(19) TZZ_Z_T

(11) EP 1 797 099 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 495/04 (2006.01) A61K 31/519 (2006.01) 11.08.2010 Bulletin 2010/32 A61P 9/10 (2006.01) A61P 9/12 (2006.01)

(21) Application number: 05800014.2 (86) International application number: PCT/US2005/034862 (22) Date of filing: 23.09.2005 (87) International publication number: WO 2006/034511 (30.03.2006 Gazette 2006/13)

(54) PIPERIDINYLAMINO-THIENO[2,3-D] PYRIMIDINE COMPOUNDS PIPERIDINYLAMINO-THIENO[2,3-D]-PYRIMIDINVERBINDUNGEN COMPOSÉS PIPÉRIDINYLAMINO-THIÉNO[2,3-D]PYRIMIDINES

(84) Designated Contracting States: • SHARADENDU, Anurag AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Washington DC, 20016 (US) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • CHEN, Dongli SK TR Brighton, MA 02135 (US) Designated Extension States: • MARANTZ, Yael AL BA HR MK YU 60920 Kadima (IL) • SHACHAM, Sharon (30) Priority: 23.09.2004 US 947995 44851 Alfey Menashe (IL) 08.03.2005 US 75565 • HEIFETZ, Alexander Bnel-Brak (IL) (43) Date of publication of application: • INBAL, Boaz 20.06.2007 Bulletin 2007/25 99788 Kfar Shmuel (IL) • KESAVAN, Venkitasamy (73) Proprietor: Epix Delaware, Inc. Woburn, MA 01801 (US) Lexington, MA 02421 (US) • BAR-HAIM, Shay Netanya (IL) (72) Inventors: • CHERUKU, Srinivasa Rao • DHANOA, Dale, S. Lexington, MA 02420 (US) Wakefield, MA 01880 (US) • BECKER, Oren (74) Representative: Cornish, Kristina Victoria Joy et al Mevaseret Zion (IL) Kilburn & Strode LLP • NOIMAN, Silvia 20 Red Lion Street Herzliya (IL) London • ALLA, Sekar, Reddy WC1R 4PJ (GB) Burlington, MA 01803 (US) • MELENDEZ, Rosa, E. (56) References cited: Woburn, MA 01801 (US) WO-A-2004/089312 US-A- 4 146 716 US-A- 6 159 962 US-B1- 6 222 034

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 797 099 B1

Printed by Jouve, 75001 PARIS (FR) EP 1 797 099 B1

Description

FIELD OF THE INVENTION

5 [0001] The invention generally relates to the field of serotonin (5-hydroxytryptamine, or 5-HT) receptor modulators, e.g., antagonists, and more particularly to new piperidinylamino-thieno [2,3-d] pyrimidine compounds which are also 5- HT modulators, and use of these compounds, e.g., in the treatment, modulation and/or prevention of physiological conditions associated with serotonin action, such as in treating vascular disorders, e.g., angina, migraine, pulmonary hypertension and systemic hypertension. 10 BACKGROUND OF THE INVENTION

[0002] The serotonergic neural system of the brain has been shown to influence a variety of physiologic functions which manifest themselves in a variety of disorders such as eating disorders, schizophrenia, neuralgia, and addiction 15 disorders; depression, obsessive compulsive disorders, panic disorders, anxiety, sexual dysfunctions caused by the central nervous system and disturbances in sleep and the absorption of food, alcoholism, pain, memory deficits, unipolar depression, dysthymia, bipolar depression, treatment-resistant depression, depression in the medically ill, panic disorder, obsessive-compulsive disorder, eating disorders, social phobia, premenstrual dysphoric disorder, pulmonary hyperten- sion and systemic hypertension. 20 [0003] 5-HT receptor modulators e.g., antagonists, partial agonists or agonists, and/or selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, fluvoxamine, sertraline, lorazepam, imipramine, citalopram, and nortriptyline, may be used for the treatment of the above conditions, as well as for vasodilation, smooth muscle contraction, bronchoconstriction, brain disorders such as vascular disorders such as angina and migraine; and neuropathological disorders including Parkinson’s disease and Alzheimer’s disease. These compounds are also suitable for the modulation 25 of the cardiovascular system and pulmonary disorders including pulmonary hypertension and pulmonary fibrosis. They also [0004] intervene in the regulation of the cerebral circulation and thus represent effective agents for controlling migraine. They are also suitable for the prophylaxis and control of the effects of occurrences of cerebral infarct (Apoplexia cerebri) such as stroke or cerebral ischemia. They are also suitable for the control of disorders of the intestinal tract which are 30 characterized by disturbances of the serotoninergic system and also by disturbances of the carbohydrate metabolism. [0005] Trazodone controls 5-HT actions, and fluoxetine and fluvoxamine facilitate serotoninergic neurotransmission via potent and selective inhibition of serotonin reuptake into presynaptic neurons. 3-chloroimipramine inhibits both 5- HT and norepinephrine reuptake. Other compounds of current interest for use as antidepressants include zimeldine, bupropion and nomifensine. 35 [0006] Type 2 serotonin inhibitors (5-HT2) mediate the action of several drugs used in treating, e.g., schizophrenia, feeding disorders, perception, depression, migraines, hypertension, anxiety, hallucinations, and gastrointestinal dys- functions. The 5-HT2A,B or C receptor subtypes show considerable homology at genetic, structural and functional levels, and all are G-protein coupled receptors (GPCRs.) 5-HT2A receptors have been found in high density in the cerebral cortex and in interneuronal regions, as well as, in lower density, in the hippocampus, striatum, other cerebral regions, 40 platelets, and vascular and uterine smooth muscle. [0007] 5-HT2B receptors are widely distributed in mammalian peripheral tissue, e.g., heart, skeletal and vascular muscle, adipose tissue, intestine, ovary, uterus, testis, liver, lung, pancreas, trachea, spleen, thymus, thyroid, prostate and salivary gland, as well as in the CNS, e.g., in the cerebral cortex and the whole brain. Serotonin binds to the receptor with an affinity of 2-10 nM (Rothman et al. 2000; Kursar et al. 1994). 5-HT2B receptors are present in many vascular 45 beds and have been localized to both vascular smooth muscle and vascular endothelial cells in humans (Ullmer et al. 1995; Marcos et al. 2004). The receptor was characterized initially in the rat gastric (fundus) smooth muscle cells (SMC) as the receptor responsible mediating serotonin (5-HT)-induced contraction in this tissue (Kursar et al. 1994). [0008] US 6,222,034 describes a class of 3-substituted 3,4,5,6,7,8-hexahydropyrido(4’,3’:4,5)thieno[2,3-d]pyrimidine compounds of which are used as antagonists of 5HT1B and 5HT1A. 50 [0009] US 6,159,962 describes Class 3-substituted 3,4-dihydrocyano[2,3-d]pyrimidine derivatives and specifies their use as selective 5HT1B and 5HT1A antagonists. [0010] US 4,146,716 describes a class of cyano pyrimidine derivatives and their use as plant growth regulators and for combating fungal, viral and bacterial diseases of plants and insect pests. [0011] WO2004/089312 describes piperidinylamino-thieno[2,3-d]pyrimidine compounds as 5-HT receptor antago- 55 nists.

2 EP 1 797 099 B1

SUMMARY OF THE INVENTION

[0012] The invention is as defined in the appended claims. [0013] The present invention relates to the discovery of new compounds which are 5-HT modulators, e.g., antagonists, 5 partial agonists, or agonists, that can be used for treating, preventing or curing 5-HT-related conditions, such as in treating vascular disorders, e.g., angina, migraine, pulmonary hypertension and systemic hypertension. In particular, it has been found that certain piperidinylamino-thieno[2,3-d] pyrimidine compounds are selective 5- HT receptor modula- tors. In an embodiment, such compounds include those having the formula

10

15

20

wherein R1 and R2 may independently be halogens including F, Cl, Br, I; or substituted or unsubstituted aryl or heteroaryl; R3 may be H; halogen; CN; NH2; lower alkyl; R7;OR7; NHR7;N(R7)2; or substituted or unsubstituted aryl or heteroaryl; 25 R4 may be H, R7, Or substituted or unsubstituted aryl or heteroaryl; Q is any one of

30

35 and

40

wherein Ra may be hydrogen, halogen, or lower alkyl and * indicates attachment points; 45 R5 and R6 are independently selected from hydrogen, halogen COOH; CN; NH2;NO2; OH; lower alkyl; substituted lower alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7: NHR7;N(R7)2;R7-alkoxy; and R7-haloalkyl; R7- haloalkoxy; or R1 and R6, taken together with their bonded carbons, form is substituted or unsubstituted unsaturated 5- or 6- membered carbocyclic ring or a substituted or unsubstituted saturated 5-, 6-, or 7-membered carbocyclic ring, wherein the carbocyclic 50 ring may be a fused biaryl ring or a hererocarbocyclic ring comprising at least one hetero atom chosen from O, N, S and P; and the substituted ring comprises at least one hydrogen, halogen, COOH; CN; NH2;NO2; OH; lower alkyl; substituted lower alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR2; NHR7;N(R7)2; R7-alkoxy; and R7-haloalkyl; R7-haloalkoxy; R7 is substituted or unsubstituted (C1-C6)alkyl or a (C3-C6)cycloalkyl or cycloheteroalkyl; 55 n is 2, 3, 4 or 5, wherein a substituted aryl or heteroaryl group can be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, carboxylate, alkylcarbo- nyl, cyano, amino, acylamino, sulthydryl, alkylthio, arylthio, nitro and trifluoromethyl,

3 EP 1 797 099 B1

wherein a substituted alkyl may be substituted by one or more substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonyloxy; alkynyl, alkylcarbonyl, alkylthio, alkythiocarbonyl, thiocarboxylate, arylthio, arylcarbonyl, arylcarbonyloxy, acylamino, carboxylate, cyano, halogen, haloalkyl, cycloalkoxy, acetamide, amine, hy- droxyl, nitro, sulfhydryl, sulfonamido and trifluoromethyl 5 [0014] Also provided in the invention are any one or more pharmaceutically acceptable salts and/or esters of the formula IV compound. [0015] In another embodiment, compounds of the invention further include those of the formula

10

15

wherein 20 R1 and R2 are independently hydrogen, COOH; CN; NH2;NO2; OH; substituted C1-6 alkyl; substituted or unsubstituted, aryl or heteroaryl; COOR7; CONHR7; CON(R7)2; OR7; NHR7; N(R7)2; R7-alkoxy; R1-haloalkyl; or R7-haloalkoxy; R3 is independently H; halogen; CN; NH2;C1-6alkyl; R7;OR7; NHR7;N(R7)2; or substituted or unsubstituted aryl or heteroaryl; R4 is H, R7, or substituted or unsunbstituted aryl or heteroaryl; 25 Q is chosen from

30

35

wherein R6 is hydrogen, halogen, or C1-6 alkyl and * indicates attachment points; R5 and R6 are independently selected from hydrogen, halogen. COOH; CN; NH2;NO2; OH; C1-6 alkyl; substituted C1-6 alkyl; substituted or unsubstituted aryl or heteroaryl; R1; COOR7; CONBR7; CON(R7)2 OR7; NHR7; N(R7)2-; R7-akoxy; R7-haloalkyl; and R7-haloalkoxy; or R5 and R6, taken together with their bonded carbons, form a substituted or unsubstituted unsaturated 5- or 6- membered 40 carbocyclic ring or a substituted or unsubstituted saturated 5-, 6-, or 7-membered carbocyclic ring, wherein

- the carbocyclic ring may be a heterocarbocyclic ring comprising at least one hetero atom chosen from O, N and S, - wherein the substituted ring comprises at least one hydrogen, halogen, COOH; CN; NH2;NO2; OH; C1-6 alkyl; substituted C1-6 alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; NHR7; 45 N(R7)2; R7-alkoxy; R7-haloalkyl; or R7-haloalkoxy; - wherein R7 is substituted or unsubstituted (C1-C6) alkyl or a (C3-C6) cycloalkyl or cycloheteroalkyl; and - n is 2, 3,4 or 5,

wherein a substituted aryl or heteroaryl group can be substituted by one or more substituents selected from the group 50 consisting of halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, carboxylate, alkylcarbo- nyl, cyano, amino, acylamino, sulfhydryl, alkylthio, arylthio, nitro and trifluoromethyl; wherein a substituted alkyl may be substituted by one or more substituents selected from the group consisting of alkenyl alkoxy, alkoxycarbonyl, alkoxycarbonyloxy; alkynyl, alkylcarbonyl, alkylthio, alkythiocarbonyl, thiocarboxylate, arylthio, arylcarbonyl, arylcarbonyloxy, acylamino, carboxylate, cyano, halogen, haloalkyl, cycloalkoxy, acetamide, amine, hy- 55 droxyl, nitro, sulfhydryl, sulfonamido and trifluoromethyl; or a pharmaceutically acceptable salt and/or ester thereof. [0016] In another embodiment, compounds of the invention further include those of the formula

4 EP 1 797 099 B1

5

10

15

wherein R1 may be halo, lower alkyl, cyano, or trihalomethyl; each R2 may independently be hydrogen, trihalomethyl, carboxylate, an amide, or a sulfonyl group, and n is 1 or 2, provided that when n is 1, R2 is not hydrogen, and when n 20 is 2, both R2 groups are not hydrogen, or a pharmaceutically acceptable salt and/or ester thereof. Examples of amides include amido, N-methylamido and dimethylamido groups; examples of sulfonyl groups include trifluoromethylsulfonyl, sulfonyl and methylsulfonyl groups. [0017] This embodiment encompasses pharmaceutically acceptable salts of the formula II compounds, including maleate, hydrochloride, and fumarate salts. 25 Specific compounds having the formula

30

35

40 are included in the invention, wherein R1 and R2 independently are one or more of hydrogen; halogen, halo-substituted alkyl, lower alkyl C1-C6 cycloalkyl, C1-C6 cycloheteroalkyl, aryl, halo-substituted aryl or heteroaryl; or R1 and R2. taken together, form a C5-C7 cycloalkyl or cycloheteroalkyl ring; R3 and R3’ are independently H, halogen, CN or R5; 45 Cy is heteroaryl; and R4 is hydrogen; halogen, halo-substituted alkyl, lower alkyl CN, COOH, COOR5,OR5, CONH2, CONHR5, CON(R5)2, halo-substituted or unsubstituted NR5, halo-substituted or unsubstituted, SOOR5, aryl, halo-substituted aryl or heteroaryl, C1-C6 cycloalkyl, or C3-C4 cycloheteroalkyl; wherein R5 is a substituted or unsubstituted lower alkyl wherein a substituted alkyl may be substituted by one or more 50 substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonyloxy, alkynyl, alkylcar- bonyl, alkylthio, alkylthiocarbonyl, thiocarboxylate, arylthio, arylcarbonyl, arylcarbonyloxy, acylamino, carboxylate, cy- ano, halogen, haloalkyl, cycloalkoxy, acetamide, amine, hydroxyl, nitro, sulfhydryl, sulphonamido and trifluromethyl; R6 is hydrogen and C1-6alkyl; and n is 1, 2, 3, 4 or 5. Pharmaceutically acceptable salts and/or esters of Formula V compounds are also provided. 55 [0018] Compounds of the invention are desirably 5-HT receptor antagonists, e.g., 5-HT2 receptor antagonists including 5-HT2A, B or C receptors, and desirably 5-HT2B receptor antagonists. [0019] In certain embodiments of a compound of Formula VI, R is hydrogen and R2 is halogen; or R, is C1-6 alkyl and R2 is halogen; or R1 and R2 are C1-6alkyl; or one of R1 and R2 is C1-6alkyl and the other is hydrogen; or R1 is halo-

5 EP 1 797 099 B1

substituted or unsubstituted benzyl and R2 is hydrogen or halogen, or R1 and R2 are each hydrogen. Preferably, Cy is pyrimidinyl or pyridinyl, R4 is hydrogen, halogen, halo-substituted alkyl, C1-6alkyl, CN, COOH, COOR5,OR5, CONH2, CONHR5, CON(R5)2, halo-substituted or unsubstituted NR5, halo-substituted or unsubstituted SOOR5,C1-C6 cycloalkyl, C3-C6 cycloheteroalkyl, aryl, halo-substituted aryl or heteroaryl; and R6 is hydrogen. 5 [0020] In certain embodiments of a compound of Formula VI, R4 is F, n is 1, 2 or 3, R3 and R3, are independently H or R5, and R6 is H. [0021] In certain embodiments of a compound of Formula VI, Cy is substituted or unsubstituted pyridinyl, R4 is hydrogen, halogen, hydroxyl or R5, R3 and R3, are independently hydrogen or R5; and R6 is hydrogen. [0022] In another embodiment compounds of the invention may also be 5-HT receptor partial agonists, e.g., 5-HT2 10 receptors partial agonists including 5-HT2A, B or C receptors, and desirably 5-HT2B receptor partial agonists. [0023] In another embodiment compounds of the invention may also be 5-HT receptors agonists, e.g., 5-HT2 receptor agonists including 5-HT2A, B or C receptors, and desirably 5-HT2B receptor agonists. [0024] Another aspect of the invention is a pharmaceutical compositions comprising an effective amount of a compound according to Formula II, III, IV or VI and a pharmaceutically acceptable carrier. The pharmaceutical composition may 15 be for use to treat depression, diseases of the central nervous system, erectile dysfunction, systemic hypertension, pulmonary hypertension or conditions associated with vascular disorders, e.g., angina, migraine, pulmonary hypertension and systemic hypertension. [0025] Also provided are various compound according to Formula II, III, IV or VI for use in treating a disease state that is alleviated by treatment with a 5-HT2B antagonist. Disease states that are alleviated by treatment with a 5-HT2B 20 antagonist include, but are not limited to, e.g, pulmonary arterial hypertension, migraine, congestive heart failure (CHF), hypertension, disorders of the gastrointestinal tract, restenosis, asthma, obstructive airway disease, prostatic hyperplasia, erectile dysfunction, priapism, inflammatory pain, neuropathic pain, cancer pain, acute pain or chronic pain; allergic asthma, irritable bowel syndrome, hypertonic lower esophageal sphincter, motility disorders, benign prostatic hyperplasia, depression, anxiety, attention deficit hyperactivity disorder, obesity, sleeping disorder, Alzheimer’s disease, Parkinson 25 disease, carcinoid tumours, teratocarcinoma, acromegaly, a CNS disorder or vascular disorders, e.g., angina, migraine, pulmonary hypertension and systemic hypertension [0026] Another aspect of the invention provides a compound of the following formula:

30

35

wherein 40 R1 and R2 are independently hydrogen, halogen, COOH; CN; NH2;NO2; OH; lower alkyl; substituted C1-6 alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR; CONHR7; CON(R7)2;OR7; NHR7;N(R7)2;R7-alkoxy; R7-haloalkyl; R7-haloalkoxy; or R1 and R2, taken together with their bonded carbons, form a substituted or unsubstituted C4-C7 cycloalkyl or cycloheter- oalkyl ring, 45

- wherein a heteroatom in the C4-C7 cycloheteroalkyl ring comprises at least one of O, N and S, and - wherein the substituted C4-C7 cycloalkyl or cycloheteroalkyl ring comprises at least one substituent selected from hydrogen halogen, COOH; CN; NH2;NO2; OH; C1-6alkyl; substituted C1-6 alkyl; substituted or unsubstituted C1-C6 cycloalkyl or cycloheteroalkyl; substituted or unsubstituted aryl or heteroaryl; R1; COOR7; CONHR7; CON(R7)2; 50 OR7; NHR7; N(R7)2; R7-alkoxy, R7-haloalkyl; and R7-haloalkoxy;

R3 is independently H; halogen; CN; NH2; lower alkyl; R7;OR7; NHR7;N(R7)2; or substituted or unsubstituted aryl or heteroaryl; R4 is H, R7, or substituted or unsubstituted aryl or heteroaryl; 55 Q is chosen from

6 EP 1 797 099 B1

5

wherein R8 is hydrogen, halogen, or C1-6, alkyl and indicates attachment points; 10 R5 and R6 are independently selected from hydrogen, halogen, COOH; CN; NH2;NO2; OH; C1-6 alkyl; substituted C1-6 alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; NHR7;N(R7)2;R7-alkoxy; R7-haloalkyl; and R7-haloalkoxy; or R5 and R6, taken together with their bonded carbons, form a substituted or unsubstituted unsaturated 5- or 6- membered carbocyclic ring or a substituted or unsubstituted saturated 5-, 6-, 7-membered carbocyclic ring, wherein 15 the carbocyclic ring may be a heterocarbocyclic ring comprising at least one hetero atom chosen from O, N and S, wherein the substituted ring comprises at least one hydrogen, halogen, COOH; CN; NH2;NO2; OH; C1-6 alkyl; substituted C1-4 alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; NHR7;N(R7)2; R7-alkoxy, R7-haloalkyl; or R7-haloalkoxy; wherein R7 is substituted or unsubstituted (C1-C6) alkyl or a (C3-C6) cycloalkyl or cycloheteroalkyl; 20 n is 2, 3, 4 or 5, or is branched; wherein a substituted aryl or heteroaryl group can be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, carboxylate, alkylcarbo- nyl, cyano, amino, acylamino, sulfhydryl, alkylthio, arylthio, nitro and trifluoromethyl; and wherein a substituted alkyl may be substituted by one or more substituents selected from the group consisting of alkenyl, 25 alkoxy, alkoxycarbonyl, alkoxycarbonyloxy; alkynyl, alkylcarbonyl, alkylthio, alkythiocarbonyl, thiocarboxylate, arylthio, arylcarbonyl, arylcarbonyloxy, acylamino, carboxylate, cyano, halogen, haloalkyl, cycloalkoxy, acetamide, amine, hy- droxyl, nitro, sulfhydryl, sulfonamido and trifluoromethyl; or a pharmaceutically acceptable salt thereof, for use in treating congestive heart failure (CHF), heart failure, restenosis, asthma, obstructive airway disease, prostatic hyperplasia, priapism, erectile dysfunction, inflammatory pain, neuropathic 30 pain, cancer pain, acute pain, chronic pain, irritable bowel syndrome, hypertonic lower oesophageal sphincter, motility disorders, benign prostatic hyperplasia, attention deficit hyperactivity disorder, obesity, carcinoid tumors, teratocarcino- ma, hyperprolactinemia or acromegaly. [0027] Another aspect of the invention provides a compound of the following formula:

35

40

45

50

55 wherein X is halo; R3 is hydrogen, halo, cyano, or trihalomethyl; and n is 1 or 2, provided that when n is 1, R3 is not hydrogen, and when n is 2, both R3 groups are not hydrogen;

7 EP 1 797 099 B1

or a pharmaceutically acceptable salt and/or ester thereof, for use in treating congestive heart failure (CHF), heart failure, restenosis, asthma, obstructive airway disease, prostatic hyperplasia, priapism, erectile dysfunction, inflammatory pain, neuropathic pain, cancer pain, acute pein, chronic pain, irritable bowel syndrome, hypertonic lower oesophageal sphineter, motility disorders, benign prostatic hyperplasia, at- 5 tention deficit hyperactivity disorder, obesity, carcinoid tumors, teratocarcinoma, hyperprolactinemia or acromegaly. [0028] As explained above, compounds of the invention can have antagonistic activity at 5-HT2B receptors, which will counteract the negative feedback mechanism induced by the inhibition of serotonin reuptake; this is thereby expected to improve the effect of the serotonin reuptake inhibiting activity of the compounds of the invention.

10 DETAILED DESCRIPTION OF THE INVENTION

[0029] The features and other details of the invention will now be more particularly described with reference to the accompanying drawings and pointed out in the claims. It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be 15 employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise specified.

Definitions

20 [0030] For convenience, certain terms used in the specification, examples, and appended claims are collected here. [0031] "5-HT receptor modulator" or "5-HT modulator" includes compounds having effect at the 5-HT1,5-HT2,5-HT3, 5-HT4,5-HT5,5-HT6 or 5-HT7 receptors, including the subtypes of each receptor type, such as 5-HT1A,B,C,D,E or F; 5- HT2A,B or C; and 5-HT5A or B. 5-HT modulators may be agonists, partial agonists or antagonists. [0032] "Treating", includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improve- 25 ment of the condition, disease, disorder, etc. [0033] "Alkyl" includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched-chain alkyl groups (e.g., isopropyl, tert-butyl, isobutyl, isoamyl), cycloalkyl (e.g., alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. "Alkyl" further includes alkyl groups which have oxygen, 30 nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbon atoms. In certain embod- iments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and more preferably four or fewer. Likewise, preferred cycloalkyls have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure. "C1-C6" includes alkyl groups containing one to six carbon atoms. 35 [0034] The term "alkyl" also includes both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkoxyl, alkoxycarbonyl, alkoxycarbonyloxy, alkyl, alkynyl, alkylcarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfinyl, alkylthio, alkylthiocarbonyl, thiocarboxylate, arylthio, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyloxy, amino (including alkylamino, dialkylamino, 40 arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, azido, carboxylate, cyano, halogen, haloalkyl, haloalkoxy, cycloalkoxyl, acetamide, alkyla- cetamide, cycloalkylacetamide, amine, cycloamine, heterocyclyl, hydroxyl, nitro, phosphate, phosphonato, phosphinato, sulfates, sulfonato, sulfamoyl, sulfhydryl, sulfonamido, trifluoromethyl, alkylaryl, or an aromatic or heteroaromatic moiety, or any other substituent or its equivalent disclosed herein. Cycloalkyls can be further substituted, e.g., with the substituents 45 described herein and or their equivalents known in the art. An "alkylaryl" or an "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). "Alkyl" also includes the side chains of natural and unnatural amino acids. [0035] A "substituted" moiety is non-limiting as to the type of substituent. As used herein, a substitutent includes any one or more chemical moieties disclosed herein, or any equivalent known in the art. [0036] "Aryl" includes groups with aromaticity, including 5- and 6-membered "unconjugated", or single-ring, aromatic 50 groups that may include from zero to four heteroatoms, as well as "conjugated", or multicyclic, systems with at least one aromatic ring. Examples of aryl groups include benzene, phenyl, benzoxazole, benzthiazole, benzo[d][1,3]dioxole, naph- thyl, quinolinyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxa- zole, pyridine, pyridinyl, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, 55 benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles," "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,

8 EP 1 797 099 B1

arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylamino- carbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminoc- arbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl 5 and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, akylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety, or any other substituent disclosed herein or its equivalent. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl). [0037] "Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls 10 described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. The term "alkenyl" further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing 15 one or more hydrocarbon backbone carbons. In certain embodiments, a straight chain or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain.) Likewise, cycloalkenyl groups may have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure. The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. [0038] The term "alkenyl" also includes both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which 20 refers to alkenyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, ami- nocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphina- to, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including 25 alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocar- boxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alky- laryl, or an aromatic or heteroaromatic moiety. [0039] "Alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups 30 (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. The term "alkynyl" further includes alkynyl groups having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons. In certain em- bodiments, a straight chain or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. 35 [0040] The term "alkynyl" also includes both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcar- bonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocar- bonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cy- 40 ano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkyl- carbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0041] Unless the number of carbons is otherwise specified, "lower alkyl" includes an alkyl group, as defined above, 45 but having from one to ten, more preferably from one to six, carbon atoms in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms. [0042] "Acyl" includes compounds and moieties which contain the acyl radical (CH3CO-) or a carbonyl group. "Sub- stituted acyl" includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbox- 50 ylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio- carbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diar- ylamino, and allcylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. 55 [0043] "Acylamino" includes moieties wherein an acyl moiety is bonded to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups. [0044] "Aroyl" includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.

9 EP 1 797 099 B1

[0045] "Alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more hydrocarbon backbone carbon atoms, e.g., oxygen, nitrogen or sulfur atoms. [0046] The term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked 5 to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxy- carbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylami- nocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, di- 10 alkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy. 15 [0047] The terms "heterocyclyl" or "heterocyclic group" include closed ring structures, e.g., 3- to 10-, or 4- to 7- membered rings, which include one or more heteroatoms. Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperizine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy- 20 carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety. 25 [0048] The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom. [0049] The term "ether" includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group. 30 [0050] The term "ester" includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are as defined above. [0051] The term "thioether" includes compounds and moieties which contain a sulfur atom bonded to two different 35 carbon or heteroatoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthio- alkynyls. The term "alkthioalkyls" include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls" refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group. [0052] The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O-. 40 [0053] The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term "perhalogenated" generally refers to a moiety wherein all hydrogens are replaced by halogen atoms. [0054] "Polycyclyl" or "polycyclic radical" refers to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalky- nyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings. Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with 45 [0055] such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylamino- carbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthi- ocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), 50 amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0056] "Heteroatom" includes atoms of any element other than carbon or hydrogen. Examples ofheteroatoms include nitrogen, oxygen, sulfur and phosphorus. [0057] It will be noted that the structure of some of the compounds of the invention includes asymmetric carbon atoms. 55 It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Alkenes can include

10 EP 1 797 099 B1

either the E- or Z-geometry, where appropriate. [0058] Combination therapy" (or "co-therapy") includes the administration of a 5-HT modulator of the invention and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co- action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic 5 or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). "Combination therapy" may, but generally is not, intended to encompass the adminis- tration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. "Combination therapy" is intended to embrace administra- 10 tion of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent 15 can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intra- 20 venous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. "Combination therapy" also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. 25 For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks. [0059] One suitable combination therapy would include treating PAH by administration of one or more compounds of the invention, e.g., compounds of formula III, with other vasodilators such as the prostacyclin epoprostenol (FLOLAN); bosentan (TRACLEER®); isosorbide dinitrate (DILATRATE-SR, ISO-BID, ISONATE, ISORBID, ISORDIL, ISOTRATE, 30 SORBITRATE); isorbide mononitrate (IMDUR); hydralazine (APRESOLINE); treprostinil (REMODULIN); phosphodi- esterase type 5 (PDE5) inhibitors such as sildenafil; and calcium channel blockers, in appropriate dosage regimes. [0060] An "anionic group," as used herein, refers to a group that is negatively charged at physiological pH. Preferred anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phos- phinate, or phosphorothioate or functional equivalents thereof. "Functional equivalents" of anionic groups are intended 35 to include bioisosteres, e.g., bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisosteric equivalents and non-classical bioisosteric equivalents. Classical and non-classical bioisosteres are known in the art (see, e.g., Silverman, R. B. The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc: San Diego, Calif., 1992, pp.19-23). A particularly preferred anionic group is a carboxylate. [0061] The term "heterocyclic group" is intended to include closed ring structures in which one or more of the atoms 40 in the ring is an element other than carbon, for example, nitrogen, or oxygen or sulfur. Heterocyclic groups can be saturated or unsaturated and heterocyclic groups such as pyrrole and furan can have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. Heterocyclic groups can also be substituted at one or more constituent atoms with, for example, a halogen, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, 45 -CF3, -CN, or the like. [0062] The present invention relates to the discovery of new compounds which are 5-HT modulators, e.g., antagonists, and/or SSRIs, that can be used for treating, preventing or curing 5-HT-related conditions. In particular, it has been found that certain piperidinylamino-thieno[2,3-d] pyrimidine compounds are effective 5-HT receptor modulators and/or SSRIs. [0063] Compounds of the invention may also be 5-HT receptor antagonists, e.g., 5-HT2 receptor antagonists including 50 5-HT2A, BorC receptors, and desirably 5-HT2B receptor antagonists. [0064] Included in the invention is the use of the compounds disclosed herein for the manufacture of a medicament for treatment of a disease state that can be alleviated by treatment with a 5-HT2B antagonist. In one embodiment the disease state is selected from the diseases pulmonary arterial hypertension, migraine, hypertension, disorders of the gastrointestinal tract, restenosis, asthma, obstructive airway disease, prostatic hyperplasia and priapism. In a related 55 embodiment the disease state comprises inflammatory pain, neuropathic pain, cancer pain, acute pain or chronic pain. In a variant embodiment the disease state comprises allergic asthma, irritable bowel syndrome, hypertonic lower es- ophageal sphineter. motility disorders or benign prostatic hyperplasia. In a further embodiment, the disease state com- prises depression, anxiety, attention deficit hyperactivity disorder, obesity, sleeping disorder, Alzheimer’s disease, or

11 EP 1 797 099 B1

Parkinson disease. [0065] In various embodiments the compound is a 5-HT receptor antagonist, and may be a 5-HT2 receptor antagonist, including, e.g., a 5-HT2A, B or C receptor antagonist. A preferred compound is a 5-HT2B receptor antagonist. [0066] Compounds of the invention are useful in the treatment of hypoxia, pulmonary arterial hypertension (PAH) and 5 other hypoxia-induced PAH syndromes caused by chronic obstructive pulmonary disease, mountain sickness, and cardiac valve disease. (Other conditions include congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), scleroderma, valvular heart disease, cor pulmonale, chronic hypoxic lung conditions, sickle cell anemia, portal hypertension, altitude sickness, congenital heart abnormalities, and respiratory distress syndrome.) Several studies have suggested a role for 5-HT in the etiology of PAH. Furthermore, circulating 5-HT levels are increased (10-30X) in 10 both primary PAH and PAH secondary to anorexigen intake. Recently, it has been demonstrated that 5-HT is not only a potent pulmonary vasoconstrictor, but also a growth amplification factor that possibly plays a crucial role in proliferation of pulmonary vascular smooth muscle cells. It has been shown that isolated smooth muscle and endothelial cells from pulmonary arteries express mRNAs for several 5-HT receptors. Thus, by activating its cognate receptors, 5-HT has a dual effect on the pulmonary vascular beds contributing to both vasoconstriction and vascular remodeling that are 15 associated with PAH.

d) Q is any one of

20

25

wherein R8 may be hydrogen, halogen, or a substituted or unsubstituted lower alkyl, e.g., CN or CF3, wherein * indicates the bonds that connect the structure with the rest of the backbone; 30

e) R5 and R6 are variously:

i) R5 and R6 are independently selected from hydrogen, halogen, COOH; CN; NH2;NO2; OH; lower alkyl; substituted lower alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; 35 NHR7; N(R7)2; R7-alkoxy; and R7-haloalkyl; R7-haloalkoxy; or

ii) R5 and R6, taken together with their bonded carbons, form a substituted or unsubstituted unsaturated 5- or 6- membered carbocyclic ring or a substituted or unsubstituted saturated 5-, 6-, or 7-membered carbocyclic ring, wherein the carbocyclic ring may be a fused biaryl ring or a heterocarbocyclic ring comprising at least one 40 hetero atom chosen from O, N, S and P; and the substituted ring comprises at least one hydrogen, halogen, COOH; CN; NH2;NO2; OH; lower alkyl; substituted lower alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; NHR7;N(R7)2;R7-alkoxy; and R7-haloalkyl; R7-haloalkoxy or optionally other radicals; and R5 and R6, taken together with their bonded carbons, is desirably an aromatic ring structure, e.g., phenyl, naphthyl, diphenylmethyl, biaryl; and optionally substitutions on the adjacent carbon atoms may 45 form 5 or 6 membered unsaturated or saturated cyclic rings such as

50

and 55

f) R7 is substituted or unsubstituted (C1-C6) alkyl or a (C3-C6) cycloalkyl or cycloheteroalkyl;

g) n is 0, 1, 2, 3, 4, 5 or 6, and is straight or is branched. In various desirable compounds n is 2,3,4 or 5. Also

12 EP 1 797 099 B1

provided in the invention are any one or more pharmaceutically acceptable salts and/or esters of the formula I compound.

[0067] An alternative depiction of Q, which is defined above, is sometimes shown by the formula below, namely 5

10

wherein m is 0, 1 or 2. Where m=2, —( )m -is meant to depict the carbons at the 2, 3 positions of the piperidine; m =1, —()m, -is meant to depict one carbon to yield pyrrolidine, and where m=0, the -()m - moiety is absent, and only the open chain alkylamine is meant to be depicted, i.e., a straight chain alkylamine. 15 [0068] In one embodiment, R1 may desirably be H, -CH3, -CH(CH3)2, or Cl. In another embodiment, R2 may desirably be H, Cl, lower alkyl, e.g., straight or branched C1,C2,C3 (e.g., iso- or tert-butyl), C4 or C5 alkyl, or aryl, e.g., phenyl or fluorophenyl. R1 and R2 may also, taken together with the bonded carbons from the thieno, desirably form a cyclohexyl ring. The Q group is preferably an N-substituted alkyl or cycloalkyl. The linking group denoted by ()n may be a substituted or unsubstituted, straight or branched, and may be a single bond, or made up of 1, 2, 3, 4 or 5 carbons or more. 20 [0069] In another embodiment compounds of the invention include those having the formula

25

30

35

wherein R1 through R4 are as defined for Formula I. Cy is preferably phenyl, but may be a substituted or unsubstituted, saturated or unsaturated 4-, 5-, 6- or 7- membered cycloalkyl or aryl ring. A cycloalkyl or aryl ring may include, e.g., mono-, di-, or tri-substituted phenyl, naphthyl, or biphenyl with lower alkyl, e.g., methyl, ethyl, propyl, allyl, n-butyl, n- 40 pentyl, n-hexyl; alkoxy or aryloxy, e.g., methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclopenty- loxy; halo, e.g., fluoro, chloro, bromo, and iodo; amino, dimethylamino, nitro, cyano, carboxy, carboxy esters, carboxa- mides, N-alkylcarboxamide, N.N-dialkylcarboxamide, trifluoromethyl, trifluoromethoxy, tetrazolo, sulphonyl, thiomethyl, thioethyl, phenylthio, 2,3-methylenedioxy, and 3,4-methylenedioxy. Substituents on Cy are designated R5, which may be hydrogen; halogen, halo-substituted alkyl, lower alkyl, CN, COOH, COOR7,OR7, CONH2, CONHR7, CON(R7)2, 45 halo-substituted or unsubstituted NR7, halo-substituted or unsubstituted SOOR7, aryl, halo-substituted aryl or heteroaryl, C1-C6 cycloalkyl, or C3-C6 cycloheteroalkyl, wherein n is 0,1, 2, 3, 4 or 5, and R7 is a substituted or unsubstituted lower alkyl. The linker group may be branched or unbranched, and p may be 0, 1, 2, 3, 4, 5, 6 or more. Where the linker group is branched, p is 1 or higher, and R6 and R6’ are independently H, halogen, CN or R7, wherein R7 is a substituted or unsubstituted, branched or unbranched lower alkyl. Pharmaceutically acceptable salts and/or esters of Formula II com- 50 pounds are also provided. [0070] In various embodiments, R1 may desirably be H, -CH3, -CH(CH3)2, or Cl. In another embodiment, R2 may desirably be H, lower alkyl, e.g., straight or branched C1,C2,C3 (e.g., iso- or tert-butyl), C4 or C5 alkyl, or aryl, e.g., phenyl or fluorophenyl. R1 and R2 may also, taken together with the bonded carbons from the thieno, desirably form a cyclohexyl ring. R3 and R4 are independently H, halogen or R7, wherein H is preferred. 55 [0071] Specific compounds having the formula

13 EP 1 797 099 B1

5

10

wherein 15 R1 and R2 independently are one or more of hydrogen; halogen, halo-substituted alkyl, lower alkyl, C1-C6 cycloalkyl, C3-C6 cycloheteroalkyl, aryl, halo-substituted aryl or heteroaryl; or R1 and R2, taken together, form a C5-C7 cycloalkyl or cycloheteroalkyl ring; R3 and R3 are independently H, halogen, CN or R5; Cy is a single or conjugated substituted or unsubstituted cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; and 20 R4 is hydrogen; halogen, halo-substituted alkyl, lower alkyl, CN, COOH, COOR5,OR5, CONH2, CONHR5, CON(R5)2, halo-substituted or unsubstituted NR5, halo-substituted or unsubstituted SOOR5, aryl, halo-substituted aryl or heteroaryl, C1-C6 cycloalkyl, or C3-C6 cycloheteroalkyl; wherein R5 is a substituted or unsubstituted lower alkyl; and n is 1, 2, 3, 4 or 5. Pharmaceutically acceptable salts and/or esters of Formula III compounds are also provided. 25 [0072] Compounds of the invention may also be 5-HT receptor antagonists, e.g., 5-HT2 receptor antagonists including 5-HT2A, BorC receptors, and desirably 5-HT2B receptor antagonists. [0073] In a particular embodiment; the invention includes those compounds having the formula (Ia)

30

35

40

wherein:

I R1 and R2 are 45

- independently hydrogen; halogen such as Cl, F, Br, I; CN; NO2;NH2; lower alkyl such as Me, Et, n-Pr, i-Pr, n- Bu, i-Bu, t-Bu, n-pentyl, i-amyl, n-hexyl; substituted or unsubstituted phenyl, thiophenyl, furyl, pyridinyl, triazolyl, tetrazolyl, COOH, COO(C1-C6) alkyl, COO(C3-C6) cycloalkyl, CONH(C1-C6) alkyl, CONH(C3-C6) cycloalkyl, CON(C1-C6)2 alkyl, CON(C3-C6)2 cycloalkyl, O-(C1-C6)alkyl, O-(C3-C6) cycloalkyl, C3-C6 cycloalkyl or cy- 50 cloheteroalkyl; mono, di or tri halo-substituted (C1-C6) alkyl; or

- R1 and R2 together with the carbon atoms to which they are bonded form a C4-C7 cycloalkyle or cycloheteroalkyl ring containing hetero atoms such as O, N or S in place of CH2 and which is optionally substituted by 1,2 or 3 identical or different groups, these groups being halogen, OH, Cyano, NO2,NH2,NH(C1-C6) alkyl, NH(C3-C6) 55 cycloalkyl, N(C1-C6)2 alkyl, N(C3-C6)2 cycloalkyl, (C1-C4)- alkyl, C3-C6 cycloalkyl or cycloheteroalkyl, (C1-C4)- alkoxy, (C3-C6) cycloalkoxy, (C1-C4)-haloalkyl, (C1-C4)- haloalkoxy, COOH, COO(C1-C6) alkyl, COO(C3-C6) cycloalkyl, CONH(C1-C6) alkyl, CONH(C3-C6) cycloalkyl, CON(C1-C6)2 alkyl, CON(C3-C6)2 cycloalkyl, mono, di or tri halo-substituted (C1-C6) alkyl; or

14 EP 1 797 099 B1

- R1 and R2 together with the carbon atoms to which they are bonded form an unsaturated 5- or 6- membered carbocyclic ring, which can contain a hetero atom such as O, S or N in place of CH2 and which 5- or 6- membered ring is optionally substituted by 1,2 or 3 identical or different groups, these groups

5 being halogen, OH, Cyano, NO2,NH2,NH(C1-C6) alkyl, NH(C3-C6) cycloalkyl, N(C1-C6)2 alkyl, N(C3-C6)2 cycloalkyl, (C1-C4)- alkyl, C3-C6 cycloalkyl or cycloheteroalkyl, (C1-C4)- alkoxy, (C3-C6) cycloalkoxy, (C1-C4)-haloalkyl, (C1-C4)- haloalkoxy, COOH, COO(C1-C6) alkyl, COO(C3-C6) cycloalkyl, CONH(C1-C6) alkyl, CONH(C3-C6) cycloalkyl, CON (C1-C6)2 alkyl, CON(C3-C6)2 cycloalkyl, mono, di or tri halo-substituted (C1-C6) alkyl;

10 I R3 is selected from the group consisting of H, F, CF3, Cl, Br, I, CN, NH2,C1-C6 alkyl, O-(C1-C6)akoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH(C1-C6) alkyl, NH(C3-C6) cycloalkyl, N(C1-C6)2 alkyl, N(C3-C6)2 cycloalkyl, unsub- stituted or substituted phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl, CH2 aryl, CH2 hetero aryl;

I R4 is H, C1-C6 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted phenyl, pyridinyl, pyrimidinyl, pyrrolyl, CH2 15 aryl, CH2 hetero aryl;

I n is an integer from 0, 1, 2, 3, 4, 5 or 6;

I R5 and R6 are 20 - independently selected from the group consisting of substituted or unsubstituted aryl, arylalkyl, aryloxy groups where in aryl group represents groups like phenyl, naphthyl, thiophenyl, furyl, pyridinyl, quinolinyl, triazolyl, tetrazolyl, hydrogen; halogen such as Cl, F, Br, I; CN; NO2;NH2; lower alkyl such as Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, n-pentyl, i-amyl, n-hexyl etc., or 25 - R5 and R6 together with the carbon atoms to which they are bonded form an unsaturated 5- or 6- membered carbocyclic ring which can contain hetero atoms such as O, S, and N in place of CH2 and in which 5- or 6- membered ring is optionally substituted by 1-5 identical or different radicals, these radicals being halogen, OH, Cyano, NO2,NH2,NH(C1-C6) alkyl, NH(C3-C6) cycloalkyl, N(C1-C6)2 alkyl, N(C3-C6)2 cycloalkyl, (C1-C4)- alkyl, C3-C6 cycloalkyle or cycloheteroalkyl, (C1-C4)- alkoxy, (C3-C6) cycloalkoxy, (C1-C4)-haloalkyl, (C1-C4)- 30 haloalkoxy, COOH, COO(C1-C6) alkyl, COO(C3-C6) cycloalkyl, CONH(C1-C6) alkyl, CONH(C3-C6) cycloalkyl, CON(C1-C6)2 alkyl, CON(C3-C6)2 cycloalkyl,, mono, di or tri halo-substituted (C1-C6) alkyl etc., or - R5 and R6 together with the carbon atoms to which they are bonded form an unsaturated 5- or 6- membered carbocyclic ring which can contain hetero atoms such as O, S, and N in place of CH2 and in which 5- or 6- membered ring is optionally substituted by 1-5 identical or different radicals, in which substitutions on the 35 adjacent carbon atoms may form 5 or 6 membered unsaturated or saturated cyclic rings such as

40

- R5 and R6 together with the carbon atoms to which they are bonded form a saturated 5-, 6-, 7-membered 45 carbocyclic ring which can contain O, S, N, in place of CH2 and which is optionally substituted by 1, 2 or 3 (C1-C6) alkyl groups, OH, NH2, etc., f) Q is any one of

50

55

wherein R8 may be hydrogen, halogen, or a substituted or unsubstituted lower alkyl, and its pharmaceutical compositions, prodrugs and all stereoisomers.

15 EP 1 797 099 B1

[0074] Included in the invention is the use of the compounds disclosed herein for the manufacture of a medicament for treatment of a disease state that can be alleviated by treatment with a 5-HT2B antagonist. In one embodiment the disease state is selected from the diseases pulmonary arterial hypertension, migraine, hypertension, disorders of the gastrointestinal tract, restenosis, asthma, obstructive airway disease, prostatic hyperplasia and priapism. In a related 5 embodiment the disease state comprises inflammatory pain, neuropathic pain, cancer pain, acute pain or chronic pain. In a variant embodiment the disease state comprises allergic asthma, irritable bowel syndrome, hypertonic lower es- ophageal sphincter, motility disorders or benign prostatic hyperplasia. In a further embodiment, the disease state com- prises depression, anxiety, attention deficit hyperactivity disorder, obesity, sleeping disorder, Alzheimer’s disease, or Parkinson disease. 10 [0075] In various embodiments the compound is a 5-HT receptor antagonist, and may be a 5-HT2 receptor antagonist, including, e.g., a 5-HT2A, BorC receptor antagonist. A preferred compound is a 5-HT2B receptor antagonist. [0076] In a specific embodiment, R3 is selected from a group consisting of H, NH2 or CF3. In another embodiment R4 is either H or methyl. Preferably R1 and R2 are independently selected from the group consisting of H, CH3, Et, n-Pr, i- Pr, i- Bu, Cl, CF3, Br, F. When R1 and R2 join together, they may form a cyclic ring such as cyclohexane, cyclopentane, 15 cycloheptane or cyclooctane. Compounds are also provided wherein R5 and R6 are independently selected from a group consisting of H, Me, CF3, Et, n-pr, i-Pr, n-bu, i-Bu, Ph, 3-fluorophenyl, 3-chlorophenyl, 3-cyanophenyl, 3-cyano-4-fluor- ophenyl, phenylcarbonyl, pyridinyl, pyrimidinyl or pyrrolyl. [0077] In another embodiment compounds of the invention include those having the formula

20

25

30

wherein R1 through R4 are as defined for Formula I. Cy is preferably phenyl, but may be a substituted or unsubstituted, saturated or unsaturated 4-, 5-, 6- or 7- membered cycloalkyl or aryl ring. A cycloalkyl or aryl ring may include, e.g., 35 mono-, di-, or tri-substituted phenyl, naphthyl, or biphenyl with lower alkyl, e.g., methyl, ethyl, propyl, allyl, n-butyl, n- pentyl, n-hexyl; alkoxy or aryloxy, e.g., methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclopenty- loxy, halo, e.g., fluoro, chloro, bromo, and iodo; amino, dimethylamino, nitro, cyano, carboxy, carboxy esters, carboxa- mides, N-alkylcarboxamide, N.N-dialkylcarboxamide, trifluoromethyl, trifluoromethoxy, tetrazolo, sulphonyl, thiomethyl, thioethyl, phenylthio, 2,3-methylenedioxy, and 3,4-methylenedioxy. Substituents on Cy are designated R5, which may 40 be hydrogen; halogen, halo-substituted alkyl, lower alkyl, CN, COOH, COOR7,OR7, CONH2, CONHR7, CON(R7)2, halo-substituted or unsubstituted NR7, halo-substituted or unsubstituted SOOR7, aryl, halo-substituted aryl or heteroaryl, C1-C6 cycloalkyl, or C3-C6 cycloheteroalkyl, wherein n is 0,1,2,3,4 or 5, and R7 is a substituted or unsubstituted lower alkyl. The linker group may be branched or unbranched, and p may be 0, 1, 2, 3,4,5,6 or more. Where the linker group is branched, p is 1 or higher, and R6 and R6’ are independently H, halogen, CN or R7, wherein R7 is a substituted or 45 unsubstituted, branched or unbranched lower alkyl. Pharmaceutically acceptable salts and/or esters of Formula II com- pounds are also provided. [0078] Compounds of the invention are useful in the treatment of hypoxia, pulmonary arterial hypertension (PAH) and other hypoxia-induced PAH syndromes caused by chronic obstructive pulmonary disease, mountain sickness, and cardiac valve disease. (Other conditions include congestive heart failure (CHF), chronic obstructive pulmonary disease 50 (COPD), scleroderma, valvular heart disease, cor pulmonale, chronic hypoxic lung conditions, sickle cell anemia, portal hypertension, altitude sickness, congenital heart abnormalities, and respiratory distress syndrome.) Several studies have suggested a role for 5-HT in the etiology of PAH. Furthermore, circulating 5-HT levels are increased (10-30X) in both primary PAH and PAH secondary to anorexigen intake. Recently, it has been demonstrated that 5-HT is not only a potent pulmonary vasoconstrictor, but also a growth amplification factor that possibly plays a crucial role in proliferation 55 of pulmonary vascular smooth muscle cells. It has been shown that isolated smooth muscle and endothelial cells from pulmonary arteries express mRNAs for several 5-HT receptors. Thus, by activating its cognate receptors, 5-HT has a dual effect on the pulmonary vascular beds contributing to both vasoconstriction and vascular remodeling that are associated with PAH.

16 EP 1 797 099 B1

[0079] 5-HT2B receptors are found in pulmonary arteries in rats and humans and are up-regulated in PAH patients. Moreover, metabolites of anorexigens such as Redux or Fen-Phen, have been associated with an increased risk of primary PAH and are potent 5-HT2B receptor agonists. In a recent pivotal study using the chronic-hypoxic-mouse model of pulmonary hypertension, Lanuay and colleagues (2002) showed that 5-HT2B antagonists can prevent arterial hyper- 5 trophy in hypoxia-induced PAH in mice by blocking smooth muscle cell proliferation. Mice with genetically inactive 5- HT2B receptors did not demonstrate the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling that was observed in the wild type mice. In addition, Teoh et al. (2005) recently demonstrated that 5-HT2B receptor protein expression is increased in arteries taken from rats exposed to hypoxic conditions for 16-48 hours, suggesting that 5-HT2B receptors play a crucial role in hypoxia-induced PAH. Overall, these findings suggest that 5-HT2B antagonists 10 can potentially induce selective and sustained pulmonary vasodilatation in patients with hypoxic or primary pulmonary hypertension without having a marked effect on systemic arterial pressure and therefore afford both acute and chronic treatment for PAH. [0080] The new compounds of the invention, such as those of formula IIL, are highly selective. For example, 5-((4-(6- Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluoro benzonitrile ("compound A") is a highly selective 15 and potent(Ki =1.8 nM) 5-HT2B receptor antagonist with more than 500-fold differences in receptor affinities for compared with all other 5-HT receptor subtypes, except for the 5-HT1A(Ki = 100nM) receptor. This compound has almost no affinity (Ki >1mM) for more than 51 receptors tested including GPCRs, ion channels and receptor tyrosine kinases; and is active on the dopamine D4.4 receptor (Ki = 5.4 nM) and displays moderate activity for the dopamine D3 receptor (Ki ∼ 310 nM). However, blocking of the dopamine D3 and D4 receptors is not associated with extrapyramidal side effects. 20 Compound A appears to be a weak dopamine D2 receptor (IC50 = 0.67mM) antagonist and did not show any dopamine D1 and D5 receptor activity (Ki >5mM). Compound A displayed moderate binding to the σ1 and σ2 receptors (Ki =100 nM and 110 nM, respectively). However, in functional assays the compound demonstrated very weak agonist activity for σ receptors (EC50 ≈ 10 mM). [0081] In in vitro functionality assays, compound A potently inhibits the 5-HT-induced inositol phosphate formation, 25 with an IC50 = 0.79 nM, without affecting basal inositol levels (indicating that the compound does not possess any inverse agonist activity). In the rat stomach fundus assay, the compound inhibited the 5-HT-induced contractile response with a calculated IC50 of ∼27 nM. In a series of in vitro studies designed to test the effect of compound A on the 5-HT-induced vascular muscularization, the compound inhibited the 5-HT-induced mitogen-activated protein kinase (MAPK) activation (IC50 ≈ 12nM) and markedly reduced thymidine incorporation (IC50 ≈ 3nM) in Chinese Hamster Ovary (CHO) cells 30 expressing the human 5-HT2B receptor. These studies confirm that 5-HT2B receptor inhibitors have the potential to block the 5-HT-mediated mitogenic activity through this receptor and therefore indicate that compounds of the invention can be effective inhibitors of 5-HT2B receptor-mediated pulmonary vascular remodeling. Compound A was also able to inhibit 5-HT-induced contraction in endothelial denuded pulmonary arterial rings from normoxic and hypoxic rats, with IC50s of - 5nM and a maximal inhibition of 60-70% of the 5-HT-induced contraction. The vasodilatory effect of compound A 35 was confirmed by measuring the right ventricular systolic pressure (RVSP) in the chronic-hypoxic-mouse model of pulmonary hypertension following administration of PRX-08066 (50 mg/kg i.p.). Administration of the compound (60 minutes pre-measurement) produced an acute decrease of the RVSP (human equivalent dose 4-5mg/kg or ≈ 300mg), similar to that measured following administration of 5-HT2B receptor antagonist RS-127445 (Roche/Syntex; 20 mg/kg i.p.). The compound also showed 41.87% inhibition of the hERG channel at 1mM (estimated IC50 = 1.4mM), which 40 compares favorably with other serotonergic agents (e.g., hERG IC50s for ondansetron, citalopram, and fluoxetine are 0.81 mM (Kuryshev et al. 2000), 3.97mM and 1.50mM (Witchel et al. 2002), respectively. [0082] Together, these findings suggest that compounds of the invention such as those of formula III may be used for treating patients with PAH with a rapid effect on exercise tolerance (quality of life) due to its direct and selective vasodilatory action on pulmonary smooth muscle cells (PSMC) and a disease modifying agent by means of inhibiting 45 the disease progression as a result of blocking the 5-HT-mediated detrimental mitogenic effect on pulmonary arterial SMC. [0083] Congestive heart failure (CHF) is significant area of medical need. Heart failure is most commonly a chronic condition that is often associated with remodeling of the heart, leading to enlargement of the myocardium (hypertrophy.) These maladaptive changes lead to increased morbidity and mortality, so there is a need for new treatments in this area. Cardiac remodeling (ventricular hypertrophy and dilation) is a prelude to heart failure, and a characteristic of established 50 heart failure. Myocardium remodeling is associated with myocyte growth, dysregulation of myocyte function and mocyte apoptosis. Pathological hypertrophy is often mediated by up-regulation of systemic and/or local mediators wuch as angiotensin II and endothelin. These mediators activate Gq-coupled receptors which are thought to play a major role in the cardiac hypertrophic response. Sustained or excessive activation of the Gq signaling pathway has been noted to result in myocyte hypertrophy and apoptosis. 55 [0084] Studies by Nebigil et al. have noted the role of the 5-HT2B receptor in cardiac development. Inactivation of the gene leads to embryonic and neonatal death caused by heart defects. Surviving newborns display a severe ventricular hypoplasia caused by impaired proliferative capacity of myocytes and adult mice consistently exhibited myocyte disarray and ventricular dilation. Ablation of the Gq-coupled receptors in mice leads to cardiomyopathy with left ventricular

17 EP 1 797 099 B1

dysfunction, dilation and an abnormal tissue structure, consistent with that of dilated cardiomyopathy, but no morpho- logical signs of hypertrophy or hypertrophy related gene expression were found. Overexpression of the 5-HT2B receptor in mice hearts was found to lead to cardiac hypertrophy, accompanied by mitochondrial proliferation and enzyme activity. Overexpression of Gq-coupled receptors including 5-HT2B or their signaling molecules, GQ, phospholipase C, or p39 5 MAPK, is believed to trigger a hypertrophic response (optionally including extensive hypertrophy) that leads to cardiac hypertrophy. A study by Rothman et al. implies that activation of 5-HT2B receptors can produce valvular heart disease, but serotonergic compounds that are not 5-HT2B receptor-specific are unlikely to produce valvular heart disease. [0085] Myotonia is induced by any of a number of factors or a combination thereof for example, cervico-omo-brachial syndromes accompanying stiffness or pain in the neck, shoulder, arm, lumbar and dorsal skeletal muscles due to 10 abnormal posture, fatigue, changes in the backbone with aging etc., shoulder periarthritis accompanying inflammation in the tissues constituting the shoulder joint due to changes in the shoulder joint caused by trauma, and the like, and spastic paralysis wherein accelerated limb muscle tonus hinders voluntary movements. In particular, spastic paralysis is a disease which accompanies limb muscle tonus, stiffening, walking difficulty, etc., and thus seriously restrains daily life. These conditions have been treatable with central or peripheral muscle relaxants, e.g., central muscle relaxants 15 like Tolperisone hydrochloride, Baclofen, Tizanidine hydrochloride, Chlorzoxazone, and Diazepam; and peripheral mus- cle relaxants such as suxamethonium chloride, Pancuronium bromide, and dantrolene sodium. [0086] Central muscle relaxants act selectively on the central nervous system so as to relax muscles. Therefore, it is expected that those action on the upper center would exhibit a more potent muscle relaxant effect. However, there arise at the same time some problems including extrapyramidal symptoms and neurologic manifestations such as sleepiness, 20 sluggishness, and atony. It is believed that the compounds of the invention, e.g., those of formula III, may be used as a muscle relaxant and avoid the above problems. [0087] Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I effective in treating conditions associated with vascular disorders, e.g., angina, migraine, pulmonary hy- pertension and systemic hypertension. 25 [0088] Another aspect of the invention is a method of treating conditions associated with vascular disorders, e.g., angina, migraine, pulmonary hypertension and systemic hypertension. [0089] The compounds of the invention are valuable for treating a wide variety of clinical conditions which are char- acterized by serotonin excess or absence, e.g., serotonergic hypofunction or hyperfunction. Such conditions include schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delu- 30 sional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallu- cinations; gastrointestinal disorders like Crohn’s disease, eating disorders, neuralgia, and addiction disorders; obsessive compulsive disorders, panic disorders, sexual dysfunctions caused by the central nervous system and disturbances in sleep and the absorption of food, alcoholism, pain, memory deficits, unipolar depression, dysthymia, bipolar depression, treatment-resistant depression, depression in the medically ill, panic disorder, obsessive-compulsive disorder, eating 35 disorders, social phobia, premenstrual dysphoric disorder, mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder, anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, e.g., specific animal phobias, social phobias, stress disorders including post-traumatic stress disorder and acute stress dis- 40 order, and generalized anxiety disorders; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer’s disease, senile dementia, dementia of the Alzheimer’s type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson’s disease, Huntington’s disease, Pick’s disease, Creutzfeldt-Jakob disease, or due to multiple etiologies; Parkinson’s disease and other extrapyramidal move- ment disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neu- 45 roleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-in- duced tardive dyskinesia and medication-induced postural tremor, substance-related disorders arising from the use of alcohol, amphetamines (or amphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which sub- stance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication delirium, withdrawal de- 50 lirium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep dis- orders; epilepsy; Down’s syndrome; demyelinating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid hemorrhage or cerebral edema. 55 [0090] Compounds of the invention may be used for the treatment of the above conditions, as well as for vasodilation, smooth muscle contraction, bronchoconstriction, brain disorders such as vascular disorders, e.g., blood flow disorders caused by vasodilation and vasospastic diseases such as angina, vascular headache, migraine and Reynaud’s disease; pulmonary hypertension and systemic hypertension; and neuropathological disorders including Parkinson’s disease and

18 EP 1 797 099 B1

Alzheimer’s disease; modulation of the cardiovascular system; prophylaxis and control of the effects of occurrences of cerebral infarct (Apoplexia cerebri) such as stroke or cerebral ischemia; and for the control of disorders of the intestinal tract which are characterized by disturbances of the serotoninergic system and also by disturbances of the carbohydrate metabolism. 5 [0091] The compounds may also be useful in treating a variety of other conditions including stress-related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia and incontinence; and pain or nociception attributable to or associated with any of the foregoing conditions, especially pain transmission in migraine. [0092] For treating certain conditions it may be desirable to employ the compounds of the invention in conjunction 10 with another pharmacologically active agent. The compounds of the invention may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use. Such combined preparations may be, for example, in the form of a twin pack. [0093] Compounds of the invention may be used in combination with a or another 5-HT antagonist and/or SSRI, e.g., a5-HT3 antagonist such as ondansetron, granisetron, tropisetron or zatisetron. Additionally, the compounds of the 15 invention may be administered in combination with an anti-inflammatory corticosteroid, such as dexamethasone. Fur- thermore, the compounds of the invention may be administered in combination with a chemotherapeutic agent such as an alkylating agent, anti-metabolite, mitotic inhibitor or cytotoxic antibiotic, as described above. In general, the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable. [0094] According to a further or alternative aspect, the invention provides compounds of the invention for use in the 20 manufacture of a medicament for the treatment or prevention of physiological disorders associated with serotonin excess or absence, e.g., serotonergic hypofunction or hyperfunction. [0095] Compounds of the invention may be used in methods for treating or preventing physiological disorders asso- ciated with serotonin excess or absence, e.g., serotonergic hypofunction or hyperfunction, which method comprises administration to a patient in need thereof of an effective amount of a compound of the invention or a composition 25 comprising a compound of the invention. [0096] For treating or preventing migraine, the compounds of the invention may be used in conjunction with other anti- migraine agents, such as ergotamines or 5-HT1 agonists, especially sumatriptan or rizatriptan. Likewise, for treating behavioral hyperalgesia, the compounds of the invention may be used in conjunction with an antagonist of N-methyl D- aspartate (NMDA), such as dizocilpine. 30 [0097] It will be further appreciated that for treating or preventing depression and/or anxiety, the compounds of the invention may be used in combination with an antidepressant agent or anti-anxiety agent. Suitable classes of antide- pressant agents of use in the invention include: norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, reversible monoamine oxidase inhibitors, serotonin and noradrenaline reuptake inhibitors, corticotropin releasing factor (CRF) antagonists, β-adrenoreceptor antagonists and atypical antidepressants. Another 35 class of antidepressant agent of use in the invention is noradrenergic and specific serotonergic antidepressants, such as mirtazapine. Suitable examples of norepinephrine reuptake inhibitors include amitripdyline, clomipramine, doxepine, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, reboxetine and protriptyline and pharma- ceutically acceptable salts thereof. Suitable examples of selective serotonin inhibitors include fluoxetine, fluvoxamine, paroxetine, and sertraline and pharmaceutically acceptable salts thereof. Suitable examples of monoamine oxidase 40 inhibitors include isocarboxazid, phenelzine, tranylcypromain and selegiline, and pharmaceutically acceptable salts thereof. Suitable examples of reversible monoamine oxidase inhibitors include moclobemide, and pharmaceutically acceptable salts thereof. Suitable examples of serotonin and noradrenaline reuptake inhibitors include venlafaxine, and pharmaceutically acceptable salts thereof. Suitable examples of corticotropin releasing factor (CRF) antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, 45 WO 94/13676 and WO 94/13677. Suitable examples of atypical antidepressants include bupropion, lithium, nefazoedone, sibutramine, trazodone and viloxazine, and pharmaceutically acceptable salts thereof. Other antidepressants of use in the invention include adinozolam, alaproclate, amineptine, amitryptyline/chlordiazepoxide combination, atipamezole, azamianserin, bazinaprine, fefuraline, bifemelane, binodaline, bipenamol, brofaromine, bupropion, caroxazone, ceri- clamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dasepinil, deanol, demexiptiline, dibenzepin, 50 dothiepin, droxidopa, enefexine, setazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, in- dalpine, indeloxazine, iprindole, levoprotiline, litoxetine, lofepramine, medifoxamine, metapramine, metralindole, mian- serin, milnacipran, minaprine, mirtazapine, montirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, orotirelin, oxaflozane, pinazepam, pirindole, pizotyline, ritaserin, rolipram, sercloremine, setiptiline, sibutramine, sulbu- tiamine, sulpride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin, tofisopam, toloxatone, to- 55 moxetine, veralipride, viqualine, zimelidine, and zometapine, and pharmaceutically acceptable salts thereof, and St. John’s wort herb, or Hypericum perforatum, or extracts thereof. Preferred antidepressant agents include selective se- rotonin reuptake inhibitors, in particular, fluoxetine, fluvoxamine, paroxetine, and sertraline and pharmaceutically ac- ceptable salts thereof.

19 EP 1 797 099 B1

[0098] Suitable classes of anti-anxiety agents of use in the invention include benzodiazepines and 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. In addition to benzodiazepines, other suitable classes of anti-anxiety agents are nonbenzodiazepine sedative-hypnotic drugs such as zolpidem; mood-stabilizing drugs such as clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stirip- 5 entol and vigabatrin; and barbiturates. Suitable benzodiazepines of use in the invention include alprazolam, chlord- izepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorezepam, oxazepam and prazepam, and pharmaceuti- cally acceptable salts thereof. Suitable examples of 5-HT1A agonists or antagonists of use in the invention include, in particular, the 5-HT1A partial agonists buspirone, flesinoxan, gepirone, ipsapirone and pindolol, and pharmaceutically acceptable salts thereof. Another class of anti-anxiety agent of use in the invention are compounds having muscarinic 10 cholinergic activity. Suitable compounds in this class include ml muscarinic cholinergic receptor antagonists such as those compounds described in European Patent Specification Nos. 0 709 093, 0 709 094 and 0 773 021 and International Patent Specification No. WO 96/12711. Another class of anti-anxiety agent of use in the invention are compounds acting on ion channels. Suitable compounds in this class include carbamazepine, lamotrigine and valproate, and pharmaceu- tically acceptable salts thereof. 15 [0099] Therefore, in a further aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention and an antidepressant or an anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient. [0100] Suitable antipsychotic agents of use in combination with the compounds of the invention include phenothiazines, e.g., chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine; thi- 20 oxanthenes, e.g., chlorprothixene or thiothixene; heterocyclic dibenzazepines, e.g., clozapine or olanzapine; butyroph- enones, e.g., haloperidol; diphenylbutylpiperidines, e.g., pimozide; and indolones, e.g., molindolene. Other antipsychotic agents include loxapine, sulpiride and risperidone. It will be appreciated that the antipsychotic agents when used in combination with the compounds of the invention may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphena- 25 zine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydro- chloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, cloz- apine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. [0101] Other classes of antipsychotic agent of use in combination with the compounds of the invention include dopamine receptor antagonists, especially D2, D3 and D4 dopamine receptor antagonists, and muscarinic ml receptor agonists. 30 An example of a D3 dopamine receptor antagonist is the compound PNU-99194A. An example of a D4 dopamine receptor antagonist is PNU-101387. An example of a muscarinic ml receptor agonist is xanomeline. [0102] Another class of antipsychotic agent of use in combination with the compounds of the invention is the 5-HT2A receptor antagonists, examples of which include MDL100907 and fananserin. Also of use in combination with the com- pound of the invention are the serotonin dopamine antagonists (SDAs) which are believed to combine 5-HT2A and 35 dopamine receptor antagonist activity, examples of which include olanzapine and ziperasidone. [0103] Therefore, in a further aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention and an antipsychotic agent, together with at least one pharmaceutically acceptable carrier or excipient. [0104] The compounds of the invention and another other pharmacologically active agent may be administered to a patient simultaneously, sequentially or in combination. It will be appreciated that when using a combination of the 40 invention, the compound of the invention and the other pharmacologically active agent may be in the same pharmaceu- tically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term "combination" further refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. [0105] The compounds of the invention may be administered to patients (animals and humans) in need of such 45 treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. 50 [0106] In the treatment of a condition associated with a serotonin excess or absence, e.g, serotonergic hypofunction or hyperfunction, an appropriate dosage level will generally be about 0.001 to 50 mg per kg patient body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. For example, in the treatment or prevention of a disorder of the central nervous system, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 55 mg/kg per day, and especially about 0.01 to 1 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. [0107] It will be appreciated that the amount of the compound of the invention required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature

20 EP 1 797 099 B1

of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician. [0108] The compositions and combination therapies of the invention may be administered in combination with a variety of pharmaceutical excipients, including stabilizing agents, carriers and/or encapsulation formulations as described herein. 5 [0109] Aqueous compositions of the present invention comprise an effective amount of the peptides of the invention, dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. [0110] "Pharmaceutically or pharmacologically acceptable" include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. "Pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and anti- 10 fungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. [0111] For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards 15 as required by FDA Office of Biologies standards. [0112] The compositions and combination therapies of the invention will then generally be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes. The preparation of an aqueous composition that contains a composition of the invention or an active component or ingredient will be known to those of skill in the art in light of the present disclosure. Typically, such 20 compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. [0113] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formu- lations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous 25 preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. [0114] Solutions of active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid 30 polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. [0115] Therapeutic or pharmacological compositions of the present invention will generally comprise an effective amount of the component(s) of the combination therapy, dissolved or dispersed in a pharmaceutically acceptable medium. Pharmaceutically acceptable media or carriers include any and all solvents, dispersion media, coatings, antibacterial 35 and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Supplementary active ingredients can also be incorporated into the therapeutic compositions of the present invention. [0116] The preparation of pharmaceutical or pharmacological compositions will be known to those of skill in the art in light of the present disclosure. Typically, such compositions may be prepared as injectables, either as liquid solutions 40 or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection; as tablets or other solids for oral administration; as time release capsules; or in any other form currently used, including cremes, lotions, mouth- washes, inhalants and the like. [0117] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. 45 Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum- drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. 50 [0118] The preparation of more, or highly, concentrated solutions for intramuscular injection is also contemplated. In this regard, the use of DMSO as solvent is preferred as this will result in extremely rapid penetration, delivering high concentrations of the active compound(s) or agent(s) to a small area. [0119] The use of sterile formulations, such as saline-based washes, by surgeons, physicians or health care workers to cleanse a particular area in the operating field may also be particularly useful. Therapeutic formulations in accordance 55 with the present invention may also be reconstituted in the form of mouthwashes, or in conjunction with antifungal reagents. Inhalant forms are also envisioned. The therapeutic formulations of the invention may also be prepared in forms suitable for topical administration, such as in cremes and lotions. [0120] Suitable preservatives for use in such a solution include benzalkonium chloride, benzethonium chloride, chlo-

21 EP 1 797 099 B1

robutanol, thimerosal and the like. Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in amounts sufficient to maintain the pH at between about pH 6 and pH 8, and preferably, between about pH 7 and pH 7.5. Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, 5 and the like, such that the sodium chloride equivalent of the ophthalmic solution is in the range 0.9 plus or minus 0.2%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpro- pylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, car- 10 boxymethylcellulose and the like. [0121] Upon formulation, therapeutics will be administered in a manner compatible with the dosage formulation, and in such amount as is pharmacologically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. [0122] In this context, the quantity of active ingredient and volume of composition to be administered depends on the 15 host animal to be treated. Precise amounts of active compound required for administration depend on the judgment of the practitioner and are peculiar to each individual. [0123] A minimal volume of a composition required to disperse the active compounds is typically utilized. Suitable regimes for administration are also variable, but would be typified by initially administering the compound and monitoring the results and then giving further controlled doses at further intervals. For example, for parenteral administration, a 20 suitably buffered, and if necessary, isotonic aqueous solution would be prepared and used for intravenous, intramuscular, subcutaneous or even intraperitoneal administration. One dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermolysis fluid or injected at the proposed site of infusion, (see for example, Remington’s Pharmaceutical Sciences 15th Edition, pages 1035-1038 and 1570-1580). [0124] In certain embodiments, active compounds may be administered orally. This is contemplated for agents which 25 are generally resistant, or have been rendered resistant, to proteolysis by digestive enzymes. Such compounds are contemplated to include chemically designed or modified agents; dextrorotatory peptides; and peptide and liposomal formulations in time release capsules to avoid peptidase and lipase degradation. [0125] Pharmaceutically acceptable salts include acid addition salts and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the 30 like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, his- tidine, procaine and the like. [0126] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable 35 oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorob- utanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the 40 use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. [0127] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of 45 sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum- drying and freeze drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [0128] The preparation of more, or highly, concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the 50 active agents to a small area. [0129] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. [0130] For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if 55 necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connec- tion, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. [0131] In addition to the compounds formulated for parenteral administration, such as intravenous or intramuscular

22 EP 1 797 099 B1

injection, other pharmaceutically acceptable forms include, e.g., tablets or other solids for oral administration; liposomal formulations; time-release capsules; and any other form currently used, including cremes. [0132] Additional formulations suitable for other modes of administration include suppositories. For suppositories, traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may 5 be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1%-2%. [0133] Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of man- nitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders. Oral formulations of compounds of the invention, e.g., compounds of formula III, may desirably be formulated for once 10 or twice-daily administration. [0134] In certain defined embodiments, oral pharmaceutical compositions will comprise an inert diluent or assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, 15 suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 75% of the weight of the unit, or preferably between 25-60%. The amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained. [0135] The tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, 20 acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. 25 For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup of elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabensas preservatives, a dye and flavoring, such as cherry or orange flavor. [0136] The pharmaceutical compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the invention, as an active 30 ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically ac- ceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in 35 manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease. [0137] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, mag- 40 nesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid prefor- mulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then 45 subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component 50 to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. [0138] The liquid forms in which the compositions of the invention may be incorporated for administration orally or by injection include aqueous solution, suitably flavored syrups, aqueous or oil suspensions, and emulsions with acceptable 55 oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, or with a solubilizing or emulsifying agent suitable for intravenous use, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium car- boxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

23 EP 1 797 099 B1

[0139] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable sol- 5 vents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. [0140] For treating clinical conditions and diseases noted above, the compound of this invention may be administered 10 orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes sub- cutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. [0141] Methods for preparing compounds of the invention are illustrated below and in the following Examples. The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the 15 invention.

20

25

30

35

40

45

50 Preparation 1:

[0142]

55

24 EP 1 797 099 B1

5

[0143] A mixture of amino ester derivative 2 (1 mmol) and ammonium formate (1.5 mmol) in formamide (4 mL) was 10 heated at reflux for 12 h. Completion of reaction was monitored via TLC. The reaction mixture was allowed to cool to room temperature and then poured into ice (50 g) to afford a creamy precipitate. The precipitate was collected by filtration, and recrystallized from acetone/water to give 3 in 70-90 % yields.

Preparation 2: 15 [0144]

20

25 [0145] A mixture of thieno[2,3-d]pyrimidin 4-ol derivative 3 (3.7 mmol), thionyl chloride (5.5 mL) and dry DMF (0.5 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature and the excess thionyl chloride was removed by vacuum distillation. To the resulting residue 200 g of ice was added and extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The product was purified by silica chromatography (100 % DCM) to afford 4-chloro-thieno[2,3-d]-pyrimidine 4 in 80-95 % yields. 30 Preparation 3:

[0146]

35

40

45 [0147] To a mixture of 4-N-Boc-amino piperidine derivative 5 (10 mmol) and aromatic aldehyde 6 (10 mmol) in 40mL of DCM or DCE (1,2-dichloroethane) was added sodium triacetoxyborohydride (15 mmol) followed by acetic acid (20 mmol) under N2 atmosphere. The resulting cloudy mixture was stirred at room temperature for 16h and quenched with aq.NaHCO3 solution. The product was extracted with EtOAc, dried (Na2SO4) and the solvent was evaporated to get the product 8 in 90-95 % yields. 50 Preparation 4:

[0148]

55

25 EP 1 797 099 B1

5

10 [0149] To a mixture of 4-N-Boc-amino piperidine 5 (10 mmol) and N,N-diisopropylethylamine (30 mmol) in 30 mL of CH3CN under N2 atmosphere was added intermediate 7 (10 mmol) at room temperature. The resulting mixture was heated at 80˚C for 16h. The reaction mixture was quenched with aq. NaHCO3 and the product was extracted with EtOAc. The organic extract was dried (Na2SO4) and the solvent was evaporated under reduced pressure to get the product 8 in 80-94% yields. 15 Preparation 5:

[0150]

20

25

[0151] The N-Boc-protection of crude 4-N-Boc-aminobenzyl piperidine derivative 8 was removed by either treating with 25% TFA-DCM at room temperature for 2h or with 2M HCl in Et2O solution at room temperature for 16-20h. In both 30 cases, the solvent was evaporated followed by addition of dry Et2O. The resulting precipitate was filtered, washed several times with dry Et2O and dried under vacuum to afford the corresponding salts of 4-amino-1-benzyl piperidine derivative 9. The free base was either isolated or generated in situ during the next coupling step.

Preparation 6: 35 [0152]

40

45

[0153] To a solution of 4-amino-piperidines 9 (1 mmol) in acetonitrile (5mL) under N2 was added N,N-diisopropyl- ethylamine (4 mmol) followed by chloro-thienopyrimidine 4 (1 mmol). The resulting solution was heated at reflux for 50 24-48 h (monitored by TLC). The solvent was evaporated and the resulting solid was dissolved in EtOAc (20mL) and washed with aq. NaHCO3 (10mL) and brine solution (10mL). The organic layer was dried (Na2SO4), concentrated and purified by silica chromatography (1% MeOH in DCM) to afford 10 in 55-60% yields.

Preparation 7: 55 [0154]

26 EP 1 797 099 B1

5

10 [0155] To a solution of 10 (1mmol) in dry DCM (1 mL) was added 2 M HCl in ether (10 mL) at 0˚C and stirred at the same temperature for 1 h. The precipitated product was filtered, washed with dry Et2O and dried under vacuum to afford pure compounds 1a in 90-94 % yields.

Preparation 8: 15 [0156]

20

25

[0157] To a solution of 10 (1 mmol) in dry EtOH / DCM (2 mL) was added maleic acid (1 mmol) in EtOH (5 mL) at room temperature and stirred for 1 h. The reaction mixture was diluted with diethyl ether (5 mL) and cooled to 0˚C for 30 6-8 h. The precipitated product was filtered, washed with dry Et2O and dried under vacuum to afford pure compounds 1b in 70-94 % yields.

35

40

45

50

55

27 EP 1 797 099 B1

Preparation 9:

[0158]

5

10

[0159] To a solution of 1-Boc-4-amino-piperidine 11 (2 mmol) in acetonitrile (5 mL) was added N,N-diisopropyl ethyl- amine (4 mmol) and stirred for 5 min. at room temperature under N2. Chloro-thienopyrimidine 4 was added to the mixture 15 and the contents were heated at reflux for 16 h (monitored by TLC). The solvent was evaporated and to the residue EtOAc (20mL) and water (10mL were added. The organic layer was dried (MgSO4) and concentrated to yield crude product It was purified by silica chromatography (1% MeOH in DCM) to afforded the pure products 12 in 55-70% yields.

Preparation 10: 20 [0160]

25

30 [0161] The Boc-protection of 12 was removed by either treating with 25 % TFA-DCM at room temperature for 2 h or with 2 M HCl in Et2O solution at room temperature for 16-20h. In both cases, the solvent was evaporated followed by addition of dry Et2O. The resulting precipitate was filtered, washed several times with dry Et2O and dried under vacuum to afford the salts 13 in 95-97% yields. The corresponding free base was either isolated or generated in situ during the 35 next coupling step.

Preparation 11:

[0162] 40

45

50 [0163] To a mixture of 13 (10 mmol) and aldehyde 6 (10 mmol) in 40 mL of DCM or DCE (1,2-dichloroethane) under N2 atmosphere was added sodium triacetoxyborohydride (15 mmol) followed by acetic acid (20 mmol) at room temper- ature. The resulting cloudy mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding aq. NaHCO3, and the product was extracted with EtOAc. The EtOAc extract was dried (MgSO4) and the solvent was evaporated to give the crude product. Purification by silica gel or crystallization afforded the pure products 10 in 55 90-95 % yields.

28 EP 1 797 099 B1

Preparation 12:

[0164]

5

10

[0165] To a mixture of 13 (10 mmol) and N,N-diisopropylethylamine (30 mmol) in 30 mL of CH3CN was added inter- mediate 7 (10 mmol) at room temperature under N2 atmosphere. The resulting mixture was stirred at reflux for 16 h. 15 The reaction mixture was quenched with aq.NaHCO3 and the product was extracted with EtOAc. The organic extract was dried (Na2SO4) and the solvent was evaporated to give the product 10 in 80-94 % yields. [0166] Non-limiting examples of reaction conditions for various compositions encompassed within the invention are provided below. Where the compounds set out within the following examples do not fall within the scope of the appended claims, they are provided as reference examples for illustrative purposes only. 20 Example 1

N-(1-(3,5-Diflaorobenzyl)piperidin-4-yl)-6-isopropylthieno[2,3-d]pyrimidin-4-amine, monomaleate.

25 [0167]

30

35

[0168] The title compound was prepared (36 mg, 75 %) from N-(1-(3,5-difluorobenzyl)piperidin-4. yl)-6-isopropylthieno 40 [2,3-d]pyrimidin-4-amine (38 mg, 0.095 mmol) by following the procedure described for preparation 8. 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, IH), 7.65 (bs, 1H),7.35 (m, 2H), 7.25 (d, 2H), 6.05 (s, 2H), 4.20 (m, 3H), 3.30 (m, 2H), 3.00 (m, 2H), 2.10 (m, 2H), 1.80 (m, 2H), 1.30 (d, 6H); MS (ESI) m/z: Calculated: 402.5; Observed: 403.2 (M++1).

Example 2 45 N-(1-(3,5-Difluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3d]pyrimidin-4-amine, monomaleate.

[0169]

50

55

29 EP 1 797 099 B1

5

10

[0170] The title compound was prepared (10 mg, 64 %) from N-(1-(3,5-difluorobenzyl)piperidinyl)-6-chlorothieno[2,3-d] pyrimidin-4-amine (12 mg, 0.03 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, 15 CD3OD) δ 833 (s, 1H), 7.46 (s, 1H), 7.18 (m, 3H), 6.23 (s, 2H, maleate), 4.38 (m, 1H), 4.30 (s, 2H), 3.51 (m, 2H), 3.16 + (m, 2H), 2.31 (m, 2H), 1.93 (m, 2H); MS (ESI) m/z: Calculated for C18H18ClF2N4S, 395.09; Observed: 395.0 (M +1).

Example 3

20 N-(1-(3-Fluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine, monomaleate

[0171]

25

30

35 [0172] The title compound was prepared (35 mg, 79 %) from N-(1-(3-fluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d] pyrimidin-4-amine (34 mg, 0.09 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.53 (m, 1H), 7.47 (s, 1H), 7.36-7.24 (m, 3H), 6.26 (s, 2H, maleate), 4.40 (m, 1H), 4.33 (s, 2H), 3.53 (m, 2H), 3.19 (m, 2H), 2.32 (m, 2H), 1.93 (m, 2H); MS (ESI) m/z: Calculated for C18H19ClFN4S, 377.1; Observed: 40 377.2 (M++1).

Example 4

N-(1-(2-Fluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine, monomaleate 45 [0173]

50

55

30 EP 1 797 099 B1

[0174] The title compound was prepared (80 mg, 96 %) from N-(1-(2-fluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d] pyrimidin-4-amine (64 mg, 0.17 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 7.57 (m, 2H), 7.47 (s, 1H), 7.32 (m, 2H), 6.25 (s, 2H, maleate), 4.41 (m, 3H), 3.59 (d, 2H), 3.29 + (m, 2H), 2.32 (d, 2H), 1.95 (m, 2H); MS (ESI) m/z: Calculated for C18H19ClFN4S, 377.1; Observed: 377.2 (M +1). 5 Example 5

3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoic acid monomaleate

10 [0175]

15

20

[0176] The title compound was prepared (45 mg, 85 %) from 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin- 25 1-yl)methyl)benzoic acid (41 mg, 0.10 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, CD3OD) δ. 8.27. (s, 1H), 7.92 (s, 1H), 7.86 (d,1H), 7.50 (s,1H), 7.42 (d, 1M, 7.33 (t, 1H), 6.02 (s, 2H, maleate), 4.11 (m, 1H), 3.60 (s, 2H), 2.98 (d, 2H), 2.21 (t, 2H), 2.01 (d, 2H), 1.69 (m, 2H); MS (ESI) m/z: Calculated for C19H20ClN4O2S, 403.1; Observed: 403.2 (M++1).

30 Example 6

3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzamide, monomaleate

[0177] 35

40

45 [0178] The title compound was prepared (17 mg, 94 %) from 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin- 1-yl)methyl)benzamide (14 mg, 0.04 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 8.09 (s, 1H), 8.00 (d, 1H), 7.78 (d, 1H), 7.61 (t, 1H), 7.50 (s, 1H), 6.27 (s, 2H, maleate), 4.44 (m, 3H), 3.60 (d, 2H), 3.27 (t, 2H), 2.32 (d, 2H), 1.99 (m, 2H); MS (ESI) m/z: Calculated for C19H21ClN5OS, 402.1; 50 Observed: 402.2 (M++1).

Example 7

3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzonitrile monomaleate 55 [0179]

31 EP 1 797 099 B1

5

10

[0180] The title compound was prepared (25 mg, 94 %) from 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin- 1-yl)methyl)benzonitrile (20 mg, 0.05 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, 15 CD3OD) δ 8.33 (s, 1H), 7.92 (s, 1H), 7.86 (m, 2H), 7.69 (t, 1H), 7.47 (s, 1H), 6.26 (s, 2H, maleate), 4.39 (m, 1H), 4.36 (s, 2H), 3.52 (m, 2H), 3.17 (m, 2H), 2.31 (m, 2H), 1.93 (m, 2H); MS (ESI) m/z: Calculated for C19H19CIN5S, 384.1; Observed: 384.2 (M++1).

Example 8 20 5-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluoro benzonitrile, monomaleate

[0181]

25

30

35

[0182] The title compound was prepared (86 mg, 99 %) from 5-((4-(6-chlorothieno[2,3-d] pyrimidin-4-ylamino)piperidin- 1-yl)methyl)-2-fluorobenzonitrile (67 mg, 0.17 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.95 (m, 1H), 7.86 (m, 1H), 7.50 (t, 1H), 7.46 (s, 1H), 6.26 (s, 1H), 4.38 (m, 1H), 4.30 40 (s, 2H), 3.47(m, 2H), 3.13 (m, 2H), 2.31 (m, 2H), 1.90 (m, 2H); ); MS (ESI) m/z: Calculated for C19H18ClFN5S, 402.1; Observed: 402.2 (M++1).

Example 9

45 6-Chloro-N-(1-((pyridin-3-yl)methyl)piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine, monomaleate

[0183]

50

55

32 EP 1 797 099 B1

[0184] The title compound was prepared (117 mg, 91 %) from 6-chloro-N-(1-((pyridin-3-yl)methyl)piperidin-4-yl)thieno [2,3-d]pyrimidin-4-amine (100 mg, 0.27 mmol) by following the procedure described for preparation 8. 1H NMR (400 MHz, DMSO-d6): δ 8.64 (brs, 1H), 8.60 (d, 1H), 8.43 (s, 1H), 7.88 (d, 1H), 7.66 (s, 1H), 7.47-7.44 (m, 1H), 6.02 (s, 2H), 4.22-4.18 (m, 1H), 3.59-3.29 (m, 2H), 3.15 (s, 2H), 2.50-2.47 (m, 2H), 2.11-2.07 (m, 2H), 1.79-1.66 (m, 2H); MS (ESI) 5 m/z: Calculated: 475.95; Observed: 360.2 (M++1).

Example 10

N-(1-(3,5-Difluorobenzyl)piperidin-4-yl)-6-chloro-5-(4-fluoropheuyl)thieno[2,3-d] pyrimidin-4-amine, monoma- 10 leate.

[0185]

15

20

25 [0186] The title compound was prepared (66 mg, 39 %) from N-(1-(3,5-difluorobenzyl)-piperidin-4-yl)-6-chloro-5-(4- fluorophenyl)thieno[2,3-d] pyrimidin-4-amine (140 mg, 0.28 mmol) by following the procedure described for Preparation 1 8. H NMR (400 MHz, CD3OD): δ 8.40 (s, 1H), 7.55 (m, 2H), 7.40 (t, 2H), 7.10 (m, 3H), 6.25 (s, 2H), 4.20 (m, 3H), 3.30 (m, 2H), 3.00 (m, 2H), 2.15 (m, 2H), 1.40 (m, 2H). MS (ESI) m/z: Calculated: 488.1; Observed. 489.2 (M++1). 30 Example 11

6-Chloro-N-(1-((pyrimidin-5-yl)methyl)piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine, monomaleate.

35 [0187]

40

45

[0188] The title compound was prepared (100 mg, 64 %) from 6-chloro-N-(1-((pyrimidin-5-yl)methyl)piperidin-4-yl) 50 thieno[2,3-d]pyiridin-4-amine (119 mg, 0.33 mmol) by following the procedure described for preparation 8. 1H NMR (400 MHz, CD3OD): δ 9.25 (s, 1H), 8.95 (s, 2H), 8.35 (s, 1H), 7.45 (s, 1H), 6.25 (s, 2H), 4.35 (m, 3H), 3.55 (m, 2H), 3.15 (m, 2H), 2.30 (m, 2H), 1.90 (m, 2H). MS (ESI) m/z: Calculated: 360.09; Observed: 361.1 (M++1).

Example 12 55 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-4-fluoro benzonitrile, monomaleate.

[0189]

33 EP 1 797 099 B1

5

10

[0190] The title compound was prepared (100 mg, 64 %) from 3-((4-(6-chlorothieno[2,3-d] pyrimidin-4-ylamino)pipe- ridin-1-yl)methyl)-4-fluorobenzonitrile (119 mg, 0.33 mmol) by following the procedure described for Preparation 8. 1H 15 NMR (400 MHz, CD3OD): δ 8.35 (s, 1H), 8.05 (m, 1H), 7.95 (m, 1H), 7.50 (m, 2H), 6.25 (s, 2H), 4.40 (m, 3H), 3.55 (m, 2H), 3.20 (m, 2H), 2.30 (m, 2H), 1.95 (m, 2H). MS (ESI) m/z: Calculated: 401.09; Observed: 402.1 (M++1).

Example 13

20 N-(1-(3-Chlorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine, monomaleate.

[0191]

25

30

35 [0192] The title compound was prepared (62 mg, 69 %) from N-(1-(3-chlorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3- d]pyrimidin-4-amine (70 mg, 0.18 mmol) by following the procedure described for preparation 8. 1H NMR (400 MHz, CD3OD): δ 8.40 (s, 1H), 7.60 (s, 1H), 7.45 (m, 4H), 6.25 (s, 2H), 4.30 (m, 3H), 3.50 (m, 2H), 3.20 (m, 2H), 2.30 (m, 2H), 1.90 (m, 2H). MS (ESI) m/z: Calculated: 392.06; Observed: 393.2 (M++1). 40 Example 14

3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-N-methyl benzamide, monomaleate

45 [0193]

50

55

34 EP 1 797 099 B1

[0194] The title compound was prepared (71 mg, 96 %) from N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-chlorothieno [2,3-d]pyrimidin-4-amine (58 mg, 0.14 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, 1 CD3OD) δ H NMR (400 MHz, CD3OD): δ 8.34 (s,1H), 7.98 (s, 1H), 7.91 (d, 1H), 7.69 (d, 1H), 7.60 (t, 1H), 7.47 (s, 1H), 6.26 (s, 2H, maleate), 4.40 (m, 3H), 3.55 (d, 2H), 3.28 (t, 2H), 2.94 (s, 3H), 2.34 (d, 2H), 1.91 (m, 2H); MS (ESI) m/z: 5 + Calculated for C20H23ClN5OS, 416.13; Observed: 416.2 (M +1).

Example 15

3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-N,N-dimethylbenzamide, monomaleate 10 [0195]

15

20

25

[0196] The title compound was prepared (82 mg, 97 %) from 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin- 1-yl)methyl)-N,N-dimethylbenzamide (67 mg, 0.16 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.58 (m, 4H), 7.47 (s, 1H), 6.26 (s, 2H, maleate), 4.37 (m, 3H), 3.55 (d, 2H), 30 3.26 (t, 2H), 3.13 (s, 3H), 3.01 (s, 3H), 2.33 (d, 2H), 1.91 (m, 2H); MS (ESI) m/z: Calculated for C21H25ClN5OS, 430.15; Observed: 430.3 (M++1).

Example 16

35 N-(1-(3-(Methylsulfonyl)benzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine, monomaleate

[0197]

40

45

50 [0198] The title compound was prepared (50 mg, 76 %) from N-(1-(3-(methylsulfonyl)benzyl)piperidin-4-yl)-6-chlo- rothieno[2,3-d]pyrimidin-4-amine (53 mg, 0.12 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, CD3OD): δ 8.35 (s, 1H), 8.15 (s, 1H), 8.10 (d, 1H), 7.85 (d, 1H), 7.75 (t, 1H), 7.45 (s, 1H), 6.25 (s, 2H), 4.40 (m, 3H), 3.55 (m, 2H), 3.10-3.25 (m, 5H), 2.30 (m, 2H), 1.90 (m, 2H). MS (ESI) m/z: Calculated: 436.98; Observed: 55 437.2 (M++1).

35 EP 1 797 099 B1

Example 17

N-(1-(3-Trifluoromethyl)benzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine, monomaleate

5 [0199]

10

15

20 [0200] The title compound was prepared (25 mg, 79 %) from N-(1-(3-trifluoromethyl)benzyl)piperidin-4-yl)-6-chloroth- ieno[2,3-d]pyrimidin-4-amine (25 mg, 0.06 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.85 (s, 1H) 7.81 (m, 2H), 7.74 (m, 1H), 7.42 (s, 1H), 6.26 (s, 2H), 4.96 (bs, 3H), 4.41 (m, 2H), 3.53 (m, 3H), 3.24 (m, 2H), 2.25 (m, 2H), 1.87 (m, 2H). MS (ESI) m/z: Calculated: 426. 2; Observed: 427.2 (M++1).

25 Example 18

N-(1-(3-Trifluoromethylsulfonyl)benzyl)piperidin-4-yl)-6-chlorothieno[2,3-d] pyrimidin-4-amine, monomaleate

[0201] 30

35

40

45 [0202] The title compound was prepared (150 mg, 81 %) from N-(1-(3-trifluoromethylsulfonyl) benzyl)piperidin-4-yl)- 6-chlorothieno[2,3-d]pyrimidin-4-amine (153 mg, 0.31 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, CDCl3): δ 8.38 (s, 2H), 8.21 (s, 1H) 8.16 (d, 1H), 7.93 (t, 1H), 7.43 (s, 1H), 6.26 (s, 2H), 4.95 (bs, 3H), 4.44 (s, 2H), 4.38 (m, 1H), 3.59 (m, 2H), 3.28 (m, 2H), 2.23 (m, 2H), 1.91 (m, 2H). MS (ESI) m/z: Calculated: 490.2; 50 Observed: 491.2 (M++1).

Example 19

N-(1-(3,5-Difluorobenzyl)piperidin-4-yl)-6-isopropylthieno[2,3-d]pyrimidin-4-amine, dihydrochloride. 55 [0203]

36 EP 1 797 099 B1

5

10

[0204] The title compound was prepared (110 mg, 93 %) from N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-isopropylth- ieno[2,3-d]pyrimidin-4-amine (100 mg, 0.25 mmol) by following the procedure described for preparation 7. 1H NMR (400 15 MHz, CD3OD): 8 8.50 (s,1H), 7.60 (s,1H), 7.30 (m, 2H), 7.15 (m, 1H), 4.65 (m, 1H), 4.40 (s, 2H), 3.65 (m, 2H), 3.30 (m, 3H), 2.35 (m, 2H), 2.15 (m, 2H), 1.40 (d, 6H). MS (ESI) m/z: Calculated: 402.5; Observed: 403.1 (M++1).

Example 20

20 N-(1-(3,5-Difluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine, dihydrochloride

[0205]

25

30

35 [0206] The title compound was prepared (39 mg, 66 %) from N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-chlorothieno [2,3-d]pyrimidin-4-amine (50 mg, 0.13 mmol) by following the procedure described for Preparation 7. 1H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 7.70 (s, 1H), 7.27 (d, 2H), 7.17 (s, 1H), 4.56 (s, 1H), 4.40 (s, 2H), 3.62 (d, 2H), 3.29 (d, 2H), + 2.35 (d, 2H), 2.05 (m, 2H); MS (ESI) m/z: Calculated for C18H18ClF2N4S, 395.09; Observed: 395.0 (M +1).

40 Example 21

N-(1-(3-Fluorobenzyl)piperidin4-yl)-6-chlorothieno[2,3-d]pyrimidin-amine, dihydrochloride

[0207] 45

50

55

[0208] The title compound was prepared (62 mg, 90 %) from N-(1-(3-fluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]

37 EP 1 797 099 B1

pyrimidin-4-amine (58 mg, 0.15 mmol) by following the procedure described for Preparation 7. 1H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 7.70 (s, 1H), 7.55 (dt, 1H), 7.39 (m, 2H), 7.28 (t, 2H), 4.56 (m, 1H), 4.39 (s, 2H), 3.62 (d, 2H), + 3.29 (d, 2H), 2.35 (d, 2H), 2.04 (m, 2H); MS (ESI) m/z: Calculated for C18H19ClFN4S, 377.1; Observed: 377.2 (M +1).

5 Example 22

N-(1-(1-(3-Fluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine, dihydrochloride

[0209] 10

15

20

[0210] The title compound was prepared (66 mg, 73 %) from N-(1-(1-(3-fluorophenyl)ethyl)piperidin-4-yl)-6-isobutylth- 25 ieno[2,3-d]pyrimidin-4-amine (77 mg, 0.186 mmol) by following the general procedure described for Preparation 7. 1H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 7.40-7.60 (m, 5H), 4.55 (m, 2H), 3.95 (d, 1H), 3.40 (d, 1H), 3.20 (m, 1H), 3.10 (m, 1H), 2.85 (d, 2H), 2.25-2.45 (m, 3H), 2.15 (m, 1H), 2.00 (m, 1H), 1.85 (d, 3H), 1.00 (d, 6H). MS (ESI) m/z: Calculated: 412.57; Observed: 413.1 (M++1).

30 Example 23

N-(1-(1-(3,5-Difluorophenylmethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine, dihydrochloride

[0211] 35

40

45

[0212] The title compound was prepared (77 mg, 53 %) from N-(1-(1-(3,5-difluorophenyl)ethyl) piperidin-4-yl)-6-iso- 50 butylthieno[2,3-d]pyrimidin-4-amine (125 mg, 0.29 mmol) by following the general procedure described for Preparation 1 7. H NMR (400 MHz, CD3OD): δ 8.65 9s, 1H), 7.55 (s, 1H), 7.35 (m, 2H), 7.15 (m, 1H), 4.60 (m, 2H), 3.95 (d, 1H), 3.45 (d, 1H), 3.05-3.25 (m, 2H), 2.85 (d, 2H), 2.40 (m, 1H), 2.30 (m, 2H), 2.00 (m, 1H), 1.80 (d, 3H), 1.00 (d, 6H). MS (ESI) m/z: Calculated: 430.56; Observed: 431.1 (M++1).

55

38 EP 1 797 099 B1

Example 24

4-N-(3-(1-(3-Fluorophenyl)ethylamino) propylamino)-5,6,7,8-tetrahydro-benzo[4,5] thieno[2,3-d]pyrimidine, di- hydrochloride. 5 [0213]

10

15

20 [0214] The title compound was prepared (186 mg, 54 %) from 4-N-(3-(1-(3-fluorophenyl)ethylamino) propylamino)- 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d] pyrimidine (262 mg, 0.76 mmol) by following the general procedure described 1 for Preparation 7. H NMR (400 MHz, CD3OD): δ 8.60 (s, 1H), 7.45 (m, 1H), 7.35 (m, 2H), 7.15 [0215] (m, 1H), 4.45 9(q, 1H), 3.80 (m, 2H), 2.80-3.10 (m, 6H), 2.15 (m, 2H), 1.95 (m, 2H), 1.65 (d, 3H); MS (ESI) 25 m/z: Calculated: 384.51; Observed: 385.1 (M++1).

Example 25

4-N-(3-(3-Fluorobenzyl amino) propylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidine, dihydro- 30 chloride.

[0216]

35

40

45

[0217] The title compound was prepared (105 mg, 61 %) from 4-N-(3-(3-fluorobenzyl amino) propylamino)-5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (145 mg, 0.39 mmol) by following the general procedure described for 1 Preparation 7. H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 7.50 (m, 1H), 7.35 (m, 2H), 7.10 (m, 1H), 4.25 (s, 2H), 3.90 50 (t, 2H), 320 (t, 2H), 3.05 (m, 2H), 2.90 (m, 2H), 2.10 (m, 2H), 1.95 (m, 4H); MS (ESI) m/z: Calculated: 370.49; Observed: 371.1 (M++1).

Example 26

55 N-(3-(1-(3-Fluorophenyl)ethylamino)propyl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine, dihydrochloride

[0218]

39 EP 1 797 099 B1

5

10

[0219] The title compound was prepared (142 mg, 76 %) from N-(3-(1-(3-fluorophenyl)ethylamino) propyl)-isobutylth- 15 ieno[2,3-d]pyrimidin-4-amine (157 mg, 0.4 mmol) by following the general procedure described for Preparation 7. 1H NMR (400 MHz, CD3OD): δ 8.60 (s, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.15 (m, 1H), 4.45 (m, 1H), 3.80 (m, 2H), 3.10 (m, 1H), 2.95 (m, 1H), 2.85 (d, 2H), 2.15 (m, 2H), 2.00 (m, 1H), 1.70 (d, 3H), 1.00 (d, 6H); MS (ESI) m/z: Calculated: 386.53; Observed: 387.1 (M++1).

20 Example 27

N-(1-(1-(2,4,6-Trifluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d] pyrimidin-4-amine, dihydrochloride

[0220] 25

30

35

[0221] The title compound was prepared (90 mg, 71 %) from N-(1-(1-(2,4,6-trifluorophenyl) ethyl)piperidin-4-yl)-6- isobutylthieno[2,3-d]pyimidin-4-amine (110 mg, 0.25 mmol) by following the general procedure described for Preparation 40 1 7. H NMR (400 MHz, CD3OD): δ 8.05 (s, 1H), 7.60 (s, 1H), 7.15 9m, 2H), 5.00 (m, 1H), 4.60 (m, 1H), 3.65-3.90 (m, 2H), 3.10-3.35 (m, 2H), 2.85 (d, 2H), 2.10-2.45 (m, 4H), 2.00 (m, 1H), 1.90 (d, 3H), 1.05 (d, 6H). MS (ESI) m/z: Calculated: 448.55; Observed: 449.1 (M++1).

Example 28 45 N-(1-(1-(2,6-Difiuorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine, dihydrochloride

[0222]

50

55

40 EP 1 797 099 B1

5

10

[0223] The title compound was prepared (105 mg, 87 %) from N-(1-(1-(2,6-difluorophenyl)ethyl)piperidin-4-yl)-6-iso- 15 butylthieno[2,3-d]pyrimidin4-amine (104 mg, 0.24 mmol) by following the general procedure described for Preparation 1 7. H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 7.65 (m, 1H), 7.60 (s, 1H), 7.20 (t, 2H), 5.00 (m, 1H), 4.60 (m, 1H), 3.90 (d, 1H), 3.70 (d, 1H), 3.30 (m, 1H), 3.15 (m, 1H), 2.85 (d, 2H), 2.10-2.45 (m, 4H), 2.00 (m, 1H), 1.90 (d, 3H), 1.00 (d, 6H). MS (ESI) m/z: Calculated: 430.56; Observed: 431.2 (M++1).

20 Example 29

N-(1-(Cyclohexylmethyl)piperidin-4-yl)-5,6-dimethylthieno[2,3-d]pyrimidin-4-amine, dihydrochloride

[0224] 25

30

35

[0225] The title compound was prepared (83 mg, 85 %) from N-(1-(cyclohexylmethyl)piperidin-4-yl)-5,6-dimethylthieno [2,3-d]pyrimidin-4-amine (81 mg, 0.23 mmol) by following the procedure described for Preparation 7. 1H NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 4.70 (m, 1H), 3.71 (d, 2H), 3.20 (m, 2H), 3.01 (d, 2H), 2.61 (s, 3H), 2.53 (s, 3H), 2.40-2.20 (m, 40 4H), 1.88-1.71 (m, 6H), 1.39-1.26 (m, 3H), 1.09 (m, 2H); MS (ESI) m/z: Calculated for C20H31N4S, 359.23; Observed: 359.2 (M++1).

Example 30

45 N-(1-(3-Fluorobenzyl)piperidin-4-yl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-4-amine, dihydrochloride.

[0226]

50

55

41 EP 1 797 099 B1

5

10

15 [0227] The title compound was prepared (98 mg, 70 %) from N-(1-(3-fluorobenzyl)pipeidin-4-yl)-6-chloro-5-methylth- ieno[2,3-d]pyrimidin-4-amine (119 mg, 0.3 mmol) by following the general procedure described for Preparation 7. 1H NMR (400 MHz, CD3OD): 8 8.05 (s, 1H), 7.55 (m, 1H), 7.40 (m, 2H), 7.25 (m, 1H), 4.65 (m, 1H), 4.40 (s, 2H), 3.65 (m, 2H), 3.25 (m, 2H), 2.65 (s, 3H), 2.35 (m, 2H), 2.15 (m, 2H). MS (ESI) m/z: Calculated: 390.91; Observed: 391.2 (M++1).

20 Example 31

2-((4-(6-Chloro-5-methylthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl) benzonitrile, dihydrochloride

[0228] 25

30

35

[0229] The title compound was prepared (94 mg, 80 %) from 2-((4-(6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ylamino) 40 piperidin-1-yl)methyl)benzonitrile (100 mg, 0.25 mmol) by following the general procedure described for Preparation 1 7. H NMR (400 MHz, CD3OD): 8 8.70 (s, 1H), 7.95 (m, 2H), 7.85 (t, 1H), 7.75 (t, 1H), 4.70 (m, 1H), 4.60 (s, 2H), 3.70 (d, 2H), 3.45 (m, 2H), 2.65 (s, 3H), 2.15-2.45 (m, 4H). MS (ESI) m/z: Calculated: 397.92; Observed: 398.1 (M++1).

Example 32 45 N-(1-(2-Methoxybenzyl)piperidin-4-yl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-4-amine, dihydrochloride

[0230]

50

55

42 EP 1 797 099 B1

5

10

[0231] The title compound was prepared (129 mg, 95 %) from N-(1-(2-methoxybenzyl)pipendin-4-yl)-6-chloro-5-meth- ylthieno[2,3-d]pyrimidin-4-amine (115 mg, 029 mmol) by following the general procedure described for Preparation 7. 1H 15 NMR (400 MHz, CD3OD): δ 8.90 (s, 1H), 7.50 (m, 2H), 7.15 (m, 1H), 7.05 (t, 1H), 4.65 (m, 1H), 4.40 (s, 2H), 3.95 (s, 3H), 3.65 (m, 2H), 3.30 (m, 2H), 2.65 (s, 3H), 2.35 (m, 2H), 2.20 (m, 2H). MS (ESI) m/z: Calculated: 402.94; Observed: 403.3 (M++1).

Example 33 20 N-(1-(3-Fluorobenzyl)piperidin4-yl)5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d] pyrimidin-4-amine, dihydrochlo- ride

[0232] 25

30

35

[0233] The title compound was prepared (427 mg, 91 %) from N-(1-(3-fluorobenzyl)piperidin-4-yl)5,6,7,8-tetrahydro- 40 benzo[4,5]thieno[2,3-d] pyrimidin-4-amine (396 mg, 1 mmol) by following the procedure described for Preparation 7. 1H NMR (400 MHz, CD3OD): 8 8.75 (s, 1H), 7.58-7.49 (m, 1H), 7.48-7.40 (m, 2H), 7.60 (t, 1H), 4.70 (m, 1H), 4.39 (s, 2H), 3.61 (m, 2H), 3.30 (t, 2H), 3.24-3.12 (m, 2H), 2.99-2.81 (m, 2H), 2.41-2.29 (m, 4H), 2.02-1.91 (m, 4H); MS (ESI) m/z: Calculated: 396.5; Observed: 397.5 (M++1).

45 Example 34

N-(1-(1-(3-Fluorophenyl)ethyl)piperidin-4-yl)5,6,7,8-tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidin-4-amine, di- hydrochloride

50 [0234]

55

43 EP 1 797 099 B1

5

10

[0235] The title compound was prepared (213 mg, 91 %) from N-(1-(1-(3-fluorophenyl)ethyl) piperidin-4-yl)5,6,7,8- tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-amine (200 mg, 0.47 mmol) by following the procedure described for 15 1 Preparation 7. H NMR (400 MHz, CD3OD) 8 8.67 (s, 1H), 7.57-7.43 (m, 3H), 7.26 (t, 1H), 4.62 (m, 1H), 4.53 (q, 1H), 3.18-3.01 (m, 2H), 2.91 (t, 2H), 2.56-2.39 (m, 4H), 1.96-1.95 (m, 4H), 1.83 (d, 3H); MS (ESI) m/z: Calculated: 410. 5; Observed: 411.2 (M++1).

Example 35 20 N-(1-(1-(3-Fluorophenyl)ethyl)piperidin-4-yl)-5,6-dimethylthieno[2,3-d]pyrimidin-4-amine, dihydrochloride

[0236]

25

30

35

[0237] The title compound was prepared (149 mg, 84 %) from N-(1-(1-(3-fluorophenyl)ethyl)piperidin-4-yl)-5,6-dimeth- ylthieno[2,3-d]pyrimidin-4- amine (150 mg, 0.39 mmol) by following the procedure described for Preparation 7. 1H NMR 40 (400 MHz, CD3OD) δ 8.66 (s, 1H), 7.37-7.22 (m, 1H), 7.17-7.03 (m, 3H), 4.51-4.37 (m, 1H), 4.20 (q, 1H), 3.70-3.56 (m, 4H), 2.64 (s, 3H), 2.62 (s, 3H), 2.54-2.49 (m, 2H), 2.02-1.89(m, 2H), 1.82 (d, 3H); MS (ESI) m/z: Calculated: 384.5; Observed: 385.2 (M++1).

Example 36 45 N-(1-(1-(3,5-Difluorophenyl)ethyl)piperidin-4-yl)5,6,7,8-tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidin-4-amine, dihydrochloride

[0238] 50

55

44 EP 1 797 099 B1

5

10

[0239] The title compound was prepared (93 mg, 89 %) from N-(1-(1-(3,5-difluorophenyl)ethyl)piperidin-4-yl)5,6,7,8- 15 tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidin-4-amine (90 mg, 0.21 mmol) by following the procedure described for Prep- 1 aration 7. H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 7.34 (m, 2H), 7.16 (m, 1H), 4.83 (bs, 3H), 4.63 (m, 1H), 4.56 (m, 1H), 3.91 (m, 1H), 3.51-2.87 (m, 4H), 2.39-1.85 (m, 11H), 1.81 (d, 3H); MS (ESI) m/z: Calculated: 428. 5; Observed: 429.1 (M++1).

20 Example 37

N-(1-(2-Fluorobenzyl)piperidin-4-yl)5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d] pyrimidin-4-amine, dihydro- chloride

25 [0240]

30

35

40 [0241] The title compound was prepared (208 mg, 88 %) from N-(1-(2-fluorobenzyl)piperidin-4-yl)5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d] pyrimidin-4-amine (200 mg, 0.50 mmol) by following the procedure described for Preparation 1 7. H NMR (400 MHz, CD3OD): δ 8.72 (s, 1H), 7.58-7.49 (m, 1H), 7.48-7.40 (m, 2H), 7.60 (t, 1H), 4.70 (m, 1H), 4.39 (s, 2H), 3.61 (m, 2H), 3.30 (t, 2H), 3.04-3.12 (m, 2H), 2.89-2.91 (m, 2H), 2.21-2.39 (m, 4H), 1.91-2.02 (m, 4H); MS (ESI) m/z: Calculated: 396.5; Observed: 397.5 (M++1). 45 Example 38

N-(1-(4-Fluorobenzyl)piperidin-4-yl)5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d] pyrimidin-4-amine, dihydro- chloride 50 [0242]

55

45 EP 1 797 099 B1

5

10

[0243] The title compound was prepared (132 mg, 89 %) from N-(1-(4-fluorobenzyl)piperidin4-yl)5,6,7,8-tetrahydro- benzo[4,5]thieno[2,3-d] pyrimidin-4-amine (125 mg, 0.31 mmol) by following the procedure described for Preparation 15 1 7. H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 7.54-7.40 (m, 2H), 7.22-7.14 (m, 2H), 4.64 (m, 1H), 4.32 (s, 2H), 3.78-3.65 (m, 2H), 3.59-3.41 (m, 4H), 2.95-2.87 (m, 4H), 2.45-2.31 (m, 4H), 2.15-2.01 (m, 4H); MS (ESI) m/z: Calculated: 396.5; Observed: 397.5 (M++1).

Example 39 20 3-((4-(5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzonitrile, dihy- drochloride

[0244] 25

30

35

[0245] The title compound was prepared (194 mg, 91 %) from 3-((4-(5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyri- midin-4-ylamino)piperidin-1-yl)methyl)benzonitrile (180 mg, 0.44 mmol) by following the procedure described for Prep- 40 1 aration 7. H NHR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.02 (s, 1H), 7.96 (d, 1H), 7.90 (d, 1H), 7.70(t, 1H), 4.71 (m, 1H), 4.45 (s, 2H), 3.62-3.59 (m, 2H), 3.07 (t, 2H), 2.90 (t, 2H), 2.34-2.15 (m, 4H), 1.98-1.92 (m, 6H); MS (ESI) m/z: Calculated: 403.5; Observed: 404.3 (M++1).

Example 40 45 N-(1-(1-(3-Fluorophenyl)ethyl)piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine, dihydrochloride

[0246]

50

55

46 EP 1 797 099 B1

5

10

[0247] The title compound was prepared (246 mg, 82 %) from N-(1-(1-(3-fluorophenyl)ethyl)piperidin-4-yl)thieno[2,3- 15 d]pyrimidin-4-amine (250 mg, 0.70 mmol) by following the procedure described for Preparation 7. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.22-7.14 (m, 3H), 4.69-4.50 (m, 1H), 4.52 (q, 1H), 3.50-3.37 (m, 4H), 2.39-1.85 (d, 2H), 1.80 (d, 3H); MS (ESI) m/z: Calculated: 356.4; Observed: 357.2 (M++1).

Example 41 20 2-(3-Fluorophenyl)-2-(4-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d] pyrimidin-4-ylamino)piperidin-1-yl)pro- panenitrile, dihydrochloride

[0248] 25

30

35

[0249] The title compound was prepared (533 mg, 92 %) from 2-(3-fluorophenyl)-2-[4-((5,6,7,8-tetrahydro-benzo[4,5] thieno[2,3-d]pyrimidin-4-ylamino]piperidin-1-yl)propane- nitrile (500 mg, 1.14 mmol) by following the general procedure 40 1 described for Preparation 7. H NMR (400 MHz, CD3OD): δ 8.11 (s, 1H), 7.46-7.31 (m, 2H), 7.07 (t, 1H), 6.92 (t, 1H), 4.01-3.91 (m, 1H), 3.26-3.10 (m, 4H), 2.57-2.42 (m, 4H), 2.06-1.99 (m, 4H), 1.44 (s, 3H). MS (ESI) m/z: Calculated: 508.48; Observed: 436.1 (M++1, free base).

Example 42 45 N-(1-(2-(3-Fluorophenyl)propan-2-yl)piperidin-4-yl)5,6,7,8-tetrahydro-benzo[4,5] thieno[2,3-d]pyrimidin- 4-amine, dihydrochloride

[0250] 50

55

47 EP 1 797 099 B1

5

10

[0251] The title compound was prepared (109 mg, 91 %) from N-(1-(2-(3-Fluorophenyl)propan-2-yl)piperidin-4-yl) 15 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d] pyrimidin-4-amine (100 mg, 0.235 m. mol) by following the general procedure 1 described for Preparation 7. H NMR (400 MHz, CD3OD): δ 8.55 (s, 1H), 7.43-7.29 (m, 3H), 7.22 (t, 1H), 4.42 (m, 1H), 3.18-3.01 (m, 2H), 2.91 (t, 2H), 2.56-2.39 (m, 4H), 1.96-1.95 (m, 4H), 1,46 (s, 3H), 1.44 (s, 3H); MS (ESI) m/z: Calculated: 424. 5; Observed: 425.1 (M++1).

20 Example 43

N-(1-(3,5-Difluorobenzyl)piperidin-4-yl)thieno[2,3-d]pyrmidin-4-amine, dihydrochloride

[0252] 25

30

35

[0253] The title compound was prepared (177mg, 82 %) from N-(1-(3,5-Difluorobenzyl)piperidin-4-yl)thieno[2,3-d] 1 pyrimidin-4-amine (180mg, 0.5 mmol) following the procedure described in Preparation 7. H NMR (400 MHz, CD3OD) 40 δ 8.70 (s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.22-7.14 (m, 3H), 4.66 (m, 1H), 3.91 (s, 2H), 3.50-3.37 (m, 4H), 2.39-1.85 (d, 2H); MS (ESI) m/z: Calculated: 360.42; Observed: 361.1 (M++1).

Example 44

45 N-(1-(3,5-Difluorobenzyl)piperidin-4-yl)-6-isopropylthieno[2,3-d]pyrimidin-4-amine

[0254]

50

55

48 EP 1 797 099 B1

5

10

[0255] The title compound was prepared (264 mg, 56 %) from 4-chloro-6-isopropylthieno[2,3-d]pyrimidine (0.25 g, 15 1.18 mmol) and 1-(3,5-difluorobenzyl)piperidin-4-amine (0.4 g, 1.77 mmol) by following the general procedure described 1 for Preparation 6. H NMR (400 MHz, CDCl3): S 8.40 (s, 1H), 6.90 (m, 2H), 6.80 (s, 1H), 6.70 (m, 1H), 4.95 (d, 1H), 4.20 (m, 1H), 3.50 (s, 2H), 3.20 (m, 1H), 2.85 (m, 2H), 2.25 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H), 1.40 (d, 6H). MS (ESI) m/z: Calculated: 402.5; Observed: 403.1 (M++1).

20 Example 45

N-(1-(3,5-Difluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimldin4-amine

[0256] 25

30

35

[0257] The title compound was prepared (0.80 g, 51 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (1.38 g, 4.05 mmol) and 1-(bromomethyl)-3,5-difluorobenzene (0.84 g, 4.05 mmol) by following the 1 general procedure described for Preparation 12. H NMR (400 MHz, CDCl3) 8 8.44 (s, 1H), 6.99 (s, 1H), 6.89 (d, 2H), 40 6.70 (t, 1H), 4.89 (d, 1H), 4.19 (m, 1H), 3.50 (s, 2H), 2.86 (d, 2H), 2.24 (t, 2H), 2.01 (d, 2H), 1.59 (m, 2H); MS (ESI) m/z: + Calculated for C18H18ClF2N4S, 395.09; Observed: 395.0 (M +1).

Example 46

45 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzonitrile

[0258]

50

55

49 EP 1 797 099 B1

[0259] The title compound was prepared (282 mg, 75 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4- amine dihydrochloride (333 mg, 0.98 mmol) and 3-(bromometbyl)benzonitrile (191 mg, 0.98 mmol) by following the 1 general procedure described for Preparation 12. H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.68 (s, 1H), 7.57 (d, 2H), 7.43 (t, 1H), 7.00 (s, 1H), 4.88 (d, 1H), 4.20 (m, 1H), 3.56 (s, 2H), 2.85 (d, 2H), 2.25 (dt, 2H), 2.12 (d, 2H), 1.59 (m, 2H); 5 + MS (ESI) m/z: Calculated for C19H19ClN5S, 384.1; Observed: 384.2 (M +1).

Example 47

5-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluoro benzonitrile 10 [0260]

15

20

25 [0261] The title compound was prepared (392 mg, 41 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4- amine dihydrochloride (655 mg, 2.4 mmol) and 2-fluoro-5-formylbenzonitrile (399 mg, 2.7 mmol) by following the general 1 procedure described for Preparation 11. H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.63 (m, 1H), 7.55 (m, 1H), 7.16 (m, 1H), 7.00 (s, 1H), 4.93 (d, 1H), 4.19 (m, 1H), 3.50 (s, 2H), 2.83 (d, 2H), 2.23 (dt, 2H), 2.10 (d, 2H), 1.59 (m, 2H); MS + (ESI) m/z: Calculated for C19H18ClFN5S, 402.1; Observed: 402.2 (M +1). 30 Example 48

N-(1-(3-Fluorobenzyl)piperidin-4-yl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-4-amine

35 [0262]

40

45

50 [0263] The title compound was prepared (119 mg, 91 %) from 6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyri- midin-4-amine (95 mg, 0.336 mmol) and 1-(bromomethyl)-3-fluorobenzene (70 mg, 0.37 mmol) by following the general 1 procedure described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.30 (m, 1H), 7.10 (m, 2H), 6.95 (m, 1H), 5.30 (d, 1H), 4.05 (m, 1H), 3.55 (s, 2H), 2.95 (m, 2H), 2.50 (s, 3H), 2.25 (m, 2H), 2.15 (m, 2H), 1.60 (m, 2H). 55 MS (ESI) m/z: Calculated: 390.91; Observed: 391.2 (M++1).

50 EP 1 797 099 B1

Example 49

2-((4-(6-Chloro-5-methylthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl) benzonitrile

5 [0264]

10

15

[0265] The title compound was prepared (100 mg, 75 %) from 6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyri- 20 midin-4-amine (95 mg, 0.336 mmol) and 2-(bromomethyl) benzonitrile (73 mg, 0.37 mmol) by following the general 1 procedure described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.65 (d, 1H), 7.55 (m, 2H), 7. 35 (m, 1H), 5.30 (d, 1H), 4.25 (m, 1H), 3.7 (s, 2H), 2.85 (m, 2H), 2.50 (s, 3H), 2.40 (m, 2H), 2.10 (m, 2H), 1.40 (m, 2H). MS (ESI) m/z: Calculated: 397.92; Observed: 398.2 (M++1).

25 Example 50

N-(1-(2-Methoxybenzyl)piperidin-4-yl-6-chloro-5-methylthieno [2,3-d]pyrimidin-4-amine

[0266] 30

35

40

[0267] The title compound was prepared (115 mg, 85 %) from 6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyri- midin-4-amine (95 mg, 0.336 mmol) and 1-(chloromethyl)-2-methoxybenzene (58 mg, 0.37 mmol) by following the 45 1 general procedure described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 6.95 (m, 1H), 6.85 (d, 1H), 5.35 (d, 1H), 4.25 (m, 1H), 3.85 (s, 3H), 3.60 (s, 2H), 2.90 (m, 2H), 2.50 (s, 3H), 2.35 (m, 2H), 2.10 (m, 2H), 1.40 (m, 2H). MS (ESI) m/z: Calculated: 402.94; Observed: 403.2 (M++1).

Example 51 50 N-(1-(3-Fluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine

[0268]

55

51 EP 1 797 099 B1

5

10

[0269] The title compound was prepared (58 mg, 53 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine 15 dihydrochloride (100 mg, 0.29 mmol) and 1-(bromomethyl)-3-fluorobenzene (55 mg, 0.29 mmol) by following the general 1 procedure described for Preparation 12. H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.28 (dd, 1H), 7.09 (d, 1H), 7.08 (d, 1H), 6.98 (s, 1H), 6.95 (dt, 1H), 4.85 (d, 1H), 4.19 (m, 1H), 3.49 (s, 2H), 2.87 (d, 2H), 2.23 (dt, 2H), 2.09 (d, 2H), 1.60 + (m, 2H); MS (ESI) m/z: Calculated for C18H19ClFN4S, 377.1; Observed: 377.2 (M +1).

20 Example 52

N-(1-(2-Fluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine

[0270] 25

30

35

[0271] The title compound was prepared (65 mg, 37 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (160 mg, 0.47 mmol) and 2-fluorobenzaldehyde (58 mg, 0.47 mmol) by following the general procedure 1 described for Preparation 11. H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.37 (t, 1H), 7.25 (m, 1H), 7.13 (t, 1H), 7.07 (t, 40 1H), 6.97 [0272] (s, 1H), 4.85 (d, 1H), 4.16 (m, 1H), 3.63 (s, 2H), 2.92 (d, 2H), 2.29 (t, 2H), 2.08 (d, 2H), 1.61 (m, 2H); MS (ESI) + m/z: Calculated for C18H19ClFN4S, 377.1; Observed: 377.2 (M +1).

Example 53 45 Methyl 3-((4-(6-chlorothieno [2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl) benzoate

[0273]

50

55

52 EP 1 797 099 B1

5

10

[0274] The title compound was prepared (430 mg, 33 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4- amine (848 mg, 3.15 mmol) and methyl 3-(bromomethyl)benzoate (867 mg, 3.76 mmol) by following the general pro- 1 cedure described for Preparation 12. H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.00 (s, 1H), 7.95 (d, 1H), 7.54 (d, 1H), 15 7.41 (t, 1H), 6.98 (s, 1H), 4.83 (d, 1H), 4.18 (m, 1H), 3.93 (s, 3H), 3.58 (s, 2H), 2.87 (d, 2H), 2.24 (dt, 2H), 2.11 (d, 2H), + 1.59 (m, 2H); MS (ESI) m/z: Calculated for C20H22ClN4O2S, 417.1; Observed: 417.2 (M +1).

Example 54

20 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoic acid

[0275]

25

30

35 [0276] Methyl 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoate (127 mg, 0.3 mmol) was heated in a 25 % MeOH-H2O solution at 90˚C for 3 h in the presence of LiOH·H2O (12.7 mg, 0.3 mmol). The solvent was removed under reduced pressure; the residue was dissolved in MeOH and filtered. The filtrate was evaporated to 1 collect product in 79 % yield (97 mg). H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.92 (s, 1H), 7.85 (d, 1H), 7.50 (s, 1H), 7.42 (d, 1H), 7.33 (t, 1H), 4.11 (m, 1H), 3.59 (s, 2H), 2.98 (d, 2H), 2.20 (t, 2H), 2.00 (d, 2H), 1.68 (m, 2H); MS (ESI) 40 + m/z: Calculated for C19H20ClN4O2S, 403.1; Observed: 403.2 (M +1).

Example 55

3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzamide 45 [0277]

50

55

53 EP 1 797 099 B1

[0278] 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoic acid (60 mg, 0.15 mmol) was heated in 5 mL of thionylchloride at 80˚C for 3h. The reaction was cooled to room temperature and thionylchloride was removed by rotary evaporation; the residue was dissolved in 10 mL of DCM and NH3 (g) was bubbled through at 0 ˚C for 1h. After removal of solvent the crude product was purified by silica chromatography in 5 % MeOH-DCM to obtain 5 1 the title product (14 mg, 23 %). H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H), 7.98 (s, 1H), 7.86 (m, 1H), 7.66 (d, 1H), 754 (m, 2H), 4.26 (m, 1H), 3.97 (s, 2H), 3.22 (d, 2H), 2.64 (m, 2H), 2.13 (d, 2H), 1.85 (m, 2H); MS (ESI) m/z: Calculated for + C19H21CIN50S, 402.1; Observed: 402.2 (M +1).

Example 56 10 N-(1-(1-(3-Fluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine

[0279]

15

20

25

[0280] The title compound was prepared (291 mg, 64 %) from 4-chloro-6-isobutylthieno[2,3-d]pyrimidine (250 mg, 1.1 mmol) and 1-(1-(3-fluorophenyl)ethyl)piperidin-4-amine (0.49 mg, 2.2 mmol) by following the general procedure 1 described for Preparation 6. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.75 30 (s, 1H), 5.00 (m, 1H), 4.10 (m, 1H), 3.45 (m, 1H), 3.00 (d, 1H), 2.80 (d, 1H), 2.70 (d, 2H), 1.85-2.25 (m, 5H), 1.45-1.65 (m, 2H), 1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 412.57; Observed: 413.3 (M++1).

Example 57

35 N-(1-(1-(3,5-Difluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine

[0281]

40

45

50

[0282] The title compound was prepared (127 mg, 69 %) from 6-isobutyl-N-piperidin-4-yl)thieno[2,3-d]pyrimidin-4- amine (125 mg, 0.43 mmol) and 1-(3,5-difluorophenyl)ethyl methanesulfonate (243 mg, 1.03 mmol) by following the 1 general procedure described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.75 (s, 1H), 6.70 55 [0283] (m, 1H), 4.95 (d, 1H), 4.15 (m, 1H), 3.45 (m, 1H), 2.95 (m, 1H), 2.80 (m, 1H), 2.70 (d, 2H), 2.20 (m, 4H), 1.95 (m, 1H), 1.55 (m, 2H), 1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 430.56; Observed: 431.1 (M++1).

54 EP 1 797 099 B1

Example 58

2-(3-Fluorophenyl)-2-(4-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl amino)piperidin-1-yl)pro- panenitrile 5 [0284]

10

15

20 [0285] To a mixture of N-(piperidin-4-yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d] pyrimidin-4-amine (2.86 g, 10 mmol) and 3-fluorophenylacetophenone (1.38 g, 10 mmol) in dryDCM (25 mL) was added titanium isopropoxide (2.85 g, 10 m.mol) at room temperature and stirred for 24 h. 1 M solution of diethylaluminumcyanide in toluene (1.2 mL, 10mmol) was added to the above solution and the mixture was allowed to stir for 24h. The reaction was quenched by 25 the addition of saturated aq. NaHCO3 solution (15 mL) and the organic layer was separated, dried and concentrated 1 under reduced pressure to get the title compound (4.3 g, 100 %) as pale yellow powder. H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.35-724 (m, 2H). 6.99 (t, 1H), 6.78 (t, 1H), 4.21 (brs, 1H, NH), 3.91-3.86 (m, 1H), 3.11-3.03 (m, 2H), 2.91 (t, 2H), 2.49-2.27 (m, 4H), 2.00-1.92 (m, 4H), 1.42 (s, 3H). MS (ESI) m/z: Calculated: 435.56; Observed: 436.2 (M++1).

30 Example 59

N-(1-(2-(3-Fluorophenyl)propan-2-yl)piperidin-4-yl)-5,6,7,8-tetrahydro-benzo[4,5] thieno[2,3-d]pyrimidin- 4-amine

35 [0286]

40

45

[0287] 2-(3-Fluorophenyl)-2-(4-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl amino)piperidin-1-yl)pro- 50 panenitrile (435 mg, 1 mmol) was dissolved in dry THF (20 mL) and was added 1 M solution of MeMgBr in butyl ether (1.7 mL, 12 mmol) at 0˚ C The reaction was stirred at room temperature for 3 h. The mixture was poured into a cold saturated NH4Cl solution (10 mL) and extracted with DCM (2x25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and evaporated under reduced pressure. Purification by silica chromatography (2 % MeOH-DCM) 1 afforded the title compound (331 mg, 78 %). H NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.29-7.21 (m, 3H), 6.83 (t, 1H), 55 3.81-3.72 (m, 1H), 3.08-3.01 (m, 2H), 2.81 (t, 2H), 2.36-2.20 (m, 4H), 1.96-1.95 (m, 4H), 1,31 (s, 3H), 130 (s, 3H). MS (ESI) m/z: Calculated: 424. 5; Observed: 425.1 (M++1).

55 EP 1 797 099 B1

Example 60

6-Chloro-N-(1-((pyridin-3-yl)methyl)piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine

5 [0288]

10

15

[0289] The title compound was prepared (338 mg, 94 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4- amine (341 mg, 1.0 mmol) and 3-pyridinecarboxaldehyde (107 mg, 1.0 mmol) by following the general procedure de- 20 1 scribed for Preparation 11. H NMR (400 MHz, CDCl3): 8.57 (d, 1H), 8.52 (dd, 1H), 8.43 (s, 1H), 7.68-7.65 (m, 1H), 7.29 (d, 1H), 7.02 (s, 1H), 5.14 (d, 1H), 4.21-4.17 (m, 1H), 3.54 (s, 2H), 2.88 (d, 2H), 2.43 (t, 2H), 2.10-2.07 (m, 2H), 1.62-1.52 (m, 2H); MS (ESI) m/z: Calculated: 359.88; Observed: 360.2 (M++1).

Example 61 25 N-(1-(3,5-Difluorobenzyl)piperidin-4-yl)-6-chloro-5-(4-fluorophenyl)thieno[2,3-d] pyrimidin-4-amine

[0290]

30

35

40

[0291] The title compound was prepared (140 mg, 49 %) from 4,6-dichloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (175 mg, 0.59 mmol) and 1-(3,5-difluorobenzyl)piperidin-4-amine (170 mg, 0.7 mmol) by following the general procedure 1 described for Preparation 6. H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.45 (m, 2H), 7.30 (m, 2H), 6.85 (m, 2H), 6.65 45 (m, 1H), 4.65 (m, 1H), 4.05 (bs, 1H), 3.40 (s, 2H), 2.40 (m, 2H), 2.15 (m, 2H), 1.85 (m, 2H), 1.15 (m, 1H). MS (ESI) m/z: Calculated: 488.1; Observed: 489.2 (M++1).

Example 62

50 6-Chloro-N-(1-((pyrimidin-5-yl)methyl)piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine

[0292]

55

56 EP 1 797 099 B1

5

10

[0293] The title compound was prepared (119 mg, 45 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4- amine (200 mg, 0.74 mmol) and pyrimidine-5-carbaldehyde (80 mg, 0.74 mmol) by following the general procedure 1 described for Preparation 11. H NMR (400 MHz, CDCl3): 8 9.05 (s, 1H), 8.65 (s, 2H), 8.35 (s, 1H), 7.00 (s, 1H), 5.50 15 (bs, 1H), 4.10 (m, 1H), 3.45 (s, 2H), 2.80 (m, 2H), 2.20 (m, 2H), 2.00 (m, 2H), 1.50 (m, 2H). MS (ESI) m/z: Calculated: 360.09; Observed: 361.1 (M++1).

Example 63

20 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-4-fluorobenzonitrile

[0294]

25

30

35

[0295] The title compound was prepared (119 mg, 45 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4- amine (150 mg, 0.56 mmol) and 4-fluoro-3-formylbenzonitrile (83 mg, 0.56 mmol) by following the general procedure 1 described for Preparation 11. H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.85 (m, 1H), 7.60 (m, 1H), 7.15 (t, 1H), 7.00 40 (s, 1H), 5.00 (d, 1H), 4.20 (m, 1H), 3.60 (s, 2H), 2.90 (m, 2H), 2.35 (m, 2H), 2.15 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 401.09; Observed: 402.1 (M++1).

Example 64

45 N-(1-(3-Chlorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine

[0296]

50

55

57 EP 1 797 099 B1

5

10

[0297] The title compound was prepared (70 mg, 43 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (110 mg, 0.41 mmol) and 1-(bromomethyl)-3-chlorobenzene (93 mg, 0.45 mmol) by following the general procedure 15 1 described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 735 (s, 1H), 7.10 (m, 4H), 5.25 (d, 1H), 4.20 (m, 1H), 3.50 (s, 2H), 2.90 (m, 2H), 2.35 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 392.06; Observed: 393.2 (M++1).

Example 65 20 4-N-(3-(1-(3-Fluorophenyl)ethylamino) propylamino)-5,6,7,8-tetrahydro-benzo(4,5) thieno[2,3-d]pyrimidine.

[0298]

25

30

35 [0299] The title compound was prepared (291 mg, 100 %) from 5,6,7,8-tetrahydro-benzo[4,5] thieno[2,3-d]pyrimidine (172 mg, 0.76 mmol) and N-1-(1-(3-fluorophenyl)ethyl)propane-1,3-diamine (150 mg, 0.76 mmol) by following the general 1 procedure described for Preparation 6. H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 5.90 (bs, 1H), 3.60-3.80 (m, 3H), 2.85 (m, 2H), 2.80 (m, 2H), 2.70 (m, 1H), 2.55 (m, 1H), 1.75- 1.95 (m, 6H), 1.40 40 (d, 3H). MS (ESI) m/z: Calculated: 384.51; Observed: 385.1 (M++1).

Example 66

4-N-(3-(3-Fluorobenzyl amino) propylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidine 45 [0300]

50

55

58 EP 1 797 099 B1

[0301] The title compound was prepared (145 mg, 69 %) from 3-N-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimi- dine-4-yl)-1,3-diaminopropane (150 mg, 0.57 mmol) and 3-fluorobenzaldehyde (70 mg, 0.57 mmol) by following the 1 general procedure described for Preparation 3. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.30 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.20 (bs, 1H), 3.80 (s, 2H), 3.70 (m, 2H), 2.80 (m, 6H), 1.80 (m, 6H), 1.70 (bs, 1H). MS (ESI) m/z: Calculated: 5 370.49; Observed: 371.1 (M++1).

Example 67

N-(3-(1-(3-Fluorophenyl)ethylamino)propyl)-6-isobutylthieno[2,3-d]pyrimidin-4-amine 10 [0302]

15

20

25 [0303] The title compound was prepared (157 mg, 62 %) from 4-chloro-6-isobutylthieno[2,3-d]pyrimidine (150 mg, 0.662 mmol) and N-1-(1-(3-fluorophenyl)ethyl)propane-1,3-diamine [0304] (130 mg, 0.662 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.40 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.75 (bs, 1H), 6.70 (s, 1H), 3.85 (m, 1H), 3.70 (m, 2H), 2.80 (m, 1H), 2.70 (d, 2H), 2.65 (m, 1H), 1.95 (m, 1H), 1.85 (m, 2H), 1.45 (d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 30 386.53; Observed: 387.1 (M++1).

Example 68

N-(1-(1-(2,4,6-Trifluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d] pyrimidin-4-amine 35 [0305]

40

45

50 [0306] The title compound was prepared (110 mg, 55 %) from 6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4- amine (130 mg, 0.45 mmol) and 1-(2,4,6-trifluorophenyl)ethyl methanesulfonate (228 mg, 0.9 mmol) by following the 1 general procedure described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 6.75 (s, 1H), 6.65 (m, 2H), 4.95 (d, 1H), 4.15 9q, 1H), 4.05 (m, 1H), 3.00 (m, 2H), 2.70 (d, 2H), 2.20 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H), 1.55 (d, 3H), 1.25-1.65 (m, 2H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 448.55; Observed: 449.2 (M++1). 55

59 EP 1 797 099 B1

Example 69

N-(1-(1-(2,6-Difluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno [2,3-d]pyrimidin-4-amine

5 [0307]

10

15

[0308] The title compound was prepared (104 mg, 54 %) from 6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4- amine (130 mg, 0.45 mmol) and 1-(2,6-difluorophenyl)ethyl methanesulfonate (211 mg, 0.9 mmol) by following the 1 general procedure described for Preparation 12. H NMR (400 MHz, CDCl3): 8 8.40 (s, 1H), 7.10 (m, 1H), 6.90 (m,2H), 20 6.75 (s, 1H), 4.90 (d, 1H), 4.25 (q, 1H), 4.05 (m, 1H), 3.05 (m, 2H), 2.70 (d, 2H), 2.15 (m, 1H), 2.10 (m, 3H), 1.95 (m, 1H), 1.40 (d, 3H), 1.45-1.65 (m, 2H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 430.56; Observed: 431.2 (M++1).

Example 70

25 N-(1-(Cyclohexylmethyl)piperidin-4-yl)-5,6-dimethylthieno[2,3-d]pyrimidin-amine

[0309]

30

35

40 [0310] The title compound was prepared (81 mg, 28 %) from 4-chloro-5,6-dimethylthieno[2,3-d]pyrimidine (325 mg, 1.21 mmol) and 1-(cyclobexylmethyl)piperidin-4-amine dihydrochloride (160 mg, 0.81 mmol) by following the general 1 procedure described for Preparation 6. H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 5.36 (d, 1H), 4.22 (m, 1H), 2.80 (d, 2H), 2.44 (s, 3H), 2.41 (s, 3H), 2.21-2.09 (m, 7H), 1.79-1.45 (m, 6H), 120 (m, 4H), 0.88 (m, 2H); MS (ESI) m/z: Calculated + for C20H31N4S, 359.23; Observed: 359.2 (M +1). 45 Example 71

3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-N-methyl benzamide

50 [0311]

55

60 EP 1 797 099 B1

5

10

[0312] 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoic acid (118 mg, 0.29 mmol) was 15 heated in 3 mL of thionylchloride at 80 ˚C for 3h. The reaction was cooled to room temperature and the thionylchloride was removed under reduced pressure. The residue obtained was dissolved in 25 mL of DCM followed by addition of methylamine hydrochloride (60 mg, 0.88 mmol) and DIEA (227 mg, 1.76 mmol). The reaction was allowed to stir at room temperature for 16 h and washed with 25 mL of water. The DCM layer was dried over Na2SO4 and evaporated under reduced pressure; the crude product was purified by silica chromatography in 5 % MeOH-DCM to obtain 58 mg of 20 1 product in 48 % yield. H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.76 (s, 1H), 7.65 (d, 1H), 7.45 (d, 1H), 7.39 (t, 1H), 7.02 (s, 1H), 6.22 (bs, 1H), 4.96 (bs, 1H), 4.18 (m, 1H), 3.57 (s, 2H), 3.03 (d, 3H), 2.87 (d, 2H), 2.23 (t, 2H), 2.08 (d, + 2H), 1.59 (m, 2H); MS (ESI) m/z: Calculated for C20H23ClN5OS, 416.13; Observed: 416.2 (M +1).

Example 72 25 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl-N,N-dimethylbenzamide

[0313]

30

35

40

[0314] 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoic acid (104 mg, 0.26 mmol) was heated in 3 mL of thionylchloride at 80 ˚C for 3h. The reaction was cooled to room temperature and the thionylchloride 45 was removed under reduced pressure. The residue obtained was dissolved in 25 mL of DCM followed by addition of dimethylamino hydrochloride (63 mg, 0.77 mmol) and DIEA (200 mg, 1.55 mmol). The reaction was allowed to stir at room temperature for 16 h and extracted with 25 mL of water. The DCM layer was dried over Na2SO4 and evaporated under reduced pressure; the crude product was purified by silica chromatography in 5 % MeOH-DCM to obtain 67 mg 1 of product in 60 % yield. H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.33 (m, 4H), 7.03 (s, 1H), 5.03 (d, 1H), 4.17 (m, 50 1H), 3.55 (s, 2H), 3.13 (s, 3H), 2.99 (s, 3H), 2.86 (d, 2H), 2.22 (t, 2H), 2.19 (d, 2H), 1.55 (dq, 2H); MS (ESI) m/z: Calculated + for C21H25ClN5OS, 430.15; Observed: 430.2 (M +1).

Example 73

55 N-(1-(3-(Methylsulfonyl)benzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine

[0315]

61 EP 1 797 099 B1

5

10

[0316] The title compound was prepared (70 mg, 43%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine 15 (100 mg, 0.37 mmol) and 1-(bromomethyl)-3-(methylsulfonyl)benzene (139 mg, 0.55 mmol) by following the general 1 procedure described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.95 (s, 1H), 7.80 (d, 1H), 7.60 (d, 1H), 7.50 (t, 1H), 7.05 (s, 1H), 5.25 (d, 1H), 4.20 (m, 1H), 3.60 (s, 2H), 3.05 (s, 3H), 2.80 (m, 2H), 2.20 (m, 2H), 2.05 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 436.98; Observed: 437.2 (M++1).

20 Example 74

N-(1-(3-Trifluoromethyl)benzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine

[0317] 25

30

35

40 [0318] The title compound was prepared (25 mg, 49 %) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (32 mg, 0.12 mmol) and 3-(trifluoromethyl)benzylbromide (34 mg, 0.14 mmol) by following the general 1 procedure described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.43.(s, 1H), 7.65 (s, 1H) 7.57 (m, 2H), 7.44 (m, 1H), 6.97 (s, 1H), 4.96 (d, 1H), 4.22 (m, 1H), 3.61 (s, 2H), 2.89 (m, 2H), 2.36-2.11 (m, 4H), 1.62 (m, 2H). MS (ESI) m/z: Calculated: 426. 2; Observed: 427.2 (M++1). 45 Example 75

N-(1-(3-Trifluoromethylsulfonyl)benzyl)piperidin-4-yl)-6-chlorothieno[2,3-d] pyrimidin-4-amine

50 [0319]

55

62 EP 1 797 099 B1

5

10

15 [0320] The title compound was prepared (153 mg, 60 %) from 6-chloro-N-(piperidin4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (140 mg, 0.52 mmol) and 1-(bromomethyl)-3-(trifluoromethylsulfonyl)benzene (190 mg, 0.63 mmol) by 1 following the general procedure described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 8.06 (s, 1H) 7.94 (d, 1H), 7.81 (d, 1H), 7.63 (t, 1H), 7.02 (s, 1H), 5.09 (d, 1H, 4.22 (m, 1H), 3.61 (s, 2H), 2.82 (m, 2H), 2.33 (m, 2H), 2.16 (m, 2H), 1.61 (m, 2H). MS (ESI) m/z: Calculated: 490. 2; Observed: 491.2 (M++1). 20 Example 76

{1-[1-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperidin-4-yl}-(5,6,7,8-tetrahydro-benzo [4,5]thieno[2,3-d] pyrimidin4-yl)-amine 25 [0321]

30

35

[0322] The title compound was prepared (97 mg, 81 %) from (4-methyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5] 40 thieno[2,3-d]pyrimidin-4-yl)-amine (150 mg, 0.28 mmol) and methanesulfonic acid 1-(3-fluoro-phenyl)-ethyl ester 1 (61.1mg, 0.28 mmol) by following the procedure described for preparation 12. H NMR (400 MHz, CDCl3): δ (ppm) 8.38 (s, 1H), 7.20 (s, 1H), 6.89-6.79 (m, 3H), 3.91 (q, 1H), 2.80-2.74(m, 4H), 2.20-2.09(M, 2H), 1.90 (m, 2H), 1.89-1.85 (m, 4H), 1.55 (m, 4H), 1.31 (s, 3H); MS (SEI): m/z: Calculated: 424.2; Observed: 425.2 (M++1).

45 Example 77

4-(4-(3-(4-Fluorophenyl)propyl)piperazine-1-yl)(5,6,7,8-tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidine

[0323] 50

55

63 EP 1 797 099 B1

[0324] The title compound was prepared (150 mg, 49 %) from N-(piperidine-4-yl)(5,6,7,8-Tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidine bis(trifluoroacetic acid) (370 mg, 0.72 mmol) and 1-(2,6-difluorophenyl)ethyl methanesulfonate (190 1 mg, 0.79 mmol) by following the general procedure described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.26-7.18 (m, 1H), 6.80 (t, 2H), 5.17 (d, 1H), 4.24 (q, 1H), 4.15-4.11 (m, 1H), 2.90 (t, 2H), 2.70 (t, 2H), 2.36-2.11 5 (m, 4H), 2.09-1.87 (m, 4H), 1.59 (d, 3H). MS (ESI) m/z: Calculated: 428. 5; Observed: 429.1 (M++1).

Example 78

6-Chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine 10 [0325]

15

20

[0326] The title compound was prepared (289 mg, 64 %) from tert-butyl 4-(6-chloro-5-methylthieno[2,3-d]pyrimidin- 4-ylamino)piperidine-1-carboxylate (611 mg, 1.6 mmol) by following the general procedure described for Preparation 25 1 10. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 5.30 (d, 1H), 4.25 (m, 1H), 3.15 (m, 2H), 2.85 (m, 2H), 2.55 (s, 3H), 2.15 (m, 2H), 1.95 (bs, 1H), 1.45 (m, 2H).

Example 79

30 3-(5,6,7,8-Tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidin-4-yl)-1,3-diaminopropane

[0327]

35

40

[0328] A solution of 4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidine (0.5 g, 2.43 m. mol) in 1,3-diamine- propane (5 ml) was heated at 80 ˚C for 1 dray. It was cooled to room temperature and then diluted with water (50 mL). 45 The clear solution was cooled at 0 ˚C for overnight The resulting solid was filtered and dried to get the title compound 1 (0.3 g, 52 %) as a brown color solid. H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 3.65 (t, 2H), 2.95 (m, 2H), 2.80 (m, 4H), 1.80-2.00 (m, 6H). MS (ESI) m/z: Calculated: 262.37; Observed: 263.1 (M++1).

Example 80 50 6-Isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine

[0329]

55

64 EP 1 797 099 B1

5

10 [0330] The title compound was prepared (628 mg, 94 %) from tert-butyl 4-(6-isobutylthieno[2,3-d]pyrimidin-4-ylamino) piperidine-1-carboxylate (900 mg, 2.3 mmol) by following the general procedure described for Preparation 10. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 6.80 (s, 1H), 4.95 (d, 1H), 4.30 (m, 1H), 3.20 (m, 2H), 2.85 (m, 2H), 2.75 (d, 2H), 2.40 (bs, 2H), 2.15 (m, 2H), 1.95 (m, 1H), 1.50 (m, 2H), 1.00 (d, 6H). 15 Example 81

(4-Methyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine.

20 [0331]

25

30 [0332] The title compound was prepared (179 mg, 97 %) from 4-methyl-4-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.35 mmol) by following the procedure 1 described for preparation 10. H NMR (400 MHz, CDCl3): δ 8.51 (bs, 2H), 8.27 (s, 1H), 3.15 (m, 2H), 3.03 (m, 4H), 2.77 (m, 2H), 2.68 (m, 2H), 1.82 (m, 6H), 1.51 (s, 3H); MS (ESI): m/z: Calculated:302.2; Observed: 303.1 (M++1). 35 Example 82

6-Chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride

40 [0333]

45

50 [0334] The title compound was prepared (1.2 g, 99 %) from 1-butyl 4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)pip- eridine-1-carboxylate (1.4 g, 3.7 mmol) by following the procedure described for Preparation 10. 1H NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 7.84 (s, 1H), 4.60 (m, 1H), 3.54 (m, 2H), 3.24 (m, 2H), 2.31 (m, 2H), 2.03 (m, 2H); MS (ESI) + m/z: Calculated for C11H14ClN4S, 269.06; Observed: 269.1 (M +1). 55

65 EP 1 797 099 B1

Example 83

tert-Butyl-4-(6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate

5 [0335]

10

15

[0336] The title compound was prepared (611 mg, 82 %) from 4,6-dichloro-5-methylthieno[2,3-d]pyrimidine (425 mg, 1.94 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (582 mg, 2.9 mmol) by following the general procedure 1 described for Preparation 9. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 5.25 (d, 1H), 4.35 (m, 1H), 4.30 (m, 2H), 3.00 20 (m, 2H), 2.55 (s, 3H), 2.15 (m, 2H), 1.45 (s, 9H), 1.35-1.55 (m, 2H).

Example 84

tert-Butyl 4-(6-isobutylthieno[2,3-d]pyrimidin4-ylamino)piperidine-1-carboxylate 25 [0337]

30

35

[0338] The title compound was prepared (337 mg, 65 %) from 4-chloro-6-isobutylthieno[2,3-d]pyrimidine (300 mg, 1.32 m. mol) and tert-butyl 4-aminopiperidine-1-carboxylate (400 mg, 1.99 m. mol) by following the general procedure 1 described for Preparation 9. H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 6.80 (s, 1H), 4.95 (m, 1H), 4.35 (m, 1H), 4.15 40 (m, 2H), 2.95 (m, 2H), 2.75 9d, 2H), 2.15 (m, 2H), 1.95 (m, 1H), 1.45 (s, 9H), 1.40-1.50 (m, 2H), 0.95 (d, 6H).

Example 85

t-Butyl 4-(6-chlorothleno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate 45 [0339]

50

55

[0340] A mixture of t-butyl 4-(thieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (1.00 g, 3.00 mmol) and N-

66 EP 1 797 099 B1

chlorosuccinimide (0.39 g, 3.00 mmol) were heated in 50 mL of acetic acid for 3 h. After cooling to room temperature acetic acid was removed under reduced pressure and the remaining residue was partition in 1 M NaOH and DCM. The DCM layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica 1 chromatography in 5 % MeOH-DCM to collect 0.78 g of product (71 % yield). H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 5 7.01 (s, 1H), 4.94 (d, 1H), 4.32 (m, 1H), 4.15 (m, 2H), 2.94 (m, 2H), 2.11 (m, 2H), 1.48 (s, 9H), 1.44 (m, 2H); MS (ESI) + m/z: Calculated for C16H21ClN4O2S, 368.11; Observed: 368.8 (M +1).

Example 86

10 4-Methyl-4-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert- butyl ester

[0341]

15

20

[0342] The title compound was prepared (373.9 mg, 93 %) from 4-cbloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d] 25 pyrimidine (224 mg, 1 mmol) and 4-amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (235.4 mg, 1.1 mmol) 1 by following the procedure described for preparation 9. H NMR (400 MHz, CDCl3): δ (ppm) 8.39 (s, 1H), 3.33 (m, 4H), 3.10 (m, 2H), 2.87 9M, 2H), 1.93 (m, 4H), 1.66 (m, 4H), 1.40 (s, 9H), 1.22 (s, 3H); MS (ESI): m/z: Calculated: 402.6; Observed: 403.2 (M++1).

30 Example 87

1-(3,5-Difluorobenzyl)piperidin-4-amine

[0343] 35

40

45 [0344] The title compound was prepared (1.92 g, 85 %) from tert-butyl 1-(3,5-difluorobenzyl)piperidin-4-ylcarbamate 1 (3.26 g, 10 mmol) by following the general procedure described for Preparation 5. H NMR (400 MHz, CD3OD): δ 6.90 (m, 2H), 6.75 (m, 1H), 3.50 (s, 2H), 3.15 (m, 1H), 2.85 (m, 2H), 2.10 (m, 2H), 1.85 (m, 2H), 1.50 (m, 2H). MS (ESI) m/z: Calculated: 226.27; Observed: 227.1 (M++1). 50 Example 88

N-1-(1-(3-fluorophenyl)ethyl)propane-1,3-diamine

55 [0345]

67 EP 1 797 099 B1

5

10 [0346] The title compound was prepared (0.66 g, 100 %) from tert-butyl 3-(1-(3-fluorophenyl)ethylamino)propylcar- 1 bamate (1 g, 3.38 mmol) by following the general procedure described for Preparation 10. H NMR (400 MHz, CD3OD): δ 7.35 (m, 1H), 7.15 (m, 2H), 6.95 (m, 1H), 3.75 (q, 1H), 2.85 (m, 2H), 2.55 (m, 1H), 2.45 (m, 1H), 1.75 (m, 2H), 1.35 (d, 3H). MS (ESI) m/z: Calculated: 196.26; Observed: 197.0(M++1). 15 Example 89

tert-Butyl 3-(3-(3-fluorophenyl)ethylamino)propylcarbamate

20 [0347]

25

30

[0348] A solution of tert-butyl 3-aminopropylcarbamate (0.7g, 4.05 mmol) and 1-(3-fluorophenyl)ethanone (0.5 g, 3.6 mmol) in titanium(IV) isopropoxide (1.8 mL, 6 mmol) was stirred at room temperature for 3 h. It was diluted with methanol (10 mL) and then sodium borohydride (0.22 g, 5.76 mmol) was added carefully and stirred for 10 minutes. The reaction 35 mixture was quenched with 0.1 N NaOH (10 mL) solution. It was filtered through celite and washed with dichloromethane (2x20 mL). The organic layer was separated, dried over CaCl2 and evaporated to get the title product (1.07 g, 100 %) 1 as thick liquid. H NMR (400 MHz, CDCl3): δ 7.30 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 5.10 (bs, 1H), 3.75 (q, 1H), 3.15 (m, 2H), 2.55 (m, 1H), 2.45 (m, 1H), 1.60 (m, 2H), 1.45 (s, 9H), 1.35 (d, 3H). MS (ESI) m/z: Calculated: 296.38; Observed: 297.0 (M++1). 40 Example 90

1-(Cyclohexylmethyl)piperidin-4-amine, dihydrochloride

45 [0349]

50

55 [0350] The title compound was prepared (1.17 g, 71 %) from tert-butyl 1-(cyclohexylmethyl)piperidin-4-ylcarbamate 1 (1.82 g, 6.17 mmol) by following the general procedure described for Preparation 5. H NMR (400 MHz, CD3OD) δ 3.69 (dt, 2H), 3.49 (m, 1H), 3.11 (t, 2H), 2.98 (d, 2H), 2.24 (m, 2H), 2.11 (m, 2H), 1.90-1.70 (m, 4H), 1.43-1.19 (m, 4H), 1.06

68 EP 1 797 099 B1

+ (m, 2H); MS (ESI) m/z: Calculated for C12H25N2, 197.2; Observed: 197.2 (M +1).

Example 91

5 t-Butyl 1-(cyclohexylmethyl)piperidin-4-ylcarbamate

[0351]

10

15

[0352] The title compound was prepared (1.83 g, 83 %) from tert-butyl piperidin-4-ylcarbamate (1.50 g, 7.48 mmol) 20 and cyclohexanecarbaldehyde (0.84 g, 7.48 mmol) by following the general procedure described for Preparation 3. 1H NMR (400 MHz, CDCl3) δ 4.80 (bs, 1H), 3.71 (m, 1H), 3.63 (m, 2H), 2.53 (m, 2H), 2.43 (m, 2H), 2.00-1.61 (m, 9H), 1.44 + (s, 9H), 1.23 (m, 4H), 0.95 (m, 2H); MS (ESI) m/z: Calculated for C17H33N2O2, 297.25; Observed: 297.1 (M +1).

Example 92 25 tert-Butyl 1-(3,5-difluorobenzyl)pipendin-4-ylcarbamate

[0353]

30

35

40 [0354] The title compound was prepared (3.3 g, 100 %) from tert-butyl piperidin-4-ylcarbamate (2 g, 10 m mol) and 3,5-difluorobenzaldehyde (1.42 g, 10 mmol) by following the general procedure described for Preparation 3. 1H NMR (400 MHz, CDCl3): δ 6.85 (m, 2H), 6.65 (m, 1H), 4.45 (bs, 1H), 3.50 (m, 1H), 3.05 (s, 2H), 2.75 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.45 (m, 11H). MS (ESI) m/z: Calculated: 326.38; Observed: 327.0 (M++1). 45 Example 93

4-Chloro-6-isopropylthieno[2,3-d]pyrimidine

50 [0355]

55

[0356] The title compound was prepared (13 g, 80 %) from 6-isopropylthieno[2,3-d] pyrimidin-4-ol (15 g, 0.077 mol)

69 EP 1 797 099 B1

1 by following the general procedure described for Preparation 2. H NMR (400 MHz, CDCl3): 8 8.80 (s, 1H), 7.10 (s, 1H), 3.30 (m, 1H), 1.45 (d, 6H). MS (ESI) m/z: Calculated: 212.7; Observed: 213.2 (M++1).

Example 94 5 4-Chloro-6-isobutylthieno[2,3-d]pyridine

[0357]

10

15 [0358] The title compound was prepared (0.96 g, 88 %) from 6-isobutylthieno[2,3-d] pyrimidin-4-ol (1 g, 4.8 mmol) by 1 following the general procedure described for Preparation 2. H NMR (400 MHz, CDCl3): δ 8.95 (s, 1H), 7.10 (s, 1H), 2.80 (d, 2H), 2.05 (m, 1H), 1.05(d, 6H). MS (ESI) m/z: Calculated: 226.73; Observed: 227.1 (M++1).

20 Example 95

4-Chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine

[0359] 25

30

[0360] The title compound was prepared (6.3 g, 90%) from 5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol 1 (6.5g, 32 mmol) by following the procedure described for preparation 2. H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 3.10 35 (m, 2H), 2.89 (m, 2H), 1.94 (m, 4H); MS (ESI): m/z: Calculated: 224; Observed: 225 (M++1).

Example 96

4,6-Dichloro-5-methylthieno[2,3-d]pyrimidine 40 [0361]

45

[0362] The title compound was prepared (428 mg, 98 %) from 6-chloro-5-methylthieno[2,3-d]pyrimidin-4-ol (400 mg, 50 1 2.0 m. mol) by following the general procedure described for Preparation 2. H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 2.65 (s, 3H).

Example 97

55 4,6-Dichloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine

[0363]

70 EP 1 797 099 B1

5

10 [0364] To a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (1 g, 4.06 mmol) in acetic acid (15 mL), N- chlorosuccinimide (1.08 g, 8.1 m. mol) was added and the mixture was stirred at 90˚C for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (30 mL) and washed with sat. NaHCO3 solution (3 x 20 mL). The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by column 15 1 chromatography to get the title product (200 mg, 16 %) as pale yellow solid. H NMR (400 MHz, CDCl3 and CDCl3): δ 8.85 (s, 1H), 7.35 (m, 2H), 7.20 (m, 2H). MS (ESI) m/z: Calculated: 297.95; Observed: 299.2 (M++1).

Example 98

20 6-Isobutylthieno[2,3-d]pyrimidin4-ol

[0365]

25

30 [0366] The title compound was prepared (3.58 g, 82 %) from ethyl 2-amino-5-isobutylthiophene-3-carboxylate (4.68 1 g, 21 mmol) by following the general procedure described for Preparation 1. H NMR (400 MHz, CD3OD): δ 8.50 (s, 1H), 7.20 (s, 1H), 2.80 (d, 2H), 1.95 (m, 1H), 1.00 (d, 6H). MS (ESI) m/z: Calculated: 208.28; Observed: 209.2 (M++1).

Example 99 35 6-Isopropylthieno[2,3-d]pyrimidin-4-ol

[0367]

40

45 [0368] The title compound was prepared (15 g, 70 %) from ethyl 2-amino-5-isopropylthiophene-3-carboxylate (23.5 1 g, 0.11 mol) by following the general procedure described for Preparation 1. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.10 (s, 1H), 3.00 (m, 1H), 1.40 (d, 6H). MS (ESI) m/z: Calculated:194.25; Observed: 195.3 (M++1).

50 Example 100

6-Chloro-5-methylthieno[2,3-d]pyrimidin-4-ol

[0369] 55

71 EP 1 797 099 B1

5

[0370] To a solution of 5-methylthieno[2,3-d]pyrimidin-4-ol (2 g,12 mmol) in acetic acid (30 mL) at room temperature, chlorine gas was bubbled for 3 h. The reaction mixture was stirred at same temperature for 2 days. The solvent was 10 evaporated under reduced pressure at 40˚C and the residue was dissolved in ethyl acetate (30 mL) and washed with sat NaHCO3 solution (3 x 20 mL). The organic layer was dried over sodium sulfate and evaporated to get the title 1 compound as a pale yellow solid (2 g, 82 %). H NMR (400 MHz, CDCl3 and CD3OD): δ 7.90 (s, 1H), 2.55 (s, 3H). MS (ESI) m/z: Calculated: 200.65; Observed: 201.3 (M++1).

15 Example 101

6-Chloro-5-methylthieno[2,3-d]pyrimidin-4-ol

[0371] 20

25

[0372] The title compound was prepared (3.38 g, 75 %) from ethyl 2-amino-5-chloro-4-methylthiophene-3-carboxylate 1 (5 g, 27 mmol) by following the general procedure described for Preparation 1. H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.00 (s, 1H), 2.55 (s, 3H). MS (ESI) m/z: Calculated: 166.2; Observed: 167.1 (M++1). 30 Example 102

5,6,7,8-Tetrahydro-benzo[4,5]-thieno[2,3-d]pyrimidin-4-ol

35 [0373]

40

[0374] The title compound was obtained in 92 % following the procedure described in Preparation 1. 1H NMR (400 45 MHz, DMSO-d6): δ 12.35 (bs, 1H), 8.0 (s, 1H), 2.88 (t, 2H), 2.74 (t, 2H), 1.74-1.82 (m, 4H). MS (ESI) m/z: Calculated: 206.2; Observed: 207.2 (M++1).

Example 103

50 N-(1-(4-Fluoro-3-methoxybenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine, monomaleate

[0375]

55

72 EP 1 797 099 B1

5

10

[0376] The title compound was prepared (40 mg, 49 %) from N-(1-(4-fluoro-3-methoxybenzyl)piperidin-4-yl)-6-chlo- rothieno[2,3-d]pyrimidin-4-amine (64 mg, 0.16 mmol) by following the procedure described for Preparation 8. 1H NMR (400 MHz, CD3OD): δ 8.35 (s, 1H), 7.50 (s, 1H), 7.15-7.30 (m, 2H), 7.10 (m, 1H), 6.25 (s, 2H), 4.40 (m, 1H), 4.30 (s, 15 2H), 3.95 (s, 3H), 3.55 (m, 2H), 3.20 (m, 2H), 2.35 (m, 2H), 1.90 (m, 2H). MS (ESI) m/z: Calculated: 406.90; Observed: 407.2 (M++1).

Example 104

20 N-(1-(4-Fluoro-3-methoxybenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine

[0377]

25

30

35 [0378] The title compound was prepared (64 mg, 43%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.37 mmol) and 4-fluoro-3-methoxybenzaldehyde (57 mg, 0.37 mmol) by following the general procedure 1 described for Preparation 11. H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.00 (m, 3H), 6.85 (m, 1H), 5.00 (d, 1H), 4.20 (m, 1H), 3.90 (s, 3H), 3.50 (s, 2H, 2.90 (m, 2H), 2.20 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 40 406.90; Observed: 407.2 (M++1).

Example 105

N-(1-((Benzo[d][1,3]dioxol-5-yl)methyl)-4-piperidin-4-yl)-6-chlorothieno[2,3-d] pyrimidin-4-amine, monoma- 45 leate

[0379]

50

55

73 EP 1 797 099 B1

5

10

[0380] The title compound was prepared (42 mg, 48 %) from N-(1-((benzo[d][1,3]dioxol-5-yl)methyl)piperidin-4-yl)-6- chlorothieno[2,3-d] pyrimidin-4-amine (69 mg, 0.17 mmol) by following the procedure described for Preparation 8. 1H 15 NMR (400 MHz, CD3OD): δ 8.35 (s, 1H), 7.50 (s, 1M, 7.05 (m, 2H), 6.95 (d, 1H), 6.25 (s, 2H), 6.00 (s, 2H), 4.40 (m, 1H), 4.25 (s, 2H), 3.60 (m, 2H), 3.15 (m, 2H), 2.35 (m, 2H), 1.90 (m, 2H). MS (ESI) m/z: Calculated: 402.90; Observed: 403.2 (M++1).

Example 106 20 N-(1-((Benzo[d][1,3]dioxol-5-yl)methyl)piperidin4-yl)-6-chlorothieno[2,3-d] pyrimidin-4-amine

[0381]

25

30

35

[0382] The title compound was prepared (69 mg, 47%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.37 mmol) and 5-(chloromethyl)benzo[d][1,3]dioxole (63 mg, 0.37 mmol) by following the general procedure 1 described for Preparation 12. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.25 (s, 1H), 6.95 (s, 1H), 6.75-7.05 (m, 2H), 40 5.95 (s, 2H), 5.85 (d, 1H), 4.25 (m, 1H), 3.65 (s, 2H), 3.10 (m, 2H), 2.40 (m, 2H), 2.15 (m, 2H), 1.90 (m, 2H). MS (ESI) m/z: Calculated: 402.90; Observed: 403.2 (M++1).

Example 107

45 [0383]

50

55

74 EP 1 797 099 B1

5

10

15

20

25

30

35 [0384] Ethyl 2-amino-3-carboxythiophene 2 is refluxed with ammonium formate and formamide to give the cyclized intermediate 3 which is then treated with thionyl chloride to afford the chloro derivative 4. Boc-protected aminopiperidine 5 is reductively alkylated with a variety of arylaldehydes 6 to provide the corresponding intermediates 7. Deprotection of 7 with trifluoroacetic acid treatment yields the free amine intermediate 8. Reflux of a mixture of the key intermediates 4 and 8 in i-propanol or acetonitrile in the presence of triethylamine yields the final compound 1. 40 [0385] The following compounds of the invention made by the above synthetic method are expected to also have good activity:

45

50

55 (5,6,7,8-Tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[1-(4-trifluoromethyl-benzyl)-piperidin-4-yl]-amine

75 EP 1 797 099 B1

5

10

15 (1-Phenethyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

20

25

30 [1-(3-Phenyl-propyl)-piperidin-4-yl]-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine

EXAMPLE 108

Compound Activity 35 [0386] Compounds of the invention were made according to the respective syntheses noted above, and their activity and selectivity was determined. These compounds were found to be active (e.g., at concentrations from about 0.1 to about 10mM) and selective 5-HT2B modulators. Test data are shown in Tables A and B. The compounds accordingly are expected to be useful as 5-HT2B receptor modulators, e.g., in the treatment of a wide variety of clinical conditions 40 which are characterized by serotonin excess or absence, e.g., serotoninergic hypofunction or hyperfunction. Such conditions include those noted above, and conditions associated with vascular disorders, e.g., allergic asthma, irritable bowel syndrome; hypertonic lower esophageal sphincter; motility disorders or benign prostatic hyperplasia; CNS disorder, attention deficit hyperactivity disorder; obesity; sleeping disorder; Alzheimer’s disease; Parkinson; anxiety; depression; schizophrenia; neural injury; stroke; migraine; angina; hypertension including pulmonary arterial hypertension and sys- 45 temic hypertension; disorders of the gastrointestinal tract; restenosis; asthma; obstructive airway disease; pain including inflammatory pain, neuropathic pain, cancer pain, acute pain or chronic pain; prostatic hyperplasia and priapism.

Biological Data Table

50 [0387]

55

76 EP 1 797 099 B1

# Structure Chemical Name Ki HLM T1/2 Other Activity Data

B1 N-(1-benzylpiperidin-4-yl) 13 nM (5HT2B) <15 min IC50 5 5,6,7,8-tetrahydro-benzo[4,5] (Functional): thieno[2,3-d]pyrimidin-4-amine 110 nM (Antagonist at 0.11uM) Rat pK: T1/2: 60 min 10 (po)

B2 N-(1-(4-fluorobenzyl)piperidin4- 8.2 nM (5HT2B) yl)5,6,7,8-tetrahydro-benzo[4,5] thieno[23-d]pyrimidin-4-amine

15

B3 N-(1-(3-fluorobenzyl)piperidin- 2.3 nM (5HT2B) 4.3 min IC50 4-yl)5,6,7,8-tetrahydro-benzo 240 nM (D2S) (Functional): 20 [4,5] thieno[2,3-d]pyrimidin-4- 100 nM amine (Antagonist at 0.10uM) IC50 (IP3): 22.46 nM hERG (% 25 Inhibition at 1uM): 58.5

B4 N-(1-(2-fluorobenzyl)piperidin- 6.3 nM (5HT2B) hERG(% 4-yl)5,6,7,8-tetrahydro-benzo Inhibition at [4,5] thieno[2,3-d]pyrimidin-4- lung: 58.5 30 amine

35 B5 N-methyl-N-(1-methylpiperidin- -2%/10 nM 4-yl)5,6,7,8-tetraliydro-benzo 11%/100 nM [4,5] thieno[2,3-d]pyrimidin-4- 67%/1000nM amine

40 B6 N-(1-benylpiperidin-4-yl)-5- 7.7 nM or 38%/ <15 min phenylthieno[2,3-d]pyrimidin-4- 10 nM 91%/ amine 100nM 101%/ 1000nM

45

B7 2-(4-(5-phenylthieno[2,3-d] 3%/10 nM 4%/ pyrimidin-4-ylamino)piperidin-1- 100 nM 30%/ 50 yl)-5-(trifluoromethyl)pyridin-3- 1000nM ol

55

77 EP 1 797 099 B1

(continued)

# Structure Chemical Name Ki HLM T1/2 Other Activity Data 5 B8 N-(1-benzylpiperidin-4-yl)thieno 35 nM or 130/o/ [2,3-d]pyrimidin-4-amine 10nM62%/100 nM 96%/ 1000nM

10

B9 N-(1-benzylpipendin-4-yl)-5- 38 nM or 15%/ methylthieno[2,3-d]pyrimidin-4- 10nM62%/100 amine nM 97%/ 15 1000nM

B10 N-(1-(1-(3-fluorophenyl)ethyl) 4.0 nM (5HT ) <15 min 20 2B piperidin-4-yl)-(5,6,7,8- tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidin-4-amine, dihydrochloride

25

B11 3-((4-(5,6,7,8-tetrahydro-benzo 5HT2B: 35%/ <15 min hERG (% [4,5]thieno[2,3-d]pyrimidin-4- 1nM 82%/ Inhibition at 30 ylamino)piperidin-1-yl) methyl) 10nM 101%/ 1uM): 44.9 benzonitrile, dihydrochloride 100nM

35 B12 N-(1-(1-(3-fluorophenyl) ethyl) 14 nM (5- 11 min hERG (% piperidin-4-yl)thieno [2,3-d] HT2B) 250 nM Inhibition at pyrimidin-4-amine, (D2S) 1uM): 58.5 dihydrochloride 40

B13 N-(1-(1-(3-fluorophenyl) ethyl) 4.6 nM <15 min

45 piperidin-4-yl)-5,6- dimethylthieno[2,3-d] pyrimidin- 4-amine, dihydrochloride

50

55

78 EP 1 797 099 B1

(continued)

# Structure Chemical Name Ki HLM T1/2 Other Activity Data 5 B14 N-(1-(1-(3-fluorophenyl)ethyl) 0.97 nM <15 min RatpK:%F =4% piperidin-4-yl)-6-isobutylthieno T1/2: 0.5h (po); [2,3-d] pyrimidin-4-amine, 0.5h (iv) hERG dihydrochloride (%Inhibition at 1uM): 76.1 IC50 10 (Functional): 5.3 uM

B15 N-(1-(1-(3-fluorophenyl)ethyl)4- 1.2uM <15 min 15 methylpiperidin-4-yl)5,6,7,8- tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidin-4-amine, dihydrochloride

20

B16 N-(1-(1-(3-fluorophenyl)-3- 84 nM <15 min 25 methylbutyl)piperidin-4-yl) 5,6,7,8-tetrahydro-benzo[4,5] thieno[2,3-d]pyrimidin-4-amine, dihydrochloride

30

B17 N-(1-(1-(3,5-difluorophenyl) 3.2 nM <15 min IC50 ethyl) piperidin-4-yl)5,6,7,8- (Functional): tetrahydro-benzo [4,5]thieno 1.3 uM 35 [2,3-d]pyrimidin-4-amine, dihydrochloride

40

B18 N-(1-(1-(3,5-difluorophenyl) 4.2 nM 7 min IC50 ethyl)piperidin-4-yl)-6- (Functional): isobutylthieno [2,3-d]pyrimidin- 5.7uM Rat pK: 45 4-amine, dihydrochloride % F =3% T1/2: 0.4h (po); 0.2h (iv) hERG (%Inhibition at 1uM): 31 % 50 Protein Binding = 93.8%

55

79 EP 1 797 099 B1

(continued)

# Structure Chemical Name Ki HLM T1/2 Other Activity Data 5 B19 N-(1-(1-(2,4,6-tiifluorophenyl) 70 nM <15 min hERG ethyl)piperidin-4-yl)-6- (%Inhibition at isobutylthieno [2,3-d]pyrimidin- 1uM): 50.2 4-amine, dihydrochloride

10

B20 N-(1-(1-(2,6-difluorophenyl) 20 nM <15 min hERG 15 ethyl) piperidin-4-yl)-6- (%Inhibition at isobutylthieno[2,3-d] pyrimidin- 1uM): 73.4 4-amine, dihydrochloride

20

B21 N-(1-(1-(2,6-difluorophenyl) 52 nM <15 min ethyl) piperidin-4-yl) 5,6,7,8- tetrahydro-benzo[4,5]thieno

25 [2,3-d]pyrimidin-4-amine, dihydrochloride

30 B22 N-(1-(1-(2,4,6-trifluorophenyl) 72 nM ethyl) piperidin-4-yl) 5,6,7,8- tetrahydro-benzo[4,5]thieno [2,3-d]pyrimidin-4-amine,

35 dihydrochloride

B23 2-(3-fluorophenyl)- 120 nM <15 min 40 2-(4-(5,6,7,8-tetrahydro-benzo [4,5]thieno[2,3-d] pyrimidin-4- ylamino)piperidin-1-yl) propanenitrile, dihydrochloride

45

B24 N-(1-(2-(3-fluorophenyl)propan- 15 nM <15 min 2-yl) piperidin-4-yl) 5,6,7,8- 50 tetrahydro- benzo[4,5]thieno [2,3-d]pyrimidin-4-amine, dihydrochloride

55

80 EP 1 797 099 B1

(continued)

# Structure Chemical Name Ki HLM T1/2 Other Activity Data 5 B25 N-(3-(3-fluorobenzylamino) 17 nM <15 min propyl) 5,6,7,8-tetrahydro- benzo[4,5] thieno[2,3-d] pyrimidin-4-amine, dihydrochloride 10

B26 N-(3-(1-(3-fluorophenyl) 44 nM <15 min

15 ethylamino)propyl) 5,6,7,8- tetrahydro-benzo[4,5]thieno [2,3-d] pyrimidin-4-amine, dihydrochloride

20

B27 N-(3-(1-(3-fluorophenyl) 150 nM <15 min ethylamino)propyl)-6- isobutylthieno [2,3-d]pyrimidin- 4-amine, dihydrochloride 25

B28 N-(1-(2,2,2-trifluoro-1-(3- 0.95 uM 11 min 30 fluorophenyl)ethyl)piperidin -4- yl) 5,6,7,8-tetrahydro-benzo [4,5] thieno[2,3-d]pyrimidin-4- amine, dihydrochloride

35

B29 N-(3,5-difluorobenzyl)-1-(6- 1.3 uM 18 min isobutylthieno[2,3-d]pyrimidin- 4-yl) piperidin-4-amine, 40 dihydrochloride

B30 N-(1-(3,5-difluorobenzyl) 18 nM (5HT2B) 19 min IC50 45 piperidin-4-yl)thieno[2,3-d] (Functional): pyrimidin-4-amine, 1.6 uM Rat pK: dihydrochloride % F =17% T1/2: 0.8h(po)hERG (%Inhibition at

50 1uM): 62

55

81 EP 1 797 099 B1

(continued)

# Structure Chemical Name Ki HLM T1/2 Other Activity Data 5 B31 N-(1-(3,5-difluorobenzyl) 0.99 nM (5- 8 min IC50 piperidin-4-yl)-b-isopropylthieno HT2B) 230 nM (Functional): [2,3-d] pyrimidin-4-amine, (D2S) 0.83 uM Rat pK: dihydrochloride % F =10% T1/2: 0.5 h (po) 10

15 B32 N-(1-(3,5-difluorobenzyl) 0.57 nM IC50 piperidin-4-yl)-6-isopropylthieno (5HT2B) (Functional): [2,3-d] pyrimidin-4-amine, 0.45 uM IC50 monomaleate (IP3): 1.53 nM

20

B33 N-(1-(3,5-difluorobenzyl) 1.9 nM 13 min hERG piperidin-4-yl)-6-chlorothieno (5HT2B) (1/ohAnbitionat [2,3-d]pyrimidin-4-amine, 1uM): 22.8 25 dihydrochloride

30 B34 N-(1-(3,5-difluorobenzyl) 0.79 nM (5- Functional piperidin-4-yl)-6-chlorothieno HT2B) 66 nM Activity: IC50: [2,3-d]pyrimidin-4-amine, (D2S) 140 nM 0.68 uM monomaleate (D3) 35 nM (5HT2B) IC50: 35 (5HT1A) 17.2 nM (D2L) 260nM(5HT2 IC50: 63.3 nM A) 2.4/6.6 nM (D2S) IC50:Not (σ1) 3.4 nM Active (5HT2A) (D4.4) IC50: Not Active 40 (5HT1A) IC50: 0.74 nM (IP3) Rat pK:%F = 29.1 % T1/2: 1.1 h (po); 0.4 h (iv) 45 hERG (%Inhibition at 1uM): 29.4 % Protein Binding = 99% AMES 50 Test: Negative B35 N-(1-cyclohexylmethyl)piperidin 7.8 nM (5- <15 min hERG -4-yl)-5,6-dimethylthieno[2,3-d] HT2B) (%Inhibition at pyrimidm-4-amine, 1uM): 91.7 dihydrochloride 55

82 EP 1 797 099 B1

(continued)

# Structure Chemical Name Ki HLM T1/2 Other Activity Data 5 B36 2-((4-(5,6-dimethylthieno[2,3-d] 210 nM (5- hERG pyrimidin-4-ylamino)piperidin-1- HT2B) (%Inhibition at yl)methyl)benzonitrile, 1uM): 21.7 dihydrochloride

10

B37 N-(1-(3-fluorobenzyl)piperidin- 2.5 nM (5- 11 min 4-yl)-6-chloro-5-methylthieno HT ) 15 2B [2,3-d]pyrimidin-4-amine, dihydrochloride

20

B38 N-(1-(3-fluorobenzyl) piperidin4- 1.8nM (5HT2B) IC50 yl)-6-chloro-5-methylthieno[2,3- 170 nM (D2S) (Functional): d]pyrimidin-4-amine, 560 nM IC50 25 monomaleate (IP3): 2.27 nM Rat pK: % F =18.2% T1/2: 0.9 h (po); 0.4 h (iv) hERG

30 (%inhibition at 1uM): 78.1 % Protein Binding= 93.8%

B39 2-((4-(6-chloro-5-methylthieno 80 nM (5HT2B) <15 min 35 [2,3-d] pyrimidin-4-ylamino) piperidin-1-yl) methyl) benzonitrile, dihydrochloride

40

B40 N-(1-(2-methoxybenzyl) 6.1 nM (5HT2B) <15 min piperidin-4-yl)-6-chloro-5- methylthieno[2,3-d] pyrimidin-4- 45 amine, dihydrochloride

50

B41 N-(1-(3-fluorobenzyl) piperidin- 2.8 nM (5HT2B) 10 min 4-yl)-6-chlorothieno [2,3-d] pyrimidin-4-amine, dihydrochloride 55

83 EP 1 797 099 B1

(continued)

# Structure Chemical Name Ki HLM T1/2 Other Activity Data 5 B42 N-(1-(3-fluorobenzyl) piperidin4- 1.1 nM Functional yl)-6-chlorothieno [2,3-d] (5HT2B) 170 Activity: IC50: pyrimidin-4-amine, nM (D2S) 250 110nM(5HT2B) monomaleate nM (Na chan) IC50: 162 nM 26 nM(D3) (D2L)IC50: 292 10 6.7nM(σ1) nM (D2S)IC50: 17nM (5HT1A) 340nM(5HT2A) 52nM (5HT2A) IC50: Not Active 4.7 nM (D4.4) (5HT1A) IC50 (IP3): 1.70 nM 15 AMES Test: Negative Rat pK: % F = 22.4 % T1/2:1.2h (po); 0.4 h (iv) 20 hERG (%Inhibition at lung): 50.1 % ProteinBinding: 98.3% 25 B43 3-((4-(6-chlorothieno[2,3-d] 0.57 nM 22 min Functional pyrimidin-4-ylamino) piperidin- (5HT2B) 1 uM Activity: IC50: 1-yl)methyl) benzonitrile, (D2S) 11 nM 17.5 nM monomaleate (σ1) 25nM (5HT2B) EC50 30 (D4.4) 280 nM (agonist): 920 (5HT1A) 970 nM (D2) IC50: nM (Na+) 1.2 No antagonist uM (D1) 1.3 uM activity (D2) (D3) IC50(IP3): 1.48 35 nM AMES Test: Negative Rat pK: % F =17.2% T1/2: 1.53 h (po); 0.74 h (iv) 40 Mouse pK: % F=87% T1/2:26 min (iv); 30 min (iP) hERG (%Inhibition at 45 1uM): 47.3 % ProteinBinding: 98.2% B44 3-((4-(6-chlorothieno[2,3-d] 260 nM pyrimidin-4-ylamino) piperidin- (5HT2B) 50 1-yl)methyl)benzoic acid, dihydrochloride

55

84 EP 1 797 099 B1

(continued)

# Structure Chemical Name Ki HLM T1/2 Other Activity Data 5 B45 3-((4-(6-chlorothieno[2,3-d] 170 nM 86 min pyrimidin-4-ylamino) piperidin- (5HT2B) 1-yl)methyl) benzamide, monomaleate

10

15 B46 N-(1-(2-fluorobenzyl) piperidin- 4.3 nM (5HT2B) <15 min hERG (% 4-yl)-6-chlorothieno [2,3-d] Inhibition at pyrimidin-4-amine, 1uM): 39.5 monomaleate

20

B47 6-chloro-N-(1-((pyridin-3-yl) 51 nM (5HT2B) 12 min methyl)pipendin-4-yl)thieno >10uM (D2S) 25 [2,3-d]pyrimidin-4-amine, monomaleate

30 B48 N-(1-(3,5-difluorobenzyl) 150 nM <15 min piperidin-4-yl)-6-chloro-5-(4- (5HT2B) 1.1 fluorophenyl)thieno[2,3-d] uM (D2S) pyrimidin-4-amine, 5HT1A: not 35 monomaleate Active

B49 6-chloro-N-(1-((pyrimidin-5-yl) 170 nM 60 min methyl)piperidin-4-yl)thieno (5HT ) 40 2B [2,3-d]Pyrimidin-4-amine, monomaleate

45

B50 5-((4-(6-chlorothieno[2,3-d] 1.8 nM (5HT2B) 28 min IC50 pyrimidin-4-ylamino)piperidin-1- 2.2 nM (5HT2B) (Functional): 27 yl)methyl)-2-fluorobenzonitrile, 100 nM nM Rat pK: % F monomaleate (5HT1A) 670 = 22.57 % T1/2: 50 nM (D2S) 5.4 0.89h(po);0.62 nM (D4.4) h (iv) hERG (% Inhibition at 1uM): 23.7 AMES Test: 55 Negative

85 EP 1 797 099 B1

(continued)

# Structure Chemical Name Ki HLM T1/2 Other Activity Data 5 B51 3-((4-(6-chlorothieno[2,3-d] 0.74 nM 10 min pyrimidin-4-ylamino)piperidin-1- (5HT2B) yl)methyl)4-fluorobenzonitrile, monomaleate

10

B52 N-(1-(3-chlorobenzyl) 0.74 nM 11 min 15 piperidin4-yl)-6-chlorothieno (5HT2B) [2,3-d]pyrimidin-4-amine, monomaleate

20

B53 N-(1-(3-fluorobenzyl)piperidin- 13 nM (5HT2B) 8 min 4-yl)-6-chloro-5-isopropylthieno 25 [2,3-d]pyrimidin-4-amine, monomaleate

30

B54 N-(1-(3-(trifluoromethyl)benzyl) 5.7 nM 16 min piperidin-4-yl)-6-chlorothieno (5HT2B) [2,3-d]pyrimidin-4-amine, monomaleate 35

40 B55 3-((4-(6-chlorothieno[2,3-d] 25 nM (5HT2B) 34 min pyrimidin-4-ylamino)piperidin-1- NA (D2S) 330 yl)methyl)-N-methylbenzamide, nM (D4) NA: monomaleate Not Active

45

50 B56 N-(1-(3-(trifluoromethylsulfonyl) 45 nM (5HT2B) <15 min benzyl)piperidin-4-yl)-6- 3.1 uM (D2S) chlorothieno[2,3-d] pyrimidin-4- 180 nM (D4) amine, monomaleate

55

86 EP 1 797 099 B1

(continued)

# Structure Chemical Name Ki HLM T1/2 Other Activity Data 5 B57 3-((4-(6-chlorothieno[2,3-d] 50 nM (5HT2B) 24 min pyrimidin-4-ylamino)piperidin-1- NA* (D2S) 540 yl)methyl)-N,N- nM (D4) *NA: dimethylbenzamide, Not Active monomaleate 10

B58 N-(1-(3-(methylsulfonyl)benzyl) 45 nM (5HT2B) 27 min 15 piperidin-4-yl)-6-chlorothieno >10uM (D2S) [2,3-d]pyrimidin-4-amine, 430 nM (D4) monomaleate

20

EQUIVALENTS

25 [0388] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the invention and are covered by the following claims. Various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. Other aspects, advantages, and modifications are within the scope of the invention. The contents of all references, issued 30 patents, and published patent applications cited throughout this application are hereby incorporated by reference. The appropriate components, processes, and methods of those patents, applications and other documents may be selected for the invention and embodiments thereof.

Reference List 35 [0389]

Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G & Begaud B 1996 Appetite-suppressant drugs and the risk of primary pulmonary hypertension. 40 International Primary Pulmonary Hypertension Study Group. N.Engl.J.Med. 335 609-616.

Farber HW & Loscalzo J 2004 Pulmonary arterial hypertension. N.Engl.J.Med. 351 1655-1665.

Fishman AP 1998 Etiology and pathogenesis of primary pulmonary hypertension: a perspective. Chest 114 242S- 45 247S.

Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun JH, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ & Robertson DW 2000 Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol.Pharmacol. 57 75-81. 50 Kennett GA, Ainsworth K, Trail B & Blackburn TP 1997 BW 723C86, a 5-HT2B receptor agonist, causes hyperphagia and reduced grooming in rats. Neuropharmacology 36 233-239.

Kursar JD, Nelson DL, Wainscott DB & Baez M 1994 Molecular cloning, functional expression, and mRNA tissue 55 distribution of the human 5-hydroxytryptamine2B receptor. Mol.Pharmacol. 46 227-234.

Kuryshev YA, Brown AM, Wang L, Benedict CR & Rampe D 2000 Interactions of the 5-hydroxytryptamine 3 antagonist

87 EP 1 797 099 B1

class of antiemetic drugs with human cardiac ion channels. J.Pharmacol.Exp.Ther. 295 614-620.

Launay JM, Herve P, Peoc’h K, Tournois C, Callebert J, Nebigil CG, Etienne N, Drouet L, Humbert M, Simonneau G & Maroteaux L 2002 Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. 5 Nat.Med 8 1129-1135.

MacLean MR 1999 Pulmonary hypertension, anorexigens and 5-HT: pharmacological synergism in action? Trends Pharmacol.Sci. 20 490-495.

10 Marcos E, Fadel E, Sanchez O, Humbert M, Dartevelle P, Simonneau G, Hamon M, Adnot S & Eddahibi S 2004 Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ.Res. 94 1263-1270.

Nauser TD & Stites SW 2001 Diagnosis and treatment of pulmonary hypertension. Am.Fam.Physician 63 1789-1798. 15 Nebigil CG, Launay JM, Hickel P, Tournois C & Maroteaux L 2000 5-hydroxytryptamine 2B receptor regulates cell- cycle progression: cross-talk with tyrosine kinase pathways. Proc.Natl.Acad.Sci. U.SA 97 2591-2596.

Poissonnet G, Parmentier JG, Boutin JA & Goldstein S 2004 The emergence of selective 5-HT 2B antagonists 20 structures, activities and potential therapeutic applications. Mini.Rev.Med Chem. 4 325-330.

Rich S, Rubin L, Walker AM, Schneeweiss S & Abenhaim L 2000 Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension. Chest 117 870-874.

25 Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ & Roth BL 2000 Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102 2836-2841.

Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB & Roth BL 2003 3,4- 30 methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human car- diac valvular interstitial cells in vitro. Mol.Pharmacol. 63 1223-1229.

Teoh, H., Wang, G. and Ward, M.E. Hypoxia Enhances 5-HT2B 2005 Receptor Response and Expression in the Rat Pulmonary Artery. International Conference of the American Thoracic Society. San Diego 35 Ullmer C, Boddeke HG, Schmuck K & Lubbert H 1996 5-HT2B receptor-mediated calcium release from ryanodine- sensitive intracellular stores in human pulmonary artery endothelial cells. Br.J.Pharmacol.117 1081-1088.

Ullmer C, Schmuck K, Kalkman HO & Lubbert H 1995 Expression of serotonin receptor mRNAs in blood vessels. 40 FEBS Lett. 370 215-221.

Witchel HJ, Hancox JC & Nutt DJ 2003 Psychotropic drugs, cardiac arrhythmia, and sudden death. J.Clin.Psychop- harmacol. 23 58-77.

45 Witchel HJ, Pabbathi VK, Hofinann G, Paul AA & Hancox JC 2002 Inhibitory actions of the selective serotonin re- uptake inhibitor citalopram on HERG and ventricular L-type calcium currents. FEBS Lett. 512 59-66.

Yamada J & Sugimoto Y 2000 The 5-HT(2C/2B) receptor agonist, m-chlorophenylpiperazine, increases plasma glucagon levels in rats. Eur.J.Pharmacol. 406 153-157. 50

Claims

1. A compound having the formula 55

88 EP 1 797 099 B1

5

10

15

20

wherein 25 R1 is selected from the group consisting of halo, C1-6 alkyl, cyano, and trihalomethyl; each R2 is independently hydrogen, trihalomethyl, carboxylate, an amide, or a sulfonyl group; and n is 1 or 2, provided that when n is 1, R2 is not hydrogen, and when n is 2, both R2 groups are not hydrogen; or a pharmaceutically acceptable salt and/or ester thereof.

30 2. A compound having the formula

35

40

45 wherein R1 and R2 are independently halogen, unsubstituted aryl, unsubstituted heteroaryl, or a substituted aryl or heteroaryl group; R3 is independently H; halogen; CN; NH2;C1-6 alkyl; R7;OR7; NHR7;N(R7)2; or substituted or unsubstituted aryl or heteroaryl; 50 R4 is H, R7, or substituted or unsubstituted aryl or heteroaryl; Q is chosen from

55

89 EP 1 797 099 B1

5

10 wherein R8 is hydrogen, halogen, or C1-6 alkyl and * indicates attachment points; R5 and R6 are independently selected from hydrogen, halogen, COOH; CN; NH2;NO2; OH; C1-6 alkyl; substituted C1-6 alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2; OR7; NHR7; N(R7)2; R7-alkoxy; R7-haloalky; and R7-haloalkoxy; or R5 and R6, taken together with their bonded carbons, form a substituted or unsubstituted unsaturated 5- or 6- 15 membered carbocyclic ring or a substituted or unsubstituted saturated 5-, 6-, or 7-membered carbocyclic ring, wherein

- the carbocyclic ring may be a heterocarbocyclic ring comprising at least one hetero atom chosen from O, N and S, - wherein the substituted ring comprises at least one hydrogen, halogen, COOH; CN; NH2;NO2; OH; C1-6 alkyl; 20 substituted C1-6 alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; NHR7; N(R7)2; R7-alkoxy; R7-haloalkyl; or R7-haloalkoxy;

wherein R7 is substituted or unsubstituted (C1-C6) alkyl or a (C3-C6) cycloalkyl or cycloheteroalkyl; n is 2, 3, 4, or 5; 25 wherein a substituted aryl or heteroaryl group can be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, carboxylate, alkylcarbonyl, cyano, amino, acylamino, sulfhydryl, alkylthio, arylthio, nitro, trifluoromethyl and cyano; and wherein a substituted alkyl may be substituted by one or more substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonyloxy; alkynyl, alkylcarbonyl, alkylthio, alkythiocarbonyl, thiocarboxy- 30 late, arylthio, arylcarbonyl, arylcarbonyloxy, acylamino, carboxylate, cyano, halogen, haloalkyl, cycloalkoxy, aceta- mide, amine, hydroxyl, nitro, sulfhydryl, sulfonamido and trifluoromethyl; or a pharmaceutically acceptable salt and/or ester thereof.

3. A compound having the formula 35

40

45

wherein R1 and R2 are independently hydrogen, COOH; CN; NH2;NO2; OH; substituted C1-6 alkyl; substituted or unsubsti- tuted aryl or heteroaryl; COOR7; CONHR7; CON(R7)2;OR7; NHR7;N(R7)2;R7-alkoxy; R7-haloalkyl; or 50 R7-haloalkoxy; R3 is independently H; halogen; CN; NH2;C1-6 alkyl; R7;OR7; NHR7;N(R7)2; or substituted or unsubstituted aryl or heteroaryl; R4 is H, R7, or substituted on unsubstituted aryl or heteroaryl ; Q is chosen from

55

90 EP 1 797 099 B1

5

10

wherein R8 is hydrogen, halogen, or C1-6alkyl and * indicates attachment points; R5 and R6 are independently selected from hydrogen, halogen, COOH; CN; NH2;NO2; OH; C1-6 alkyl; substituted C1-6 alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; NHR7;N(R7)2; R7-alkoxy; R7-haloalkyl; and R7-haloalkoxy; or 15 R5 and R6, taken together with their bonded carbons, form a substituted or unsubstituted unsaturated 5- or 6- membered carbocyclic ring or a substituted or unsubstituted saturated 5-, 6-, or 7-membered carbocyclic ring, wherein

- the carbocyclic ring may be a heterocarbocyclic ring comprising at least one hetero atom chosen from O, N and S, 20 - wherein the substituted ring comprises at least one hydrogen, halogen, COOH; CN; NH2;NO2; OH; C1-6 alkyl; substituted C1-6 alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; NHR7; N(R7)2; R7-alkoxy; R7-haloalkyl; or R7-haloalkoxy; - wherein R7 is substituted or unsubstituted (C1-C6) alkyl or a (C3-C6) cycloalkyl or cycloheteroalkyl; and - n is 2, 3, 4 or 5, 25 wherein a substituted aryl or heteroaryl group can be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, carboxylate, alkylcarbonyl, cyano, amino, acylamino, sulfhydryl, alkylthio, arylthio, nitro, trifluoromethyl and cyano; wherein a substituted alkyl may be substituted by one or more substituents selected from the group consisting of 30 alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonyloxy; alkynyl, alkylcarbonyl, alkylthio, alkythiocarbonyl, thiocarboxy- late arylthio, arylcarbonyl, arylcarbonyloxy, acylamino, carboxylate, cyano, halogen, haloalkyl, cycloalkoxy, aceta- mide, amine, hydroxyl, nitro, sulfhydryl, sulfonamido and trifluoromethyl; or a pharmaceutically acceptable salt and/or ester thereof.

35 4. The compound of claim 3, wherein n is 2 or 3.

5. The compound of claim 3, wherein said C1-6 alkyl is C1-C5 alkyl.

6. The compound of claim 3, wherein said compound is a 5-HT2B receptor antagonist. 40 7. A compound selected from the group consisting of:

3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl) benzonitrile; 5-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile; 45 N-(1-(2-Fluorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine; Methyl 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl) methyl) benzoate; 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl) benzoic acid; 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl) benzamide; N-(1-(1-(3-Fluorophenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d] pyrimidin-4-amine; 50 6-Chloro-N-(1-(pyridine-3-yl)-(methyl)piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine; N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-chloro-5-(4-fluorophenyl)thieno[2,3-d] pyrimidin-4-amine; 6-Chloro-N-(1-((pyrimidin-5-yl)methyl)piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine; 3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-4-fluorobenzonitrile; N-(1-(3-Chlorobenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine; 55 2-(4-(5-phenylthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)-5-(trifluoromethyl)pyridin-3-ol; N-(1-(4-Fluoro-3-methoxybenzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine; N-(1-((Benzo[d][1,3]dioxol-5-yl)methyl)piperidin-4-yl)-6-chlorothieno[2,3-d] pyrimidin-4-amine. 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzonitrile;

91 EP 1 797 099 B1

5-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile; 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-N-methylbenzamide; 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-N,N-dimethylbenzamide; N-(1-(3-(methylsulfonyl)benzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine; 5 N-(1-(3-trifluoromethyl)benzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine; N-(1-(3-trifluoromethylsulfonyl)benzyl)piperidin-4-yl)-6-chlorothieno[2,3-d]pyrimidin-4-amine; N-methyl-N-(1-methylpiperidin-4-yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-amine; N-(1-benzylpiperidin-4-yl)-5-phenylthieno[2,3-d]pyrimidin-4-amine; N-(1-benzylpiperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine; 10 N-(1-benzylpiperidin-4-yl)-5-methylthieno[2,3-d]pyrimidin-4-amine; and N-(1-(3-fluorobenzyl)piperidin-4-yl)-6-chloro-5-isopropylthieno[2,3-d]pyrimidin-4-amine.

8. A compound having the formula

15

20

25

wherein R1 and R2 independently are one or more of hydrogen; halogen, halo-substituted alkyl, C1-6 alkyl, C1-C6 cycloalkyl, 30 C3-C6 cycloheteroalkyl, aryl, halo-substituted aryl or heteroaryl; or R1 and R2, taken together, form a C5-C7 cycloalkyl or cycloheteroalkyl ring; R3 and R3’ are independently H, halogen, CN or R5; Cy is heteroaryl; and R4 is hydrogen; halogen, halo-substituted alkyl, C1-6 alkyl, CN, COOH, COOR5,OR5, CONH2, CONHR5, CON(R5)2, 35 halo-substituted or unsubstituted NR5, halo-substituted or unsubstituted SOOR5, aryl, halo-substituted aryl or het- eroaryl, C1-C6 cycloalkyl, or C3-C6 cycloheteroalkyl; wherein R5 is a substituted or unsubstituted C1-6 alkyl, wherein a substituted alkyl may be substituted by one or more substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonyloxy; alkynyl, alkylcarbonyl, alkylthio, alkythiocarbonyl, thiocarboxylate, arylthio, arylcarbonyl, arylcarbonyloxy, acylamino, car- 40 boxylate, cyano, halogen, haloalkyl, cycloalkoxy, acetamide, amine, hydroxyl, nitro, sulfhydryl, sulfonamido and trifluoromethyl; R6 is hydrogen or C1-6 alkyl; and n is 1, 2, 3, 4 or 5; and pharmaceutically acceptable salts and/or esters thereof. 45 9. The compound of claim 8, wherein

(a) R1 is hydrogen and R2 is a halogen. (b) wherein R1 is C1-6 alkyl and R2 is halogen; 50 (c) wherein R1 and R2 are C1-6 alkyl; (d) wherein one of R1 and R2 is C1-6 alkyl and the other is hydrogen; (e) wherein R1 is halo-substituted or unsubstituted benzyl and R2 is hydrogen or halogen; or (f) wherein R1 and R2 are each hydrogen.

55 10. The compound of claim 9, wherein Cy is pyrimidinyl, or pyridinyl, R4 is hydrogen; halogen, halo-substituted alkyl, C1-6 alkyl, CN, COOH, COOR5,OR5, CONH2, CONHR5, CON(R5)2, halo-substituted or unsubstituted NR5, halo- substituted or unsubstituted SOOR5,C1-C6 cycloalkyl, C3-C6 cycloheteroalkyl, aryl, halo-substituted aryl or heter- oaryl; and R6 is hydrogen.

92 EP 1 797 099 B1

11. The compound of any one of claim 8 to 10, wherein R4 is fluorine, n is 1, 2 or 3, and R3 and R3, are independently hydrogen or R5; and R6 is hydrogen.

12. The compound of any one of claims 8 to 11, wherein Cy is substituted or unsubstituted pyridinyl, R4 is hydrogen, 5 halogen, hydroxyl or R5,R3 and R3. are independently hydrogen or R5; and R6 is hydrogen; wherein a substituted aryl or heteroaryl group can be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, carboxylate, alkylcarbonyl, cyano, amino, acylamino, sulfhydryl, alkylthio, arylthio, nitro, trifluoromethyl and cyano.

10 13. The compound of claim 3 in an amount effective to treat depression, a CNS disorder, migraine, pulmonary hyper- tension, or erectile dysfunction further comprising a pharmaceutical carrier.

14. A pharmaceutically acceptable salt of a compound of any of the preceding claims which is a maleate, hydrochloride or fumarate salt. 15 15. The compound 5-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile or a phar- maceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of any one of claims 1-15 and a pharmaceutically acceptable 20 carrier.

17. The pharmaceutical composition of claim 16, wherein the compound is 5-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylami- no)piperidin-1-yl)methyl-2-fluorobenzonitrile.

25 18. A compound as claimed in any of the preceding claims for use in the treatment of pulmonary hypertension, erectile dysfunction, systemic hypertension, congestive heart failure (CHF), migraine, hypertension, disorders of the gas- trointestinal tract, restenosis, asthma, obstructive airway disease, prostatic hyperplasia, priapism, inflammatory pain, neuropathic pain, cancer pain, acute pain, chronic pain, irritable bowel syndrome, hypertonic lower esophageal sphincter, motility disorders, benign prostatic hyperplasia, depression, anxiety, attention deficit hyperactivity disorder, 30 obesity, sleeping disorder, Alzheimer’s disease, Parkinson’s disease, carcinoid tumours, teratocarcinoma, hyper- prolactinemia, acromegaly, CNS disorder or any other disease state that is alleviated by treatment with a 5-HT2B antagonist.

19. Use of a compound as claimed in any of the preceding claims in the manufacture of a medicament for the treatment 35 of pulmonary hypertension, erectile dysfunction, systemic hypertension, congestive heart failure (CHF), migraine, hypertension, disorders of the gastrointestinal tract, restenosis, asthma, obstructive airway disease, prostatic hy- perplasia, priapism, inflammatory pain, neuropathic pain, cancer pain, acute pain, chronic pain, irritable bowel syndrome, hypertonic lower esophageal sphincter, motility disorders, benign prostatic hyperplasia, depression, anxiety, attention deficit hyperactivity disorder, obesity, sleeping disorder, Alzheimer’s disease, Parkinson’s disease, 40 carcinoid tumours, teratocarcinoma, hyperprolactinemia, acromegaly, CNS disorder or any other disease state that is alleviated by treatment with a 5-HT2B antagonist.

20. The compound 5-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile or a phar- maceutically acceptable salt thereof for use in treating pulmonary arterial hypertension. 45 21. The compound 5-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile or a phar- maceutically acceptable salt thereof for use in treating systemic hypertension.

22. A compound of the following formula: 50

55

93 EP 1 797 099 B1

5

10

wherein R1 and R2 are independently hydrogen, halogen, COOH; CN; NH2;NO2; OH; lower alkyl; substituted C1-6alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR; CONHR7; CON(R7)2;OR7; NHR7;N(R7)2;R7-alkoxy; 15 R7-haloalkyl; R7-haloalkoxy; or R1 and R2, taken together with their bonded carbons, form a substituted or unsubstituted C4-C7 cycloalkyl or cy- cloheteroalkyl ring,

- wherein a heteroatom in the C4-C7 cycloheteroalkyl ring comprises at least one of O, N and S, and 20 - wherein the substituted C4-C7 cycloalkyl or cycloheteroalkyl ring comprises at least one substituent selected from hydrogen, halogen, COOH; CN; NH2;NO2; OH; C1-6alkyl; substituted C1-6alkyl; substituted or unsubstituted C1-C6 cycloalkyl or cycloheteroalkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2; OR7; NHR7; N(R7)2; R7-alkoxy, R7-haloalkyl; and R7-haloalkoxy;

25 R3 is independently H; halogen; CN; NH2; lower alkyl; R7;OR7; NHR7;N(R7)2; or substituted or unsubstituted aryl or heteroaryl; R4 is H, R7, or substituted or unsubstituted aryl or heteroaryl; Q is chosen from

30

35

wherein R8 is hydrogen, halogen, or C1-6 alkyl and * indicates attachment points; R5 and R6 are independently selected from hydrogen, halogen, COOH; CN; NH2;NO2; OH; C1-6 alkyl; substituted 40 C1-6 alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; NHR7;N(R7)2; R7-alkoxy; R7-haloalkyl; and R7-haloalkoxy; or R5 and R6, taken together with their bonded carbons, form a substituted or unsubstituted unsaturated 5- or 6- membered carbocyclic ring or a substituted or unsubstituted saturated 5-, 6-, 7-membered carbocyclic ring, wherein the carbocyclic ring may be a heterocarbocyclic ring comprising at least one hetero atom chosen from O, N and S, 45 wherein the substituted ring comprises at least one hydrogen, halogen, COOH; CN; NH2;NO2; OH; C1-6alkyl; substituted C1-6 alkyl; substituted or unsubstituted aryl or heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; NHR7; N(R7)2; R7-alkoxy, R7-haloalkyl; or R7-haloalkoxy; wherein R7 is substituted or unsubstituted (C1-C6) alkyl or a (C3-C6) cycloalkyl or cycloheteroalkyl; n is 2, 3, 4 or 5, or is branched; 50 wherein a substituted aryl or heteroaryl group can be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, carboxylate, alkylcarbonyl, cyano, amino, acylamino, sulfhydryl, alkylthio, arylthio, nitro, trifluoromethyl, and cyano; and wherein a substituted alkyl may be substituted by one or more substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonyloxy; alkynyl, alkylcarbonyl, alkylthio, alkythiocarbonyl, thiocarboxy- 55 late, arylthio, arylcarbonyl, arylcarbonyloxy, acylamino, carboxylate, cyano, halogen, haloalkyl, cycloalkoxy, aceta- mide, amine, hydroxyl, nitro, sulfhydryl, sulfonamido and trifluoromethyl; or a pharmaceutically acceptable salt thereof, for use in treating congestive heart failure (CHF), heart failure, rest- enosis, asthma, obstructive airway disease, prostatic hyperplasia, priapism, erectile dysfunction, inflammatory pain,

94 EP 1 797 099 B1

neuropathic pain, cancer pain, acute pain, chronic pain, irritable bowel syndrome, hypertonic lower oesophageal sphincter, motility disorders, benign prostatic hyperplasia, attention deficit hyperactivity disorder, obesity, carcinoid tumors, teratocarcinoma, hyperprolactinemia or acromegaly.

5 23. A compound represented by the following formula:

10

15

20

25

30 wherein X is halo; R3 is hydrogen, halo, cyano, or trihalomethyl; and n is 1 or 2, provided that when n is 1, R3 is not hydrogen, and when n is 2, both R3 groups are not hydrogen; or a pharmaceutically acceptable salt and/or ester thereof, 35 for use in treating congestive heart failure (CHF), heart failure, restenosis, asthma, obstructive airway disease, prostatic hyperplasia, priapism, erectile dysfunction, inflammatory pain, neuropathic pain, cancer pain, acute pain, chronic pain, irritable bowel syndrome, hypertonic lower oesophageal.sphincter, motility disorders, benign prostatic hyperplasia, attention deficit hyperactivity disorder, obesity, carcinoid tumors, teratocarcinoma, hyperprolactinemia or acromegaly. 40 24. The compound of claim 22 or 23, wherein the use is treating congestive heart failure (CHF).

Patentansprüche 45 1. Verbindung mit der Formel

50

55

95 EP 1 797 099 B1

5

10

15

20

worin R1 ausgewählt ist aus der Gruppe bestehend aus Halogen, C1-6-Alkyl, Cyano und Trihalogenmethyl; jedes R2 unabhängig Wasserstoff, Trihalogenmethyl, Carboxylat, ein Amid oder eine Sulfonylgruppe darstellt; und 25 n 1 oder 2 ist, mit der Maßgabe, dass wenn n 1 ist, R2 nicht für Wasserstoff steht, und wenn n 2 ist, beide R2-Gruppen nicht für Wasserstoff stehen; oder ein pharmazeutisch annehmbares Salz und/oder pharmazeutisch annehmbarer Ester davon.

2. Verbindung mit der Formel 30

35

40

45 worin R1 und R2 unabhängig Halogen, unsubstituiertes Aryl, unsubstituiertes Heteroaryl oder eine substituierte Aryl- oder Heteroarylgruppe darstellen; R3 unabhängig H; Halogen; CN; NH2;C1-6-Alkyl; R7;OR7; NHR7;N(R7)2 oder substituiertes oder unsubstituiertes Aryl oder Heteroaryl darstellt; 50 R4 für H, R7 oder substituiertes oder unsubstituiertes Aryl oder Heteroaryl steht; Q ausgewählt ist aus

55

96 EP 1 797 099 B1

5

10 worin R8 Wasserstoff, Halogen oder C1-6-Alkyl darstellt und * Anbindungspunkte anzeigt; R5 und R6 unabhängig ausgewählt sind aus Wasserstoff, Halogen, COOH; CN; NH2;NO2; OH; C1-6-Alkyl; substi- tuiertem C1-6-Alkyl; substituiertem oder unsubstituiertem Aryl oder Heteroaryl; R7; COOR7; CONHR7; CON(R7)2; OR7; NHR7; N(R7)2; R7-Alkoxy; R7-Halogenalkyl und R7-Halogenalkoxy; oder R5 und R6, zusammen genommen mit ihren gebundenen Kohlenstoffen, einen substituierten oder unsubstituierten 15 ungesättigten 5- oder 6-gliedrigen carbocyclischen Ring oder einen substituierten oder unsubstituierten gesättigten 5-, 6- oder 7-gliedrigen carbocyclischen Ring bilden, wobei

- der carbocyclische Ring ein heterocarbocyclischer Ring sein kann, welcher mindestens ein Heteroatom, ausgewählt aus O, N und S, umfasst, 20 - wobei der substituierte Ring mindestens ein Wasserstoff, Halogen, COOH; CN; NH2;NO2; OH; C1-6-Alkyl; substituiertes C1-6-Alkyl; substituiertes oder unsubstituiertes Aryl oder Heteroaryl; R7; COOR7; CONHR7; CON (R7) 2; OR7; NHR7; N(R7)2; R7-Alkoxy; R7-Halogenalkyl oder R7-Halogenalkoxy umfasst;

worin R7 substituiertes oder unsubstituiertes (C1-C6)-Alkyl oder ein (C3-C6)-Cycloalkyl oder Cycloheteroalkyl dar- 25 stellt; n 2, 3, 4 oder 5 ist; worin eine substituierte Aryl- oder Heteroarylgruppe durch einen oder mehrere Substituenten substituiert sein kann, ausgewählt aus der Gruppe bestehend aus Halogen, Hydroxyl, Alkoxy, Alkylcarbonyloxy, Arylcarbonyloxy, Alkoxy- carbonyloxy, Carboxylat, Alkylcarbonyl, Cyano, Amino, Acylamino, Sulfhydryl, Alkylthio, Arylthio, Nitro, Trifluorme- 30 thyl und Cyano; und worin ein substituiertes Alkyl substituiert sein kann durch einen oder mehrere Substituenten, ausgewählt aus der Gruppe bestehend aus Alkenyl, Alkoxy, Alkoxycarbonyl, Alkoxycarbonyloxy; Alkinyl, Alkylcarbonyl, Alkylthio, Al- kylthiocarbonyl, Thiocarboxylat, Arylthio, Arylcarbonyl, Arylcarbonyloxy, Acylamino, Carboxylat, Cyano, Halogen, Halogenalkyl, Cycloalkoxy, Acetamid, Amin, Hydroxyl, Nitro, Sulfhydryl, Sulfonamido und Trifluormethyl; 35 oder ein pharmazeutisch annehmbares Salz und/oder pharmazeutisch annehmbarer Ester davon.

3. Verbindung mit der Formel

40

45

50

worin R1 und R2 unabhängig Wasserstoff, COOH; CN; NH2,NO2, OH, substituiertes C1-6-Alkyl; substituiertes oder un- substituiertes Aryl oder Heteroaryl; COOR7; CONHR7; CON (R7) 2;OR7; NHR7;N(R7)2;R7-Alkoxy; R7-Halogenalkyl 55 oder R7-Halogenalkoxy darstellen; R3 unabhängig H; Halogen; CN; NH2;C1-6-Alkyl; R7;OR7; NHR7;N(R7)2 oder substituiertes oder unsubstituiertes Aryl oder Heteroaryl darstellt; R4 für H, R7 oder substituiertes oder unsubstituiertes Aryl oder Heteroaryl steht;

97 EP 1 797 099 B1

Q ausgewählt ist aus

5

10

worin R8 Wasserstoff, Halogen oder C1-6-Alkyl darstellt und * Anbindungspunkte anzeigt; R5 und R6 unabhängig ausgewählt sind aus Wasserstoff, Halogen, COOH; CN; NH2;NO2; OH; C1-6-Alkyl; substi- tuiertem C1-6-Alkyl; substituiertem oder unsubstituiertem Aryl oder Heteroaryl; R7; COOR7; CONHR7; CON (R7) 2; OR7; NHR7; N(R7)2; R7-Alkoxy; R7-Halogenalkyl und R7-Halogenalkoxy; oder 15 R5 und R6, zusammen genommen mit ihren gebundenen Kohlenstoffen, einen substituierten oder unsubstituierten ungesättigten 5- oder 6-gliedrigen carbocyclischen Ring oder einen substituierten oder unsubstituierten gesättigten 5-, 6- oder 7-gliedrigen carbocyclischen Ring bilden, wobei

- der carbocyclische Ring ein heterocarbocyclischer Ring sein kann, welcher mindestens ein Heteroatom, 20 ausgewählt aus O, N und S, umfasst, - wobei der substituierte Ring mindestens ein Wasserstoff, Halogen, COOH; CN; NH2;NO2; OH; C1-6-Alkyl; substituiertes C1-6-Alkyl; substituiertes oder unsubstituiertes Aryl oder Heteroaryl; R7; COOR7; CONHR7; CON (R7)2; OR7; NHR7; N(R7)2; R7-Alkoxy; R7-Halogenalkyl oder R7-Halogenalkoxy umfasst; - worin R7 substituiertes oder unsubstituiertes (C1-C6)-Alkyl oder ein (C3-C6)-Cycloalkyl oder Cycloheteroalkyl 25 darstellt; und - n 2, 3, 4 oder 5 ist;

worin eine substituierte Aryl- oder Heteroarylgruppe durch einen oder mehrere Substituenten substituiert sein kann, ausgewählt aus der Gruppe bestehend aus Halogen, Hydroxyl, Alkoxy, 30 Alkylcarbonyloxy, Arylcarbonyloxy, Alkoxycarbonyloxy, Carboxylat, Alkylcarbonyl, Cyano, Amino, Acylamino, Sulf- hydryl, Alkylthio, Arylthio, Nitro, Trifluormethyl und Cyano; worin ein substituiertes Alkyl substituiert sein kann durch einen oder mehrere Substituenten, ausgewählt aus der Gruppe bestehend aus Alkenyl, Alkoxy, Alkoxycarbonyl, Alkoxycarbonyloxy; Alkinyl, Alkylcarbonyl, Alkylthio, Al- kylthiocarbonyl, Thiocarboxylat, Arylthio, Arylcarbonyl, Arylcarbonyloxy, Acylamino, Carboxylat, Cyano, Halogen, 35 Halogenalkyl, Cycloalkoxy, Acetamid, Amin, Hydroxyl, Nitro, Sulfhydryl, Sulfonamido und Trifluormethyl; oder ein pharmazeutisch annehmbares Salz und/oder pharmazeutisch annehmbarer Ester davon.

4. Verbindung nach Anspruch 3, worin n 2 oder 3 ist.

40 5. Verbindung nach Anspruch 3, worin besagtes C1-6-Alkyl C1-C5-Alkyl ist.

6. Verbindung nach Anspruch 3, worin besagte Verbindung ein 5-HT2B-Rezeptor-Antagonist ist.

7. Verbindung, ausgewählt aus der Gruppe, bestehend aus: 45 3-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-benzonitril; 5-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorbenzonitril; N-(1-(2-Fluorbenzyl)piperidin-4-yl)-6-chlorthieno[2,3-d]pyrimidin-4-amin; Methyl-3-((4-(6-chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)-methyl)benzoat; 50 3-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoesäure; 3-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzamid; N-(1(1-(3-Fluorphenyl)ethyl)piperidin-4-yl)-6-isobutylthieno[2,3-d]pyrimidin-4-amin; 6-Chlor-N-(1-(pyridin-3-yl)-(methyl)piperidin-4yl)thieno-[2,3-d]pyrimidin-4-amin; N-(1-(3,5-Difluorbenzyl)piperidin-4-yl)-6-chlor-5-(4-fluorphenyl)thieno-[2,3-d]-pyrimidin-4-amin; 55 6-Chlor-N-(1-((pyrimidin-5-yl)methyl)piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amin; 3-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-4-fluorbenzonitril; N-(1-(3-Chlorbenzyl)piperidin-4-yl)-6-chlorthieno[2,3-d]pyrimidin-4-amin; 2-(4-(5-Phenylthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)-5-(trifluormethyl)pyridin-3-ol;

98 EP 1 797 099 B1

N-(1-(4-Fluor-3-methoxybenzyl)piperidin-4-yl)-6-chlorthieno[2,3-d]pyrimidin-4-amin; N-(1-((Benzo[d][1,3]dioxol-5-yl)methyl)piperidin-4-yl)-6-chlorthieno[2,3-d]pyrimidin-4-amin; 3-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzonitril; 5-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorbenzonitril; 5 3-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-N-methylbenzamid; 3-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-N,N-dimethylbenzamid; N-(1-(3-(Methylsulfonyl)benzyl)piperidin-4-yl)-6-chlorthieno[2,3-d]pyrimidin-4-amin; N-(1-(3-Trifluormethyl)benzyl)piperidin-4-yl)-6-chlorthieno[2,3-d]pyrimidin-4-amin; N-(1-(3-Trifluormethylsulfonyl)benzyl)piperidin-4-yl)-6-chlorthieno[2,3-d]pyrimidin-4-amin; 10 N-Methyl-N-(1-methylpiperidin-4-yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-amin; N-(1-Benzylpiperidin-4-yl)-5-phenylthieno[2,3-d]pyrimidin-4-amin; N-(1-Benzylpiperidin-4-yl)thieno[2,3-d]pyrimidin-4-amin; N-(1-Benzylpiperidin-4-yl)-5-methylthieno[2,3-d]pyrimidin-4-amin; und N-(1-(3-Fluorbenzyl)piperidin-4-yl)-6-chlor-5-isopropylthieno[2,3-d]pyrimidin-4-amin. 15 8. Verbindung mit der Formel

20

25

30

worin R1 und R2 unabhängig eines oder mehrere von Wasserstoff; Halogen, halogensubstituiertem Alkyl, C1-6Alkyl, C1-C6-Cycloalkyl, C3-C6-Cycloheteroalkyl, Aryl, halogensubstituiertem Aryl oder Heteroaryl darstellen; oder R1 und 35 R2 zusammen genommen einen C5-C7-Cycloalkyl- oder Cycloheteroalkylring bilden; R3 und R3, unabhängig H, Halogen, CN oder R5 darstellen; Cy für Heteroaryl steht; und R4 für Wasserstoff; Halogen, halogensubstituiertes Alkyl, C1-6-Alkyl, CN, COOH, COOR5,OR5, CONH2, CONHR5, CON(R5)2, halogensubstituiertes oder unsubstituiertes NR5, halogensubstituiertes oder unsubstituiertes SOOR5, 40 Aryl, halogensubstituiertes Aryl oder Heteroaryl, C1-C6-Cycloalkyl oder C3-C6-Cycloheteroalkyl steht; worin R5 ein substituiertes oder unsubstituiertes C1-6-Alkyl darstellt, worin ein substituiertes Alkyl substituiert sein kann durch einen oder mehrere Substituenten, ausgewählt aus der Gruppe bestehend aus Alkenyl, Alkoxy, Alk- oxycarbonyl, Alkoxycarbonyloxy; Alkinyl, Alkylcarbonyl, Alkylthio, Alkylthiocarbonyl, Thiocarboxylat, Arylthio, Aryl- carbonyl, Arylcarbonyloxy, Acylamino, Carboxylat, Cyano, Halogen, Halogenalkyl, Cycloalkoxy, Acetamid, Amin, 45 Hydroxyl, Nitro, Sulfhydryl, Sulfonamido und Trifluormethyl; R6 für Wasserstoff oder C1-6-Alkyl steht; und n 1, 2, 3, 4 oder 5 ist; und pharmazeutisch annehmbare Salze und/oder Ester davon.

50 9. Verbindung nach Anspruch 8, worin

(a) R1 Wasserstoff darstellt und R2 Halogen darstellt; (b) worin R1 für C1-6-Alkyl steht und R2 Halogen darstellt; (c) worin R1 und R2 für C1-6-Alkyl stehen; 55 (d) worin eines von R1 und R2 für C1-6-Alkyl steht und das andere für Wasserstoff steht; (e) worin R1 halogensubstituiertes oder unsubstituiertes Benzyl darstellt und R2 Wasserstoff oder Halogen darstellt; oder (f) worin R1 und R2 jeweils Wasserstoff darstellen.

99 EP 1 797 099 B1

10. Verbindung nach Anspruch 9, worin Cy für Pyrimidinyl oder Pyridinyl steht, R4 für Wasserstoff; Halogen, halogen- substituiertes Alkyl, C1-6-Alkyl, CN, COOH, COOR5,OR5, CONH2, CONHR5, CON(R5)2, halogensubstituiertes oder unsubstituiertes NR5, halogensubstituiertes oder unsubstituiertes SOOR5,C1-C6-Cycloalkyl, C3-C6-Cycloheteroal- kyl, Aryl, halogensubstituiertes Aryl oder Heteroaryl steht; und R6 Wasserstoff darstellt. 5

11. Verbindung nach einem von Ansprüchen 8 bis 10, worin R4 für Fluor steht, n 1, 2 oder 3 ist und R3 und R3, unabhängig Wasserstoff oder R5 darstellen; und R6 Wasserstoff darstellt.

12. Verbindung nach einem von Ansprüchen 8 bis 11, worin Cy substituiertes oder unsubstituiertes Pyridinyl darstellt, 10 R4 für Wasserstoff, Halogen, Hydroxyl oder R5 steht, R3 und R3, unabhängig Wasserstoff oder R5 darstellen; und R6 Wasserstoff darstellt; worin eine substituierte Aryl- oder Heteroarylgruppe substituiert sein kann durch einen oder mehrere Substituenten, ausgewählt aus der Gruppe bestehend aus Halogen, Hydroxyl, Alkoxy, Alkylcarbony- loxy, Arylcarbonyloxy, Alkoxycarbonyloxy, Carboxylat, Alkylcarbonyl, Cyano, Amino, Acylamino, Sulfhydryl, Al- kylthio, Arylthio, Nitro, Trifluormethyl und Cyano. 15 13. Verbindung nach Anspruch 3 in einer Menge, welche wirksam ist, um Depression, eine ZNS-Störung, Migräne, Lungenhochdruck oder erektile Dysfunktion zu behandeln, welche ferner einen pharmazeutischen Träger umfasst.

14. Pharmazeutisch annehmbares Salz einer Verbindung nach einem der vorangehenden Ansprüche, welches ein 20 Maleat-, Hydrochlorid-oder Fumaratsalz ist.

15. Verbindung 5-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorbenzonitril oder ein phar- mazeutisch annehmbares Salz davon.

25 16. Pharmazeutische Zusammensetzung, welche eine Verbindung nach einem von Ansprüchen 1-15 und einen phar- mazeutisch annehmbaren Träger umfasst.

17. Pharmazeutische Zusammensetzung nach Anspruch 16, worin die Verbindung 5-((4-(6-Chlorthieno[2,3-d]pyrimidin- 4-ylamino)piperidin-1-yl)methyl-2-fluorbenzonitril ist. 30 18. Verbindung wie in einem der vorangehenden Ansprüche beansprucht zur Verwendung in der Behandlung von Lungenhochdruck, erektiler Dysfunktion, systemischer Hypertonie, kongestivem Herzversagen (CHF), Migräne, Bluthochdruck, Störungen des Magen-Darm-Trakts, Restenose, Asthma, obstruktiver Atemwegserkrankung, Pro- statahyperplasie, Priapismus, entzündlichem Schmerz, neuropathischem Schmerz, Krebsschmerz, akutem 35 Schmerz, chronischem Schmerz, Reizdarmsyndrom, hypertonischem unteren Ösophagussphinkter, Motilitätsstö- rungen, gutartiger Prostatahyperplasie, Depression, Angstzustand, Aufmerksamkeitsdefizit-Hyperaktivitätsstörung, Fettsucht, Schlafstörung, Alzheimer-Krankheit, Parkinson-Krankheit, Karzinoid-Tumoren, Teratokarzinom, Hyper- prolaktinämie, Akromegalie, ZNS-Störung oder irgend einem anderen Krankheitszustand, der durch Behandlung mit einem 5-HT2B-Antagonisten gelindert wird. 40 19. Verwendung einer Verbindung wie in einem der vorangehenden Ansprüche beansprucht in der Herstellung eines Medikaments zur Behandlung von Lungenhochdruck, erektiler Dysfunktion, systemischer Hypertonie, kongestivem Herzversagen (CHF), Migräne, Bluthochdruck, Störungen des Magen-Darm-Trakts, Restenose, Asthma, obstruk- tiver Atemwegserkrankung, Prostatahyperplasie, Priapismus, entzündlichem Schmerz, neuropathischem Schmerz, 45 Krebsschmerz, akutem Schmerz, chronischem Schmerz, Reizdarmsyndrom, hypertonischem unteren Ösophagus- sphinkter, Motilitätsstörungen, gutartiger Prostatahyperplasie, Depression, Angstzustand, Aufmerksamkeitsdefizit- Hyperaktivitätsstörung, Fettsucht, Schlafstörung, Alzheimer-Krankheit, Parkinson-Krankheit, Karzinoid-Tumoren, Teratokarzinom, Hyperprolaktinämie, Akromegalie, ZNS-Störung oder irgend einem anderen Krankheitszustand, der durch Behandlung mit einem 5-HT2B-Antagonisten gelindert wird. 50 20. Verbindung 5-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorbenzonitril oder ein phar- mazeutisch annehmbares Salz davon zur Verwendung beim Behandeln von pulmonaler arterieller Hypertonie.

21. Verbindung 5-((4-(6-Chlorthieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorbenzonitril oder ein phar- 55 mazeutisch annehmbares Salz davon zur Verwendung beim Behandeln von systemischer Hypertonie.

22. Verbindung der folgenden Formel:

100 EP 1 797 099 B1

5

10

worin R1 und R2 unabhängig Wasserstoff, Halogen, COOH; CN; NH2;NO2; OH; nied.-Alkyl; substituiertes C1-6-Alkyl; substituiertes oder unsubstituiertes Aryl oder Heteroaryl; R7; COOR; CONHR7; CON(R7)2;OR7; NHR7;N(R7)2; 15 R7-Alkoxy; R7-Halogenalkyl; R7-Halo-genalkoxy darstellen; oder R1 und R2 zusammen genommen mit ihren gebundenen Kohlenstoffen einen substituierten oder unsubstituierten C4-C7-Cycloalkyl-oder Cycloheteroalkylring bilden,

- wobei ein Heteroatom in dem C4-C7-Cycloheteroalkylring mindestens eines von 0, N und S umfasst; und 20 - wobei der substituierte C4-C7-Cycloalkyl- oder Cycloheteroalkylring mindestens einen Substituenten umfasst, ausgewählt aus Wasserstoff, Halogen, COOH; CN; NH2;NO2; OH; C1-6-Alkyl; substituiertem C1-6-Alkyl; sub- stituiertem oder unsubstituiertem C1-C6-Cycloalkyl oder Cycloheteroalkyl; substituiertem oder unsubstituiertem Aryl oder Heteroaryl; R7; COOR7; CONHR7; CON(R7)2 ;OR7; NHR7;N(R7)2;R7-Alkoxy, R7-Halogenalkyl; und R7-Halogenalkoxy; 25

R3 unabhängig H; Halogen; CN; NH2; nied.-Alkyl; R7;OR7; NHR7;N(R7)2; oder substituiertes oder unsubstituiertes Aryl oder Heteroaryl darstellt; R4 für H, R7 oder substituiertes oder unsubstituiertes Aryl oder Heteroaryl steht; Q ausgewählt ist aus 30

35

40 worin R8 Wasserstoff, Halogen oder C1-6-Alkyl darstellt und * Anbindungspunkte anzeigt; R5 und R6 unabhängig ausgewählt sind aus Wasserstoff, Halogen, COOH; CN; NH2;NO2; OH; C1-6-Alkyl; substi- tuiertem C1-6-Alkyl; substituiertem oder unsubstituiertem Aryl oder Heteroaryl; R7; COOR7; CONHR7; CON(R7)2; OR7; NHR7; N(R7)2; R7-Alkoxy; R7-Halogenalkyl und R7-Halogenalkoxy; oder R5 und R6, zusammen genommen mit ihren gebundenen Kohlenstoffen, einen substituierten oder unsubstituierten 45 ungesättigten 5- oder 6-gliedrigen carbocyclischen Ring oder einen substituierten oder unsubstituierten gesättigten 5-, 6-, 7- gliedrigen carbocyclischen Ring bilden, wobei der carbocyclische Ring ein heterocarbocyclischer Ring sein kann, welcher mindestens ein Heteroatom, ausgewählt aus O, N und S, umfasst, wobei der substituierte Ring mindestens ein Wasserstoff, Halogen, COOH; CN; NH2;NO2: OH; C1-6-Alkyl; substi- 50 tuiertes C1-6-Alkyl; substituiertes oder unsubstituiertes Aryl oder Heteroaryl; R7; COOR7; CONHR7; CON(R7)2;OR7; NHR7; N(R7)2; R7-Alkoxy: R7-Halogenalkyl oder R7-Halogenalkoxy umfasst, worin R7 substituiertes oder unsubstituiertes (C1-C6)-Alkyl oder ein (C3-C6)-Cycloalkyl oder Cycloheteroalkyl dar- stellt; n 2, 3, 4 oder 5 ist oder verzweigt ist; 55 worin eine substituierte Aryl- oder Heteroarylgruppe durch einen oder mehrere Substituenten substituiert sein kann, ausgewählt aus der Gruppe bestehend aus Halogen, Hydroxyl, Alkoxy, Alkylcarbonyloxy, Arylcarbonyloxy, Alkoxy- carbonyloxy, Carboxylat, Alkylcarbonyl, Cyano, Amino, Acylamino, Sulfhydryl, Alkylthio, Arylthio, Nitro, Trifluorme- thyl und Cyano; und

101 EP 1 797 099 B1

worin ein substituiertes Alkyl substituiert sein kann durch einen oder mehrere Substituenten, ausgewählt aus der Gruppe bestehend aus Alkenyl, Alkoxy, Alkoxycarbonyl, Alkoxycarbonyloxy; Alkinyl, Alkylcarbonyl, Alkylthio, Al- kylthiocarbonyl, Thiocarboxylat Arylthio, Arylcarbonyl, Arylcarbonyloxy, Acylamino, Carboxylat, Cyano, Halogen, Halogenalkyl, Cycloalkoxy, Acetamid, Amin, Hydroxyl, Nitro, Sulfhydryl, Sulfonamido und Trifluormethyl; 5 oder ein pharmazeutisch annehmbares Salz davon, zur Verwendung beim Behandeln von kongestivem Herzver- sagen (CHF), Herzversagen Restenose, Asthma, obstruktiver Atemwegserkrankung, Prostatahyperplasie, Priapis- mus, erektiler Dysfunktion, entzündlichem Schmerz, neuropathischem Schmerz, Krebsschmerz, akutem Schmerz, chronischem Schmerz, Reizdarmsyndrom, hypertonischem unteren Ösophagussphinkter, Motilitätsstörungen, gut- artiger Prostatahyperplasie, Aufmerksamkeitsdefizit-Hyperaktivitätsstörung, Fettsucht, Karzinoid-Tumoren, Tera- 10 tokarzinom, Hyperprolaktinämie oder Akromegalie.

23. Verbindung, dargestellt durch die folgenden Formel:

15

20

25

30 worin X Halogen darstellt; R3 für Wasserstoff, Halogen, Cyano oder Trihalogenmethyl steht; und n 1 oder 2 ist, mit der Maßgabe, dass wenn n 1 ist, R3 nicht für Wasserstoff steht, und wenn n 2 ist, beide R3-Gruppe 35 nicht für Wasserstoff stehen; oder ein pharmazeutisch annehmbares Salz und/oder Ester davon, zur Verwendung beim Behandeln von kongestivem Herzversagen (CHF), Herzversagen, Restenose, Asthma, ob- struktiver Atemwegserkrankung, Prostatahyperplasie, Priapismus, erektiler Dysfunktion, entzündlichem Schmerz, neuropathischem Schmerz, Krebsschmerz, akutem Schmerz, chronischem Schmerz, Reizdarmsyndrom, hyperto- 40 nischem unteren Ösophagussphinkter, Motilitätsstörungen, gutartiger Prostatahyperplasie, Aufmerksamkeitsdefizit- Hyperaktivitätsstörung, Fettsucht, Karzinoid-Tumoren, Teratokarzinom, Hyperprolaktinämie oder Akromegalie.

24. Verbindung nach Anspruch 22 oder 23, wobei die Verwendung Behandeln von kongestivem Herzversagen (CHF) ist.

45 Revendications

1. Composé de formule

50

55

102 EP 1 797 099 B1

5

10

15

dans laquelle 20 R1 est choisi dans le groupe constitué d’un halogène, un alkyle en C1 à C6, un cyano, et un trihalométhyle ; chaque R2 représente indépendamment l’hydrogène, un groupement trihalométhyle, carboxylate, amide, ou sulfonyle ; et n vaut 1 ou 2, à condition que lorsque n vaut 1, R2 n’est pas un hydrogène, et lorsque n vaut 2, l’un et l’autre groupes R2 ne sont pas un hydrogène ; 25 ou un sel et/ou un ester acceptables sur le plan pharmaceutique d’un tel composé.

2. Composé de formule

30

35

dans laquelle 40 R1 et R2 représentent indépendamment un halogène, un aryle non substitué, un hétéroaryle non substitué, ou un groupement aryle substitué ou hétéroaryle ; R3 représente indépendamment H ; un halogène ; CN ; NH2 ; un alkyle en C1 àC6 ;R7;OR7 ; NHR7 ;N(R7)2;ou un aryle ou hétéroaryle substitué ou non substitué ; R4 représente H, R7, ou un aryle ou hétéroaryle substitué ou non substitué ; 45 Q est choisi parmi

50

55 où R8 représente l’hydrogène, un halogène, ou un alkyle en C1 à C6 et * indique des points de fixation ; R5 et R6 sont indépendamment choisis parmi l’hydrogène, un halogène, COOH ; CN ; NH2 ;NO2 ; OH ; un alkyle en C1 àC6 ; un alkyle substitué en C1 àC6 ; un aryle ou hétéroaryle substitué ou non substitué ; R7 ; COOR7 ; CONHR7 ; CON (R7) 2 ; OR7 ; NHR7 ; N (R7) 2 ; un R7-alcoxy ; un R7-haloalkyle, et un R7-haloalcoxy, ou

103 EP 1 797 099 B1

R5 et R6, pris ensemble avec leurs carbones liés, forment un noyau carbocyclique insaturé substitué ou non substitué comportant 5 ou 6 éléments ou un noyau carbocyclique saturé substitué ou non substitué comportant 5, 6 ou 7 éléments, où

5 - le noyau carbocyclique peut être un noyau hétérocarbocyclique comprenant au moins un hétéroatome choisi parmi 0, N et S, - où le noyau substitué comprend au moins un hydrogène, un halogène, COOH ; CN ; NH2 ;NO2 ;OH;un alkyle en C1 àC6 ; un alkyle substitué en C1 àC6 ; un aryle ou hétéroaryle substitué ou non substitué ; R7 ; COOR7 ; CONHR7 ; CON (R7) 2 ;OR7 ; NHR7 ;N(R7) 2 ;unR7-alcoxy ; un R7-haloalkyle ; ou un R7-haloalcoxy, 10 où R7 est un alkyle en C1 àC6 substitué ou non substitué ou un cycloalkyle en C3 àC6 ou un cyclohétéroalkyle ;

n vaut 2, 3, 4 ou 5 ; dans laquelle un groupe aryle substitué ou hétéroaryle peut être remplacé par un ou plusieurs substituants choisis parmi le groupe constitué d’un halogène, un hydroxyle, un alcoxy, un alkylcarbonyloxy, un arylcarbonyloxy, un 15 alcoxycarbonyloxy, un carboxylate, un alkylcarbonyl, un cyano, un amino, un acylamino, un sulfhydryle, un alkylthio, un arylthio, un nitro, un trifluorométhyle et un cyano ; et dans laquelle un alkyle substitué peut être remplacé par un ou plusieurs substituants choisis parmi le groupe constitué d’un alcényle, un alcoxy, un alcoxycarbonyle, un alcoxycarbonyloxy ; un alcynyle, un alkylcarbonyle, un alkylthio, un alkythiocarbonyle, un thiocarboxylate arylthio, un arylcarbonyle, un arylcarbonyloxy, un acylamino, un 20 carboxylate, un cyano, un halogène, un haloalkyle, un cycloalcoxy, un acétamide, une amine, un hydroxyle, un nitro, un sulfhydryle, un sulfonamido et un trifluorométhyle ; ou un sel et/ou un ester acceptables sur le plan pharmaceutique d’un tel composé :

3. Composé de formule 25

30

35 dans laquelle R1 et R2 représentent indépendamment l’hydrogène, COOH ; CN ; NH2 ;NO2 ; OH ; un alkyle substitué en C1 à C6 ; un aryle ou hétéroaryle substitué ou non substitué ; COOR7; CONHR7 ; CON (R7) 2 ;OR7 ; NHR7 ;N(R7)2 ; un R7-alcoxy ; un R7-haloalkyle ; ou un R7-haloalcoxy ; 40 R3 représente indépendamment H ; un halogène ; CN ; NH2 ; un alkyle en C1à6;R7 ;OR7 ; NHR7 ;N(R7)2 ;ou un aryle ou hétéroaryle substitué ou non substitué ; R4 représente H, R7, ou un aryle ou hétéroaryle substitué ou non substitué ; Q est choisi parmi

45

50

où R8 représente l’hydrogène, un halogène, ou un alkyle en C1 à C6 et * indique des points de fixation ; 55 R5 et R6 sont indépendamment choisis parmi l’hydrogène, un halogène, COOH ; CN ; NH2 ;NO2 ; OH ; un alkyle en C1 àC6 ; un alkyle substitué en C1 àC6 ; un aryle ou hétéroaryle substitué ou non substitué ; R7 ; COOR7 ; CONHR7 ; CON (R7) 2 ; OR7 ; NHR7 ; N (R7) 2 ; un R7-alcoxy ; un R7-haloalkyle ; et un R7-haloalcoxy ; ou R5 et R6, pris ensemble avec leurs carbones liés, forment un noyau carbocyclique insaturé substitué ou non substitué

104 EP 1 797 099 B1

comportant 5 ou 6 éléments ou un noyau carbocyclique saturé substitué ou non substitué comportant 5, 6 ou 7 éléments, où

- le noyau carbocyclique peut être un noyau hétérocarbocyclique comprenant au moins un hétéroatome choisi 5 parmi O, N et S, - où le noyau substitué comprend au moins un hydrogène, un halogène, COOH ; CN ; NH2 ;NO2 ;OH;un alkyle en C1 àC6 ; un alkyle substitué en C1 àC6 ; un aryle ou hétéroaryle substitué ou non substitué ; R7 ; COOR7 ; CONHR7 ; CON (R7) 2 ;OR7 ; NHR7 ;N(R7) 2 ;unR7-alcoxy ; un R7-haloalkyle ; ou un R7-haloalcoxy ; -oùR7 est un alkyle en C1 àC6 substitué ou non substitué ou un cycloalkyle en C3 àC6 ou un cyclohétéroalkyle ; et 10 - n vaut 2, 3, 4 ou 5,

dans laquelle un groupe aryle substitué ou hétéroaryle peut être remplacé par un ou plusieurs substituants choisis parmi le groupe constitué d’un halogène, un hydroxyle, un alcoxy, un alkylcarbonyloxy, un arylcarbonyloxy, un alcoxycarbonyloxy, un carboxylate, un alkylcarbonyl, un cyano, un amino, un acylamino, un sulfhydryle, un alkylthio, 15 un arylthio, un nitro, un trifluorométhyle et un cyano ; dans laquelle un alkyle substitué peut être remplacé par un ou plusieurs substituants choisis dans le groupe constitué d’un alcényle, un alcoxy, un alcoxycarbonyle, un alcoxycarbonyloxy, un alcynyle, un alkylcarbonyle, un alkylthio, un alkythiocarbonyle, un thiocarboxylate arylthio, un arylcarbonyle, un arylcarbonyloxy, un acylamino, un carboxy- late, un cyano, un halogène, un haloalkyle, un cycloalcoxy, un acétamide, une amine, un hydroxyle, un nitro, un 20 sulfhydryle, un sulfonamido et un trifluorométhyle ; ou un sel et/ou un ester acceptables sur le plan pharmaceutique d’un tel composé :

4. Composé selon la revendication 3, dans lequel n vaut 2 ou 3.

25 5. Composé selon la revendication 3, dans lequel ledit alkyle en C1 à C6 est un alkyle en C1 à C5.

6. Composé selon la revendication 3, où ledit composé est un antagoniste des récepteurs de 5-HT2B.

7. Composé choisi dans le groupe constitué par : 30 le 3-((4-(6-chlorothiéno[2,3-d]pyrimidin-4-ylamino)pipéridin-1-yl)méthyl) benzonitrile ; le 5-((4,(6-chlorothiéno[2,3-d]pyrimidin-4-ylamino)pipéridin-1-yl)méthyl)-2-fluorobenzonitrile ; la N-(1-(2-fluorobenzyl)pipéridin-4-yl)-6-chlorothiéno[2,3-d]pyrimidin-4-amine ; le méthyl 3-((4-(6-chlorothiéno[2,3-d]-pyrimidin-4-ylamino)pipéridin-1-yl)méthyl) benzoate ; 35 l’acide 3-((4-(6-chlorothiéno[2,3-d]pyrimidin-4-ylamino)pipéridin-1-yl)méthyl) benzoïque ; le 3-((4-(6-chlorothiéno[2,3-d]pyrimidin-4-ylammo)pipéridin-1-yl)méthyl) benzamide ; la N-(1-(1-(3-fluorophényl)éthyl)pipëridin-4-yl)-6-isobutylthiéno[2,3-d]pyrimidin-4-amine ; la 6-chloro-N-(1-(pyridine-3-yl)-méthyl)-pipéridin-4-yl)thiéno[2,3-d]pyrimidin-4-amine ; la N-(1-(3,5-difluorobenzyl)pipéridin-4-yl)-6-chloro-5-(4-fluorophënyl)thiéno[2,3-d]pyrirmdin-4-amine ; 40 la 6-chloro-N-(1-((pyrimidin-5-yl)méthyl)-pipéridin-4-yl)thiéno[2,3-d]pyrimidin-4-amine ; le 3-((4-(6-chlorothiéno[2,3-d]pyrimidin-4-ylamino)pipéridin-1-yl)méthyl)-4-fluorobenzonitrile ; la N-(1-(3-chlorobenzyl)pipéridin-4-yl)-6-chlorothiéno[2,3-d]pyrimidin-4-amine ; le 2-(4-(5-phénylthiéno[2,3-d]pyrimidin-4-ylamino)pipéridin-1-yl)-5-(trifluorométhyl)pyridin-3-ol ; le N-(1-(4-fluoro-3-méthoxybenzyl)pipéridin-4-yl)-6-chlorothiéno[2,3-d]pyrimidin-4-amine ; 45 la N- (1-((benzo[d][1,3]dioxol-5-yl)méthyl) - pipéridin-4-yl)-6-chlorothiéno[2,3-d]pyrimidin-4-amine ; le 3-((4-(6-chlorothiéno[2,3-d]pyrimidin-4-ylamino)pipéridin-1-yl)méthyl)benzonitrile ; le 5-(4-(6-chlorothiéno[2,3-d]pyrimidin-4-ylamino)pipéridin-1-yl)méthyl)-2-fluorobenzonitrile ; le 3-((4-(6-chlorothiéno[2,3-d]pypéridin-1-yl)méthyl)-N-méthylbenzamide ; le 3-((4-(6-chlorothiéno[2,3-d]pyrimidin-4-ylamino)pipéridin-1 -yl)méthyl)-N,N-diméthylbenzamide ; 50 la N-(1-(3-(méthylsulfonyl)benzyl)pipéridin-4-yl)-6-chlorothiéno[2,3-d]pyrimidin-4-amine ; la N-(1-(3-trifluorométhyl)benzyl)pipéridin-4-yl)-6-chlorothiéno[2,3-d]pyrimidin-4-amine ; la N-(1-(3-trifluorométhylsulfonyl)benzyl) pipéridin-4-yl)-6-chlorothiéno[2,3-d]pyrimidin-4-amine ; la N-méthyl-N-(1-méthylpipéridin-4-yl)-5,6,7,8-tétrahydro-benzo[4,5]thiéno[2,3-d]pyrimidin-4-amine ; la N-(1-benzylpipéridin-4-yl)-5-phénylthiéno-[2,3-d]pyrimidin-4-amine ; 55 la N-(1-benzylpipéridin-4-yl)thiéno[2,3-d]pyrimidin-4-amine ; la N-(1-benzylpipéridin-4-yl)-5-méthylthiéno [2,3-d]pyrimidin-4-amine ; et la N-(1-(3-fluorobenzyl)pipéridin-4-yl)-6-chloro-5-isopropylthiéno[2,3-d]pyrimidin-4-amine.

105 EP 1 797 099 B1

8. Composé de formule

5

10

15 dans laquelle R1 et R2 représentent indépendamment un ou plusieurs parmi l’hydrogène ; un halogène, un alkyle à substitution halogène, un alkyle en C1 àC6, un cycloalkyle en C1 àC6, un cyclohétéroalkyle en C3 àC6, un aryle, un aryle à substitution halogène ou un hétéroaryle ; ou R1 et R2, pris ensemble, forment un noyau cycloalkyle en C5 àC7 ou 20 cyclohétéroalkyle ; R3 et R3’ représentent indépendamment H, un halogène, CN ou R5 ; Cy est un hétéroaryle ; et R4 représente l’hydrogène ; un halogène, un alkyle à substitution halogène, un alkyle en C1 àC6, CN, COOH, COOR5,OR5, CONH2, CONHR5, CON(R5)2,NR5 à substitution halogène ou non substitué, SOOR5 à substitution 25 halogène ou non substitué, un aryle, un aryle à substitution halogène ou un hétéroaryle, un cycloalkyle en C1 àC6, ou un cyclohétéroalkyle en C3 à C6 ; dans laquelle R5 est un alkyle en C1 àC6 substitué ou non substitué, où un alkyle substitué peut être substitué par un ou plusieurs substituants choisis parmi le groupe constitué d’un alcényle, un alcoxy, un alcoxycarbonyle, un alcoxycarbonyloxy ; un alcynyle, un alkylcarbonyle, un alkylthio, un alkythiocarbonyle, un thiocarboxylate arylthio, 30 un arylcarbonyle, un arylcarbonyloxy, un acylamino, un carboxylate, un cyano, un halogène, un haloalkyle, un cycloalcoxy, un acétamide, une amine, un hydroxyle, un nitro, un sulfhydryle, un sulfonamido et un trifluorométhyle ; R6 représente l’hydrogène ou un alkyle en C1 à C6; et n vaut 1, 2, 3, 4 ou 5 ; ou des sels et/ou esters acceptables sur le plan pharmaceutique d’un tel composé : 35 9. Composé selon la revendication 8, dans lequel

(a) R1 représente l’hydrogène et R2 représente un halogène. (b) où R1 représente un alkyle en C1 à C6 et R2 représente un halogène ; 40 (c) où R1 et R2 représentent un alkyle en C1 à C6 ; (d) où l’un parmi R1 et R2 est un alkyle en C1 à C6 et l’autre représente l’hydrogène ; (e) où R1 représente un benzyle à substitution halogène ou non substitué et R2 représente l’hydrogène ou un halogène ; ou (f) dans lequel R1 et R2 représentent chacun l’hydrogène. 45

10. Composé selon la revendication 9, dans lequel Cy représente un pyrimidinyle ou un pyridinyle, R4 représente l’hydrogène ; un halogène, un alkyle à substitution halogène, un alkyle en C1 àC6, CN, COOH, COOR5,OR5, CONH2, CONHR5, CON(R5)2,NR5 à substitution halogène ou non substitué, SOOR5 à substitution halogène ou non substitué, un cycloalkyle en C1 àC6, un cyclohétéroalkyle en C3 àC6, un aryle, un aryle à substitution halogène 50 ou un hétéroaryle ; et R6 représente l’hydrogène.

11. Composé de l’une quelconque des revendications 8 à 10, dans lequel R4 représente le fluor, n vaut 1, 2 ou 3, et R3 et R3, représentent indépendamment l’hydrogène ou R5 ; et R6 représente l’hydrogène.

55 12. Composé selon l’une quelconque des revendications 8 à 11, dans lequel Cy représente un pyridinyle substitué ou non substitué, R4 représente l’hydrogène, un halogène, un hydroxyle ou R5,R3 et R3’ représentent indépendamment l’hydrogène ou R5 ;etR6 représente l’hydrogène ; dans laquelle un groupe aryle substitué ou hétéroaryle peut être remplacé par un ou plusieurs substituants choisis parmi le groupe constitué d’un halogène, un hydroxyle, un alcoxy,

106 EP 1 797 099 B1

un alkylcarbonyloxy, un arylcarbonyloxy, un alcoxycarbonyloxy, un carboxylate, un alkylcarbonyl, un cyano, un amino, un acylamino, un sulfhydryle, un alkylthio, un arylthio, un nitro, un trifluorométhyle et un cyano.

13. Composé selon la revendication 3 en une quantité efficace pour traiter une dépression, une maladie neurodégé- 5 nérative, une migraine, une hypertension pulmonaire, ou une dysfonction érectile comprenant en outre un support pharmaceutique.

14. Sel acceptable sur le plan pharmaceutique d’un composé selon l’une quelconque des revendications précédentes qui est un sel maléate, chlorhydrate ou fumarate. 10 15. Composé 5-((4-(6-chlorothiénol[2,3-d]pyrimidin-4-ylamino)pipéridin-1-yl)méthyl)-2-fluorobenzonitrile ou un sel ac- ceptable sur le plan pharmaceutique de celui-ci.

16. Composition pharmaceutique comprenant un composé selon l’une quelconque des revendications 1 à 15 et un 15 support acceptable sur le plan pharmaceutique.

17. Composition pharmaceutique selon la revendication 16, où le composé est le 5-((4-(6-chlorothiéno[2,3-d]pyrimidin- 4-ylamino)pipéridin-1-yl)méthyl-2-fluorobenzonitrile.

20 18. Composé selon l’une quelconque des revendications précédentes pour une utilisation dans le traitement de l’hy- pertension pulmonaire, d’une dysfonction érectile, d’une hypertension systémique, d’une insuffisance cardiaque congestive (CHF), d’une migraine, d’une hypertension, de troubles de l’appareil gastro-intestinal, d’une resténose, de l’asthme, d’une maladie obstructive des voies aériennes, d’une hyperplasie prostatique, du priapisme, d’une douleur inflammatoire, d’une douleur neuropathique, d’une douleur cancéreuse, d’une douleur aiguë, d’une douleur 25 chronique, du syndrome du côlon irritable, d’un sphincter oesophagien inférieur hypertonique, de troubles de mobilité, d’une hyperplasie prostatique bénigne, d’une dépression, d’une anxiété, d’un trouble d’hyperactivité avec déficit d’attention, d’une obésité, d’un trouble du sommeil, de la maladie d’Alzheimer, de la maladie de Parkinson, de tumeurs carcinoïdes, d’un tératocarcinome, d’une hyperprolactinémie, d’une acromégalie, d’une maladie neurodé- générative ou de n’importe quel autre état maladif qui est atténué par un traitement avec un antagoniste de 5-HT2B. 30 19. Composé selon l’une quelconque des revendications précédentes dans la fabrication d’un médicament pour le traitement de l’hypertension pulmonaire, d’une dysfonction érectile, d’une hypertension systémique, d’une insuffi- sance cardiaque congestive (CHF), d’une migraine, d’une hypertension, de troubles de l’appareil gastro-intestinal, d’une resténose, de l’asthme, d’une maladie obstructive des voies aériennes, d’une hyperplasie prostatique, du 35 priapisme, d’une douleur inflammatoire, d’une douleur neuropathique, d’une douleur cancéreuse, d’une douleur aiguë, d’une douleur chronique, du syndrome du côlon irritable, d’un sphincter oesophagien inférieur hypertonique, de troubles de mobilité, d’une hyperplasie prostatique bénigne, d’une dépression, d’une anxiété, d’un trouble d’hy- peractivité avec déficit d’attention, d’une obésité, d’un trouble du sommeil, de la maladie d’Alzheimer, de la maladie de Parkinson, de tumeurs carcinoïdes, d’un tératocarcinome, d’une hyperprolactinémie, d’une acromégalie, d’une 40 maladie neurodégénérative ou de n’importe quel autre état maladif qui est atténué par un traitement avec un antagoniste de 5-HT2B.

20. Composé 5-((4-(6-chlorothiéno[2,3-d]pyrimidin-4-ylamino)pipéridin-1-yl)méthyl)-2-fluorobenzonitrile ou un sel ac- ceptable sur le plan pharmaceutique de celui-ci pour une utilisation dans le traitement de l’hypertension artérielle 45 pulmonaire.

21. Composé 5-((4-(6-chlorothiéno[2,3-d]pyrimidin-4-ylamino)pipéridin-1-yl)méthyl)-2-fluorobenzonitrile ou un sel ac- ceptable sur le plan pharmaceutique de celui-ci pour une utilisation dans le traitement de l’hypertension systémique.

50 22. Composé de formule suivante :

55

107 EP 1 797 099 B1

5

10 dans laquelle R1 et R2 représentent indépendamment l’hydrogène, un halogène, COOH ; CN ; NH2 ;NO2 ; 1 OH ; un alkyle inférieur ; un alkyle substitué en C1 àC6 ; un aryle ou hétéroaryle substitué ou non substitué ; R7 ; COOR ; CONHR7 ; CON(R7)2 ; OR7 ; NHR7 ; N(R7)2 ; un R7-alcoxy, un R7-haloalkyle ; un R7-haloalcoxy, ou 15 R1 et R2, pris ensemble avec leurs carbones liés, forment un noyau cycloalkyle ou cyclohétéroalkyle en C4 àC7 substitué ou non substitué ,

- dans lequel un hétéroatome dans le noyau cyclohétéroalkyle en C4 àC7 comprend au moins un élément parmi 0, N et S, et 20 - dans lequel un noyau cycloalkyle ou cyclohétéroalkyle en C4-C7 substitué comprend au moins un substituant choisi parmi l’hydrogène, un halogène, COOH ; CN ; NH2 ; NO2 ; OH ; un alkyle en C1 àC6 ; un alkyle substitué en C1 àC6 ; un cycloalkyle ou cyclohétéroalkyle en C1 àC6 substitué ou non substitué ; un aryle ou hétéroaryle substitué ou non substitué ; R7 ; COOR7 ; CONHR7 ; CON(R7)2 ;OR7 ; NHR7 ;N(R7)2 ;unR7-alcoxy, un R7-haloalkyle ; et un R7-haloalcoxy ; 25

R3 représente indépendamment H ; un halogène ; CN ; NH2 ; un alkyle inférieur ; R7 ;OR7; NHR7 ;N(R7)2 ;ouun aryle ou hétéroaryle substitué ou non substitué ; R4 représente H, R7, ou un aryle ou hétéroaryle substitué ou non substitué ; Q est choisi parmi

30

35

où R8 représente l’hydrogène, un halogène, ou un alkyle en C1 àC6 et * indique des points de fixation ; R5 et R6 sont indépendamment choisis parmi l’hydrogène, un halogène, COOH ; CN ; NH2 ;NO2 ; OH ; un alkyle en C1 à 40 C6 ; un alkyle substitué en C1 àC6 ; un aryle ou hétéroaryle substitué ou non substitué ; R7 ; COOR7 ; CONHR7 ; CON (R7) 2 ; OR7 ; NHR7 ; N(R7)2 ; un R7-alcoxy, un R7-haloalkyle ; et un R7-haloalcoxy ; ou R5 et R6, pris ensemble avec leurs carbones liés, forment un noyau carbocyclique insaturé substitué ou non substitué comportant 5 ou 6 éléments ou un noyau carbocyclique saturé substitué ou non substitué comportant 5, 6 ou 7 éléments, où 45 le noyau carbocyclique peut être un noyau hétérocarbocyclique comprenant au moins un hétéroatome choisi parmi O, N et S, où le noyau substitué comprend au moins un hydrogène, un halogène, COOH ; CN ; NH2 ;NO2 ; OH ; un alkyle en C1 àC6 ; un alkyle substitué en C1 àC6 ; un aryle ou hétéroaryle substitué ou non substitué ; R7 ; COOR7 ; CONHR7 ; CON(R7)2 ; OR7 ; NHR ; N(R7)2 ; un R7-alcoxy, un R7-haloalkyle ; ou R7-haloalcoxy ; 50 où R7 est un alkyle en (C1 àC6) substitué ou non substitué ou un cycloalkyle en (C3 àC6) ou un cyclohétéroalkyle ; n vaut 2, 3, 4 ou 5, ou est ramifié ; dans laquelle un groupe aryle substitué ou hétéroaryle peut être remplacé par un ou plusieurs substituants choisis parmi le groupe constitué d’un halogène, un hydroxyle, un alcoxy, un alkylcarbonyloxy, un arylcarbonyloxy, un alcoxycarbonyloxy, un carboxylate, un alkylcarbonyl, un cyano, un amino, un acylamino, un sulfhydryle, un alkylthio, 55 un arylthio, un nitro, un trifluorométhyle et un cyano ; et dans laquelle un alkyle substitué peut être remplacé par un ou plusieurs substituants choisis parmi le groupe constitué d’un alcényle, un alcoxy, un alcoxycarbonyle, un alcoxycarbonyloxy ; un alcynyle, un alkylcarbonyle, un alkylthio, un alkythiocarbonyle, un thiocarboxylate arylthio, un arylcarbonyle, un arylcarbonyloxy, un acylamino, un

108 EP 1 797 099 B1

carboxylate, un cyano, un halogène, un haloalkyle, un cycloalcoxy, un acétamide, une amine, un hydroxyle, un nitro, un sulfhydryle, un sulfonamido et un trifluorométhyle ; ou un sel de celui-ci acceptable sur le plan pharmaceutique pour une utilisation dans le traitement d’une insuffisance cardiaque congestive (CHF), d’une attaque cardiaque, d’une resténose, de l’asthme, d’une maladie obstructive des 5 voies aériennes, d’une hyperplasie prostatique, du priapisme, d’une dysfonction érectile, d’une douleur inflamma- toire, d’une douleur neuropathique, d’une douleur cancéreuse, d’une douleur aiguë, d’une douleur chronique, du syndrome du côlon irritable, du sphincter oesophagien inférieur hypertonique, de troubles de mobilité, d’hyperplasie prostatique bénigne, du trouble d’hyperactivité avec déficit d’attention, de l’obésité, de tumeurs carcinoïdes, de tératocarcinome, d’hyperprolactinémie ou d’acromégalie. 10 23. Composé représenté par la formule suivants :

15

20

25

30

dans laquelle X représente un halogène ; 35 R3 représente l’hydrogène, un halogène, un cyano ou un trihalométhyle ; et n vaut 1 ou 2, à condition que lorsque n vaut 1, R3 n’est pas un hydrogène, et lorsque n vaut 2, l’un et l’autre groupes R3 ne sont pas un hydrogène ; ou un sel et/ou un ester acceptables sur le plan pharmaceutique d’un tel composé :

pour une utilisation dans le traitement d’une insuffisance cardiaque congestive (CHF), d’une attaque cardiaque, 40 d’une resténose, de l’asthme, d’une maladie obstructive des voies aériennes, d’une hyperplasie prostatique, du priapisme, d’une dysfonction érectile, d’une douleur inflammatoire, d’une douleur neuropathique, d’une douleur cancéreuse, d’une douleur aiguë, d’une douleur chronique, du syndrome du côlon irritable, du sphincter oesophagien inférieur hypertonique, de troubles de mobilité, d’hyperplasie prostatique bénigne, du trouble d’hyperactivité avec déficit d’attention, de l’obésité, de tumeurs carcinoïdes, de tératocarcinome, d’hyperpro- 45 lactinémie ou d’acromégalie.

24. Composé selon la revendication 22 ou 23, dans lequel l’utilisation est le traitement d’une insuffisance cardiaque congestive (CHF).

50

55

109 EP 1 797 099 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 6222034 B [0008] • WO 9413676 A [0102] • US 6159962 A [0009] • WO 9413677 A [0102] • US 4146716 A [0010] • EP 0709093 A [0103] • WO 2004089312 A [0011] • EP 0709094 A [0103] • WO 9413643 A [0102] • EP 0773021 A [0103] • WO 9413644 A [0102] • WO 9612711 A [0103] • WO 9413661 A [0102]

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• Rothman RB ; Baumann MH ; Savage JE ; Rauser • Ullmer C ; Boddeke HG ; Schmuck K ; Lubbert H. L ; McBride A ; Hufeisen SJ ; Roth BL. Evidence 5-HT2B receptor-mediated calcium release from ry- for possible involvement of 5-HT(2B) receptors in the anodine-sensitive intracellular stores in human pul- cardiac valvulopathy associated with fenfluramine monary artery endothelial cells. Br.J.Pharmacol., and other serotonergic medications. Circulation, 1996, vol. 117, 1081-1088 [0394] 2000, vol. 102, 2836-2841 [0394] • Ullmer C ; Schmuck K ; Kalkman HO ; Lubbert H. • Setola V ; Hufeisen SJ ; Grande-Allen KJ ; Vesely Expression of serotonin receptor mRNAs in blood I ; Glennon RA ; Blough B ; Rothman RB ; Roth vessels. FEBS Lett., 1995, vol. 370, 215-221 [0394] BL. 3,4-methylenedioxymethamphetamine (MDMA, • Witchel HJ ; Hancox JC ; Nutt DJ. Psychotropic ’’Ecstasy’’) induces fenfluramine-like proliferative ac- drugs, cardiac arrhythmia, and sudden death. tions on human cardiac valvular interstitial cells in J.Clin.Psychopharmacol, 2003, vol. 23, 58-77 [0394] vitro. Mol.Pharmacol., 2003, vol. 63, 1223-1229 • Witchel HJ ; Pabbathi VK ; Hofinann G ; Paul AA ; [0394] Hancox JC. Inhibitory actions of the selective sero- • Teoh, H. ; Wang, G. ; Ward, M.E. Hypoxia Enhanc- tonin re-uptake inhibitor citalopram on HERG and es 5-HT2B 2005 Receptor Response and Expression ventricular L-type calcium currents. FEBS Lett., in the Rat Pulmonary Artery. International Confer- 2002, vol. 512, 59-66 [0394] ence of the American Thoracic Society, 2005 [0394] • Yamada J ; Sugimoto Y. The 5-HT(2C/2B) receptor agonist, m-chlorophenylpiperazine, increases plas- ma glucagon levels in rats. Eur.J.Pharmacol., 2000, vol. 406, 153-157 [0394]

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