-ylboronic acid (0.011 g, 0.09 mmol), tetrakis(triphenylphosphine)palladium (0.003 g, 0.003 mmol) and potassium carbonate (0.019 g, 0.18 mmol) in DME:H ₂ O (3: 1, 1 ml) was heated at 110° C. for 3 h. The mixture was allowed to cool to RT, filtered through celite, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol 2%) to give a yellow solid (0.036 g, 61%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.67 (s, 2H), 8.45 (dd, J=4.5, 1.6 Hz, 1H), 8.32 (dd, J=8 .2, 1.6 Hz, 1H), 7.54-7.47 (m, 4H), 7.25-7.17 (m, 3H), 7.13 (dd, J=8.2, 4 .6 Hz, 1H), 6.48 (br. s, 1H), 5.48 (s, 1H), 5.09 (q, J=15.0 Hz, 2H), 2.36 (s, 6H ), 2.16 (s, 3H).

HRMS (IE) m/z calculated C ₂₉ H ₂₅ N ₃ O ₃ S [M ⁺ ]: 495.1617, found: 495.1636.

The following examples were prepared by method L.

Example L2: 4-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate.

Yellow solid (0.025 g, 51%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.83 (s, 1H), 8.65-8.54 (m, 1H), 8.45 (dd, J=4.6, 1.6 Hz , 1H), 8.33 (dd, J=8.2, 1.6 Hz, 1H), 7.87 (dt, J=8.0, 1.8 Hz, 1H), 7.50-7, 43 (m, 2H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 7.26-7.20 (m, 2H), 7.18 (s, 1H), 7 .15 (dd, J=8.2, 4.6 Hz, 1H), 6.61 (s, 1H), 5.48 (s, 1H), 5.12 (k, J=15.0 Hz, 2H), 2.36 (s, 3H), 2.36 (s, 3H), 2.16 (s, 3H).

HRMS (IE) m/z calculated C ₂₉ H ₂₅ N ₃ O ₃ S [M ⁺ ]: 495.1617, found: 495.1619.

Example L3: 3-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate.

Yellow solid (0.037 g, 78%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.65 (d, J=4.8 Hz, 2H), 8.42 (dd, J=4.8, 1.6 Hz, 1H), 8, 31 (dd, J=8.2, 1.6Hz, 1H), 7.55 (dt, J=7.7, 1.5Hz, 1H), 7.46-7.33 (m, 4H) , 7.22 (dt, J=7.7, 1.5 Hz, 1H), 7.17 (s, 1H), 7.14-7.05 (m, 1H), 6.76 (s, 1H ), 5.48 (s, 1H), 5.23-5.04 (m, 2H), 2.36 (s, 3H), 2.35 (s, 3H), 2.15 (s, 3H) .

HRMS (IE) m/z calculated C29H25N3O3S [M ⁺ ]: 495.1566, found: 495.1541.

Example L4: 3-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate.

Yellow solid (0.26 g, 62%).

- 100 040842

1H-NMR (300 MHz, CDCl ₃ ) δ=8.77 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.42 (dd, J=4.9, 1 .6 Hz, 1H), 8.31 (dd,

J=8.2, 1.6Hz, 1H), 7.77(dt, J=7.9, 1.9Hz, 1H), 7.49(dt, J=7.7, 1.5Hz , 1H), 7.43-7.32 (m, 3H), 7.20 (dt, J=7.5,

1.5 Hz, 1H), 7.17 (s, 1H), 7.10 (dd, J=8.2, 4.5 Hz, 1H), 6.62 (s, 1H), 5.47 ( s, 1H), 5.15 (k, J=12.5 Hz, 2H), 2.36 (s, 3H), 2.35 (s, 3H), 2.14 (s, 3H).

HRMS (IE) m/z calculated C ₂₉ H ₂₅ N ₃ O ₃ S [M ⁺ ]: 495.1566, found: 495.1565.

Example L5: 2-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate.

Yellow solid (0.023 g, 45%).

1H-NMR (300 MHz, CDCl,) δ=8.75 (s, 1H), 8.52 (s, 1H), 8.41 (dd, J=4.6, 1.6 Hz, 1H), 8.13 (dd, J=8.2, 1.6 Hz, 1H), 7.54 (d, J=5.3 Hz, 1H), 7.48-7.31 (m, 2H), 7 .19 (dd, J=7.3, 1.6 Hz, 1H), 7.13 (s, 1H), 7.08-6.94 (m, 3H), 6.37 (s, 1H), 5.36 (s, 1H), 4.97 (k, J=7.3 Hz, 2H), 2.35 (s, 3H), 2.29 (s, 3H), 2.15 (s, 3H ).

HRMS (IE) m/z calculated C ₂₉ H ₂₆ N ₃ O ₃ S [M ⁺¹ ]: 496.1689, found: 496.1689.

Example L6: 2-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate.

Yellow solid (0.018 g, 48%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.53 (s, 1H), 8.42 (dd, J=4.7, 1.6 Hz, 2H), 8.16 (dd, J=8 .2, 1.6 Hz, 1H), 7.45-7.27 (m, 4H), 7.25-7.16 (m, 2H), 7.14 (s, 1H), 7.09- 6.94 (m, 1H), 6.42 (s, 1H), 5.38 (s, 1H), 4.97 (q, J=12 Hz, 2H), 2.35 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H).

HRMS (IE) m/z calculated C ₂₉ H ₂₆ N ₃ O ₃ S [M ⁺¹ ]: 496.1689, found: 496.1687.

Example L7: [3,4'-bipyridin]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridin-3- carboxylate.

Yellow solid (0.025 g, 64%).

1H-NMR (300 MHz, CDC13) δ=8.81-8.68 (m, 3H), 8.58-8.52 (m, 1H), 8.42 (dd, J=4.6, 1 .6 Hz, 1H), 8.32 (dd, J=8.2, 1.6 Hz, 1H), 7.60 (t, J=2.2 Hz, 1H), 7.37 (d, J =5.2 Hz, 2H), 7.17 (s, 1H), 7.14 (dd, J=8.2, 4.6 Hz, 1H), 6.38 (s, 1H), 5.46 (s, 1H), 5.17 (k, J=12 Hz, 2H), 2.36 (s, 6H), 2.16 (s, 3H).

HRMS (IE) m/z calculated C ₂₈ H ₂₄ N ₄ O ₃ S [M ⁺ ]: 496.1569, found: 496.1556.

Example L8: [3,3'-bipyridin]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridin-3- carboxylate.

Yellow solid (0.022 g, 57%).

1H-NMR (300 MHz, CDC13) δ=8.77-8.62 (m, 3H), 8.55-8.50 (m, 1H), 8.41 (dd, J=4.6, 1 .6 Hz, 1H), 8.33 (dd, J=8.2, 1.6 Hz, 1H), 7.73 (dt, J=8.1, 1.8 Hz, 1H), 7.56 (t, J=2.1 Hz, 1H), 7.43 (dd, J=8.0, 4.8 Hz, 1H), 7.17 (s, 1H), 7.14 (dd, J= 8.2, 4.6 Hz, 1H), 6.54 (s, 1H), 5.45 (s, 1H), 5.26-5.04 (m, 2H), 2.36 (s, 6H ), 2.15 (s, 3H).

HRMS (IE) m/z calculated C ₂₈ H ₂₄ N ₄ O ₃ S [M ⁺ ]: 496.1569, found: 496.1580.

Example L9: [2,4'-bipyridin]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridin-3- carboxylate.

Yellow solid (0.014 g, 23%).

1H-NMR (300 MHz, CDCI3) δ=8.73 (d, J=5.1 Hz, 2H), 8.59 (d, J=2.2 Hz, 1H), 8.44 (dd, J =4.6, 1.6 Hz, 1H), 8.31 (dd, J=8.2, 1.6 Hz, 1H), 7.92-7.86 (m, 2H), 7.61 ( d, J=8.1 Hz, 1H), 7.40 (dd, J=8.1, 2.2 Hz, 1H), 7.18 (s, 1H), 7.14 (dd, J=8 .2, 4.6 Hz, 1H), 6.38 (s, 1H), 5.45 (s, 1H), 5.26-5.01 (c, J=15 Hz, 2H), 2.36 (s, 6H), 2.16 (s, 3H).

HRMS (IE) m/z calculated C ₂₉ H ₂₅ N ₃ O ₃ S [M ⁺ ]: 496.1569, found: 496.1563.

Example L10: [2,3'-bipyridin]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridin-3- carboxylate.

Yellow solid (0.032 g, 72%).

1H-NMR (300 MHz, CDC13) δ=9.19 (s, 1H), 8.78-8.63 (m, 1H), 8.59 (d, J=2.3 Hz, 1H), 8 .45 (dd, J=4.6, 1.6 Hz, 1H), 8.31 (dt, J=8.0, 1.6 Hz, 2H), 7.59 (dd, J=8.0 , 0.9 Hz, 1H), 7.47-7.36 (m, 2H), 7.18 (s, 1H), 7.17-7.11 (m, 1H), 6.31 (s, 1H), 5.45 (s, 1H), 5.22-5.04 (q, J=12 Hz, 2H), 2.36 (s, 6H), 2.15 (s, 3H).

HRMS (Ie) m/z calculated C ₂₈ H ₂₄ N ₄ O ₃ S [M ⁺ ]: 496.1569, found: 496.1563.

Example L11: [2,3'-bipyridin]-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridin-3- carboxylate.

Yellow solid (0.040 g, 82%).

1H-NMR (300 MHz, CDC13) δ=9.11-9.01 (m, 1H), 8.64 (dd, J=5.0, 1.5 Hz, 1H), 8.56 (dd, J=5.0, 0.9Hz, 1H), 8.43(dt, J=4.6, 1.2Hz, 1H), 8.36(dt, J=8.2, 1.2Hz , 1H), 8.16 (dc, J=8.0, 1.5, 1.0 Hz, 1H), 7.46-7.37 (m, 2H), 7.21 (s, 1H), 7.15 (ddd, J=8.2, 4.6, 0.9 Hz, 1H), 6.96 (dt, J=5.1, 1.2 Hz, 1H), 6.76 (s, 1H), 5.51 (s, 1H), 5.27-5.03 (q, J=15 Hz, 2H), 2.38 (d, J=0.9 Hz, 3H), 2.37- 2.35 (m, 3H), 2.17 (d, J=1.0 Hz, 3H).

HRMS (IE) m/z calculated C ₂₈ H ₂₄ N ₄ O ₃ S [M ⁺ ]: 496.1569, found: 496.1570.

Example L12: [2,4'-bipyridin]-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridin-3- carboxylate.

Yellow solid (0.024 g, 50%).

1H-NMR (300 MHz, CDCl ₃ ) δ=8.78-8.62 (m, 2H), 8.57 (d, J=5.0 Hz, 1H), 8.44 (dd, J=4 .6, 1.6 Hz, 1H), 8.36 (dd, J=8.2, 1.6 Hz, 1H), 7.84-7.66 (m, 2H), 7.45 (s, 1H), 7.21 (s, 1H), 7.15 (dd, J=8.2, 4.6 Hz, 1H), 7.00 (dd,

- 101 040842

J=5.0, 1.5Hz, 1H), 6.60(s, 1H), 5.52(s, 1H), 5.12(k, J=12Hz, 2H), 2.39( s, 3H), 2.37 (s, 3H), 2.19 (s, 3H).

HRMS (IE) m/z calculated C28H24N4O3S [M ⁺ ]: 496.1569, found: 496.1545.

Example L13: Methyl-5-acetyl-2-cyclopropyl-6-methyl-4-(7-(pyridin-4-yl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.018 g, 64%) was obtained by method L using dioxane/water 3:1.

1H-NMR (300 MHz, CDCl ₃ ) δ=8.72 (br. s, 2H), 8.21 (dd, J=8.2, 1.1 Hz, 1H), 7.69-7.59 (m, 2H), 7.53 (t, J=7.7 Hz, 1H), 7.42-7.35 (m, 1H), 7.15 (s, 1H), 5.72 (br. s, 1H), 5.52 (s, 1H), 3.69 (s, 3H), 2.61 (tt, J=8.6, 5.7 Hz, 1H), 2.37 (s, 3H ), 2.16 (s, 3H), 0.98 (dtk, J=17.6, 8.6, 4.1 Hz, 2H), 0.79-0.56 (m, 2H).

HRMS (IE) m/z calculated C ₂₆ H ₂₄ N ₂ O ₃ S [M ⁺ ]: 444.1508, found: 444.1526.

Example L14: Methyl 5-acetyl-2-cyclonronyl-4-(7-cyclopropylbenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate.

The title compound as a yellow solid (0.030 g, 66%) was obtained by method L using toluene/water 19:1.

1H-NMR (300 MHz, CDCl3) δ=7.92 (d, J=8.1 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.11 (s, 1H ), 6.96 (d, J=7.7 Hz, 1H), 5.63 (br.s, 1H), 5.47 (s, 1H), 3.67 (d, J=1.4 Hz , 3H), 2.59 (tt, J=8.6, 5.7 Hz, 1H), 2.36 (s, 3H), 2.13 (s, 3H), 2.11-2.03 ( m, 1H), 1.07-0.86 (m, 4H), 0.85-0.75 (m, 2H), 0.73-0.57 (m, 2H).

HRMS (IE) m/z calculated C ₂₄ H ₂₅ NO ₃ S [M ⁺ ]: 407.1555, found: 407.1551.

Example L15: 3-(pyridin-4-yl)benzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3yl)-1,4-dihydropyridine-3- carboxylate.

The title compound was obtained as a yellow solid (0.018 g, 42%) by Method L.

1 H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.66 (d, J=4.7 Hz, 2H), 8.44 (dd, J=4.7, 1.4 Hz , 1H), 8.29 (dd, J=8.2, 1.4 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.46 (s, 1H), 7 .44-7.35 (m, 3H), 7.23 (d, J=1.4 Hz, 1H), 7.14-7.06 (m, 2H), 5.79 (br.s, 1H ), 5.49 (s, 1H), 5.24-5.10 (m, 2H), 2.71-2.55 (m, 1H), 2.35 (s, 3H), 2.14 ( s, 3H), 1.01-0.84 (m, 2H), 0.80-0.55 (m, 2H).

HRMS (IE) m/z calculated C ₃₁ H ₂₇ N ₃ O ₃ S [M ⁺ ]: 521.1773, found: 521.1783.

HPLC (95.0%): retention time 31.35 min.

M method.

Example M1: 1,1'-(2,6-dimethyl-4-(5-(pyridin-3-yl)benzo[b]myophen-3-yl)-1,4-dihydropyridine-3,5diyl)diethanone.

To a mixture of 1,1'-(4-(5-bromobenzo[b]myophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5-diyl)diethanone (53 mg, 0.13 mmol), 3-pyridylboronic acid (24.8 mg, 0.20 mmol) and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (4.6 mg, 0.0056 mmol) in dry DCM (3 ml) under nitrogen atmosphere at RT was added dropwise an aqueous solution of 2 M Cs ₂ CO ₃ (0.40 mmol). The mixture was then heated at reflux for 24 hours under N2, cooled to RT, filtered to remove the catalyst, and concentrated in vacuo. The title compound was obtained using column chromatography.

1H-NMR (400 MHz, DMSO-d6) δ=2.20 (s, 6H), 2.32 (s, 6H), 5.60 (s, 1H), 7.30 (s, 1H), 7 .56 (dd, 1H), 7.68 (dd, 1H), 8.02 (d, 1H), 8.13 (dd, 1H), 8.52 (d, 1H), 8.61 (s, 1H), 8.97 (s, 1H), 9.17 (s, 1H).

HPLC-MS: retention time 3.645 min, m/z 403.1 (MH ⁺ ).

Method N.

Example N1: methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-phenylbenzo[b]thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate.

A mixture of methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate (0.050 g, 0.11 mmol), tributyl( phenyl)stannane (0.073 ml, 0.22 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.008 g, 0.011 mmol) in toluene (2 ml) were heated at 90°C for 12 h. The mixture was allowed to cool to RT , filtered through celite, concentrated and purified by column chromatography (hexane:ethyl acetate 5:1) to give a yellow solid

- 102 040842 (0.025 g, 50%).

1H-NMR (300 MHz, CDCI3) δ=8.15-8.06 (m, 1H), 7.72-7.64 (m, 2H), 7.53-7.29 (m, 5H), 7.12 (s, 1H), 5.62 (s, 1H), 5.51 (s, 1H), 3.70 (s, 3H), 2.61 (tt, J=8.7.5, 7 Hz, 1H), 2.37 (s, 3H), 2.17 (s, 3H), 1.03-0.84 (m, 2H), 0.74-0.57 (m, 2H).

HRMS (IE) m/z calculated C ₂₇ H ₂₅ NO ₃ S [M ⁺ ]: 443.1555, found: 443.1557.

Abbreviation list

In the present description, the following abbreviations have been used:

ACN: acetonitrile;

Ac: acetyl;

Dba: dibenzylideneacetone;

DCM: dichloromethane;

DIBAL: diisobutylaluminum hydride;

DIPEA: N,N-diisopropylethylamine;

DMAP: 4-dimethylaminopyridine;

DME: 1,2-dimethoxyethane;

DMEM: Dulbecco's Modified Eagle's Medium;

DMF: dimethylformamide;

DMSO: dimethyl sulfoxide;

dppf: 1,1'-bis(diphenylphosphino)ferrocene;

EDTA: ethylenediaminetetraacetic acid;

ESI: electrospray ionization;

EtOH: ethanol;

FBS: fetal bovine serum;

HBSS: Hanks' balanced solution;

HOBT: benzotriazol-1-ol;

HPLC: high performance liquid chromatography;

HRMS: high resolution mass spectrometry;

IE: electron ionization;

and-PrOH: isopropanol;

MeOH: methanol;

MS4A: 4A molecular sieves;

MW: molecular weight;

NMP: N-methylpyrrolidone;

NMR: nuclear magnetic resonance;

PEL polyethyleneimine;

Ph: phenyl;

PPA: polyphosphoric acid;

RT: room temperature;

Rt: holding time;

tBut: tert-butyl;

TES: N-[tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran.

The following are specific embodiments of the present invention:

Embodiment 1 is a compound of formula (I) wherein R ¹ is a group selected from:

a) -COR ⁵ ,

b) -COOR ⁵ ,

c) -CN,

d) -CHO,

R ⁵ is a group selected from:

a) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from -N(R ⁶ )R ⁷ and -OR ⁶ ,

- 103 040842

b) C ₃ -C ₆ -cycloalkyl,

R ² is a group selected from:

a) -COOR ⁸ ,

b) -COR ⁸ ,

c) -C(O)N(R ⁸ )R ⁹ ,

d) -CN,

e) -S(O) _n R ⁸ where n is an integer from 1 to 2,

R ⁸ and R ⁹ are independently selected from:

a) linear or branched C ₁ -C _b -alkyl, optionally substituted with 1, 2 or 3 substituents selected from A ¹ or B ² ,

b) group A ¹ ,

c) a hydrogen atom, or

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5-6 membered heterocycle optionally containing 1 heteroatom selected from O and N, and said heterocycle is optionally substituted with 1 or 2 groups independently selected from linear or branched C ₁ -C4-alkyl,

R ³ is a group selected from:

a) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from a halogen atom, -N(R ⁶ )R ⁷ and -OR ⁶ ,

b) C ₃ -C ₆ -cycloalkyl, optionally substituted by a halogen atom,

c) a hydrogen atom,

d) -NH2,

e) -CN,

R ⁴ is a group selected from:

a) groups A ¹ ,

b) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from A ¹ or B ² ,

c) -N(R ⁶ )R ⁷ ,

d) -CN,

f) a hydrogen atom,

R ¹ and R ³ together form the group -(CR ¹⁰ R ¹¹ ) _n -, where n is an integer from 3 to 4, where 1, 2 or 3 residues -CR ¹⁰ R11 can be independently substituted with a group selected from -O-, -NR ¹² -, -S- and -C(=O)-, and where R ¹⁰ , R ¹¹ and R ¹² are independently selected from a hydrogen atom, R ⁶ , -C(=O)R ⁶ , phenyl or 5-6 -membered heteroaryl group, where the specified phenyl or heteroaryl group is optionally substituted by -R ⁶ or a halogen atom;

R ² and R ⁴ together form the group -(CR ¹⁰ R ¹¹ ) _n -, where n is an integer from 3 to 4, where 1, 2 or 3 residues -CR ¹⁰ R ¹¹ - can be independently substituted with a group selected from -O -, -NR ¹² -, -S- and -C(=O) and where R ¹⁰ , R ¹¹ and R ¹² are independently selected from a hydrogen atom, -R ⁶ , -C(=O)R ⁶ , phenyl or 5- a 6-membered heteroaryl group, wherein said phenyl or heteroaryl group is optionally substituted with -R ⁶ or a halogen atom;

X ¹ , X ² , X ³ , X ⁴ and X ⁵ are independently selected from C-B ¹ , N and C-H,

And ¹ is chosen from:

a) C ₃ -C ₆ -cycloalkyl ring, optionally substituted with 1, 2 or 3 substituents selected from =O and B ³ ;

b) a 3-6 membered saturated heterocyclyl ring containing 1, 2 or 3 heteroatoms selected from O, S and N, and the ring of which is optionally substituted with 1, 2 or 3 substituents selected from =O and B ³ ;

c) a phenyl or 5-6 membered heteroaryl group, any of which is optionally substituted

1, 2 or 3 substituents selected from B ¹ ;

each B ¹ is independently selected from a halogen atom, 5-6 membered heteroaryl, linear or branched C1-C6 alkyl, -CN, -N(R ⁶ )R ⁷ , -OR ⁶ , -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )R ⁷ , -OC(=O)-R ⁶ , -N(R ⁶ )C(=O)R ⁷ , -NR ⁷ SO2R ⁶ , -SO2N(R ⁶ )R ⁷ , -SR ⁶ , -S(O)R ⁶ and -S(O)2R ⁶ each B ² is independently selected from a halogen atom, -CN, -N(R ⁶ ) R ⁷ , -OR ⁶ , -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )R ⁷ , -OC(=O)-R ⁶ , - N(R ⁶ )C(=O)R ⁷ , -NR ⁷ SO2R ⁶ , -SO2N(R ⁶ )R ⁷ , -SR ⁶ , -S(O)R ⁶ , -S(O)2R ⁶ , each B ³ is independently selected from halogen, linear or branched C ₁ -C ₆ alkyl, -CN, -N(R ⁶ )R ⁷ , -OR ⁶ , -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )R ⁷ , -OC(=O)-R ⁶ , -N(R ⁶ )C(=O)R ⁷ , -NR ⁷ SO2R ⁶ , -SO2N(R ⁶ )R ⁷ , -SR ⁶ , -S(O)R ⁶ , -S(O)2R ⁶ , R ⁶ and R ⁷ are each independently:

hydrogen atom, linear or branched C ₁ -C ₁₂ -alkyl, C ₃ -C ₆ -cycloalkyl and C ₄ -C ₆ heterocycloalkyl, optionally substituted with 1, 2 or 3 substituents selected from =O (oxo group), halogen atom, hydroxy group, phenyl, C ₃ -C ₆ -cycloalkyl, linear or branched C ₁ -C ₆ -alkoxy group, amino group, alkylamino group, dialkylamino group, linear or branched C ₁ -C ₆ -alkylcarbonyl group,

- 104 040842 phenyl or 5-6 membered heteroaryl group optionally substituted with 1, 2 or 3 substituents selected from halogen atom, cyano group, linear or branched C ₁ -C ₆ -alkyl, linear or branched C ₁ -C ₆ haloalkyl , hydroxy, linear or branched C ₁ C ₆ alkoxy, amino, alkylamino, dialkylamino;

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 3-8 membered ring optionally containing an additional heteroatom selected from O, N and S and where the ring is optionally substituted with 1, 2 or 3 substituents selected from ═O (oxo), linear or branched C ₁ C ₆ alkyl, linear or branched C ₁ -C ₆ haloalkyl, linear or branched C ₁ -C ₆ alkylcarbonyl;

if R ¹ is -COOR ⁵ and R ² is -COOR ⁸ , then R ⁴ is not a methyl group, and their pharmaceutically acceptable salts.

Embodiment 2: The compound of Embodiment 1 wherein X ¹ , X ² , X ³ and X ⁵ are CH or C-B ¹ , where B ¹ is a halogen atom.

Embodiment 3: The compound of Embodiment 2 wherein X ⁴ is a group selected from C-B ¹ and N.

Embodiment 4: The compound of Embodiment 3 wherein B ¹ is selected from the group -CN and a halogen atom.

Embodiment 5: A compound according to any one of Embodiments 2-4, wherein R ¹ is a group selected from -COR ⁵ , -COOR ⁵ , and a -CN group.

Embodiment 6: The compound of Embodiment 5, where R ⁵ is selected from:

C ₁ -C ₃ -alkyl, and

C ₃ -C ₆ -cycloalkyl,

Embodiment 7: A compound according to any one of Embodiments 2-6, wherein R ² is -COOR ⁸ .

Embodiment 8: The compound of Embodiment 7, wherein R ⁸ is independently:

linear or branched C ₁ -C ₆ alkyl optionally substituted with 1, 2 or 3 substituents selected from A ¹ , or an A ¹ group representing C ₃ -C ₆ cycloalkyl optionally substituted with 1, 2 or 3 substituents selected from from the group consisting of fluorine atoms and C ₁ -C ₃ -alkyl groups.

group A ¹ representing a 3-6-membered saturated heterocyclyl ring containing 1, 2 or 3 heteroatoms selected from O, S and N, and where the ring is optionally substituted with 1, 2 or 3 C ₁ -C ₃ alkyl groups.

Embodiment 9: A compound according to any one of Embodiments 2-8, wherein R ³ is a group selected from linear or branched C ₁ -C ₄ alkyl and C ₃ -C ₆ cycloalkyl.

Embodiment 10: A compound according to any one of Embodiments 2-9, wherein R ⁴ is a group selected from:

linear or branched C ₁ -C ₃ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from A ¹ or B ² , group A ¹ representing C ₃ -C ₆ -cycloalkyl,

-N(R ⁶ )R ⁷ where R ⁶ and R ⁷ are independently selected from a hydrogen atom and a linear or branched C ₁ C ₃ -alkyl, cyano group.

Embodiment 11: The compound of Embodiment 1 wherein X ¹ , X ² , X ³ and X ⁵ are -CH, X ⁴ is C-B ¹ where B ¹ is a -CN group or a bromine atom, R ¹ is a group selected from -C(O)CH3, -C(O)OCH3 and CN, R ² is a group selected from -C(O)OCH3 and C(O)OCH ₂ -cyclopropyl, R ³ is a group selected from from linear or branched C1-C3 alkyl and C3-C4 cycloalkyl, and R ⁴ is a group selected from linear or branched C1-C ₃ alkyl, C ₃ -C ₄ cycloalkyl and -NH2.

Embodiment 12: The compound of Embodiment 1 wherein X ¹ , X ² , X ³ and X ⁵ are -CH, X ⁴ is nitrogen, R ¹ is a group selected from -C(O)CH3, -C (O)OCH3 and CN, R ² is a group selected from -C(O)OCH3 and C(O)OCH ₂ -cyclopropyl, R ³ is a group selected from linear or branched C1-C3 alkyl and C3-C4- cycloalkyl, and R ⁴ is a group selected from linear or branched C 1 -C ₃ -alkyl, C ₃ -C ₄ -cycloalkyl and -NH 2 .

Embodiment 13: The compound of Embodiment 1 selected from the group consisting of:

- 105 040842

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3-carboxylate (enantiomer 1)

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3-carboxylate (enantiomer 2)

5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxamide

-(4-(benzo[b]thiophen-3-yl)-5-benzoyl-2,6-dimethyl-1,4-dihydropyridin-3-yl)ethan1-one

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-phenyl-1,4-dihydropyridine-3-carboxylate

3-acetyl-4-(benzo[b]thiophen-3-yl)-2,7,7-trimethyl-4,6,7,8-tetrahydro-quinolin5(1Н)-one

1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-nicotinoyl-1,4-dihydro-pyridin-3yl)ethan-1-one

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydro-[2,3'-bipyridine]-3carboxylate

2,2,2-trifluoroethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid

-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(4-methylpiperazin-1-carbonyl)-1,4dihydropyridine in-3-yl)ethan-1-one

5-acetyl-4-(benzo[b]thiophen-3-yl)-X, X-diethyl-2,6-dimethyl-1,4-dihydropyridine-3-carboxamide

1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(morpholine-4-carbonyl)-1,4d in-3-yl)ethan-1-one hydropyride

2-methoxyethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyride in3-carboxylate

3-acetamide opropyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Benzyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3-carboxylate

2-morpholinoethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

2-(dimethylamino)ethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine in-3-carboxylate

2-acetamidoethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(methoxymethyl)-6-methyl-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-((dimethylamino)methyl)-6-methyl-1,4dihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4d and hydropyride in-3-carboxylate

4-methoxybenzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

5-(benzo[b]thiophen-3-yl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4',3'-e]pyridine4,6(7H,9H)-dione

Pyridin-2-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

- 106 040842

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(morpholino-methyl)-1,4d and hydropyride in-3-carboxylate

Dimethyl 4-(benzo[b]thiophen-3-yl)-2,6-bis(morpholinomethyl)-1,4-dihydropyridine3,5-dicarboxylate

2-hydroxyethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

1-(4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2-methyl-1,4dihydropyridine in-3-yl)ethan-1-one

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(1-(tert-butoxycarbonyl)azetidin-3yl)-6-methyl-1,4-dihydropyridine-3-carboxylate

3-acetyl-4-(benzo[b]thiophen-3-yl)-2-methyl-1,4,7,8-tetrahydro-5H-6,8-methano-1,6naphthyridin-5-one (1- (tert-Butoxycarbonyl)piperidin-4-yl)methyl-5-acetyl-4-(benzo[b]thiophen-3yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate

Cyclohexylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Methyl 4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-2,6-dicyclopropyl-1,4dihydropyridine-3-carboxylate

5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-M-phenyl-1,4-dihydropyridine-3-carboxamide

Tetrahydro-2H-pyran-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate (Tetrahydro-2H-pyran-4- yl)methyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl1,4-dihydropyridine-3-carboxylate

Cyclohexyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(2-methoxy-2-oxoethyl)-6-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-2,6-dimethyl-4-(2-methylbenzo[b]thiophen-3-yl)-1,4-dihydropyridine3-carboxylate

Cyclopropylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(2-methoxyethyl)-6-methyl-1,4dihydropyridine in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-((benzyloxy)methyl)-6-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(phenoxymethyl)-1,4dihydropyridine-3-carboxylate

Phenethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3 carboxylate

- 107 040842

Methyl 4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2-methyl1,4-dihydropyridine-3-carboxylate

3-acetyl-4-(benzo[b]thiophen-3-yl)-2-methyl-4,8-dihydro-1H-pyrano[3,4-b]pyridin5(6H)-one

Methyl 4-(benzo[b]thiophen-3-yl)-2-methyl-5-oxo-4,5,6,8-tetrahydro-1H-pyrano[3,4b]pyridine-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-benzyl-2-methyl-1,4-dihydropyride in-3-carboxylate

Methyl 4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(2-phenylacetyl)-1,4d and hydropyride in-3-carboxylate

3-acetyl-4-(benzo[b]thiophen-3-yl)-2-methyl-4,8-dihydro-1H-thiopyrano[3,4b]pyridin-5(6H)-one

Methyl 4-(benzo[b]thiophen-3-yl)-5-(2-methoxyacetyl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-(methoxymethyl)-2-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(fluoromethyl)-6-methyl-1,4dihydropyride in-3-carboxylate

Cyclopropylmethyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

1-(tert-butoxycarbonyl)piperidin-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate

Cyclopentylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Cyclopropylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyride in-3-carboxylate

1-methylpiperidin-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyride in-3-carboxylate

Cyclopentyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

4,4-dimethylcyclohexyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Cyclobutyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-2,6-dimethyl-4-(thieno[3,2-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate

- 108 040842

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-methyl-6-(trifluoromethyl)-1,4dihydropyride in-3-carboxylate

Cyclopropylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Cyclohexylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Cyclohexylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Cyclopentylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Cyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Cyclopentyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate

Benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3carboxylate (Tetrahydro-2H-pyran-4-yl)methyl- 5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3yl)-1,4-d ihydropyridine-3-carboxylate

Benzyl 5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

Benzyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine in3-carboxylate (Tetrahydro-2H-pyran-4-yl)methyl- 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate (Tetrahydro-2H-pyran-4-yl)methyl-5-acetyl -4-(5-fluorobenzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate

Benzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4d and hydropyride in-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

4-fluorobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4d and hydropyride in-3-carboxylate

6-acetyl-5-(benzo[b]thiophen-3-yl)-1,3,7-trimethyl-5,8-dihydro-pyrido[2,3d] pyrimide in-2,4( 1Н, 3Н)- d ion

3-acetyl-4-(benzo[b]thiophen-3-yl)-2-methyl-4,7-dihydrofuro[3,4-b]pyridin-5(1H)one

- 109 040842

1,1'-(4-(benzo[b]thiophen-3-yl)-2-benzyl-6-methyl-1,4-dihydropyridine-3,5diyl)bis(ethan-1-one)

-(5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyride in-3-yl)-2phenylethan-1-one

Methyl 5-acetyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-2-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate

-(2-methyl-5-(piperidine-1-carbonyl)-4-(thieno[2,3-b]pyridin-3-yl)-6(trifluoromethyl)-1,4-dihydropyridin-3-yl )ethane-1-one

4-(((5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydro-pyridine in-3carbonyl)oxy)methyl)benzoic acid

Benzyl-5-acetyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-2-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Pyridin-3-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

4-(cyclopropylcarbamoyl)benzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl1,4-dihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4d ihydropyr idine-3-carboxylate

4-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4d and hydropyride in-3-carboxylate

3-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyride in-3-carboxylate

2-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate (3-fluoropyridin-4-yl )methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)1,4-dihydropyridine-3-carboxylate

Pyrimidin-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridin-3-carboxylate (5-bromopyrimdin-3-yl) methyl 5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3yl)-1,4-dihydropyridine-3-carboxylate

- 110 040842

2-phenylpropan-2-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4d and hydropyride in-3-carboxylate

-cyanobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

4-cyanobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridine-3-yl)-1,4dihydropyridine in-3-carboxylate (6-chloropyridine-3- yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

3-morpholinobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyride in-3-carboxylate

4,4-dimethylcyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridine in-3-yl)-1,4dihydropyride in-3-carboxylate (2-chloropyridine- 4-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

Tetrahydro-2H-pyran-4-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine in-3-carboxylate

4,4-difluorocyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridine-3-yl)-1,4-dihydropyride in-3-carboxylate

5-acetyl-X-benzyl-X,2,6-trimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4d and in-3-carboxamide hydropyride

Oxetan-3-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate

Isopropyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4dihydropyridine-3-carboxylate

Cyclopropylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-(2,2,2trifluoroacetyl)benzo[b]thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate

2-phenylpropan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4d and hydropyride in-3-carboxylate

Methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate

Methyl 2-amino-4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-methyl-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-2-amino-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Methyl 5-acetyl-2-amino-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

- 111 040842

Methyl 5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Cyclopentyl-5-acetyl-2-amino-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine3,5-dicarboxylate

Cyclopentyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl 2,6-diamino-4-(benzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate

Cyclopropylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

4,4-difluorocyclohexyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3-carboxylate

Methyl 2-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

4-fluorobenzyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Methyl 5-acetyl-2-amino-4-(5-fluorothieno[2,3-b]pyridin-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Methyl 2-acetamido-5-acetyl-4-(5-fluorothieno[2,3-b]pyridin-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Cyclopentylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-

1,4-dihydropyridine-3,5-dicarboxylate

Dimethyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4d and in-3,5-dicarboxylate hydropyride

3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6cyclopropyl-1,4-dihydropyride in-3,5-dicarboxylate

Dimethyl 2,6-diamino-4-(7-cyanobenzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate

5-(cyclopropylmethyl)-3-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6cyclopropyl-1,4-dihydropyride in-3,5-dicarboxylate

-(4-fluorobenzyl) 5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyride in-3,5-dicarboxylate

3-(4-fluorobenzyl) 5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl1,4-dihydropyridine-3,5-dicarboxylate

4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile

4-(6-hydroxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5 - 112 040842 dicarbonitrile

4-(6-Methoxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile

2,6-d imethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3,5 dicarbonitrile

4-(benzo[b]thiophen-3-yl)-2-methyl-6-phenyl-1,4-dihydropyridine-3,5-dicarbonitrile

4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3,5-dicarbonitrile

-acetyl-4-(benzo[b]thiophen-3 -yl)-2,6-d imethyl-1,4-dihydropyridine-3 carbonitrile

Ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2,6-d-imethyl-1,4-dihydropyridine-3 carboxylate

Ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-methyl-6-phenyl-1,4-dihydropyridine-3-carboxylate

Ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-cyclopropyl-6-methyl-1,4d ihydropyridine-3-carboxylate

Methyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-cyclopropyl-6-methyl-1,4d ihydropyridine-3-carboxylate

1,1'-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl)diethanone

1,1'-(4-(6-hydroxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5diyl)bis(ethan-1-one)

1,1'-(4-(6-Methoxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5diyl)diethanone

1,1'-(4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3,5diyl)diethanone

9-(benzo[b]thiophen-3-yl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione

1,G-(4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5diyl)diethanone

1,G-(4-(5-Bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5diyl)diethanone

1,1'-(4-(5-Fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5diyl)bis(ethan-1-one)

1,1'-(2,6-dimethyl-4-(5-morpholinobenzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5diyl)bis(ethan-1-one)

1,1'-(2,6-dimethyl-4-(5-(4-methylpiperazin-1-yl)benzo[b]thiophen-3-yl)-1,4dihydropyridine in-3, 5-d yl) bis(ethane-1-one)

1,1'-(4-(5-(benzylamino)benzo[b]thiophen-3-yl)-2,6-d imethyl-1,4-dihydropyridine-

3,5-d uyl)bis(ethane-1-one)

3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5carbonitrile

- 113 040842

3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5carboxylic acid

N-cyclopropyl-3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyride in-4yl)benzo[b]thiophene-5-carboxamide

N-(cyclopropylmethyl)-3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4yl)benzo[b]thiophene-5-carboxamide

1,1'-(2,6-dimethyl-4-(5-(4-methylpiperazin-1-carbonyl)benzo[b]thiophen-3-yl)-1,4d ihydropyride in-3,5-d yl) bis(ethane-1-one)

1,1'-(2,6-dimethyl-4-(5-(morpholine-4-carbonyl)benzo[b]thiophen-3-yl)-1,4d ihydropyride in-3,5-d yl)bis( ethane-1-one)

1,1'-(2,6-dimethyl-4-(thieno[3,2-c]pyridin-3-yl)-1,4-dihydropyridine-3,5diyl)bis(ethan-1-one)

1,1'-(2,6-dimethyl-4-(thieno[2,3-c]pyridin-3-yl)-1,4-dihydropyridin-3,5diyl)bis(ethan-1-one)

1,1'-(2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridin-3,5diyl)bis(ethan-1-one)

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl 4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate

Ethyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

3-acetyl-4-(benzo[b]thiophen-3-yl)-2-methyl-4,6,7,8-tetrahydroquinolin-5(1H)-one

Methyl 4-(benzo[b]thiophen-3-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylate

1,1'-(4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-d ihydropyridine-3,5diyl)diethanone

3-acetyl-4-(benzo[b]thiophen-3-yl)-1,4,6,7-tetrahydro-2methylcyclopenta[b]pyridin-5-one

3-acetyl-4-(benzo[b]thiophen-3-yl)-1,4,6,7,8-pentahydro-2-methyl-7phenylcyclohexa[b]pyridin-5-one

3-acetyl-4-(benzo[b]thiophen-3-yl)-7-(4-fluorophenyl)-2-methyl-4,6,7,8tetrahydroquinolin-5 (1 H)-one

1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(methylsulfonyl)-1,4-dihydro-pyridin 3-yl)ethanone

Methyl 5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

Methyl-5-acetyl-4-(5-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin- 114 040842

3-carboxylate

Methyl 5-acetyl-4-(5-cyanobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine3-carboxylate

-(3-acetyl-5-(methoxycarbonyl)-2,6-dimethyl-1,4-dihydropyride in-4yl)benzo[b]thiophene-5-carboxylic acid

Methyl 5-acetyl-4-(5-(cyclopropylcarbamoyl)benzo[b]thiophen-3-yl)-2,6-dimethyl1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(5-((cyclopropylmethyl)carbamoyl)benzo[b]thiophen-3-yl)-2,6dimethyl-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2,6-dimethyl-4-(5-(4-methylpiperazine-1-carbonyl)benzo[b]thiophen3-yl)-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2,6-dimethyl-4-(5-(morpholine-4-carbonyl)benzo[b]thiophen-3-yl)1,4-dihydropyridine-3-carboxylate

Methyl-5-acetyl-2,6-d-imethyl-4-(thieno[3,2-c]pyridin-3-yl)-1,4-dihydropyridine-3 carboxylate

Methyl 5-acetyl-2,6-dimethyl-4-(thieno[2,3-c]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-cyclopropyl-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4d and hydropyride in-3-carboxylate

Dimethyl 2,6-dicyclopropyl-4-(5-fluorobenzo[b]thiophen-3-yl)-1,4-dihydropyride in3,5-dicarboxylate

Methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Dimethyl 2,6-dicyclopropyl-4-(thieno[2,3-b]pyridine-3-yl)-1,4-dihydropyride in3,5-dicarboxylate

Methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine3-carboxylate

Methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl 4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine 3,5-dicarboxylate

Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4d and hydropyride in-3-carboxylate

Methyl 5-acetyl-2-cyclopropyl-4-(7-(cyclopropylcarbamoyl)benzo[b]thiophen-3yl)-6-methyl-1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate

Dimethyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine- 115 040842

3,5-dicarboxylate

Methyl 5-acetyl-2-cyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3-carboxylate

Dimethyl-2,6-dicyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-1,4d and in-3,5-dicarboxylate hydropyride

3-(3-acetyl-6-cyclopropyl-5-(methoxycarbonyl)-2-methyl-1,4-dihydropyridin-4yl)benzo[b]thiophene-7-carboxylic acid

Benzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyride in-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate

Bis(pyridin-4-ylmethyl)-2,6-dicyclopropyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3,5-dicarboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate

Pyridin-4-ylmethyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3yl)-1,4-dihydropyridine-3-carboxylate

Benzyl-5-acetyl-2-cyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3-carboxylate

Dibenzyl-2,6-dicyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-1,4dihydropyride in-3,5-dicarboxylate

Benzyl-5-acetyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate

Methyl 3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-7carboxylate

3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-7carbonitrile

Pyridin-4-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-dihydropyridine-3-carboxylate

4-fluorobenzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Bis(4-fluorobenzyl)-2,6-dicyclopropyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4d and in-3,5-dicarboxylate hydropyride

4-cyanobenzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyride in-3-carboxylate

Methyl 5-acetyl-4-(7-chlorobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4- 116 040842 dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-(trifluoromethyl)benzo[b]thiophen-3yl)-1,4-d ihydropyridine-3-carboxylate

-chl orbenz yl-5 -acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyride in-3-carboxylate

2-phenylpropan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-d ihydropyridine-3-carboxylate

Cyclohexyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

2-phenylpropan-2-yl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3yl)-1,4-d ihydropyridine-3-carboxylate

1-(4-(7-bromobenzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2methyl-1,4-d ihydropyridin-3-yl)ethan-1-one

3-chlorobenzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

2-(4-fluorophenyl)propan-2-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)1,4-dihydropyridine-3-carboxylate

2-(4-fluorophenyl)propan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate

2-(4-fluorophenyl)propan-2-yl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3b]pyridin-3-yl)-1,4-dihydropyridine-3 -carboxylate

Methyl 5-acetyl-2-cyclopropyl-4-(7-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

Cyclopropylmethyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridine-3yl)-1,4-d ihydropyridine-3-carboxylate

Cyclopentyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

Cyclopropylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-d ihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclobutyl-6-methyl-1,4dihydropyride in-3-carboxylate

Dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4d and in-3,5-dicarboxylate hydropyride

Methyl 5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopentyl-6-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclohexyl-6-methyl-1,4d and hydropyride in-3-carboxylate

Methyl 5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4- 117 040842 dihydropyridine-3-carboxylate

3-((4-methylpiperazin-1-yl)methyl)benzyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)2,6-dimethyl-1,4-dihydropyridine-3-carboxylate

3-(cyclopropylmethyl)-5-methyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-d-ihydropyridine-3,5-dicarboxylate

3-(cyclopropylmethyl)-5-methyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6dicyclopropyl-1,4-dihydropyride in-3,5-dicarboxylate

Cyclopropylmethyl-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6methyl-1,4-d-ihydropyridine-3-carboxylate

Dimethyl 2-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4d and in-3,5-dicarboxylate hydropyride

Dimethyl-2-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-

3,5-dicarboxylate

Methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl1,4-dihydropyridine-3-carboxylate

Methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(7-cyanobenzo[b]thiophen-3-yl)-6methyl-1,4-d ihydropyridine-3-carboxylate

Methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine in-3-carboxylate hydrochloride

Methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6methyl-1,4-d ihydropyridine-3-carboxylate trifluoromethanesulfonate

4-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4 dihydropyridine-3-carboxylate

4-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

3-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyride in-3-carboxylate

2-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

2-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate

[3,4'-bipyridine]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

[3,3'-bipyridine]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

[2,4'-bipyridin]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)1,4-dihydropyridine-3-carboxylate

[2,3'-bipyridine]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

[2,3'-bipyridine]-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

[2,4'-bipyridine]-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-

1,4-dihydropyridine-3-carboxylate

Methyl-5-acetyl-2-cyclopropyl-6-methyl-4-(7-(pyridin-4-yl)benzo[b]thiophen-3-yl)-

1,4-dihydropyridine-3-carboxylate

Methyl-5-acetyl-2-cyclopropyl-4-(7-cyclopropylbenzo[b]thiophen-3-yl)-6-methyl-

1,4-dihydropyridine-3-carboxylate

3-(pyridin-4-yl)benzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridine-

-yl)-1,4-d ihydropyride in-3-carboxylate

1,D-(2,6-dimethyl-4-(5-(pyridin-3-yl)benzo[b]thiophen-3-yl)-1,4-dihydro-pyridine-

3,5-d uyl)diethanone

- 118 -

Claims (24)

Methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-phenylbenzo[b]thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate. Embodiment 14: A compound according to any one of Embodiments 1-13 for use in the treatment of a disease or condition susceptible to amelioration by androgen receptor and/or glucocorticoid receptor antagonism. Embodiment 15: A compound for use according to Embodiment 14, wherein the disease or condition susceptible to amelioration by androgen receptor and/or glucocorticoid receptor antagonism is selected from prostate cancer, castration-resistant prostate cancer, pancreatic cancer, urinary cancer bladder, kidney cancer, gastric cancer, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian cancer and other solid tumors, melanoma, metastatic malignancies, benign prostatic hyperplasia, polycystic ovarian syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, muscle atrophy and cachexia disorders, Cushing's syndrome, antipsychotic drug-induced weight gain, obesity, post-traumatic stress disorder, and alcoholism. Embodiment 16: A pharmaceutical composition containing a compound according to any one of Embodiments 1-13 and a pharmaceutically acceptable diluent or carrier. Embodiment 17: The pharmaceutical composition of Embodiment 16 further comprising a therapeutically effective amount of a therapeutic agent selected from among agents for the treatment of prostate cancer, castration-resistant prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, cancer lung, breast cancer, colon cancer, colorectal cancer, ovarian and other solid tumors, melanoma, metastatic malignancy, benign prostatic hyperplasia, polycystic ovarian syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, muscle disease atrophy and cachexia, Cushing's syndrome caused by antipsychotic drugs, weight gain, obesity, post-traumatic stress disorder and alcoholism. Embodiment 18: Combination product containing the compound of any of Embodiments 1-13 and a therapeutic agent used to treat prostate cancer, castration-resistant prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, cancer lung, breast cancer, colon cancer, colorectal cancer, ovarian and other solid tumors, melanoma, metastatic malignancy, benign prostatic hyperplasia, polycystic ovarian syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, muscle disease atrophy and cachexia, Cushing's syndrome caused by antipsychotic drugs, weight gain, obesity, post-traumatic stress disorder and alcoholism. Embodiment 19: The combination product of Embodiment 18 wherein the therapeutic agent is selected from a GnRH receptor agonist or antagonist, an androgen receptor antagonist, a CYP17 inhibitor, a VEGF inhibitor, an EGFR inhibitor, a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, a c- Met, Src inhibitor, PARP inhibitor, angiopoietin, ALK inhibitor, ROS-1 inhibitor, anti-IGF antibodies, taxane antineoplastic agent, topoisomerase II inhibitor, antitumor antibiotic, HSP90 inhibitor, Aurora kinase inhibitor, PSA vaccine, GR antagonists, inhibitors I-beta-HSD, one or more immunotherapeutic agents selected from the group consisting of anti-CTLA4 antibodies, anti-PD1 antibodies and anti-PDL1 antibodies. Embodiment 20: The combination product of Embodiment 19 wherein the immunotherapeutic agent is selected from the group consisting of ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, AMP-224, MPDL3280A, MEDI4736 and MDX-1105. CLAIM 1. Compound of formula (I) Y ³ ^Xf X^X^A λ I H (I) where R ¹ is a group selected from: a) -COR ⁵ , - 119 040842 b) -COOR ⁵ , c) -CN, d) -C(O)NH ₂ , R ⁵ is a group selected from: a) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from -N(R ⁶ )R ⁷ and -OR ⁶ , halogen atom, C ₃ -C ₆ -cycloalkyl, ethynyl and Me-C^C-, b) C ₃ -C ₆ -cycloalkyl, R ² is a group selected from: a) -COOR ⁸ , b) -COR ⁸ , c) -C(O)N(R ⁸ )R ⁹ , d) -CN, e) -S(O) _n R ⁸ where n is an integer from 1 to 2, R ⁸ and R ⁹ are independently selected from: a) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from A ¹ or B ² , b) group A ¹ , c) a hydrogen atom, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5-6 membered heterocycle optionally containing 1 heteroatom selected from O and N, and said heterocycle is optionally substituted with 1 or 2 groups independently selected from linear or branched C ₁ -C 4 -alkyl; R ³ is a group selected from: a) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from the halogen atom, -N(R ⁶ )R ⁷ and -OR ⁶ , b) C ₃ -C ₆ -cycloalkyl, optionally substituted with 1, 2 or 3 halogen atoms, c) a hydrogen atom, d) -NH2, e) -CN, R ⁴ is a group selected from: a) groups A ¹ , b) linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from A ¹ or B ² , c) -N(R ⁶ )R ⁷ , d) -CN, e) -CO-H, f) -CO-Me and g) CO-OMe, h) a hydrogen atom, X ¹ and X ⁴ are independently selected from C-B ¹ , N and C-H, X ² , X ³ and X ⁵ are independently selected from C-B ¹ and C-H, And ¹ is chosen from: a) a C ₃ -C ₆ cycloalkyl ring optionally substituted with 1, 2, 3 or 4 substituents selected from =O and B ³ ; b) a 3-6 membered saturated heterocyclyl ring containing 1, 2 or 3 heteroatoms selected from O, S and N and where the ring is optionally substituted with 1, 2 or 3 substituents selected from =O and B ³ ; c) a phenyl or 6-membered heteroaryl group containing one or two N atoms, any of which is optionally substituted with 1, 2 or 3 substituents selected from B ¹ ; each B ¹ is independently selected from a halogen atom, a -CF ₃ group, a 6-membered heteroaryl containing one or two N atoms, a linear or branched C ₁ -C ₆ alkyl, -CN, -N(R ⁶ )R ⁷ , - OR ⁶ , -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )R ⁷ , -OC(=O)-R ⁶ , -N(R ⁶ )C(=O)R ⁷ , -NR ⁷ SO2R ⁶ , -SO2N(R ⁶ )R ⁷ , -SR ⁶ , -S(O)R ⁶ and -S(O)2R ⁶ , each B ² is independently selected from halogen atom, -CN, -N(R ⁶ )R ⁷ , -OR ⁶ , -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )R ⁷ , -OC(=O)-R ⁶ , -N(R ⁶ )C(=O)R ⁷ , -NR ⁷ SO2R ⁶ , -SO2N(R ⁶ )R ⁷ , -SR ⁶ , -S(O)R ⁶ , -S(O)2R ⁶ , ethynyl and Me-C C-, each B ³ is independently selected from a halogen atom, linear or branched C ₁ -C ₆ -alkyl, -CN, -N(R ⁶ )R ⁷ , -OR ⁶ , -C(=O)R ⁶ , -C(=O)OR ⁶ , -C(=O)N(R ⁶ )R ⁷ , -OC(=O)-R ⁶ , -N(R ⁶ )C(=O)R ⁷ , -NR ⁷ SO2R ⁶ , -SO2N(R ⁶ )R ⁷ , -SR ⁶ , -S(O)R ⁶ , -S(O)2R ⁶ , each R ⁶ and R ⁷ is independently: hydrogen atom, linear or branched C ₁ -C ₁ 2-alkyl or C ₃ -C ₆ -cycloalkyl, optionally substituted 1, 2 - 120 040842 or 3 substituents selected from =0 (oxo group), halogen atom, hydroxy group, phenyl, C3-C6 cycloalkyl, linear or branched C ₁ -C ₆ alkoxy group, amino group, C ₁ -C ₆ alkylamino group, C ₁ -C ₆ -dialkylamino, linear or branched C ₁ -C ₆ -alkylcarbonyl, phenyl or 6-membered heteroaryl group containing one or two N atoms, optionally substituted with 1, 2 or 3 substituents selected from halogen, cyano, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ haloalkyl, hydroxy group, linear or branched C ₁ -C ₆ alkoxy group, amino group, C ₁ -C ₆ alkylamino group, QC ₆ dialkylamino group; R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 3-8 membered ring optionally containing an additional heteroatom selected from O, N and S and where the ring is optionally substituted with 1, 2 or 3 substituents selected from ═O (oxo), linear or branched C ₁ C ₆ alkyl, linear or branched C ₁ -C ₆ haloalkyl, linear or branched C ₁ -C ₆ alkylcarbonyl; with the proviso that if R ¹ is -COOR ⁵ and R ² is -COOR ⁸ then R ⁴ is not a methyl group, and pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, where X ¹ , X ² , X ³ and X ⁵ represent C-H or C-B ¹ where B ¹ represents a halogen atom. 3. The compound according to claim 2, where X ⁴ is a group selected from C-B ¹ and N. 4. The compound according to claim 3, where B ¹ is selected from the group -CN and a halogen atom. 5. A compound according to any one of claims 2-4, wherein R ¹ is a group selected from -COR ⁵ , -COOR ⁵ and a -CN group. 6. The compound according to claim 5, where R ⁵ is selected from: C ₁ -C ₄ -alkyl, where the terminal methyl is unsubstituted or substituted with three fluorine atoms (-CF3), C ₁ -C ₃ -alkyl optionally substituted at any position with ethynyl and Me-C^C-, and C ₃ -C ₅ -cycloalkyl. 7. A compound according to any one of claims 2-4, wherein R ² is -COOR ⁸ . 8. The compound according to claim 7, where R ⁸ independently represents: linear or branched C ₁ -C ₆ -alkyl, optionally substituted with 1, 2 or 3 substituents selected from fluorine atoms and C ₃ -C ₅ -cycloalkyl, optionally substituted with 1, 2 or 3 fluorine atoms, or a group A ¹ representing C ₃ -C ₆ -cycloalkyl, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine atoms and C ₁ -C ₃ -alkyl groups. 9. The compound according to any one of claims 2-4, where R ³ is a group selected from linear or branched C ₁ -C ₄ -alkyl and C ₃ -C ₄ -cycloalkyl, where these groups are optionally substituted by 1, 2 or 3 atoms fluorine. 10. The compound according to any one of claims 2-4, where R ⁴ is a group selected from: N(R ⁶ )R ⁷ where R ⁶ and R ⁷ are independently selected from a hydrogen atom and a linear or branched C ₁ -C ₃ alkyl group A ¹ representing a C ₃ -C ₆ -cycloalkyl, a linear or branched C ₁ - C ₃ -alkyl optionally substituted with 1, 2 or 3 substituents selected from 1, 2 or 3 fluorine atoms or 1 hydroxyl group. 11. The compound according to claim 1, where X ¹ , X ² , X ³ and X ⁵ are -CH, X ⁴ is C-B ¹ , where B ¹ is a -CN group or a bromine atom, R ¹ is a group selected from -C(O)CH3, -C(O)OCH3, -C(O)OCH2-ethynyl, -C(O)OCH2-CΞC-Me and CN, R ² is a group selected from -C(O ) O linear or branched C1-C ₃ alkyl group optionally substituted with 1, 2 or 3 fluorine atoms and C(O)OCH ₂ -cyclopropyl optionally substituted with 1, 2 or 3 fluorine atoms, R ³ is a group selected from linear or branched C1-C3 alkyl and C3-C4 cycloalkyl, and R ⁴ is a group selected from linear or branched C1-C ₃ alkyl, C ₃ -C ₄ cycloalkyl and -NH ₂ . 12. The compound according to claim 1, where X ¹ , X ² , X ³ and X ⁵ are -CH, X ⁴ is C-B ¹ , where B ¹ is a -CN group, R ¹ is a group selected from -C(O)CH3, -C(O)OCH3, R ² is a group selected from -C(O)OCH2-cyclopropyl optionally substituted with 1, 2 or 3 fluorine atoms, and -C(O)OCH ₂ -CF ₃ , R ³ is a group selected from methyl and cyclopropyl, and R ⁴ is a group selected from cyclopropyl and -NH ₂ . 13. The compound according to claim 1, selected from the group consisting of: methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate (enantiomer 1); methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate (enantiomer 2); - 121 040842 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxamide; 1-(4-(benzo[b]thiophen-3-yl)-5-benzoyl-2,6-dimethyl-1,4-dihydropyridin-3-yl)ethan-1-one; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-phenyl-1,4-dihydropyridine-3-carboxylate; 1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-nicotinoyl-1,4-dihydropyridin-3-yl)ethan-1-one; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydro-[2,3'-bipyridine]-3-carboxylate; 2,2,2-trifluoroethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid; 1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(4-methylpiperazin-1-carbonyl)-1,4-dihydropyridin-3yl)ethan-1-one; 5-acetyl-4-(benzo[b]thiophen-3-yl)-N,N-diethyl-2,6-dimethyl-1,4-dihydropyridine-3-carboxamide; 1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(morpholine-4-carbonyl)-1,4-dihydropyridin-3-yl)ethan-1-one; 2-methoxyethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 3-acetamidopropyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; benzyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 2-morpholinoethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 2-(dimethylamino)ethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 2-acetamidoethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(methoxymethyl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-((dimethylamino)methyl)-6-methyl-1,4-dihydropyridine-3-carboxylate; pyridin-4-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 4-methoxybenzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; pyridin-2-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(morpholino-methyl)-1,4-dihydropyridine-3-carboxylate; dimethyl 4-(benzo[b]thiophen-3-yl)-2,6-bis(morpholinomethyl)-1,4-dihydropyridine-3,5-dicarboxylate; 2-hydroxyethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 1-(4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2-methyl-1,4-dihydropyridin3-yl)ethan-1-one; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(1-(tert-butoxycarbonyl)azetidin-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate; (1-(t-butoxycarbonyl)piperidin-4-yl)methyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl1,4-dihydropyridine-3-carboxylate; cyclohexylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-2,6-dicyclopropyl-1,4-dihydropyridine3-carboxylate; 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-N-phenyl-1,4-dihydropyridine-3-carboxamide; tetrahydro-2H-pyran-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; (tetrahydro-2H-pyran-4-yl)methyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate; cyclohexyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(2-methoxy-2-oxoethyl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-2,6-dimethyl-4-(2-methylbenzo[b]thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate; cyclopropylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(2-methoxyethyl)-6-methyl-1,4-dihydropyridine-3-carboxylate; - 122 040842 methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-((benzyloxy)methyl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(phenoxymethyl)-1,4-dihydropyridine-3-carboxylate; phenethyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2-methyl-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-benzyl-2-methyl-1,4-dihydropyridine-3-carboxylate; methyl 4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(2-phenylacetyl)-1,4-dihydropyridine-3-carboxylate; methyl 4-(benzo[b]thiophen-3-yl)-5-(2-methoxyacetyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-(methoxymethyl)-2-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-(fluoromethyl)-6-methyl-1,4-dihydropyridine-3-carboxylate; cyclopropylmethyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 1-(t-butoxycarbonyl)piperidin-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate; cyclopentylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; cyclopropylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 1-methylpiperidin-4-yl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; cyclopentyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 4,4-dimethylcyclohexyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; cyclobutyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-2,6-dimethyl-4-(thieno[3,2-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-methyl-6-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate; cyclopropylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; cyclohexylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; cyclohexylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; cyclopentylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; cyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; cyclopentyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate; benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; (tetrahydro-2H-pyran-4-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; benzyl 5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; benzyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; (tetrahydro-2H-pyran-4-yl)methyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate; (tetrahydro-2H-pyran-4-yl)methyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate; benzyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate; - 123 040842 pyridin-4-ylmethyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 4-fluorobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; pyridin-3-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 1,1'-(4-(benzo[b]thiophen-3-yl)-2-benzyl-6-methyl-1,4-dihydropyridin-3,5-diyl)bis(ethan-1-one); 1-(5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3-yl)-2-phenylethan-1-one; methyl 5-acetyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate; 1-(2-methyl-5-(piperidine-1-carbonyl)-4-(thieno[2,3-b]pyridin-3-yl)-6-(trifluoromethyl)-1,4dihydropyridin-3-yl)ethane -1 - she; 4-(((5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3carbonyl)oxy)methyl)benzoic acid; benzyl 5-acetyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate; pyridin-3-ylmethyl-5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; pyridin-3-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; pyridin-3-ylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; pyridin-3-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; pyridin-3-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; pyridin-4-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 4-(cyclopropylcarbamoyl)benzyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; pyridin-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 4-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 3-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 2-bromobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; (3-fluoropyridin-4-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; pyrimidin-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; (5-bromopyridin-3-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; 2-phenylpropan-2-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 3-cyanobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 4-cyanobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; (6-chloropyridin-3-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; 3-morpholinobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 4,4-dimethylcyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine3-carboxylate; (2-chloropyridin-4-yl)methyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; tetrahydro-2H-pyran-4-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 4,4-difluorocyclohexyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; - 124 040842 5-acetyl-N-benzyl-N,2,6-trimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxamide; oxetan-3-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate; isopropyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-2-(trifluoromethyl)-1,4-dihydropyridine-3-carboxylate; cyclopropylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-(2,2,2-trifluoroacetyl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3-carboxylate; 2-phenylpropan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 2-amino-4-(benzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-2-amino-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-2-amino-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; cyclopentyl-5-acetyl-2-amino-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; dimethyl 2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate; cyclopentyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; dimethyl 2,6-diamino-4-(benzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate; cyclopropylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate; 4,4-difluorocyclohexyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 2-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; 4-fluorobenzyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-2-amino-4-(5-fluorothieno[2,3-b]pyridin-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 2-acetamido-5-acetyl-4-(5-fluorothieno[2,3-b]pyridin-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; cyclopentylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate; 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; dimethyl 2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate; 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4dihydropyridine-3,5-dicarboxylate; dimethyl 2,6-diamino-4-(7-cyanobenzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate; 5-(cyclopropylmethyl)-3-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4dihydropyridine-3,5-dicarboxylate; 3-(4-fluorobenzyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine 3,5-dicarboxylate; 3-(4-fluorobenzyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4dihydropyridine-3,5-dicarboxylate; cyclopropylmethyl-2-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine3-carboxylate; 4-fluorobenzyl-2-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; cyclopropylmethyl-6-amino-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-1,4-dihydropyridine-3-carboxylate; 3-cyclopentyl-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate; cyclopropylmethyl-5-acetyl-2-amino-4-(6-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate; cyclohexyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; cyclohexylmethyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine3-carboxylate; cyclopropylmethyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-methyl1,4-dihydropyridine-3-carboxylate; 3-fluorobenzyl-5-acetyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; 3-(cyclobutylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; 3-((3,3-difluorocyclobutyl)methyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate ; cyclopropylmethyl-2-amino-5-carbamoyl-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate; 3-((2,2-difluorocyclopropyl)methyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate ; 5-cyclopropyl-3-(cyclopropylmethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; 3-((2,2-difluorocyclopropyl)methyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6cyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate ; 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyano-5-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyano-4-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; 3-isopropyl-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate; 3-((2,2-difluoro-3,3-dimethylcyclopropyl)methyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)6-methyl-1,4- dihydropyridine-3,5-dicarboxylate; 5-methyl-3-neopentyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate; 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanotheno[3,2-b]pyrudin-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; 5-methyl-3-neopentyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4dihydropyridine-3,5-dicarboxylate; bis(cyclopropylmethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate; 3-(cyclopropylmethyl)-5-(prop-2-yn-1-yl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3, 5-dicarboxylate; 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(5,7-dicyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; 5-(but-2-yn-1-yl)-3-(cyclopropylmethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3, 5-dicarboxylate; 5-methyl-3-(2,2,2-trifluoroethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; 3-(cyclopropylmethyl)-5-(2,2,2-trifluoroethyl)-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5- dicarboxylate; 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(6-chloro-7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; 3-(2-fluoro-2-methylpropyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyano-6-(trifluoromethyl)benzo[b]thiophen-3-yl)-6methyl-1,4-dihydropyridine-3,5-dicarboxylate ; 5-methyl-3-prop-2-yn-1-yl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine3,5-dicarboxylate; 3-(cyclopropylmethyl)-5-methyl-2-amino-4-(7-cyanobenzo[b]thiophen-3-yl)-6-(trifluoromethyl)-1,4dihydropyridine-3,5-dicarboxylate; 4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile; - 126 040842 4-(6-hydroxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile; 4-(6-methoxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile; 2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarbonitrile; 4-(benzo[b]thiophen-3-yl)-2-methyl-6-phenyl-1,4-dihydropyridine-3,5-dicarbonitrile; 4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3,5-dicarbonitrile; 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonitrile; ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-methyl-6-phenyl-1,4-dihydropyridine-3-carboxylate; ethyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 4-(benzo[b]thiophen-3-yl)-5-cyano-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate; 1,1'-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5-diyl)diethanone; 1,1'-(4-(6-hydroxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5-diyl)bis(ethan-1-one); 1,1'-(4-(6-methoxybenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5-diyl)diethanone; 1,1'-(4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridin-3,5-diyl)diethanone; 1,1'-(4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5-diyl)diethanone; 1,1'-(4-(5-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl)diethanone; 1,1'-(4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5-diyl)bis(ethan-1-one); 1,1'-(2,6-dimethyl-4-(5-morpholinobenzo[b]thiophen-3-yl)-1,4-dihydropyridin-3,5-diyl)bis(ethan-1-one); 1,1'-(2,6-dimethyl-4-(5-(4-methylpiperazin-1-yl)benzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5diyl)bis(ethane -1-she); 1,1'-(4-(5-(benzylamino)benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5-diyl)bis(ethan1-one); 3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5-carbonitrile; 3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5-carboxylic acid; N-cyclopropyl-3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5carboxamide; N-(cyclopropylmethyl)-3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5carboxamide; 1,1'-(2,6-dimethyl-4-(5-(4-methylpiperazin-1-carbonyl)benzo[b]thiophen-3-yl)-1,4-dihydropyridine3,5-diyl)bis(ethane -1 - she); 1,1'-(2,6-dimethyl-4-(5-(morpholine-4-carbonyl)benzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5diyl)bis(ethane-1 -she); 1,1'-(2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridin-3,5-diyl)bis(ethan-1-one) ; dimethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-2,3-dicarboxylate; dimethyl 5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-2,3-dicarboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate; dimethyl 4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate; ethyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 1,1'-(4-(benzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridin-3,5-diyl)diethanone; 1-(4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-5-(methylsulfonyl)-1,4-dihydropyridin-3-yl)ethanone; methyl 5-acetyl-4-(5-fluorobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(5-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(5-cyanobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; 3-(3-acetyl-5-(methoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-5carboxylic acid; methyl 5-acetyl-4-(5-(cyclopropylcarbamoyl)benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(5-((cyclopropylmethyl)carbamoyl)benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-2,6-dimethyl-4-(5-(4-methylpiperazin-1-carbonyl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-2,6-dimethyl-4-(5-(morpholine-4-carbonyl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-2-cyclopropyl-4-(5-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; - 127 040842 dimethyl-2,6-dicycloiroyl-4-(5-fluoro-benzo[b]thiophen-3-yl)-1,4-dihydroiridin-3,5-dicarboxylate; methyl 5-acetyl-2-cycloiroyl-6-methyl-4-(thieno[2,3-b]iiridin-3-yl)-1,4-dihydroiiridine-3-carboxylate; dimethyl 2,6-dicyclopropyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate; methyl 5-acetyl-4-(benzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate; dimethyl 4-(5-chlorobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate; methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-2-cycloiroyl-4-(7-(cycloiroylcarbamoyl)benzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate; dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate; methyl 5-acetyl-2-cycloiroyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate; dimethyl-2,6-dicyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate; 3-(3-acetyl-6-cyclopropyl-5-(methoxycarbonyl)-2-methyl-1,4-dihydropyridin-4yl)benzo[b]thiophene-7-carboxylic acid; benzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; iiridin-4-ylmethyl-5-acetyl-4-(benzo[b]thiophen-3-yl)-2-cycloiroyl-6-methyl-1,4dihydropyridine-3-carboxylate; bis(pyridin-4-ylmethyl)-2,6-dicyclopropyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine 3,5-dicarboxylate; pyridin-4-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; iiridin-4-ylmethyl-5-acetyl-4-(5-chlorobenzo[b]thiophen-3-yl)-2-cycloiroyl-6-methyl-1,4dihydropyridine-3-carboxylate; iiridin-4-ylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cycloiroyl-6-methyl-1,4dihydropyridine-3-carboxylate; iiridin-4-ylmethyl-5-acetyl-2-cycloiroyl-6-methyl-4-(thieno[2,3-b]iiridin-3-yl)-1,4-dihydropyridine-3-carboxylate; benzyl-5-acetyl-2-cycloiroyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate; dibenzyl-2,6-dicyclopropyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-1,4-dihydropyridine 3,5-dicarboxylate; benzyl-5-acetyl-4-(7-(methoxycarbonyl)benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate; methyl 3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydro-iiridin-4-yl)benzo[b]thiophene-7-carboxylate; 3-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)benzo[b]thiophene-7-κcarbonitrile; iiridin-4-ylmethyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cycloiroiyl-6-methyl-1,4dihydroiiridine-3-carboxylate; 4-fluorobenzyl-5-acetyl-2-cycloiroyl-6-methyl-4-(thieno[2,3-b]iiridin-3-yl)-1,4-dihydroiiridine3-carboxylate; bis(4-fluorobenzyl)-2,6-dicycloiroyl-4-(thieno[2,3-b]iiridin-3-yl)-1,4-dihydroiiridine-3,5-dicarboxylate; 4-cyanobenzyl-5-acetyl-2-cycloiroyl-6-methyl-4-(thieno[2,3-b]iiridin-3-yl)-1,4dihydroiridin-3-carboxylate; methyl 5-acetyl-4-(7-chlorobenzo[b]thiophen-3-yl)-2-cycloiroyl-6-methyl-1,4-dihydroiiridine-3-carboxylate; methyl 5-acetyl-2-cycloiroyl-6-methyl-4-(7-(trifluoromethyl)benzo[b]thiophen-3-yl)-1,4-dihydro-yridine-3-carboxylate; 3-chlorobenzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]iiridin-3-yl)-1,4-dihydroiiridine-3-carboxylate; 2-phenyliroyan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cycloiroyl-6-methyl-1,4-128 040842 dihydropyridine-3-carboxylate; cyclohexyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine3-carboxylate; 2-phenylpropan-2-yl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 1-(4-(7-bromobenzo[b]thiophen-3-yl)-5-(cyclopropanecarbonyl)-6-cyclopropyl-2-methyl-1,4dihydropyridin-3-yl)ethan-1-one; 3-chlorobenzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine3-carboxylate; 2-(4-fluorophenyl)propan-2-yl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; 2-(4-fluorophenyl)propan-2-yl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate; 2-(4-fluorophenyl)propan-2-yl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate ; methyl 5-acetyl-2-cyclopropyl-4-(7-fluorobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; cyclopropylmethyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; cyclopentyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine3-carboxylate; cyclopropylmethyl-5-acetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclobutyl-6-methyl-1,4-dihydropyridine-3-carboxylate; dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate; methyl 5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclopentyl-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2-cyclohexyl-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4-dihydropyridine-3-carboxylate; 3-((4-methylpiperazin-1-yl)methyl)benzyl-5-acetyl-4-(7-bromobenzo[b]thiophen-3-yl)-2,6-dimethyl-1,4dihydropyridine-3-carboxylate; 3-(cyclopropylmethyl)-5-methyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3,5-dicarboxylate; 3-(cyclopropylmethyl)-5-methyl-4-(7-cyanobenzo[b]thiophen-3-yl)-2,6-dicyclopropyl-1,4dihydropyridine-3,5-dicarboxylate; cyclopropylmethyl-5-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-methyl-1,4dihydropyridine-3-carboxylate; dimethyl 2-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-cyclopropyl-1,4-dihydropyridine-3,5-dicarboxylate; dimethyl 2-cyano-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate; methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(7-bromobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-2-((2-aminoethoxy)methyl)-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4dihydropyridine-3-carboxylate; dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate; dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-cyclopropyl-6-(hydroxymethyl)-1,4-dihydropyridine 3,5-dicarboxylate; dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-formyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate; dimethyl 4-(7-cyanobenzo[b]thiophen-3-yl)-2-(hydroxymethyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate; dimethyl-2-cyano-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate; - 129 040842 cycloiroylmethyl-5-acetyl-4-(6-cyanobenzo[b]thiophen-3-yl)-2-cycloiroyl-6-methyl-1,4dihydropyridine-3-carboxylate; cycloiroylmethyl-2,5-diacetyl-4-(7-cyanobenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydroiiridine-3-carboxylate; methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate hydrochloride; methyl 5-acetyl-2-amino-4-(benzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate trifluoromethanesulfonate; 4-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 4-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 3-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 3-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 2-(pyridin-4-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; 2-(pyridin-3-yl)benzyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4-dihydropyridine-3-carboxylate; [3,4'-bipyridine]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; [3,3'-bipyridin]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; [2,4'-bipyridine]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; [2,3'-bipyridine]-5-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; [2,3'-bipyridin]-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; [2,4'-bipyridin]-4-ylmethyl-5-acetyl-2,6-dimethyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-2-cyclopropyl-6-methyl-4-(7-(pyridin-4-yl)benzo[b]thiophen-3-yl)-1,4dihydropyridine-3-carboxylate; methyl 5-acetyl-2-cyclopropyl-4-(7-cyclopropylbenzo[b]thiophen-3-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate; 3-(pyridin-4-yl)benzyl-5-acetyl-2-cyclopropyl-6-methyl-4-(thieno[2,3-b]pyridin-3-yl)-1,4dihydropyridine-3-carboxylate; 1,1'-(2,6-dimethyl-4-(5-(iiridin-3-yl)benzo[b]thiophen-3-yl)-1,4-dihydroiiridin-3,5diyl)diethanone; methyl 5-acetyl-2-cycloiroyl-6-methyl-4-(7-phenylbenzo[b]thiophen-3-yl)-1,4-dihydroiiridine-3-carboxylate. 14. The use of a compound and any of ii.1-13 for the treatment of a disease or medical condition susceptible to amelioration by androgen receptor and/or glucocorticoid receptor antagonism. 15. Use of both and 14, wherein the disease or medical condition susceptible to amelioration by androgen receptor and/or glucocorticoid receptor antagonism is selected from prostate cancer, castration-resistant prostate cancer, pancreatic cancer, urinary bladder cancer, ovarian cancer , gastric cancer, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian cancer and other solid tumors, melanoma, metastatic malignancies, benign prostatic hyperplasia, ovarian iolicystic syndrome (PCOS), hair loss, hirsutism, acne, hyiogonadism, diseases with muscle atrophy and cachexia, Cushing's syndrome caused by anti-sychotic drugs, weight gain, obesity, post-traumatic stress disorder and alcoholism. 16. Pharmaceutical composition containing from 0.001 to 99% by weight of a compound and any of II.1-13 and a pharmaceutically acceptable diluent or carrier, for the treatment of a disease or medical condition susceptible to improvement by androgen receptor and/or glucocorticoid receptor antagonism. 17. Pharmaceutical composition i.o. i.16, additionally containing a therapeutically effective amount of a therapeutic agent selected from agents for the treatment of prostate cancer, castration-resistant prostate cancer, pancreatic cancer, urinary cancer - 130 040842 bladder cancer, kidney cancer, gastric cancer, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian cancer and other solid tumors, melanoma, metastatic malignant neoplasms, benign prostatic hyperplasia, polycystic ovary syndrome (PCOS) , hair loss, hirsutism, acne, hypogonadism, muscle wasting disorders and cachexia, Cushing's syndrome, antipsychotic-induced weight gain, obesity, post-traumatic stress disorder, and alcoholism. 18. Combination pharmaceutical product containing a compound according to any one of claims 1 to 13 and a therapeutic agent used for the treatment of prostate cancer, castration-resistant prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, lung cancer, cancer breast, colon cancer, colorectal cancer, ovarian and other solid tumors, melanoma, metastatic malignancies, benign prostatic hyperplasia, polycystic ovary syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, muscle wasting diseases and cachexia , Cushing's syndrome caused by antipsychotic drugs, weight gain, obesity, post-traumatic stress disorder and alcoholism. 19. The combination product of claim 18 wherein the therapeutic agent is selected from a GnRH receptor agonist or antagonist, an androgen receptor antagonist, a CYP 17 inhibitor, a VEGF inhibitor, an EGFR inhibitor, a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, a c-Met inhibitor , Src inhibitor, PARP inhibitor, angiopoietin, ALK inhibitor, ROS-1 inhibitor, anti-IGF antibodies, taxane antineoplastic agent, topoisomerase II inhibitor, antitumor antibiotic, HSP90 inhibitor, Aurora kinase inhibitor, PSA vaccine, GR antagonists, P inhibitors -beta-HSD, one or more immunotherapeutic agents selected from the group consisting of anti-CTLA4 antibodies, anti-PD1 antibodies and anti-PDL1 antibodies. 20. The combination product of claim 19 wherein the immunotherapeutic agent is selected from the group consisting of ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, AMP-224, MPDL3280A, MEDI4736 and MDX-1105. 21. The use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of a disease or condition susceptible to amelioration by androgen receptor and/or glucocorticoid receptor antagonism. 22. Use according to claim 21, wherein the disease or condition susceptible to amelioration by androgen receptor and/or glucocorticoid receptor antagonism is selected from prostate cancer, castration-resistant prostate cancer, pancreatic cancer, bladder cancer, kidney cancer , gastric cancer, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian cancer and other solid tumors, melanoma, metastatic malignancies, benign prostatic hyperplasia, polycystic ovary syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, muscle wasting disorders and cachexia, Cushing's syndrome, antipsychotic drug-induced weight gain, obesity, post-traumatic stress disorder, and alcoholism. 23. A method of treating a disease or pathological condition susceptible to improvement by androgen receptor and/or glucocorticoid receptor antagonism, comprising administering a compound according to any one of paragraphs to an individual in need thereof. 1-13. 24. The method of claim 23 wherein the disease or condition susceptible to amelioration by androgen receptor and/or glucocorticoid receptor antagonism is selected from prostate cancer, castration-resistant prostate cancer, pancreatic cancer, bladder cancer, kidney cancer , gastric cancer, lung cancer, breast cancer, colon cancer, colorectal cancer, ovarian cancer and other solid tumors, melanoma, metastatic malignancies, benign prostatic hyperplasia, polycystic ovary syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, muscle wasting disorders and cachexia, Cushing's syndrome, antipsychotic drug-induced weight gain, obesity, post-traumatic stress disorder, and alcoholism. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 - 131 -