WO2008125570A1 - New bradykinin b1 antagonists - Google Patents

Abstract

The invention relates to compounds of formula (I), wherein R1 to R5 and X1 to X4, n and m have the meaning as cited in the description and the claims. Said compounds are useful as Bradykinin B1 antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.

Description

Evotec Neurosciences GmbH 09. April 2008

EVO64642PC IB/EBU/ih

New Bradykinin Bl antagonists

The present invention relates to Bradykinin Bl antagonists, pharmaceutical compositions thereof, the preparation of such compounds as well as the production and use as medicament, especially for treatment of inflammation-related disorders including inflammatory pain, and neuropathic pain.

The patient populations for nociceptive pain and neuropathic pain are large, and are driven by separate disease trends that necessitate pain relief. Across the seven major markets in 2005 it was estimated that 170.1 million suffered from nociceptive pain and 37.6 million individuals suffered from neuropathic pain. Unfortunately, current treatments for pain are only partially effective, and many cause life-style altering, debilitating, and /or dangerous side effects. For example, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, and indomethacin are moderately effective against inflammatory pain but they are also renally toxic, and high doses tend to cause gastrointestinal irritation, ulceration, bleeding, confusion and increased cardiovascular risk. Notably, Vioxx was withdrawn from the market in 2004, due to a risk of myocardial infarction and stroke. Patients treated with opioids frequently experience confusion and constipation, and long-term opioid use is associated with tolerance and dependence. Local anaesthetics such as lidocaine and mixelitine simultaneously inhibit pain and cause loss of normal sensation. In addition, when used systemically, local anaesthetics are associated with adverse cardiovascular effects. Thus, there is currently an unmet need in the treatment of chronic pain.

Kinins are proinflammatory peptides that mediate vascular and pain responses to tissue injury, with functions in cardiovascular homeostasis, contraction or relaxation of smooth muscle, inflammation and nociception. They exert most of their effects by interacting with two classes of G-protein-coupled receptors called Bradykinin receptor 1 and 2 (Bl and B2). The classification of the kinin receptors was originally achieved by means of pharmacological studies originally carried out at the end of the 1970s. During the 1990s, the existence of kinin Bl and B2 receptors was further confirmed through cloning and genetic deletion studies (McEachern et al. 1991; Menke et al. 1994). The past 30 years of research on the kinin system has indicated that both Bl and B2 receptors are involved in pain and inflammation (for reviews see Leeb-Lundberg et al. 2005; Moreau et al. 2005; Chen and Johnson 2007).

It has been demonstrated that B2 receptors are widely expressed in a constitutive manner throughout most mammalian tissues. In contrast, Bl receptors are not constitutively expressed to a great extent under normal conditions, but are up-regulated under different inflammatory conditions such as asthma, arthritis and osteoarthritis, sepsis and type-1 diabetes, as well as by some neuropathological diseases such as epilepsy, stroke and multiple sclerosis. Therefore, Bl receptors have been suggested to have a pivotal role in several chronic diseases involving inflammation, inflammatory pain and neuropathic pain (Campos et al. 2006). The contribution of Bl receptor activation in inflammation and pain processes is supported by the demonstration that Bl receptor knockout mice have a largely decreased response to nociceptive and pro-inflammatory stimuli (Ferreira et al. 2001; Ferreira et al. 2005). The therapeutic interest of Bl receptor blockage is supported further by the pharmacological properties of Bl antagonists in many inflammatory and neuropathic pain models (Gougat et al. 2004; Fox et al. 2005). The fact that Bl receptor expression is induced under disease conditions clearly raises the possibility that therapeutic use of Bl receptor antagonists should be devoid of undesired side effects.

The development of non-peptide Bl antagonists with long-lasting efficacy and oral bioavailability, which would represent a new treatment paradigm for inflammation and pain, should clearly be advantageous over the existing treatment strategies. Such agents are provided in the present invention.

Bradykinin antagonists are described in WO-A 2006/132837, US-A 2005/234044 and Expert Opin. Ther. Targets 11 (2007), 21-35.

However there is a continuing need for new compounds useful as Bradykinin Bl antagonists.

Thus, an object of the present invention is to provide a new class of compounds as Bradykinin Bl antagonists which may be effective in the treatment of Bl receptor related diseases. Accordingly, the present invention provides compounds of formula (I)

or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein

R¹ is H; methyl; ethyl; n-propyl; i-propyl; or cyclopropyl, wherein methyl; ethyl; n- propyl; i-propyl; and cyclopropyl are optionally substituted with one or more halogen, which are the same or different;

X¹ is CR⁶R^6a; O; S; S(O); or S(O)₂;

R⁶, R^6a are independently selected from the group consisting of H; and halogen;

X² is O; S; or N(R⁷);

R²; R³; R⁴; R⁵; R⁷ are independently selected from the group consisting of H; methyl; ethyl; n-propyl; i-propyl; and cyclopropyl, wherein methyl; ethyl; n-propyl; i-propyl; and cyclopropyl are optionally substituted with one or more halogen, which are the same or different;

Optionally R², R³ or R⁴, R⁵ are joined together with the carbon atom to which they are attached to give a cyclopropyl, which is optionally substituted with one or more halogen, which are the same or different;

n is 1 or 2;

m is 0; 1 or 2; X³ is phenyl or a 5- or 6-membered aromatic heterocycle, wherein X³ is substituted in 2-position relative to the sulfonamide group in formula (I) with R⁸ and is optionally substituted with one or more R⁹, which are the same or different;

R⁸; R⁹ are independently selected from the group consisting of halogen; CN; COOR¹⁰;

OR¹⁰; C(O)N(R¹⁰R^10a); S(O)₂N(R¹⁰R^10a); S(O)N(R¹⁰R^10a); S(O)₂R¹⁰; N(R¹⁰)S(O)₂N(R^10aR^10b); SR¹⁰; N(R¹⁰R^10a); NO₂; OC(O)R¹⁰; N(R¹⁰)C(O)R^10a; N(R¹⁰)S(O)₂R^10a;N(R¹⁰)S(O)R^10a; N(R¹ °)C (O)N(R^10aR^10b); N(R¹⁰)C(O)OR^10a; OC(O)N(R¹⁰R^10a); C(O)R¹⁰; Ci_-6 alkyl; C₂.₆ alkenyl; C₂.₆ alkynyl; and T, wherein Ci_-6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R¹¹, which are the same or different;

Optionally, R⁸ and R⁹ in 2-position relative to R⁸ are joined together with the atoms to which they are attached to form benzo; or a 5- or 6-membered aromatic heterocyle; wherein benzo; and the 5- or 6-membered aromatic heterocyle; are optionally substituted with one or more R¹², which are the same or different;

Optionally, two adjacent R⁹ are joined together with the atoms to which they are attached to form benzo; or a 5- or 6-membered aromatic heterocyle; wherein benzo; and the 5- or 6-membered aromatic heterocyle; are optionally substituted with one or more R¹², which are the same or different;

R¹² is independently selected from the group consisting of halogen; CN; COOR¹⁰;

OR¹⁰; C(O)N(R¹⁰R^10a); S(O)₂N(R¹⁰R^10a); S(O)N(R¹⁰R^10a); S(O)₂R¹⁰; N(R¹⁰)S(O)₂N(R^10aR^10b); SR¹⁰; N(R¹⁰R^10a); NO₂; OC(O)R¹⁰; N(R¹⁰)C(O)R^10a;

N(R¹⁰)S(O)₂R^10a;N(R¹⁰)S(O)R^10a; N(R¹ °)C (O)N(R^10aR^10b); N(R¹⁰)C(O)OR^10a;

OC(O)N(R¹⁰R^10a); C(O)R¹⁰; Ci_-6 alkyl; C₂-₆ alkenyl; C₂-₆ alkynyl; and T, wherein Ci_-6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R¹¹, which are the same or different;

R¹⁰, R^1Oa, R^10b are independently selected from the group consisting of H; T; Ci_₆ alkyl;

C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R¹³, which are the same or different; R¹¹, R¹³ are independently selected from the group consisting of halogen; C(O)R¹⁴; CN; COOR¹⁴; OR¹⁴; C(O)N(R¹⁴R^14a); S(O)₂N(R¹⁴R^14a); S(O)N(R¹⁴R^14a); S(O)₂R¹⁴; N(R¹⁴)S(O)₂N(R^14aR^14b); SR¹⁴; N(R¹⁴R^14a); NO₂; OC(O)R¹⁴; N(R¹⁴)C(O)R^14a; N(R¹⁴)S(O)₂R^14a; N(R¹⁴)S(O)R^14a; N(R¹⁴)C(O)N(R^14aR^14b); N(R¹⁴)C(CO)OR^14a;

0C(0)N(R¹⁴R^14a); and T¹

R¹⁴, R^14a, R^14b are independently selected from the group consisting of H; T¹; Ci_₆ alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R 15 , which are independently selected from the group consisting of halogen; C(O)R¹⁶; CN; COOR¹⁶; OR¹⁶; C(O)N(R¹⁶R^16a);

S(O)₂N(R¹⁶R^16a); S(O)N(R¹⁶R^16a); S(O)₂R¹⁶; N(R¹⁶)S(O)₂N(R^16aR^16b); SR¹⁶; N(R¹⁶R^16a); NO₂; OC(O)R¹⁶; N(R¹⁶)C(0)R^16a; N(R¹⁶)S(O)₂R^16a; N(R¹⁶)S(O)R^16a; N(R¹⁶)C(O)N(R^16aR^16b); N(R¹⁶)C(CO)OR^16a; and OC(O)N(R¹⁶R^16a);

R¹⁶, R^16a, R^16b are independently selected from the group consisting of H; Ci_₆ alkyl;

C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

T, T¹ are independently selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; adamantyl; C₃_₇ cycloalkyl; 4 to 7 membered heterocyclyl; and 9 to 11 membered heterobicyclyl, wherein T, T¹ are optionally substituted with one or more R¹⁷, which are independently selected from the group consisting of halogen; CN; C(O)R¹⁸; COOR¹⁸; OR¹⁸; C(O)N(R¹⁸R^18a); S(O)₂N(R¹⁸R^18a); S(O)N(R¹⁸R^18a); S(O)₂R¹⁸; N(R¹⁸)S(O)₂N(R^18aR^18b); SR¹⁸; N(R¹⁸R^18a); NO₂; OC(O)R¹⁸; N(R¹⁸)C(O)R^18a; N(R¹⁸)S(O)₂R^18a; N(R¹⁸)S(O)R^18a;

N(R¹⁸)C(O)N(R^18aR^18b); N(R¹⁸)C(O)OR^18a; OC(O)N(R¹⁸R^18a); oxo (=0), where the ring is at least partially saturated; Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci _ 6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R¹⁸, R^18a, R^18b are independently selected from the group consisting of H; Ci_₆ alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same or different; X⁴ is OR¹⁹ or NR¹⁹R^19a;

R¹⁹, R^19a are independently selected from the group consisting of H; T²; Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R²⁰, which are the same or different;

Optionally R¹⁹, R^19a are joined together with the nitrogen to which they are attached to from a 4 to 7 membered heterocycle or 9 to 11 membered heterobicycle, wherein the 4 to 7 membered heterocycle or 9 to 11 membered heterobicycle is optionally substituted with one or more R²¹, which are the same or different;

T² is independently selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; adamantyl; C₃_₇ cycloalkyl; 4 to 7 membered heterocyclyl; and 9 to 11 membered heterobicyclyl, wherein T² is optionally substituted with one or more R²², which are the same or different;

R²¹, R²² are independently selected from the group consisting of halogen; CN;

COOR²³; OR²³; C(O)N(R²³R^23a); S(O)₂N(R²³R^23a); S(O)N(R²³R^23a); S(O)₂R²³;

N(R²³)S(O)₂N(R^23aR^23b); SR²³; N(R²³R^23a); NO₂; OC(O)R²³; N(R²³)C(O)R^23a; N(R²³)S(O)₂R^23a; N(R²³)S(O)R^23a; N(R²³)C(O)N(R^23aR^23b); N(R²³)C(O)OR^23a;

OC(O)N(R²³R^23a); oxo (=0), where the ring is at least partially saturated; C(O)R²³;

C_1-10 alkyl; C_2-10 alkenyl; C_2-10 alkynyl; and T³, wherein C_1-10 alkyl; C_2-10 alkenyl; and

C₂-₁0 alkynyl are optionally substituted with one or more R²⁴, which are the same or different;

R²³, R^23a, R^23b are independently selected from the group consisting of H; T³; Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R²⁵, which are the same or different;

R²⁰ is independently selected from the group consisting of halogen; CN; C(O)R²⁶;

COOR²⁶; OR²⁶; C(O)R²⁶; C(O)N(R²⁶R^26a); S(O)₂N(R²⁶R^26a); S(O)N(R²⁶R^26a); S(O)₂R²⁶; N(R²⁶)S(O)₂N(R^26aR^26b); SR²⁶; N(R²⁶R^26a); OC(O)R²⁶; N(R²⁶)C(O)R^26a; N(R²⁶)SO₂R^26a; N(R²⁶)S(O)R^26a; N(R²⁶)C(O)N(R^26aR^26b); N(R²⁶)C(O)OR^26a; OC(O)N(R²⁶R^26a); Ci_-6 alkyl; C₂-₆ alkenyl; C₂-₆ alkynyl and T², wherein Ci_-6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R²⁷, which are the same or different;

R²⁴, R²⁵ are independently selected from the group consisting of halogen; CN; C(O)R²⁶; COOR²⁶; OR²⁶; C(O)R²⁶; C(O)N(R²⁶R^26a); S(O)₂N(R²⁶R^26a);

S(O)N(R²⁶R^26a); S(O)₂R²⁶; N(R²⁶)S(O)₂N(R^26aR^26b); SR²⁶; N(R²⁶R^26a); OC(O)R²⁶;

N(R²⁶)C(O)R^26a; N(R²⁶)SO₂R^26a; N(R²⁶)S(O)R^26a; N(R²⁶)C(O)N(R^26aR^26b);

N(R²⁶)C(O)OR^26a; OC(O)N(R²⁶R^26a); d_₆ alkyl; C₂-₆ alkenyl; C₂-₆ alkynyl and T³, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R²⁷, which are the same or different;

R²⁶, R^26a, R^26b are independently selected from the group consisting of H; T³; Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R²⁸, which are the same or different;

R²⁷, R²⁸ are independently selected from the group consisting of halogen; CN;

COOR²⁹; OR²⁹; C(O)R²⁹; C(O)N(R²⁹R^29a); S(O)₂N(R²⁹R^29a); S(O)N(R²⁹R^29a);

S(O)₂R²⁹; N(R²⁹)S(O)₂N(R^29aR^29b); SR²⁹; N(R²⁹R^29a); NO₂; OC(O)R²⁹;

N(R²⁹)C(O)R^29a; N(R²⁹)SO₂R^29a; N(R²⁹)S(O)R^29a; N(R²⁹)C(O)N(R^29aR^29b); N(R²⁹)C(O)OR^29a; OC(O)N(R²⁹R^29a); d_₆ alkyl; C₂-₆ alkenyl; C₂-₆ alkynyl; and T⁴, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R³⁰, which are the same or different;

R²⁹, R^29a, R^29b are independently selected from the group consisting of H; Ci_₆ alkyl; C₂-6 alkenyl; C₂-6 alkynyl; and T⁴ wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R³¹, which are the same or different;

T³; T⁴ are independently selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; adamantyl; C₃_₇ cycloalkyl; 4 to 7 membered heterocyclyl; and 9 to 11 membered heterobicyclyl, wherein T³, T⁴ are optionally substituted with one or more R³², which are the same or different;

R³² is independently selected from the group consisting of halogen; CN; COOR³³; OR³³; C(O)N(R³³R^33a); S(O)₂N(R³³R^33a); S(O)N(R³³R^33a); S(O)₂R³³; N(R³³)S(O)₂N(R^33aR^33b); SR³³; N(R³³R^33a); NO₂; OC(O)R³³; N(R³³)C(O)R^33a; N(R³³)S(O)₂R^33a; N(R³³)S(O)R^33a; N(R³³)C(O)N(R^33aR^33b); N(R³³)C(O)OR^33a; OC(O)N(R³³R^33a); oxo (=0), where the ring is at least partially saturated; C(O)R³³; T⁵; Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R³⁴, which are the same or different;

R³³, R^33a, R^33b are independently selected from the group consisting of H; Ci_₆ alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same of different;

T⁵ is phenyl; C3_7 cycloalkyl; or 4 to 7 membered heterocyclyl, wherein T⁵ is optionally substituted with one or more R³⁶, which are the same or different;

R³⁰; R³¹; R³⁴ are independently selected from the group consisting of halogen; CN;

COOR³⁵; OR³⁵; C(O)R³⁵; C(O)N(R³⁵R^35a); S(O)₂N(R³⁵R^35a); S(O)N(R³⁵R^35a);

S(O)₂R³⁵; N(R³⁵)S(O)₂N(R^35aR^35b); SR³⁵; N(R³⁵R^35a); NO₂; OC(O)R³⁵;

N(R³⁵)C(O)R^35a; N(R³⁵)SO₂R^35a; N(R³⁵)S(O)R^35a; N(R³⁵)C(O)N(R^35aR^35b);

N(R³⁵)C(O)OR^35a; OC(O)N(R³⁵R^35a); d_₆ alkyl; C₂-₆ alkenyl; C₂-₆ alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more one or more halogen, which are the same of different;

R³⁵, R^35a, R^35b are independently selected from the group consisting of H; Ci_₆ alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same of different.

R³⁶ is independently selected from the group consisting of halogen; CN; COOR³⁷; OR³⁷; C(O)N(R³⁷R^37a); S(O)₂N(R³⁷R^37a); S(O)N(R³⁷R^37a); S(O)₂R³⁷; N(R³⁷)S(O)₂N(R^37aR^37b); SR³⁷; N(R³⁷R^37a); NO₂; OC(O)R³⁷; N(R³⁷)C(O)R^37a; N(R³⁷)S(O)₂R^37a; N(R³⁷)S(O)R^37a; N(R³⁷)C(O)N(R^37aR^37b); N(R³⁷)C(O)OR^37a;

OC(O)N(R³⁷R^37a); oxo (=0), where the ring is at least partially saturated; C(O)R³⁷; Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R³⁷, R^37a, R^37b are independently selected from the group consisting of H; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same of different.

In case a variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.

Within the meaning of the present invention the terms are used as follows:

"Alkyl" means a straight-chain or branched saturated aliphatic acyclic hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent.

"Alkenyl" means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent.

"Alkynyl" means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent.

"Ci_₄ alkyl" means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g. -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -C(CH₂)-, -CH₂-CH₂-CH₂-, -CH(C₂H₅)-, -CH(CH₃)₂-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_4 alkyl carbon may be replaced by a substituent.

"Ci_6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_₄ alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, n-hexyl, or e.g. -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂-CH₂-CH₂-, -CH(C₂H₅)-, -C(CH₃)₂-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent.

"Ci_io alkyl" means an alkyl chain having 1 to 10 carbon atoms, e.g. if present at the end of a molecule: Ci_4 alkyl, Ci_6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl; tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-hexyl or e.g. -CH₂-, -CH₂- CH₂-, -CH(CH₃)-, -C(CH₂)-, -CH₂-CH₂-CH₂-, -CH(C₂H₅)-, -CH(CH₃)₂-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a C_1-10 alkyl carbon may be replaced by a substituent.

"C2-6 alkenyl" means an alkenyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -CH=CH₂, -CH=CH-CH₃, -CH₂-CH=CH₂, -CH=CH-CH₂-CH₃, -CH=CH- CH=CH₂, or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a C₂-6 alkenyl carbon may be replaced by a substituent.

"C₂-6 alkynyl" means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -C≡CH, -CH₂-C≡CH, CH₂-CH₂-C=CH, CH₂-C=C-CH₃, or e.g. -C≡C- when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a C₂-6 alkynyl carbon may be replaced by a substituent.

"C₃_₇ cycloalkyl" or "C₃_₇ cycloalkyl ring" means a cyclic alkyl chain having 3 - 7 carbon atoms, e.g. cyclopropyl, cyclo butyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent.

"Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.

"4 to 7 membered heterocyclyl" or "4 to 7 membered heterocycle" means a ring with 4, 5, 6 or 7 ring atoms that may contain up to the maximum number of double bonds (aromatic or non- aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)₂-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a 4 to 7 membered heterocycles are azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydro furan, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine.

"9 to 11 membered heterobicyclyl" or "9 to 11 membered heterobicycle" means a heterocyclic system of two rings with 9 to 11 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)₂-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a 9 to 11 membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 9 to 11 membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2. ljoctane.

"5 to 6 membered aromatic heterocyclyl" or "5 to 6 membered aromatic heterocycle" means a heterocycle derived from cyclopentadienyl or benzene, where at least one carbon atom is replaced by a heteoatom selected from the group consisting of sulfur (including -S(O)-, - S(O)₂-), oxygen and nitrogen (including =N(O)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, pyranium, pyridine, pyridazine, pyrimidine, triazole, tetrazole.

Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention. With respect to all preferred compounds of the formulas (I) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts as well as their isotopic derivatives.

Preferred compounds according to the present invention are those having a stereochemistry as given in formula (Ia)

or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein R¹ to R⁵ and X¹ to X⁴, n and m have the meaning as indicated above.

In preferred embodiments of the present invention, the substituents R¹ to R⁵ and X¹ to X⁴ of the formula (I) independently have the following meaning. Hence, one or more of the substituents R¹ to R⁵ and X¹ to X⁴ can have the preferred or more preferred meanings given below.

Preferably, R¹ is H or methyl, more preferred R¹ is H.

Preferably, X¹ is O; CH₂; or CF₂.

Preferably, X² is O.

Preferably, R², R³, R⁴, R⁵ are H.

Preferably, n is 1.

Preferably, m is 1 or 2, more preferred m is 1.

Preferably, X³ is selected from the group consisting of

wherein X is substituted as indicated above. Preferably, X³ is selected from the group consisting of

wherein R , r R> 9 and R , 12 have the meaning as indicated above.

Preferably R , R > 9 , R , 12 are independently selected from the group consisting of halogen; CN; OR¹⁰; NO₂; phenyl; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen; or phenyl and wherein R¹⁰ is H; or Ci_₆ alkyl, which is optionally substituted with phenyl or one or more halogen, which are the same or different. More preferred R⁸, R⁹, R¹² are independently selected from the group consisting of F; Cl; Br; I; CN; OCH₃; NO₂; CH₃; CH₂CH₃; CH(CH₃)₂; and CF₃.

Preferably, X⁴ is NR¹⁹R^19a, wherein R¹⁹, R^19a have the meaning as indicated above.

Preferably, R^19a is selected from the group consisting of H; and Ci_6 alkyl.

Preferably, R¹⁹ is selected from the group consisting of T²; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more R²⁰ and wherein T² and R²⁰ have the meaning as indicated above. More preferred Ci_6 alkyl is substituted with one R²⁰ and wherein R²⁰ has the meaning as indicated above.

Preferably, R¹⁹, R^19a are joined together with the nitrogen to which they are attached to form a piperazinyl; a homopiperazinyl; or a thiazolidinyl ring, wherein the ring is optionally substituted with one or more R²¹ and wherein R²¹ has the meaning as indicated above. More preferred the ring is substituted with one R²¹ and wherein R²¹ has the meaning as indicated above.

Preferably, R²⁰ is selected from the group consisting of T²; and N(R²⁶R^26a), wherein R²⁶, R^26a have the meaning as indicated above.

Preferably, R²⁶, R^26a are independently selected from the group consisting of H; and Ci_6 alkyl.

Preferably, R²¹ is selected from the group consisting of Ci_io alkyl; C₂_io alkenyl; C₂_io alkynyl; and T³, wherein Ci_io alkyl; C₂_io alkenyl; and C₂_io alkynyl are optionally substituted with one or more R²⁴ and wherein T³ and R²⁴ have the meaning as indicated above. More preferred, Ci_io alkyl; C₂_io alkenyl; and C₂_io alkynyl are optionally substituted with one R²⁴ and wherein R²⁴ has the meaning as indicated above.

Preferably, R²⁴ is selected from the group consisting of T³; CN; N(R²⁶R^26a); and C(O)N(R²⁶R^26a) and wherein R²⁶, R^26a have the meaning as indicated above. Preferably, T² and T³ are independently selected from the group consisting of phenyl; cyclopentyl; cyclohexyl; tetralinyl; pyrrolidinyl; imidazolyl; piperidyl; pyridyl; mopholinyl; thiophenyl; and benzodioxolanyl, wherein T² is optionally substituted with one or more R²² and T³ is optionally substituted with one or more R³².

Preferably, T² is optionally substituted with up to 3 R²², which are the same or different and T³ is optionally substituted with up to 3 R³², which are the same or different.

Preferably, R²², R³² are independently selected from the group consisting of halogen; CN; OCi_6 alkyl; Ci_₆ alkyl; C₂-₆ alkenyl; and C₂-₆ alkynyl.

Compounds of the formula (I) in which some or all of the above-mentioned groups have the preferred or more preferred meanings are also an object of the present invention.

In a preferred embodiment of the present invention the following individual compounds are excluded from compounds of formula (I) as far as compounds as such are concerned:

1 -(2- { 1 -[(4-fluoro-2-methylphenyl)sulfonyl]piperidin-2-yl} ethyl)-3-(4-methylphenyl)urea;

1 -cyclohexyl-3-(2- { 1 -[(4-fluoro-2-methylphenyl)sulfonyl]piperidin-2-yl} ethyl)urea; 1 -(3-chlorophenyl)-3-(2- { 1 -[(2,4,6-trimethylphenyl)sulfonyl]piperidin-2-yl} ethyl)urea;

1 -(3-methylphenyl)-3-(2- { 1 -[(2,4,6-trimethylphenyl)sulfonyl]piperidin-2-yl} ethyl)urea;

1 -phenyl-3-(2- { 1 -[(2,4,6-trimethylphenyl)sulfonyl]piperidin-2-yl} ethyl)urea;

1 -(2- { 1 -[(4-fluoro-2-methylphenyl)sulfonyl]piperidin-2-yl} ethyl)-3-(3-methylphenyl)urea;

1 -tert.-butyl-3-(2- { 1 -[(4-fluoro-2-methylphenyl)sulfonyl]piperidin-2-yl} ethyl)urea; 1 -(2- { 1 -[(4-fluoro-2-methylphenyl)sulfonyl]piperidin-2-yl} ethyl)-3-phenylurea;

1 -(2- { 1 -[(2,5-dimethylphenyl)sulfonyl]piperidin-2-yl} ethyl)-3-(4-methylphenyl)urea;

1 -(4-chlorophenyl)-3-(2- { 1 -[(2,5-dimethylphenyl)sulfonyl]piperidin-2-yl} ethyl)urea;

1 -(4-methylphenyl)-3-(2- { 1 -[(2,4,6-trimethylphenyl)sulfonyl]piperidin-2-yl} ethyl)urea;

1 -(4-chlorophenyl)-3-(2- { 1 -[(2,4,6-trimethylphenyl)sulfonyl]piperidin-2-yl} ethyl)urea; 1 -(4-chlorophenyl)-3-(2- { 1 -[(4-fluoro-2-methylphenyl)sulfonyl]piperidin-2-yl} ethyl)urea.

Preferably, these individual compounds are not excluded as far as compounds of formula (I) are used in pharmaceutical compositions, as a medicament, for the manufacture of a medicament, in a method controlling, delaying or preventing in mammalian patient in need of treatment one or more conditions or prepared in a process for the preparation according to the present invention. Prodrugs of the compounds of the invention are also within the scope of the present invention. "Prodrug" means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically. Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated. These compounds can be produced from compounds of the present invention according to well-known methods.

Metabolites of compounds of formula (I) are also within the scope of the present invention.

Where tautomerism, like e.g. keto-enol tautomerism, of compounds of general formula (I) may occur, the individual forms, like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio. Same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like.

Iso topic labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S.

If desired, isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases.

Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials.

In case the compounds according to formula (I) contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

The present invention provides compounds of general formula (I) as Bradykinin Bl antagonists. There utilities are described in detail in the utility section of WO-A 2006/132837, page 8, line 9 to page 12, line 2, which paragraph is herewith incorporated by reference.

Accordingly, compounds of the present inventions may be useful for the treatment or prophylaxis of pain and inflammation including visceral pain (like pancreatitis, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuropathic pain (including postherpetic neuralgia, acute zoster pain, nerve injury, the "dynias", including vulvodynia, phantom limb pain, root avulsions, radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, carpal tunnel syndrome, ulnar neuropathy, tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system including but not limited to stroke, multiple sclerosis, spinal cord injury), and postsurgical pain syndromes (including postmastectomy syndrome, postthoracotomy syndrome, stump pain)), bone and joint pain (osteoarthritis), spine pain (including acute and chronic low back pain, neck pain, spinal stenosis), shoulder pain, repetitive motion pain, dental pain, sore throat, cancer pain, burn pain, myofascial pain (muscular injury, fibromyalgia), postoperative, perioperative pain and preemptive analgesia (including but not limited to general surgery, orthopedic, and gynecological), chronic pain, dysmenorrhea (primary and secodnary), as well as pain associated with angina, and inflammatory pain of varied origins (including osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis and gout, ankylosing spondylitis, bursitis); hyperreactive airways and to treat inflammatory events associated with airways disease like asthma including allergic asthma (atopic or non-atopic) as well as exercise- induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy- infant syndrome"; chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis (seasonal and perennial), and vasomotor rhinitis; pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis; inflammatory bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders including psoriasis and eczema, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and angioedema (including hereditary angioedema and drug-induced angioedema including that caused by angiotensin converting enzyme (ACE) or ACE/neutral endopeptidase inhibitors like omepatrilat); diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion); spasm of the gastrointestinal tract or uterus; liver disease, multiple sclerosis, cardiovascular disease, including atherosclerosis, congestive heart failure, myocardial infarct; neurodegenerative diseases, including Parkinson's and Alzheimers disease, epilepsy, septic shock, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia and hyperactive bladder.

Furthermore, from recent research it can be expected that Bl is expressed in adipocytes under healthy condition, and the blockage of Bl receptor should show an anti-obesity role, due to reduction of insulin sensitivity in adiposytes and due to inhibition of insulin-mediated glucose transporter 4 (Glut4) translocation (2^nd International Conference on "Exploring the Future of Vascular and Inflammatory Mediators" — Kinin 2007, 30^th May - 2^nd June, Max Delbruck Center (MDC) in Berlin; Kinin Bl receptor: from gene cloning to a new function in adiposity. By Pesquero, Brazil (T24, Award Lecture), Kinin Bl receptor deficiency reduces insulin responsiveness and differentiation of adipocytes, and protects from high fat diet-induced obesity. By Mori, Brazil / Germany (Tl 7)).

Accordingly, compounds of the present invention may be useful for the treatment or prophylaxis of obesity. Accordingly, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use as a medicament.

Furthermore, the compounds of the present invention can be used for the manufacture of a medicament for the treatment or prophylaxis of pain and inflammation including visceral pain (like pancreatitis, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuropathic pain (including postherpetic neuralgia, acute zoster pain, nerve injury, the "dynias", including vulvodynia, phantom limb pain, root avulsions, radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, carpal tunnel syndrome, ulnar neuropathy, tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system including but not limited to stroke, multiple sclerosis, spinal cord injury), and postsurgical pain syndromes (including postmastectomy syndrome, postthoracotomy syndrome, stump pain), bone and joint pain (osteoarthritis), spine pain (including acute and chronic low back pain, neck pain, spinal stenosis), shoulder pain, repetitive motion pain, dental pain, sore throat, cancer pain, burn pain, myofascial pain (muscular injury, fibromyalgia), postoperative, perioperative pain and preemptive analgesia (including but not limited to general surgery, orthopedic, and gynecological), chronic pain, dysmenorrhea (primary and secodnary), as well as pain associated with angina, and inflammatory pain of varied origins (including osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis and gout, ankylosing spondylitis, bursitis); hyperreactive airways and to treat inflammatory events associated with airways disease like asthma including allergic asthma (atopic or non- atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy- infant syndrome"; chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis (seasonal and perennial), and vasomotor rhinitis; pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis; inflammatory bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders including psoriasis and eczema, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and angioedema (including hereditary angioedema and drug-induced angioedema including that caused by angiotensin converting enzyme (ACE) or ACE/neutral endopeptidase inhibitors like omepatrilat); diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion); spasm of the gastrointestinal tract or uterus; liver disease, multiple sclerosis, cardiovascular disease, including atherosclerosis, congestive heart failure, myocardial infarct; neurodegenerative diseases, including Parkinson's and Alzheimers disease, epilepsy, septic shock, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia, hyperactive bladder; and obesity.

More preferred are the treatment or prophylaxis of pain and inflammation and the more specific diseases related to pain and inflammation.

The present invention also provides a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment one or more conditions selected from the group consisting of pain and inflammation including visceral pain (like pancreatitis, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuropathic pain (like postherpetic neuralgia, acute zoster pain, nerve injury, the "dynias", including vulvodynia, phantom limb pain, root avulsions, radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, carpal tunnel syndrome, ulnar neuropathy, tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system including but not limited to stroke, multiple sclerosis, spinal cord injury), and postsurgical pain syndromes (including postmastectomy syndrome, postthoracotomy syndrome, stump pain)), bone and joint pain (osteoarthritis), spine pain (including acute and chronic low back pain, neck pain, spinal stenosis), shoulder pain, repetitive motion pain, dental pain, sore throat, cancer pain, burn pain, myofascial pain (muscular injury, fibromyalgia), postoperative, perioperative pain and preemptive analgesia (including but not limited to general surgery, orthopedic, and gynecological), chronic pain, dysmenorrhea (primary and secodnary), as well as pain associated with angina, and inflammatory pain of varied origins (including osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis and gout, ankylosing spondylitis, bursitis); hyperreactive airways and to treat inflammatory events associated with airways disease like asthma including allergic asthma (atopic or non-atopic) as well as exercise- induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy- infant syndrome"; chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis (seasonal and perennial), and vasomotor rhinitis; pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis; inflammatory bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders including psoriasis and eczema, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and angioedema (including hereditary angioedema and drug-induced angioedema including that caused by angiotensin converting enzyme (ACE) or ACE/neutral endopeptidase inhibitors like omepatrilat); diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion); spasm of the gastrointestinal tract or uterus; liver disease, multiple sclerosis, cardiovascular disease, including atherosclerosis, congestive heart failure, myocardial infarct; neurodegenerative diseases, including Parkinson's and Alzheimers disease, epilepsy, septic shock, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia, hyperactive bladder; and obesity.

The present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

"Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other Bradykinin Bl antagonists.

Other active ingredients are disclosed, e.g., in WO-A 2006/132837 under the paragraph "Combination Therapy" starting on page 12, which paragraph is herewith incorporated by reference.

The active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In practical use, the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, for example, as liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous 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. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (I) are administered orally.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

Available starting materials for the synthesis of preferred embodiments of the invention may be readily available by synthesis or they may be purchased from commercially available sources such as Array, Sigma Aldrich, Fluka, ABCR or be synthesized by one skilled in the art.

In general, compound of formula (I) may be prepared starting from compounds of formula (IV). Accordingly, another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of

reacting an N-protected compound of formula (IV)

with bromo compound Br-(CR⁴R⁵)_mC(O)OC(CH₃)₃ to yield a compound of formula (III)

deprotecting compound of formula (III) at the nitrogen atom and reacting the resulting compound with Cl-S(O)₂X³ to yield a compound of formula (II)

(H) deprotecting compound formula (II) and reacting the resulting compound with H- X⁴ to yield compound of formula (I).

Examples

Biological evaluation

Calcium flux Assay for Bradykinin Bl antagonist

The potency to inhibit the Bradykinin Bl receptors was determined for the compounds of this invention in a cell-based fluorescent calcium-mobilization assay. The assay measures the ability of test compounds to inhibit Bradykinin Bl receptor agonist-induced increase of intracellular free Ca²⁺ in cell lines expressing Bl. Specifically, calcium indicator -loaded cells are pre-incubated in the absence or presence of different concentrations of test compounds followed by the stimulation with a selective Bl receptor agonist peptide. The change of the intracellular Ca²⁺ concentration is monitored with a specifically designed fluorescent plate reader (FlexStation, Molecular Devices).

CHO-Kl cell line expressing human Bl was purchased from Euroscreen (Gosselies, Belgium, with reference name hBl-Dl). CHO-Kl cell lines expressing rat Bl or mouse Bl were established in the following way: the full-length receptor-coding cDNA clones were obtained by PCR performed on rat or mouse brain cDNAs. The respective cDNAs were cloned into an expression vector under the control of a CMV promotor. The resultant plasmids were introduced into CHO-Kl cells with liposome technology (FuGENE; Roche Diagnostics, Basel), according to the standard protocols described by the manufacturer. Cell lines expressing a Bradykinin receptor were selected in the culture medium containing 400μg/ml

G418 (Sigma). From selected cell populations, monoclonal cell lines were isolated by single cell cloning. The expression of Bradykinin receptors was confirmed by immunofluorescence staining of the cells, as well as by calcium flux assay.

Human Bl -expressing cells were grown in Nutrient Mixture Ham's F 12 (Sigma) containing 10% Foetal bovine serum (Sigma) and 400μg/ml G418 (Sigma), 5μg/ml puromycim (Sigma); Rat Bl and mouse Bl -expressing cells were grown in DMEM/F12 medium (Sigma) containing 10% Foetal bovine serum (Sigma) and 400μg/ml G418 (Sigma). For the calcium flux assay, 80% confluent cells were detached from the culture vessels with Versene (Gibco; for human Bl cell- line) or with Ix trypsin-EDTA solution (Sigma; for rodent Blcell-line), and seeded into 384-well plates (Cell binding Surface; Corning, NY; #3683) at a density of 15,000 cells per well for human Bl or at a density of 20,000 cells per well for rodent Bl. Cells were seeded in a volume of 50μl in medium without antibiotics and incubated overnight in a humidified atmosphere with 5% CO₂ at 37°C. The following day, the medium was replaced with 20μl of 5μM Fluo-4AM dye (Molecular Probes) in assay buffer (2.5mM probenicid, lmg/ml pluronic acid, 0.1% BSA, 135mM NaCl, 5mM KCl, 1.8mM CaCl, ImM MgCl_2, 1OmM HEPES, 5.6mM glucose, 0.05% gelatine, pH 7.4). The calcium indicator loaded cells were incubated at 37°C for 2hrs. Extracellular dye was then removed and each well was filled with 45 μl of assay buffer. Cell plates were kept in dark until used. Test compounds were assayed at 8 concentrations in triplicate. Serial 10-fold dilutions in 100% DMSO were made at a 100-times higher concentration than the final concentration, and then diluted 1 :10 in assay buffer. 5μl of each diluted compound was added to the well of cell plates (yielding final concentration with 1% DMSO), and incubated for 30 min at 25°C before the addition of Bl agonist on the FlexStation.

Agonist plates contained the Bl agonist Lys-(Des-Arg)-Bradykinin (Bachem, Brackley) at 3.5x EC90 in assay buffer with 1% DMSO. The addition of agonist 20μl per well to the assay plate was carried out on the FlexStation while continuously monitoring Ca²⁺-dependent fluorescence at 538nm. The integrated values, normalized with the background fluorescence, were plotted against the logarithm of the antagonist concentrations.

As observed, typical EC50 values for the Bl agonist Lys-(Des-Arg)-Bradykinin were the following: 2 nM (human), 250 nM (rat) and 10 nM (mouse); typical IC50 values for the Bl antagonist Lys-(Des-Arg-Leu)-Bradykinin (Bachem, Brackley) were 0.5 nM (human), 12 nM (rat) or 15 nM (mouse).

In the embodiment of the present invention, an active compound was selected from those that exhibited an IC50 value against human Bl of < lμM. Based on their levels of potency, the selected compounds are grouped in the present invention as below:

A = 100OnM - 10OnM B = 10OnM - 1OnM C = <10nM Bradykinin 1 receptor radioligand binding assay

This study (Phagoo et al, 2001) was used to demonstrate direct interaction of the compounds with the B 1 receptor.

IMR-90 human fetal lung fibroblasts cells were obtained from the American Type Culture Collection (Rockville, MD). The fibroblasts were cultured in complete growth media comprised of Dulbecco's modified Eagle's medium (DMEM; Life Technologies, Grand Island, NY) containing 10% fetal bovine serum (Sigma, St. Louis, MO), 50 IU/ml penicillin, 50 μg/ml streptomycin, 4mM L-glutamine, and 1% nonessential amino acids (Life Technologies). The cells were maintained in a humidified atmosphere in 5% CO₂ at 37°C and were subcultured by incubating with 0.05% trypsin / 0.5mM EDTA (Life Technologies) at a ratio of 1 :3, weekly. For all experiments, cells were plated at a density of 150,000 cells/well in six-well plates and used at confluence. Prior to experimentation, the IMR-90 cells were washed once with growth medium excluding foetal bovine serum before being incubated at 37°C for 6hr in the presence of the Bl receptor agonist Lys-(Des-Arg)-Bradykinin (Bachem California, Torrance, CA) at 10OnM.

For radioligand binding, the cells after exposure to the receptor agonist were rinsed in PBS, followed by two incubations in 0.05M glycine-HCl, pH 3.0 for 6 and 0.5 min, and then two brief rinses in PBS, in order to remove surface receptor-bound agonist. Binding assays were performed at 25°C in duplicate six-well dishes in a final volume of 1.25 ml. IMR-90 cells were incubated for 60 min in the presence of 0.5nM [³H] Lys-(Des-Arg)-Bradykinin (91-105 Ci/mmol; PerkinElmer, Boston) and test compounds at 4 concentrations (lOμM, lμM O.lμM and O.OlμM) in binding buffer that was comprised of 2OmM HEPES, pH 7.4, 125mM N- methyl-D-glucamine, 5mM KCl, 0.14 g/1 bacitracin and ImM 1,10-phenanthroline. Nonspecific binding was defined as the amount of radiolabeled ligand bound in the presence of lOμM (Des-Arg-Leu.)-Bradykinin (Bachem California, Torrance, CA). After incubation, the assay buffer was removed and the cells were washed with 2 x 4 ml of ice-cold PBS. The cells were then lysed with 0.05% sodium dodecyl sulfate. Specific binding was expressed in femtomoles per milligram of protein, and protein was determined using a Bio-Rad kit (Bio- Rad Laboratories, Richmond, CA). All assay plates were carried out in duplicate and the variation between wells was < 8%. For data analysis, IC50 values were determined by a non-linear, least squares regression analysis using Data Analysis Toolbox (MDL Information Systems, San Leandro, CA, USA).

Human umbilical vein assay for Bradykinin 1 receptors

This study (Gobeil, 1996) was used to confirm the antagonist activities of compounds being part of this invention that were found to be active as antagonists in the calcium flux assay.

To do this, rings of human umbilical vein denuded of endothelium were suspended in 20-ml organ baths filled with an oxygenated (95% O₂ and 5% CO₂) and pre-warmed (37°C) physiological salt solution of the following composition: 118mM NaCl, 4.7mM KCl, 1.2mM

MgSO₄, 2,5mM CaCl₂, 1.2mM KH₂PO₄, 25mM NaHCO₃ and HmM glucose, pH 7.4.

Besides, Hoe 140 (lμM), benextramine (lμM), propranolol (lμM), pyrilamine (lμM), atropine (lμM), methysergide (lμM), mergetpa (lμM) and captopril (lμM) were also present throughout the experiments to block the bradykinin B₂, α-adrenergic, β-adrenergic, histamine

H₁, muscarinic and 5-HT₂ receptors and to prevent peptide degradation, respectively.

The tissues were connected to force transducers (FT03, Grass Instruments) for isometric tension recordings. They were stretched to a resting tension of 2g, washed several times then allowed to equilibrate overnight. The experiments were carried out using semi-automated isolated organ systems possessing eight organ baths, with multi-channel data acquisition (Grass model 7D orLinseis GmbH model L2005).

The tissues were contracted with a high K⁺ solution (8OmM KCl) to obtain a control response. Following washings and recovery of the basal tension, the tissues were exposed to a sub- maximal concentration of the reference agonist Lys-(Des-Arg)-Bradykinin (0.03μM) to obtain a contractile response either in the absence or presence of increasing concentrations of a test compound or the reference antagonist Lys-(Des-Arg-Leu)-Bradykinin, each added 30 min prior to Lys-(Des-Arg)-Bradykinin. Only one compound concentration was tested in each tissue. If it occurred, an inhibition of the Lys-(Des-Arg)-Bradykinin -induced contraction by a test compound indicated an antagonist activity at the Bi receptors. The parameter measured was the maximum change in tension induced by each compound concentration. The results are expressed as a percent of the control response to the reference agonist (mean values). References

McEachern, A.E. et al. (1991) Expression cloning of a rat B2 bradykinin receptor. Proc. Natl. Acad. Sci. USA 88, 7724-28

Menke, J. G. et al. (1994) Expression cloning of a human Bl bradykinin receptor. J Biol. Chem. 269, 21583-86

Leeb-Lundberg, L.M. et al. (2005) International Union of Pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol. Rev. 57, 27-77

Moreau, M.E et al. (2005) The kallikrein-kinin system: current and future pharmacological targets. J Pharmacol Sci. 99, 6-38

Campos, M.M. et al. (2006) Non-peptide antagonists for kinin Bl receptors: new insights into their therapeutic potential for the management of inflammation and pain. Trends Phamacol. Sci. 27, 646-51

Chen, J.J. and Johnson, E.J. (2007) Targeting the bradykinin Bl receptor to reduce pain. Expert Opin. Ther. Targets 11, 21-35

Ferreira, J. et al. (2001) Evidence for the participation of kinins in freund's adjuvant-induced inflammatory and nociceptive responses in kinin Bl and B2 receptor knockout mice. Neuropharmacology 41, 1006-12

Ferreira, J. et al. (2005) Reduced nerve injury- induced neuropathic pain in kinin Bl receptor knock-out mice. J. Neurosci. 25, 2405-2412

Fox, A. et al. (2005) Antihyperalgesic activity of a novel nonpeptide bradykinin Bl receptor antagonist in transgenic mice expressing the human Bl receptor. Br. J. Pharmacol. 144, 889- 899 Gougat, J. et al. (2004) SSR240612 [(2R)-2-[((3R)-3-(l,3-benzodioxol-5-yl)-3-[[(6-methoxy- 2-naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-[[(2R,6S)-2,6 dimethylpiperidinyl] methyl]phenyl)-N-isopropyl-Nmethylpropanamide hydrochloride], a new nonpeptide antagonist of the bradykinin Bl receptor: biochemical and pharmacological characterization. J. Pharmacol. Exp. Ther. 309, 661-669

Phagoo, S.B. (2001) Bradykinin Bl receptor up-regulation by interleukin-lbeta and Bl agonist occurs through independent and synergistic intracellular signaling mechanisms in human lung fibroblasts. J Pharmacol Exp Ther. 298, 77-85.

Gobeil, F., et al. (1996) Receptors for kinins in the human isolated umbilical vein. Brit. J. Pharmacol, 118, 289-94.

Synthesis of compounds

NMR Spectrometers Used:

Bruker AVANCE 400 MHz NMR Bruker DPX 250 MHz NMR Bruker DPX 360 MHz NMR

LCMS methods used

Prep Methods Used: Prep Method 1

Waters SunFire Prep C18

Column OBD 5um 19 x 100mm

Prep Method 2

Prep Method 3

Compound Naming

All compounds are named using ACD Labs 10.0 naming software which conforms to IUPAC naming protocols.

List of Abbreviations

AcOH acetic acid br s broad singlet cat catalytic

CDI 1 , 1 '-carbonyldiimidazole

DCE 1 ,2-dichloroethane

DCM dichloromethane

DIPEA Λ/,Λ/-diisopropylethylamine

DMAP N,Λ/-4-dimethylaminopyridine eq equivalent

Et₂O diethyl ether EtOAc ethyl acetate

EtOH ethanol

FCC flash column chromatography h hours

LCMS liquid chromatography and mass spectrometry

Mcpba meta-perchlorobenzoic acid

MeCN acetonitrile

MeOH methanol m multiplet min minutes mL millilitre mol/M mole/molar

MW molecular weight

NMR nuclear magnetic resonance

PS-DIPEA polymer-supported Λ/,Λ/-diisopropylethylamine rt retention time

TBAF tetra-n-butylammonium fluoride

TBAI tetra-n-butylammonium iodide

TBDMSCl te/t-butyldimethylsilyl chloride

TEA triethylamine

TFA 2,2,2-trifluoroacetic acid

TFE 2,2,2-trifluoroethanol

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl

General procedure for the preparation of l-[Arylsulfonyl]piperidin-2- yl} methoxy)acetamides

Scheme 1 describes the synthetic route to the products (R¹⁼R²=R³=R⁴=R⁵=H, X¹⁼CH₂; X²=O; X³=various aromatic cycles; n=l,2; m=l; X⁴=NR¹⁹R^19a) X General prodecure C

Scheme 1

General procedure A: Orthogonal protection of 2-substituted piperidine alcohols

To a stirred solution of 2-substituted piperidine alcohol (1.0 eq, 0.5 M), DIPEA (3 eq) and DMAP (1 eq) in DCM at 0 ⁰C was added TBDMSCl, 1.3 eq, 2.6 M in DCM dropwise over 1 h. The mixture was allowed to warm to ambient temperature. Upon complete consumption of the piperidine alcohol (as determined by TLC), the mixture was cooled to 0 ⁰C and benzyl chloro formate (1.2 eq) added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was washed with 10% (w/v) citric acid and water, dried over MgSO₄ and concentrated in vacuo.

Benzyl 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidine-l-carboxylate

The title compound was prepared following general procedure A using piperidine-2-methanol

(57.6 g, 0.5 mol), DIPEA (260 mL, 1.5 mol), DMAP (61.0 g, 0.5 mol), DCM (1000 mL), TBDMSCl (92.3 g, 0.61 mol) in DCM (250 mL) and benzyl chloroformate (102.78 g, 0.6 mol). The title product was obtained as a red-brown oil. No further purification was required. Yield: 188.8 g. Benzyl 2-(2-{[før*-butyl(dimethyl)silyl]oxy}ethyl)piperidine-l-carboxylate

The title compound was prepared following the general procedure A using piperidine-2- ethanol (58.1 g, 0.45 mol), DIPEA (235 mL, 1.35 mol), DMAP (54.9 g, 0.45 mol), DCM (1000 mL), TBDMSCl (88.2 g, 0.59 mol) in DCM (250 mL) and benzyl chloroformate (92.5 g, 0.54 mol). The title product was obtained as a colourless oil No further purification was required. Yield: 231 g.

General procedure B: The Deprotection of 2-substituted piperidine TBDMS ethers

To a stirred solution of crude 2-substituted piperidine TBDMS ether (1 eq) in THF (1000 mL/mol eq) at 0 ⁰C was added TBAF.2H₂O (IM in THF, 1 eq). The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was concentrated in vacuo and the residue re-dissolved in DCM (1000 mL/mol eq). The mixture was washed with water, dried over Na₂SO₄ and concentrated in vacuo to afford the title compound. No further purification was required.

Benzyl 2-(hydroxymethyl)piperidine-l-carboxylate

The title compound was prepared following general procedure B using crude benzyl 2-({[tert- butyl(dimethyl)silyl]oxy}methyl)piperidine-l-carboxylate (188.77 g, 0.5 mol) in THF (500 mL) and TBAF.2H₂O (IM in THF, 500 mL). The title compound was obtained as a yellow oil. No further purification was required Yield: 175.8 g. Benzyl 2-(2-hydroxyethyl)piperidine-l-carboxylate

The title compound was prepared following general procedure B using crude benzyl 2-(2- {[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidine-l-carboxylate (231 g, 0.45 mol) in THF (500 rnL) and TBAF.2H2O (IM in THF, 500 mL). The title compound was obtained as a colourless oil. No further purification was required. Yield: 150 g.

General procedure C: Alkylation of piperidine alcohols with førf-butylbromoacetate

To a vigorously stirred mixture of crude benzyloxycarbonyl protected 2-substituted piperidine alcohol (nominally 1 eq) and TBAI (cat, ca. 10 g/mol eq) in toluene (2000 mL/mol eq) at 0 ⁰C was added dropwise 25 % w/v NaOH (2000 mL/mol eq). Following complete addition, to the vigorously stirred reaction mixture at 0 ⁰C, was added dropwise a 1 :1 (v/v) mixture of tert- butylbromoacetate (3 eq) and toluene. The reaction mixture was allowed to warm to ambient temperature overnight. Stirring was stopped and the reaction mixture allowed to settle. The organic layer was separated, washed with sequential portions of water until the washings were neutral, dried over MgSO₄ and concentrated in vacuo. The residue was purified by dry flash column chromatography.

Benzyl 2-[(2-ført-butoxy-2-oxoethoxy)methyl]piperidine-l-carboxylate

The title compound was prepared following general procedure C for etherification with tert- butylbromoacetate using crude benzyl 2-(hydroxymethyl)piperidine-l-carboxylate (175.75 g, 0.5 mol), TBAI (cat, 5 g) in toluene (1000 mL); 25 % w/v NaOH (1000 mL); and tert- butylbromoacetate (202.0 mL, 1.51 mol). Purification by dry flash column chromatography eluting with 0-20% EtOAc in heptanes afforded the title compound as a colourless solid. Yield: 72.71 g, 40 %.

¹H NMR (CDCl₃, 400 MHz): 7.26 (5H, m), 5.04 (2H, s), 4.39 (IH, br s), 3.85 (2H, s), 3.55

(2H, m), 2.79 (IH, m), 1.72 (IH, br s), 1.50 (2 x 2H, m), 1.34-1.41 (HH, m).

Benzyl 2-[2-(2-ført-butoxy-2-oxoethoxy)ethyl]piperidine-l-carboxylate

The title compound was prepared following the general procedure C using crude benzyl 2-(2- hydroxyethyl)piperidine-l-carboxylate (146 g, 0.45 mol), TBAI (cat 5.5 g) in toluene (1100 mL); NaOH (aq., 25% (w/v), 1150 rnL); and tert-butylbromoacetate (205 mL, 1.53 mol). Purification by dry flash column chromatography eluting with 0-25% EtOAc in heptanes afforded the title compound as a colourless solid (77 g, 71 %).

¹H NMR (CDCl₃, 400 MHz): 7.26 (5H, m), 5.02 (2H, m), 4.35 (2H, br s), 3.98 (IH, br s), 3.75 (2H, br s), 3.38 (2H, br s), 2.77 (IH, m), 1.99 (IH, m), 1.66 (IH, m), 1.51 (2 x 2H, br s), 1.34-1.40 (1 IH, m).

General procedure D: The Removal of CBz protecting groups

A mixture of benzyloxycarbonyl protected 2-substituted piperidine benzyl ester (1.0 eq, 0.27 mo ldm ) and 10 % Pd/C (cat) in ethanol was purge-filled with nitrogen (3 cycles), then with hydrogen (3 cycles). Constant supply of hydrogen was maintained with a hydrogen-filled balloon. The mixture was stirred vigorously at ambient temperature. Upon complete consumption of the benzyl carbamate starting material (as determined by LCMS), the reaction mixture was filtered through celite and the filter cake washed with ethanol. The combined organic layers were concentrated in vacuo. No further purification was required.

førf-Butyl (piperidin-2-ylmethoxy)acetate

The title compound was prepared following general procedure D using benzyl 2-[(2-tert- butoxy-2-oxoethoxy)methyl]piperidine-l-carboxylate (55.95 g, 0.15 mol) and 10 % Pd/C (cat, 5 g) in ethanol (550 mL). This yielded the title compound as a colourless oil. Yield: 32 g, 93 %.

tert-Buty\ (2-piperidin-2-ylethoxy)acetate

The title compound was prepared following general procedure D using benzyl 2-[2-(2-tert- butoxy-2-oxoethoxy)ethyl]piperidine-l-carboxylate (35 g, 92.7 mmol) and 10 % Pd/C (cat, 5 g) in ethanol (350 mL). This afforded the title compound as a colourless oil. Yield: 24 g, 107 %.

General procedure E: The preparation of sulfonamides A solution of concentration 0.073 M of 2-substituted piperidine (1.0 eq) in DCE was added to a flask containing sulfonyl chloride (1.5 eq). aqueous K2CO3 (1.0 M, 4 eq) was added and the mixture shaken vigorously at ambient temperature. Upon complete consumption of starting amine (as determined by LCMS), the mixture was allowed to settle. The organic layer was separated, washed with brine (0.2 vol), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified using a Biotage column chromatography system.

tert-Buty\ ({l-[(2-cyanophenyl)sulfonyl]piperidin-2-yl}methoxy)acetate

The title compound was prepared following general procedure E using tert-butyi (piperidin-2- ylmethoxy)acetate (1.960 g, 8.55 mmol) in DCE (118 mL), 2-cyanobenzenesulfonyl chloride (2.585 g, 12.82 mmol), and aqueous K₂CO₃ (1.0 M, 34 mL). Purification by Biotage column chromatography eluting with 10-100 % DCM in heptanes) afforded the title compound as a pale yellow oil. Yield: 2.003 g, 59 %.

LCMS method A: rt 2.23 min, 100%; m/z 417 (MNa⁺, 100%) 361 (MNa⁺- CH₂=C(CH₃)₂, 18

%), 339 (MH⁺- CH₂=C(CHs)₂, 48 %).

The following intermediates were prepared using general procedure E: tert-bvXy\ ({l-[(2,3-dichlorophenyl)sulfonyl]piperidin-2-yl}methoxy)acetate tert-bvXy\ (2- { 1 -[(2,3-dichlorophenyl)sulfonyl]piperidin-2-yl} ethoxy)acetate tert-bvXy\ [( 1 - { [2-(trifluoromethyl)phenyl] sulfonyl } piperidin-2-yl)methoxy] acetate tert-bvXy\{{ 1 -[(5-chloro- 1 ,3-dimethyl- lH-pyrazol-4-yl)sulfonyl]piperidin-2- yl}methoxy)acetate tert-hvXy\ (2- { 1 -[(4-methoxyphenyl)sulfonyl]piperidin-2-yl} ethoxy)acetate tert-hvXy\ ({l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetate tert-hvXy\ (2- { 1 -[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl} ethoxy)acetate tert-bvXy\ ( { 1 - [(3 ,4-dichlorophenyl)sulfonyl]piperidin-2-yl} methoxy)acetate tert-bvXy\ (2- { 1 - [(3 ,4-dichlorophenyl)sulfonyl]piperidin-2-yl} ethoxy)acetate tert-bvXy\{ { 1 - [(5 -chloro-3 -methyl- 1 -benzothiophen-2-yl)sulfonyl]piperidin-2- yl}methoxy)acetate tert-hvXy\{2- { 1 -[(5-chloro-3-methyl- 1 -benzothiophen-2-yl)sulfonyl]piperidin-2- yl} ethoxy)acetate

General procedure F: Hydrolysis of tert-hnty\ esters

To a solution of tert-bv&y\ ester (1.0 eq) in DCM (12.5 vol.) was added TFA (2.0 vol.). The reaction mixture was shaken vigorously at ambient temperature. Upon complete consumption (as determined by LCMS) of starting material, the mixture was concentrated in vacuo. The residue was re-dissolved in DCM and washed with portions of brine until the washings were weakly acidic (ca. pH 6). The organic layer was dried over Na₂SO₄ and concentrated in vacuo to afford the title compound. No further purification was required.

({l-[(2-Cyanophenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid

The title compound was prepared following general procedure F for the hydrolysis of tert- butyl esters by using tert-bvXy\ ({l-[(2-cyanophenyl)sulfonyl]piperidin-2-yl}methoxy)acetate

(1.99 g, 5.06 mmol), DCM (25 mL), and TFA (5 rnL). The title compound was obtained as a pale yellow oil.

Yield: 1.714 g, 100 %.

LCMS method A: rt 1.63 min, 100%; m/z 361 (MNa⁺, 100 %), 339 (MH⁺, 69 %).

The following intermediates were prepared using general procedure F: ({l-[(2,3-dichlorophenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid (2- { 1 -[(2,3-dichlorophenyl)sulfonyl]piperidin-2-yl} ethoxy)acetic acid [(l-{[2-(trifluoromethyl)phenyl]sulfonyl}piperidin-2-yl)methoxy]acetic acid ( { 1 -[(5-chloro- 1 ,3-dimethyl- lH-pyrazol-4-yl)sulfonyl]piperidin-2-yl}methoxy)acetic acid (2- { 1 -[(4-methoxyphenyl)sulfonyl]piperidin-2-yl} ethoxy)acetic acid ({l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid (2- { 1 -[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl} ethoxy)acetic acid ({l-[(3,4-dichlorophenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid (2-{l-[(3,4-dichlorophenyl)sulfonyl]piperidin-2-yl}ethoxy)acetic acid (2- { 1 - [(5 -chloro-3 -methyl- 1 -benzothiophen-2-yl)sulfonyl]piperidin-2-yl} ethoxy)acetic acid ( ( 1 -[(5-chloro-3-methyl- 1 -benzothiophen-2-yl)sulfonyl]piperidin-2-yl}methoxy)acetic acid

General procedure G: The parallel synthesis of amides

• To a solution of 2-substituted piperidine acetic acid (0.15 M, 1.0 eq) in DCE were added activated molecular sieves (3-5 beads) and lj'-carbonyldiimidazole (1.0 eq). The mixture was shaken at ambient temperature for 4 h.

• A solution of each amine in DCE was prepared (for amines with MW>100, 0.18 M, 1.2 eq; for amines with MW<100, 0.3 M, 2.0 eq). • In a 7 mL vial, 1 mL of the carboxylic acid-CDI mixture was combined with 1 mL of amine solution.

• Activated molecular sieves (3-5 beads) were added to the vials.

• The vials were sealed and shaken at ambient temperature overnight. Each reaction mixture was diluted with 2 rnL DCE.

Each mixture was washed with 2 mL aqueous K2CO3 solution (1 M).

If the structure contained an amine containing an additional basic nitrogen, the organic layer was washed with 2 mL water; in all other cases the organic layer was washed with 2 mL aqueous 10 % w/v citric acid solution.

The organic layer was separated from the mixtures and filtered through a Na₂SO₄ plug into a 48 x 5 mL plate.

The master plates were concentrated in vacuo using a Genevac.

The following compounds in Table 1 were synthesised using general procedure G

Table 1

General procedure for the synthesis of Piperidinesulfonamide Carbamates

TBDMSCI DIPEA DMAP General RSO₂CI procedure B

R1 R1

^H R3 O=S=O R3 X,

PNP-chloroformate

Scheme 2 describes the synthetic route to the products (R¹⁼R²=R³=H, X¹⁼CH₂; X²=O; X³=various aromatic cycles; n=l,2; m=0; X⁴=NR¹⁹R^19a)

2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl] piperidine To a solution of piperidin-2-ylmethanol (3.8 g, 33 mmol), DIPEA (17.1 mL, 99 mmol) and DMAP (4.03 g, 33 mmol) in DCM (80 mL) was added TBDMSCl (4.97 g, 33 mmol) and the reaction stirred at ambient temperature until complete by LCMS. 2,6-Dimethyl-4- methoxybenzenesulfonyl chloride (8.5 g, 36.3 mmol) was added in one portion and the reaction stirred for 16 h at ambient temperature. The reaction was washed with water (80 mL) and then 10 % w/v citric acid solution. The organic phase was dried over MgSO₄ and concentrated in vacuo to afford a brown oil. The crude product was purified by FCC eluting with DCM to afford the title compound as a clear oil. Yield 9.58 g, 67 %.

{l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl} methanol

The title compound was prepared according to general procedure B by using 2-({[tert- butyl(dimethyl)silyl]oxy } methyl)- 1 - [(4-methoxy-2 ,6-dimethylphenyl)sulfonyl]piperidine (4.27 g, 10 mmol) and 1 M TBAF solution in THF (10 mL). The crude product required no further purification. Yield: 3.34 g, quantitative.

{l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methyl 4-(l-methylpiperidin- 4-yl)piperazine-l-carboxylate

To a solution of {l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methanol (313 mg, 1.0 mmol) and pyridine (81 μL, 1.0 mmol) in acetonitrile was added p-nitrophenyl chloroformate (201 mg, 1.0 mmol). The reaction was stirred at ambient temperature for 3 h prior to addition of DIPEA (0.35 mL, 2.0 mmol) and l-(l-methylpiperidin-4-yl)piperazine (183 mg, 1.0 mmol). The reaction was stirred at ambient temperature for 16 h and then concentrated in vacuo. A portion of the crude product was purified by injection prep HPLC using prep method 3.

The following compounds were synthesised in the same manner:

Table 2

General procedure for the preparation of l-[Arylsulfonyl]morpholine-2- yl} methoxy)acetamides

Scheme 3 describes the synthetic route to the products (R¹⁼R²=R³=R⁴=R⁵=H; X¹⁼X²=0; X³=various aromatic cycles; n=m=l; X⁴=NR¹⁹R^19a) G^eneral

General x General _χ procedure L f I RP R₄J procedure M T ¹ I R_O R₄O

^M R3 R5 O=S=O R3 R5

X₃

Scheme 3

General procedure H: Preparation of 4-ført-butyl 3-methyl morpholine-3,4- dicarboxylate

To a stirred solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (7.0 g, 30 mmol) in MeOH (30 rnL) at 0 ⁰C was added dropwise TMS diazomethane (2.0 M in hexanes, 10 mL). Upon completion of addition, the reaction was warmed to ambient temperature and the excess TMS diazomethane quenched by addition of a few drops of AcOH until colourless. The reaction was concentrated in vacuo to afford the title compound as a white solid. Yield: 8.11g, quantitative.

General procedure I: Preparation of ført-butyl 3-(hydroxymethyl)morpholine-4- carboxylate

To a stirred solution of methyl 4-tert-buty{ 3 -methyl morpholine-3,4-dicarboxylate (1.23g, 5.0 mmol) in THF (25 mL) at 0 ⁰C was added LiBH₄ (0.38g, 17.5 mmol) portionwise over 5 min. The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched by addition of aqueous 2N HCl until no further gas evolution was observed. The THF was removed in vacuo and the aqueous phase extracted with EtOAc (2 x 25 mL). The organic extracts were dried over Na₂SO₄ and concentrated in vacuo to afford the title compound. No further purification was required. Yield: 0.89 g, 82 %. 1H NMR (CDCl₃, 360MHz) 3.7-4.0 (6H, m), 3.57 (IH, dd, J 3.1 Hz, 11.8 Hz), 3.47 (IH, dt, J 11.8 Hz, 2.7 Hz), 3.17 (IH, m), 1.48 (9H, s).

Preparation of tert-buty\ 3-[(2-ført-butoxy-2-oxoethoxy)methyl]morpholine-4- carboxylate

The title compound was prepared according to general procedure C using tert-butyl 3- (hydroxymethyl)morpholine-4-carboxylate (0.43 g, 2.0 mmol), tert-butylbromoacetate (0.58 g, 3.0 mmol), TBAI (20 mg, cat), toluene (4 mL) and 35 % w/v aqueous NaOH solution (4 mL). The title compound was obtained and no further purification was required. Yield: 0.66 g, 99 %

General Procedure J: Preparation of {[4-(før*-butoxycarbonyl)morpholin-3- yljmethoxy} acetic acid

tert-Butyi 3-[(2-tert-butoxy-2-oxoethoxy)methyl]morpholine-4-carboxylate (13 g, 35.6 mmol) was dissolved in a 1 :1 mixture of aqueous 3N NaOH and MeOH (200 rnL). The reaction was heated at 60 ⁰C for 1 h, cooled, and concentrated in vacuo. The aqueous solution was acidified to pH 3 with concentrated HCl and extracted into EtOAc (3 x 50 rnL). The combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo to afford the title compound. No further purification was required. Yield: 10.2 g, quantitative.

General Procedure K: Amidation of {[4-(før*-butoxycarbonyl)morpholin-3- yl]methoxy} acetic acid

To a solution of {[4-(tert-butoxycarbonyl)morpholin-3-yl]methoxy} acetic acid (1 eq) in THF (20 vo 1) was added CDI (1 eq) and the reaction stirred for 3 h at ambient temperature. Amine (1 eq) was then added in one portion and the reaction stirred at ambient temperature overnight. The reaction mixture was diluted with MeOH (20 mL) and chromatographic silica (25 g) added prior to concentration in vacuo. The crude product, absorbed on silica, was purified by dry flash eluting with 90:10:1 DCM/MeOH/NH₄OH to afford the corresponding amides.

før^Butyl 3-({2-[4-(l-methylpiperidin-4-yl)piperazin-l-yl]-2-oxoethoxy} methyl)morpholine-4-carboxylate

The title compound was prepared according to general procedure K using {[4-(tert- butoxycarbonyl)morpholin-3-yl]methoxy} acetic acid (10 g, 36 mmol), CDI (5.89 g, 36 mmol) and l-(l-methylpiperidin-4-yl)piperazine (6.65 g, 36 mmol). The title compound was obtained as a brown oil. Yield: 11.8 g, 74 %

General Procedure L: Removal of Boc protecting group of {[4-(tert- butoxycarbonyl)morpholin-3-yl]methoxy}acetamides The boc protected amine was dissolved in a 1 :3 solution of TFA/DCM (20 vol) and stirred at ambient temperature for 1-3 h. The solvent was removed in vacuo and the residue redissolved in THF (20 vol) and Ambersep 900 OH added (I g per g of carbamate). The free basing was shaken for 1 h and filtered. The filtrate was concentrated in vacuo to afford the title compounds as their free bases.

Preparation of 3-({2-[4-(l-methylpiperidin-4-yl)piperazin-l-yl]-2-oxoethoxy} methyl) morpholine

The title compound was prepared according to general procedure L using tert-bvXy\ 3-({2-[4- ( 1 -methylpiperidin-4-yl)piperazin- 1 -yl] -2-oxoethoxy } methyl)morpholine-4-carboxylate (11.8 g, 26.7 mmol), TFA (20 mL), DCM (150 mL), THF (200 mL) and Ambersep 900 OH (12 g). This afforded the title compound as a brown oil Yield: 14 g, quantitative.

General Procedure M for the sulfonylation of {[morpholin-3-yl]methoxy}acetamides: 4- [(2-iodophenyl)sulfonyl]-3-({2-[4-(l-methylpiperidin-4-yl)piperazin-l-yl]-2- oxoethoxy} methyl)morpholine

To a suspension of the 3-({2-[4-(l-methylpiperidin-4-yl)piperazin-l-yl]-2- oxoethoxy}methyl)morpholine (67 mg, 0.2 mmol)) and PS-DIPEA (150 mg, 0.4 mmol) in DCE (1 mL) at ambient temperature was added a solution of 2-iodobenzenesulfonyl chloride (90 mg, 0.300 mmol) in MeCN (1 mL). The reaction was shaken at ambient temperature overnight, filtered and concentrated in vacuo to afford the crude product. A portion of the crude product was purified using prep method 3 to afford the title compound.

The compounds in Table 2 were prepared using general procedure M and prep methods 1 or

2. Table 3

The preparation of homochiral piperidine methanols

Scheme 4 describes the synthesis of homochiral piperidine methanol derivatives (R^R^R^R^R^H; X¹⁼CH₂; X²=O; X³=various aromatic cycles; n=m=l; X⁴=NR¹⁹R^19a) General x General x General procedure H f ¹ I procedure N f ¹ I procedure T

- RΛ ^HV O - -»A O=S=O O -

General procedure I

O=S=O R3 R5 X,

Scheme 4

Methyl (2S)-piperidine-2-carboxylate CH₃

The title compound was prepared according to general procedure H using (25)-piperidine-2- carboxylic acid (0.5 g, 3.87 mmol) in MeOH (10.0 mL) and 2.0 M TMSdiazomethane in heptanes (6.0 mL) at ambient temperature. The title compound was obtained as a white solid. Yield: 0.55 g, 99 %.

General Procedure N for the sulfonylation of Amines:

Synthesis of Methyl (2S)-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidine-2- carboxylate

To a solution of methyl (25)-piperidine-2-carboxylate (1.58 g, 11.1 mmol) and pyridine (0.9 rnL, 11.1 mmol) in THF (30 mL) was added 2,6-dimethyl-4-methoxybenzenesulfonyl chloride (2.86 g, 12.2 mmol). The reaction was stirred at ambient temperature overnight, diluted with DCM (30 mL), and washed with 10 % w/v citric acid (3 x 30 mL) and saturated aqueous NaHCOs (30 mL). The organic phase was dried over MgSO₄ and concentrated in vacuo. The crude product was purified by FCC eluting with 1-10 % MeOH in DCM to afford the title compound. Yield: 1.10 g, 29 %.

General procedure T: Ester reduction {(2S)-l-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl} methanol

To a stirred solution of methyl (25)-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidine-2- carboxylate (0.5 g, 1.47 mmol) in THF (2.5 mL) at 0 ⁰C under nitrogen atmosphere was added a 2.3 M solution of LiAlH₄ in THF (1.3 mL) dropwise ensuring the reaction temperature did not exceed 10 ⁰C. After the addition was complete the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was cooled to 0 ⁰C, and a 30% w/v aqueous solution of Rochelle's salt (0.5 mL) was added dropwise. The reaction mixture was allowed to warm to ambient temperature, filtered and the residue washed with EtOAc (2 x 5 mL). The filtrate was concentrated in vacuo. The crude mixture was taken up in EtOAc (5 mL) and filtered. The combined filtrates were evaporated in vacuo to afford the title compound which required no further purification. Yield: 0.35 g, 69 %. tert-Butyl ({(2S)-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy) acetate

The title compound was prepared according to general procedure C using [(2S)- 1 -[(4- methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methanol (0.2 g, 0.64 mmol), TBAI (10 mg, cat), toluene (2.0 mL), 35 % w/v NaOH solution (2 mL) and tert-butyl bromoacetate (0.19 g, 0.96 mmol). The crude product was absorbed onto a pad of silica, washed with heptanes and eluted with EtOAc to afford the title compound. Yield: 0.22 g, 80 %. 1H NMR (CDCl₃, 400MHz): 6.66 (2H, s), 4.05 (IH, br s), 3.94 (2H, q + IH, m), 3.85 (3H, s), 3.68 (IH, m), 3.41 (IH, m), 3.01 (IH, dt, J 15Hz, 3Hz), 2.65 (6H, s), 2.00 (IH, br s), 1.63- 1.71 (5H, m), 1.50 (9H, s), 1.45 (IH, m).

({(2S)-l-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid

The title compound was prepared according to general procedure F using tert-butyi ([(2S)-I- [(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetate (0.2 g, 0.47 mmol) and a 1 :3 mixture of TFA/DCM (4 mL). The title compound did not require any further purification. Yield: 0.167 g, quantitative.

1- [(((2S)-I- [(4-Methoxy-2,6-dimethylphenyl)sulfonyl] piperidin-2-yl}methoxy)acetyl] -4- (l-methylpiperidin-4-yl)piperazine

The title compound was prepared according to general procedure K using ({(25)-l-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid (74 mg, 0.20 mmol), THF (1.5 mL), CDI (32 mg, 0.20 mmol) and l-(l-methylpiperidin-4-yl)piperazine (42 mg, 0.23 mmol). A portion of the crude product was purified using prep method 3.

{(2S)-l-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methyl (2R)-3,3,3- trifluoro-2-methoxy-2-phenylpropanoate

{(25)-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methanol (50 mg, 0.16 mmol) and (25)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (40 mg, 0.16 mmol) were stirred at ambient temperature in a 1 :1 mixture of pyridine and DCM (1 mL) for 16 h. The crude reaction mixture was absorbed directly on to silica column and purified by FCC eluting with 0-1% MeOH in DCM to afford the title compound that was confirmed to be a single diastereoisomer by ¹H NMR spectroscopy. Yield: 38 mg, 44 %.

¹H NMR (CDCl₃, 400 MHz): 7.45 (5H, m), 6.63 (2H, s), 4.75 (IH, t, J 10.3 Hz), 4.35 (IH, dd, J 4.6 Hz, 10.9 Hz), 4.15 (IH, m), 3.82 (3H, s), 3.53 (3H, s), 3.31 (IH, dd, J 3.6 Hz, 13.3 Hz), 2.59 (6H, s), 1.56 (6H, m).

The following compounds were synthesised in the same manner: Table 4

The preparation of homochiral piperidine ethanol derivatives

Scheme 5 describes the general synthesis of homochiral piperidine ethanol derivatives (R^R^R^R^R^H; X¹⁼CH₂; X²=O; X³=various aromatic cycles; n=2; m=l ;

X⁴=NR¹⁹R^19a) { ¹ -_| Ueneral ueπeiai X₁

JL J_v,^RS< procedure C f ] R2, R₄V L- procedure O f 1 R2, R₄V JL- procedure R oo^ΛΛoo ^RR33 H R3 R5

Scheme 5

tert-Butyl (2S)-2-[2-(2-tert-butoxy-2-oxoethoxy)ethyl]piperidine-l-carboxylate

The title compound was prepared according to general procedure C using te/t-butyl (25)-2-(2- hydroxyethyl)piperidine-l-carboxylate (2.17 g, 10.0 mmol), TBAI (100 mg, cat), toluene (22 rnL), 35 % w/v NaOH solution (22 rnL) and tert-butyl bromoacetate (2.93 g, 15.0 mmol). The crude product was purified by FCC eluting with 0-5 % MeOH in DCM to afford the title compound. Yield: 2.67 g, 77 %.

General Procedure O: Removal of Boc protecting group of tert-bx\ty\ 2-[2-(2-før*-butoxy- 2-oxoethoxy)ethyl]piperidine-l-carboxylates tørt-Butyl {2- [(2S)-piperidin-2-yl]ethoxy} acetate

To a solution of tert-hvXy\ (25)-2-[2-(2-fert-butoxy-2-oxoethoxy)ethyl]piperidine-l- carboxylate (2.65 g, 7.72 mmol) in EtOAc (39 mL) was added 4 M HCl in dioxane (9.65 mL).

Reactions are stirred at ambient temperature for 5 h and concentrated in vacuo. The crude product was resolvated in MeCN (40 rnL) and Ambersep 900 OH (1 wt) added. This slurry was shaken for 16 h, filtered and concentrated in vacuo to afford the title compound. Yield: 1.74 g, 92 %.

General Procedure R: ført-Butyl (2-{(2S)-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}ethoxy) acetate

To a solution of the tert-bvXy\ {2-[(25)-piperidin-2-yl]ethoxy}acetate (0.73 g, 3.0 mmol), TEA (0.84 mL, 6.0 mmol) and DMAP (50 mg, cat) in THF (15 mL) at 0 ⁰C was added 2,6- dimethyl-4-methoxybenzenesulfonyl chloride (0.91 g, 3.9 mmol). The reaction was stirred at ambient temperature overnight, diluted with DCM (20 mL), and washed with 10 % w/v citric acid solution (20 mL). The organic phase was dried over MgSO₄ and concentrated in vacuo. The crude product was purified by FCC eluting with 1-5 % MeOH in DCM to afford the title compound. Yield: 0.95 g, 71 %.

(2-{(2S)-l-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}ethoxy)acetic acid

The title compound was prepared according to general procedure F using tert-butyl (2-{(2S)- l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}ethoxy)acetate (0.95 g, 2.1 mmol) and 1 :3 TFA/DCM (20 mL). The title compound did not require any further purification. Yield: 0.77 g, quantitative. l-[(2-{(2S)-l-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}ethoxy)acetyl]-4- (l-methylpiperidin-4-yl)piperazine

The title compound was prepared according to general procedure K using (2-{(25)-l-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}ethoxy)acetic acid (0.25 g, 0.65 mmol), THF (5 mL), CDI (0.10 g, 0.65 mmol) and l-(l-methylpiperidin-4-yl)piperazine (0.11 g, 0.59 mmol). A portion of the crude product was purified using prep method 3.

The following compounds were synthesised in the same manner: Table 5

The preparation of homochiral morpholine derivatives

Scheme 6 describes the general synthesis of homochiral morpholine derivatives. The starting material was prepared according to the procedure described by Meinzer etal (Helvetica Chimica Acta, 2004, 87 (1), 90-105). (R^R^R^R^R^H; X¹⁼O; X²=O; X³=various aromatic cycles; n=m=l; X⁴=NR¹⁹R^19a)

R5

Scheme 6

tert-Butγ\ {[(3S)-4-benzylmorpholin-3-yl]methoxy}acetate

,N.

The title compound was prepared according to general procedure C using [(3i?)-4- benzylmorpholin-3-yl]methanol (13.0 g, 62.7 mmol), TBAI (100 mg, cat), toluene (130 mL), 35 % w/v NaOH solution (130 mL) and tøt-butyl bromoacetate (12.8 g, 65.8 mmol). The crude product was purified by flash column chromatography, eluting with 10-35 % EtO Ac/heptanes to afford the title compound as a clear oil that solidified on standing. Yield: 13.8 g, 68 %.

tert-Butγ\ [(3S)-morpholin-3-ylmethoxy] acetate

O ^i

,NH

A suspension of tert-butyi {[(35)-4-benzylmorpholin-3-yl]methoxy}acetate (9.64 g, 30 mmol) and Pd(OH)₂ (2.0 g) in EtOAc (200 mL) was purge-filled with nitrogen (3 cycles), then with hydrogen (3 cycles). The reaction was stirred at ambient temperature for 90 min under an atmosphere of H₂, filtered through celite and concentrated in vacuo to afford the title compound.

Yield: 6.75 g, 97 %. General Procedure Q for the sulfonylation of amines: tert-Buty\ ({(3S)-4-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]morpholin-3-yl}methoxy) acetate

To a solution of tert-butyl [(3S)-morpholin-3-ylmethoxy]acetate (924 mg, 4.0 mmol) and TEA (1.67 mL, 12.0 mmol) in THF (20 mL) at 0 ⁰C was added 2,6-dimethyl-4- methoxybenzenesulfonyl chloride (1.17 g, 5.0 mmol). The reaction was stirred overnight at ambient temperature, diluted with DCM (20 mL) and washed with 10 % w/v citric acid solution (2 x 10 mL). The organic phase was dried over MgSO₄ and concentrated in vacuo. The crude product was purified by FCC eluting with 0-5 % MeOH/DCM to afford the product. Yield: 0.95 g, 55 %.

The following compounds were prepared according to general procedures Q or R: tert-butyl ({(35)-4-[(2-cyanophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2-chlorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2,4-difluorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2,6-difluorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2-nitrophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2-chloro-6-methylphenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl { [(35)-4-(naphthalen- 1 -ylsulfonyl)morpho lin-3 -yljmethoxy } acetate tert-butyl ({(35)-4-[(2-chloro-4-fluorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl {[(35)-4-(l-benzothiophen-3-ylsulfonyl)morpholin-3-yl]methoxy} acetate tert-butyl ( {(35)-4-[(5-chloro-3-methyl- 1 -benzothiophen-2-yl)sulfonyl]morpho lin-3 - yl}methoxy)acetate tert-butyl {[(35)-4-(l, 2, 3-benzothiadiazol-4-ylsulfonyl)morpholin-3-yl]methoxy} acetate tert-butyl ({(35)-4-[(2-chloro-4-cyanophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(4-chloro-2,5-dimethylphenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2-chloro-4-methoxyphenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl { [(3S)-4- { [2-(trifluoromethyl)phenyl]sulfonyl} morpho lin-3 -yljmethoxy} acetate tert-butyl ({(35)-4-[(2,3-dichlorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2,4-dichlorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2,6-dichlorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2-bromophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2,4-dichloro-5-methylphenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2,4-dichloro-6-methylphenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl { [(3S)-4- { [2-chloro-4-(trifluoromethyl)phenyl] sulfonyl} morpho lin-3 - yljmethoxy} acetate tert-butyl ({(35)-4-[(2,3,4-trichlorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2,4,5-trichlorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2,5,6-trichlorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(4-bromo-2-ethylphenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(4-bromo-2,5-difluorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl {[(3S)-4- {[2,4,6-tris(l -methylethyl)phenyl] sulfonyl} morpho lin-3 - yljmethoxy} acetate tert-butyl {[(35)-4-{[2,6-dichloro-4-(trifluoromethyl)phenyl]sulfonyl}morpholin-3- yljmethoxy} acetate tert-butyl ({(35)-4-[(3,6-dibromo-2-chlorophenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2-methylphenyl)sulfonyl]morpholin-3-yl}methoxy)acetate tert-butyl ({(35)-4-[(2-methoxyphenyl)sulfonyl]morpholin-3-yl}methoxy)acetate

({(3S)-4-[(2-Methylphenyl)sulfonyl]morpholin-3-yl}methoxy)acetic acid

The title compound was prepared according to general procedure F using tert-butyl ({(3S)-4- [(2-methylphenyl)sulfonyl]morpholin-3-yl}methoxy)acetate (0.23 mmol) and a 1 :3 mixture of TFA/DCM (1 mL). The title compound required no further purification.

(3S)-4-[(2-Methylphenyl)sulfonyl]-3-({2-[4-(l-methylpiperidin-4-yl)piperazin-l-yl]-2- oxoethoxy} methyl)morpholine

The title compound was prepared according to general procedure K using ({(35)-4-[(2- methylphenyl)sulfonyl]morpholin-3-yl}methoxy)acetic acid (0.23 mmol), THF (1 mL), CDI (37 mg, 0.23 mmol), and l-(l-methylpiperidin-4-yl)piperazine (42 mg, 0.23 mmol). This afforded the title compound, a portion of which was purified using prep methods 2 or 3.

The following compounds were prepared in an analogous manner Table 6

Selected ¹H NMR:

¹H NMR (CDCl₃, 400 MHz):8.31 (IH, m), 8.02 (IH, m), 7.87 (2H, m), 4.30 (2H, q), 4.05 (IH, dt, J 7.1 Hz, 2.5 Hz), 3.79-3.99 (8H, m), 3.72 (2H, d, J 11.5 Hz), 3.32-3.62 (9H, m), 3.13 (2H, m), 2.92 (3H, s), 2.46 (2H, d, J 11.7 Hz), 2.13 (2H, m).

¹U NMR (CDCl₃, 400 MHz): 7.97 (2H, m), 7.57 (IH, dd, J 8.7 Hz, 2.0 Hz), 4.27 (2H, q), 4.13 (IH, dt, J 2.9 Hz, 7.3 Hz), 3.31-3.95 (19H, m), 3.14 (2H, m), 2.92 (3H, s), 2.71 (3H, s), 2.47 (2H, d, J 12.4 Hz), 2.13 (2H, m).

¹U NMR (CDCl₃, 400 MHz): 7.96 (2H, m), 7.47-7.59 (4H, m), 7.33 (2H, m), 6.86 (IH, d, J 5.8 Hz), 6.33 (IH, dt, J 7.3 Hz, 15.8 Hz), 4.22 (2H, m), 4.11 (IH, dt, J 2.6 Hz, 7.1 Hz), 3.92 (IH, d, J 11.9), 3.70-3.84 (9H, m), 3.63 (IH, m), 3.31-3.53 (3H, m), 3.14 (4H, m), 2.69 (3H, s). The preparation of 4,4-difluoropiperidine derivatives

Scheme 7 describes the synthesis of 4,4-difluoropiperidine derivatives (R¹⁼R²=R³=R⁴=R⁵=H; X¹⁼CF₂; X²=O; X³=various aromatic cycles; n=m=l; X⁴=NR¹⁹R^19a)

General CO Et P^rocedure T

General procedure K X 'I RZ, R4?

O=S=O R3 R5 X,

Scheme 7

Ethyl [(diphenylmethyl)imino]ethanoate (150) To a stirred mixture of 50% w/w ethyl glyoxylate in toluene (12.25 g, 60.0 mmol) and powdered 4 A molecular sieves (4.00 g) in DCM (60 mL) at 0 ⁰C was added a solution of 1,1- diphenylmethylamine (8.25 g, 45.0 mmol) in DCM (30 mL). After the addition was complete the mixture was stirred at 0 ⁰C for 4 h and the solvent removed in vacuo ensuring the water bath temperature was <40 ⁰C. The crude mixture was stored at 4 ⁰C overnight to give an off- white solid that was triturated with hexanes and filtered to afford the title compound, which was stored at 4 ⁰C. Yield: 11.86 g, 99 %

Ethyl l-(diphenylmethyl)-4-oxopiperidine-2-carboxylate

To a stirred solution of ethyl [(diphenylmethyl)imino]ethanoate (4.35 g, 16.3 mmol) in TFE (45 mL) at -40 ⁰C was added TFA (1.20 mL, 16. 3 mmol) dropwise. Then 2- (trimethylsilyloxy)-l,3-butadiene was added dropwise and the reaction mixture stirred at -40 ⁰C for 1 h. The reaction mixture was allowed to warm to ambient temperature, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 5-10 % EtOAc in heptanes. Yield: 3.56 g, 65 %

Ethyl l-(diphenylmethyl)-4,4-difluoropiperidine-2-carboxylate

To a stirred solution of ethyl l-(diphenylmethyl)-4-oxopiperidine-2-carboxylate (1.00 g, 2.96 mmol) in DCM (2 mL) was added 50% w/w Deoxofluor in toluene (3.7 mL, 10.1 mmol). Then EtOH (70 μL, 1.18 mmol) was added, and the reaction mixture stirred overnight. The reaction mixture was diluted with DCM (50 mL), and poured into saturated aqueous NaHCOs (50 mL). The organic phase was separated, washed with saturated aqueous NaHCOs (50 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by FCC eluting with 0-5 %EtOAc in heptanes. Yield: 423 mg, 40 %

Ethyl 4,4-difluoropiperidine-2-carboxylate

The title compound was prepared in a method analogous to general procedure D using ethyl l-(diphenylmethyl)-4,4-difluoropiperidine-2-carboxylate (496 mg, 1.38 mmol), EtOH (20 mL), 10% Pd/C (50 mg, cat) and hydrogen. The mixture was stirred overnight, and filtered through Celite. The filtrate was concentrated in vacuo, and the crude mixture taken up in 10% w/v aqueous citric acid (10 mL) and Et₂O (10 mL). The aqueous phase was separated and washed with Et₂O (2 x 10 mL). The aqueous phase was taken up to pH 11 using solid K2CO3 and then extracted with Et₂O (3 x 10 mL). The organic phases were combined, dried over Na₂SO₄ and concentrated in vacuo to afford the title compound which required no further purification. Yield: 209 mg, 78 %

General Procedure S: Preparation of sulfonamides.

Ethyl 4,4-difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidine-2-carboxylate

To a stirred solution of ethyl 4,4-difluoropiperidine-2-carboxylate (209 mg, 1.08 mmol), DIPEA (0.94 mL, 5.40 mmol), and DMAP (13 mg, 108 μmol) in DCM (3 mL) at 0 ⁰C was added a solution of 2,6-dimethyl-4-methoxybenzene-l-sulfonyl chloride (279 mg, 1.19 mmol) in DCM (2 mL). After the addition was complete the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM (5 mL) and washed with 1 M HCl (3 x 10 mL). The organic phase was dried over MgSO₄ and concentrated in vacuo. The residue was purified using FCC eluting with 10-20 % EtOAc in heptanes. Yield: 239 mg, 57 %

{4,4-Difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methanol

The title compound was prepared according to general procedure T using ethyl 4,4-difluoro- l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidine-2-carboxylate (239 mg, 611 μmol), THF (2.5 mL) and 2.3 M solution Of LiAlH₄ in THF (0.4 niL, 916 μmol) This afforded the title compound which required no further purification. Yield: 213 mg, 100 %

tert-Buty\ ({4,4-difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2- yl} methoxy)acetate

The title compound was prepared according to general procedure C using {4,4-difluoro-l-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methanol (274 mg, 784 μmol), TBAI (7 mg, cat) and tert-butyi bromoacetate (174 μL, 1.18 mmol) in DCM (2.5 mL) and 35% w/v NaOH solution (2.5 mL). The residue was purified using flash column chromatography eluting with 10-20 % EtOAc in heptanes to afford the title compound. Yield: 222 mg, 61 %

¹H NMR (CDCl₃, 400 MHz): 6.56 (2H, s), 4.00 (IH, m), 3.83 (IH, m), 3.75 (3H, s), 3.71 (2H, s), 3.46-3.54 (2H, m), 3.14 (IH, m), 2.54 (6H, s), 1.80-2.25 (4H, m), 1.38 (9H, s).

({4,4-Difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid

The title compound was prepared according to general procedure F using tert-butyl ({4,4- difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetate (222 mg, 479 μmol) and a 1 :5 mixture of TFA and DCM. This afforded the title compound which required no further purification. Yield: 195 mg, 100 %

l-[({4,4-Difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfbnyl]piperidin-2- yl}methoxy)acetyl]-4-(l-methylpiperidin-4-yl)piperazine

The title compound was prepared according to general procedure K using ({4,4-difluoro-l- [(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid (199 mg, 488 μmol), THF (1.5 mL), CDI (79 mg, 488 μmol) and l-(l-methylpiperidin-4-yl)piperazine (89 mg, 488 μmol). A portion of the crude product was purified using preparative HPLC using method 3. Table 7

The preparation of Homochiral 4,4-difluoropiperidine derivatives

Scheme 8 describes the synthesis of homochiral 4,4-difluoropiperidine derivatives (R^R^R^R^R^H; X¹⁼CF₂; X²=CF₂; X³=various aromatic cycles; n=m=l; X⁴=NR¹⁹R^19a)

General

General procedure

O=S=O R3 R5 X,

Scheme 8

Ethyl (25)-4-oxo-l-[(li?)-l-phenylethyl]piperidine-2-carboxylate

A 50 % w/w solution of ethyl glyoxylate in toluene (10.0 g, 49 mmol) was refluxed for 30 min under

N₂ and then transferred to a mixture of 4 A molecular sieves in DCM (86 mL) at < 5 ⁰C, cooled using an ice/water bath. (R)-α-Methylbenzylamine (6.3 mL, 49 mmol) was added dropwise to the reaction mixture keeping the temp below 5 ⁰C. Upon completion of addition the mixture was stirred at < 5 ⁰C for 45 min. The mixture was cooled to - 78 ⁰C and TFA (3.6 mL, 49 mmol) was added dropwise such that the temperature did not exceed - 65 ⁰C. The BF₃OEt₂ (6.1 mL, 49 mmol) was then added dropwise such that the temperature did not exceed - 65 ⁰C. The diene (6.87 g, 49 mmol) was then added dropwise such that the temperature did not exceed - 65 ⁰C. The reaction was then stirred for 2 h at - 40 ⁰C. The cooling bath was removed and water (20 mL) added slowly. When the reaction temperature reached - 10 ⁰C water (25 mL) was added and the mixture stirred at ambient temperature overnight. The reaction was filtered and the filtrate basifϊed to pH 12 using IM aqueous NaOH. The organic phase was separated and the aqueous phase washed with DCM (2 x 100 mL). The combined organics were dried (MgSO₄) and concentrated in vacuo to afford 15 g of crude product, which solidified upon standing. The crude product was purified by flash column chroamtography eluting with 5:1 toluene/EtOAc and the resulting yellow oil (7 g) was crystallised from heptane to afford the title product as white needles. Yield: 4.51 g, 33 %. 1H NMR (CDCl₃, 400 MHz): 7.33 (2H, m), 7.26 (2H, t, J 7.41 Hz), 7.19 (IH, m), 4.13 (3H, m), 3.79 (IH, q, J 6.59 Hz), 2.79 (2H, m), 2.58 (2H, m), 2.25 (IH, m), 1.37 (3H, d, J 6.59 Hz), 1.23 (3H, t, J 7.14 Hz)

Ethyl (25)-4,4-difluoro-l-[(li?)-l-phenylethyl]piperidine-2-carboxylate

Ethyl (25)-4-oxo-l-[(lR)-l-phenylethyl]piperidine-2-carboxylate (1.0 g, 3.63 mmol) was dissolved in DCM (1.0 mL) and stirred under N₂ prior to addition of deoxofluor (50 %, 2.3 mL, 6.17 mmol). EtOH (21 μL) was added and the reaction stirred at ambient temperature under N₂ overnight. The solution was then poured into saturated aqueous NaHCO₃ solution (10 mL) and after effervescence had ceased the mixture was extracted with DCM (2 x 10 mL). The combined organics were dried (Na₂SO₄) and concentrated in vacuo to afford the crude product which was purified by flash column chromatography eluting with hexane/Et₂O to afford the desired product as a yellow oil. Yield: 345 mg, 32 %.

{(2S)-4,4-Difluoro-l-[(lΛ)-l-phenylethyl]piperidin-2-yl}methanol

The title compound was prepared according to general procedure T using ethyl (25)-4,4-difluoro-l- [(lR)-l-phenylethyl]piperidine-2-carboxylate (4.61 g, 15.5 mmol), THF (2.5 mL) and 1.0 M solution of LiAlH₄ in THF (31 mL, 31 mmol) This afforded the title compound which required no further purification.

Yield: 3.33 g, 84 %. tert-Buty\ ({(2S)-4,4-difluoro-l-[(li?)-l-phenylethyl]piperidin-2-yl}methoxy)acetate

The title compound was prepared according to general procedure C using {(25)-4,4-difluoro-l-[(lR)- l-phenylethyl]piperidin-2-yl}methanol (3.33 g, 13.1 mmol), TBAI (120 mg, cat), tert-butyl bromoacetate (2.9 mL, 19.7 mmol) in DCM (35 mL) and 35% w/v NaOH solution (35 mL). The product was purified using flash column chromatography eluting with 10-20 % EtOAc in heptanes to afford the title compound. Yield: 4.81 g, 100 %.

tert-Buty\ {[(25)-4,4-difluoropiperidin-2-yl]methoxy}acetate

tert-Butyl ({(25)-4,4-difluoro-l-[(lR)-l-phenylethyl]piperidin-2-yl}methoxy)acetate (4.8 g, 13.1 mmol) was dissolved in EtOH (53 mL) and Pd(OH)₂ (527 mg, cat.) added. The reaction was degassed by 3 cycles of vacuum/N₂ and then re-gassed with H₂ using 3 cycles of vacuum/H₂. The reaction was stirred under a H₂ atmosphere at ambient temperature and pressure overnight and then filtered through a plug of celite and concentrated in vacuo. This afforded the title compound, which required no further purififcation.

Yield: 3.42 g, 98 %.

¹H NMR (CDCl₃, 400 MHz): 10.05 (2H, br s), 3.95 (2H, s), 3.83 (2H, m), 3.6 (IH, m), 3.39 (IH, m), 3.01 (IH, m), 2.36 (2H, m), 2.15 (2H, m), 1.8 (lH br s), 1.32 (9H, s) .

tert-Buty\ ({(25)-4,4-difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2- yl}methoxy)acetate

The title compound was prepared according to general procedure S using tert-butyl {[(2S)-4,4- difluoropiperidin-2-yl]methoxy}acetate (481 mg, 1.81 mmol), 2,6-dimethyl-4-methoxybenzene-l- sulfonyl chloride (426 mg, 1.81 mmol), DIPEA (315 μL, 1.81 mmol) and DMAP (22 mg, 0.18 mmol) in DCM (5 mL). This afforded the title compound, which was purified using flash column chromatography, eluting with 10 % EtOAc in heptanes. Yield: 463 mg, 55 %.

The following compounds were prepared in an analogous manner: tert-butyl ({(25)-4,4-difluoro-l-[(2,4,6-trichlorophenyl)sulfonyl]piperidin-2-yl}methoxy)acetate tert-butyl ({(25)-l-[(2,6-dichlorophenyl)sulfonyl]-4,4-difluoropiperidin-2-yl}methoxy)acetate tert-butyl ({(25)-l-[(2-chloro-6-methylphenyl)sulfonyl]-4,4-difluoropiperidin-2-yl}methoxy)acetate tert-butyl ({(25)-l-[(2,4-dichloro-6-methylphenyl)sulfonyl]-4,4-difluoropiperidin-2- yl}methoxy)acetate tert-butyl ({(25)-l-[(2-bromo-6-ethylphenyl)sulfonyl]-4,4-difluoropiperidin-2-yl}methoxy)acetate tert-butyl {[(2S)-\ -(I -benzothiophen-3-ylsulfonyl)-4,4-difluoropiperidin-2-yl]methoxy} acetate

({(25)-4,4-difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid

The title compound was prepared according to general procedure F using tert-butyl ({(2S)-4,4- difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetate (463 mg, 1.0 mmol) and a 1:10 mixture of TFA and DCM (5.5 mL). This afforded the title compound which required no further purification. Yield: 396 mg, 97 %

The following compounds were prepared in an analogous manner:

({(25)-l-[(2,6-dichlorophenyl)sulfonyl]-4,4-difluoropiperidin-2-yl}methoxy)acetic acid ({(25)-4,4-difluoro-l-[(2,4,6-trichlorophenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid ({(25)-l-[(2,4-dichloro-6-methylphenyl)sulfonyl]-4,4-difluoropiperidin-2-yl}methoxy)acetic acid ({(25)-l-[(2-chloro-6-methylphenyl)sulfonyl]-4,4-difluoropiperidin-2-yl}methoxy)acetic acid ({(25)-l-[(2-bromo-6-ethylphenyl)sulfonyl]-4,4-difluoropiperidin-2-yl}methoxy)acetic acid {[(2iS)-l -(I -benzothiophen-3-ylsulfonyl)-4,4-difluoropiperidin-2-yl]methoxy} acetic acid

l-[({(25)-4,4-difluoro-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2- yl}methoxy)acetyl]-4-(l-methylpiperidin-4-yl)piperazine

The title compound was prepared according to general procedure K using ({(25)-4,4-difluoro-l-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]piperidin-2-yl}methoxy)acetic acid (160 mg, 0.39 mmol), THF (1.5 mL), CDI (79 mg, 488 μmol) and l-(l-methylpiperidin-4-yl)piperazine (71 mg, 0.39 mmol). A portion of the crude product was purified using preparative HPLC using method 3.

The following compounds were prepared in an analogous manner and purified using prep methods 2 & 3.

Table 8

The preparation of thiomorpholine derivatives

Scheme 9 describes the preparation of thiomorpho line-derived products

(R¹⁼R²=R³=R⁴=R⁵=H; X¹⁼S, SO, SO₂; X²=O; X³=various aromatic cycles; n=m=l; X⁴=NR¹⁹R^19a)

General

Scheme 9

Methyl 4- [(4-methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholine-3-carboxylate

The title compound was prepared according to general procedure S using methyl thiomorpholine- 3-carboxylate (3.00 g, 17.1 mmol), DIPEA (6.0 mL, 34.2 mmol), DMAP (209 mg, 1.71 mmol) and DCM (40 mL). The residue was purified using FCC eluting with 0-20 % EtOAc in heptanes. Yield: 5.86 g, 92 %

{4- [(4-Methoxy-2,6-dimethylphenyl)sulfonyl] thiomorpholin-3-yl} methanol

The title compound was prepared according to general procedure T using methyl 4-[(4-methoxy- 2,6-dimethylphenyl)sulfonyl]thiomorpholine-3-carboxylate (5.86 g, 15.7 mmol), THF (150 mL) and 2.3 M LiAlH₄ in THF (14.0 mL, 31.4 mmol). This afforded the title compound which required no further purification. Yield: 4.67 g, 90 %

tert-Butyl ({4-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholin-3-yl}methoxy) acetate

The title compound was prepared according to general procedure C using {4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]thiomorpholin-3-yl}methanol (5.36 g, 16.2 mmol), TBAI (150 mg, 405 μmol), tert-butyl bromoacetate (3.6 mL, 24.3 mmol), DCM (110 mL) and 35% w/v NaOH solution (110 mL). The crude product was purified using FCC eluting with 0-20 % EtOAc in heptanes.

Yield: 4.48 g, 62 %

¹H NMR (CDCl₃, 400 MHz): 6.56 (2H, s), 4.09 (IH, q, J 9.0 Hz), 3.98 (IH, m), 3.80 (2H, s), 3.75 (3H, s + IH br s), 3.62 (IH, dd, J 9.0 Hz, 5.1 Hz), 3.16 (IH, dt, J 13.2 Hz, 2.1 Hz), 3.02 (IH, dd, J 11.8 Hz, 3.7 Hz), 2.71 (2H, m), 2.53 (6H, s), 2.26 (IH, m), 1.40 (9H, s).

({4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholin-3-yl}methoxy)acetic acid

The title compound was prepared according to general procedure F using tert-butyl ({4-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholin-3-yl}methoxy)acetate (2.50 g, 5.61 mmol) and a 9: 1 mixture of TFA/DCM. This afforded the title compound which required no further purification.

Yield: 2.00 g, 91 %

4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-3-({2-[4-(l-methylpiperidin-4-yl)piperazin-l- yl] -2-oxoethoxy} methyl)thiomorpholine

The title compound was prepared according to general procedure K using ({4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]thiomorpholin-3-yl}methoxy)acetic acid (1.00 g, 2.56 mmol), , CDI (417 mg, 2.56 mmol), l-(l-methylpiperidin-4-yl)piperazine (424 mg, 2.31 mmol) and THF (15 mL) instead of DCE. The crude product was purified using FCC eluting with 0.5:5:95 NH₄OH/MeOH/DCM to 1: 10:90 NH₄OH /MeOH/DCM. Yield: 1.18 g, 82 %

4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-3-({2-[4-(l-methylpiperidin-4-yl)piperazin-l- yl] -2-oxoethoxy} methyl)thiomorpholine 1-oxide

To a stirred solution of 4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-3-({2-[4-(l-methylpiperidin-

4-yl)piperazin-l-yl]-2-oxoethoxy}methyl)thiomorpholine (400 mg, 721 μmol) in DCM (3 mL) at 0 ⁰C was added a mixture of 70% w/w meto-chloroperbenzoic acid (170mg, 757 μmol) in DCM (3 mL). The reaction mixture was stirred at 0 ⁰C for 4 h. The reaction mixture was diluted with DCM (6 mL), washed with saturated NaHCO₃ (3 x 10 mL), dried over MgSO₄, and concentrated in vacuo. A portion of the crude mixture was purified using preparative HPLC using method 3. ¹H NMR (CDCl₃, 400 MHz): 6.56 (2H, s), 4.10 (IH, q, J 8.8 Hz), 4.01 (2H, d, J 6.8 Hz), 3.76 (3H, s), 3.67 (IH, dt, J 14.3 Hz, 2.8 Hz), 3.60 (IH, dd, J 5.9 Hz, 8.6 Hz), 3.53 (2H, br s), 3.33 (2H, br s), 3.30 (IH, br s), 3.16 (3H, s), 2.80-3.14 (5H, m), 2.66 (2H, m), 2.52 (6H, s), 2.18-2.44 (4H, m), 1.63 (2H, br s). tert-Butyl ({4-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]-l,l-dioxidothiomorpholin-3- yl}methoxy) acetate

To a stirred solution of tert-Butyl ({4-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholin-3- yl}methoxy)acetate (200 mg, 449 μmol) in DCM (2 mL) at 0 ⁰C was added a mixture of 70% w/w mCPBA (302 mg, 1.35 mmol) in DCM (2 mL). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM (6 mL), washed with saturated NaHCO₃ (3 x 10 mL), dried over MgSO₄, and concentrated in vacuo to afford the title compound that required no further purification.

Yield: 187 mg, 87 % 1H NMR (CDCl₃, 400 MHz): 6.54 (2H, s), 4.13-4.26 (2H, m), 3.73 (3H, s), 3.54-3.84 (5H, m),

3.20-3.42 (3H, m), 2.87 (IH, dd, J 14.2 Hz, 2.6 Hz), 2.49 (6H, s), 1.34 (9H, s).

({4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-l,l-dioxidothiomorpholin-3- yl}methoxy)acetic acid

The title compound was prepared according to general procedure F using tert-butyl ({4-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]-l,l-dioxidothiomorpholin-3-yl}methoxy)acetate (187 mg, 391 μmol) and a 9: 1 mixture of DCM/TFA (0.4 mL). This afforded the title compound that required no further purification. Yield: 148 mg, 90 % 4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-3-({2-[4-(l-methylpiperidin-4-yl)piperazin-l- yl]-2-oxoethoxy}methyl)thiomorpholine 1,1-dioxide

The title compound was prepared according to general procedure K using ({4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]-l,l-dioxidothiomorpholin-3-yl}methoxy)acetic acid (148 mg, 351 μmol), CDI (57 mg, 351 μmol), l-(l-methylpiperidin-4-yl)piperazine (58 mg, 316 μmol) and THF (3 mL) instead of DCE. A portion of the crude product was purified using preparative HPLC using method 3.

The following compounds were prepared in an analogous manner Table 9

The preparation of homochiral Thiomorpholine derivatives

Scheme 10 describes the preparation of thiomorpho line-derived products

(R¹⁼R²=R³=R⁴=R⁵=H; X¹⁼S, SO, SO₂; X²=O; X³=various aromatic cycles; n=m=l; X⁴=NR¹⁹R^19a)

a

Scheme 10

Methyl Λ^L(tert-butoxycarbonyl)-₁S'-(2-methoxy-2-oxoethyl)-L-cysteinate To a stirred solution of N-boc cysteine methyl ester (6.0 g, 25.5 mmol) and TEA (6.67 mL, 38.3 mmol) in DCM (50 mL) at O ⁰C was added methyl bromoacetate (4.68 g, 30.6 mmol) dropwise. Upon completion of addition, the reaction was warmed to ambient temperature and stirred for 160 min prior to concentration in vacuo and re-dissolution in Et₂O (250 mL). The solution was washed with IM HCl (3 x 20 mL), dried (MgSO₄) and concentrated in vacuo to afford the title compound, which required no further purification. Yield: 7.34 g, 93 %.

Methyl S-(2-methoxy-2-oxoethyl)-L-cysteinate, hydrochloride salt

To a stirred solution of methyl N-(?er?-butoxycarbonyl)-5'-(2-methoxy-2-oxoethyl)-L-cysteinate (7.34 g, 23.9 mmol) in MeOH (50 mL) was added a solution of thionyl chloride (3.47 mL, 47.8 mmol) in MeOH (50 mL) and the reaction stirred at reflux for 3 h. The solvent was removed in vacuo to afford the title compound, which required no purification. Yield: 5.82g, 100 %. Methyl (3/?)-5-oxothiomorpholine-3-carboxylate

To a stirred solution of methyl 5'-(2-methoxy-2-oxoethyl)-L-cysteinate (5.82 g, 23.9 mmol) in MeOH (100 mL) at 0 ⁰C was added sodium acetate (2.08 g, 25.4 mmol) portionwise. The reaction was warmed to ambient temperature and stirred for 2 h. The reaction was filtered and the filtrate concentrated in vacuo and taken back up in DCM (100 mL) and refluxed for 3 h. The reaction was then cooled to ambient temperature and concentrated in vacuo. The crude product was purified by FCC eluting with DCM/MeOH (100:0 to 80:20) to afford the title compound. Yield: 2.66 g, 60 %.

¹H NMR (CDCl₃, 400 MHz): 7.05 (IH, br s), 4.38 (IH, m), 3.78 (3H, s), 3.29 (2H, d, J 7.14 Hz), 3.02 (2H, m).

Methyl (3/?)-thiomorpholine-3-carboxylate

To a solution of Methyl (3i?)-5-oxothiomorpholine-3-carboxylate (1.0 g, 5.7 mmol) in THF (30 mL) at 0 ⁰C under N₂ was added dropwise a IM solution Of BH₃ in THF (11.4 mL). The reaction was warmed to ambient temperature and stirred overnight. The reaction was quenched by addition of MeOH (60 mL) and concentrated in vacuo to afford the title compound as a brown oil which was used directly in the next step. Yield: 980 mg.

Methyl (3/?)-4-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholine-3-carboxylate

The title compound was prepared according to general procedure S using methyl (3R)- thiomorpholine-3-carboxylate (980 mg), 2,6-dimethyl-4-methoxybenzene-l-sulfonyl chloride (1.55 g, 6.6 mmol), DIPEA (3.1 mL, 18.2 mmol), DMAP (73 mg, 0.6 mmol) and DCM (40 mL). This afforded the title compound, which was purified by FCC eluting with 10-30 % EtOAc in heptanes. Yield: 813 mg, 37 %.

{(3/?)-4- [(4-methoxy-2,6-dimethylphenyl)sulfonyl] thiomorpholin-3-yl} methanol

The title compound was prepared according to general procedure T using methyl (3i?)-4-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholine-3-carboxylate (500 mg, 1.39 mmol), 2.3 M LiAlH₄ in THF (0.86 mL) and THF (5 mL). This afforded the title compound which required no further purification. Yield: 453 mg, 98 %. ¹H NMR (CDCl₃, 400 MHz): 6.65 (2H, s), 4.03 (2H, m), 3.98 (IH, m), 3.83 (3H, s), 3.31 (IH, m), 3.11 (IH, dd, J 3.24 Hz, 13.7 Hz), 2.78 (IH, dt, J 3.24 Hz, 12.6 Hz), 2.62 (6H, s), 2.36 (IH, m)

tert-Butyl ({(3/?)-4-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholin-3- yl}methoxy)acetate

The title compound was prepared according to general procedure C using {(3i?)-4-[(4-methoxy- 2,6-dimethylphenyl)sulfonyl]thiomorpholin-3-yl}methanol (453 mg, 1.37 mmol), tert-butyl bromoacetate (401 mg, 2.06 mmol), TBAI (13 mg, cat), DCM (5 mL) and 35 % w/v aqueous NaOH (6 mL). This afforded the title compound, which required no further purification. Yield: 511 mg, 84 %.

({(3/?)-4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholin-3-yl}methoxy)acetic acid

The title compound was prepared according to general procedure F using tert-butyl ({(3i?)-4-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]thiomorpholin-3-yl}methoxy)acetate (511 mg, 1.15 mmol) in 1:9 TFA/DCM (5 mL). This afforded the title compound, which required no further purification. Yield: 391 mg, 87 %

(3/?)-4-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]-3-({2-[4-(l-methylpiperidin-4-yl)piperazin- l-yl]-2-oxoethoxy}methyl)thiomorpholine

The title compound was prepared according to general procedure K using ({(3i?)-4-[(4-methoxy- 2,6-dimethylphenyl)sulfonyl]thiomorpholin-3-yl}methoxy)acetic acid (391 mg, 1.0 mmol), CDI

(195 mg, 1.2 mmol), l-(l-methylpiperidin-4-yl)piperazine (183 mg, 1.0 mmol) and DCM (7 mL).

The crude product was purified by FCC eluting with 1:2:97 TEA/MeOH/DCM to afford the title compound.

Yield: 367 mg, 66 %.

(3/?)-4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-3-({2-[4-(l-methylpiperidin-4- yl)piperazin-l-yl]-2-oxoethoxy}methyl)thiomorpholine 1-oxide

To a stirred solution of (3i?)-4-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]-3-({2-[4-(l- methylpiperidin-4-yl)piperazin-l-yl]-2-oxoethoxy}methyl)thiomorpholine (113 mg, 0.20 mmol) in DCM (3 mL) at 0 ⁰C was added 3-chloroperbenzoic acid (77 %, 78 mg, 0.45 mmol) and the reaction stirred at O ⁰C for 1 h. The reaction was diluted with DCM (10 mL) and washed with saturated aqueous NaHCC>3 solution (3 x 5 mL), saturated aqueous brine (5 mL) and dried (MgSO₄). The solvent was removed in vacuo, and the crude product purified using prep method 3. Yield: 5.2 mg, 4 %.

tørt-Butyl ({(3/?)-4-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]-l,l-dioxidothiomorpholin-3- yl} methoxy)acetate

To a stirred solution of tert-Butyl ({(3i?)-4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]thiomorpholin-3-yl}methoxy)acetate (300 mg, 0.67mmol) in DCM (3 mL) at 0 ⁰C was added a solution of 3-chloroperbenzoic acid (77%, 454 mg, 2.0 mmol) in DCM (3 mL). The reaction was stirred at 0 ⁰C for 30 min and then diluted with DCM (15 mL) and washed with saturated aqueous NaHCC>3 (3 x 5 mL), saturated brine (5 mL) and dried (MgSO₄). This afforded the title compound which required no further purification. Yield: 300 mg, 93 %.

({(3/?)-4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-l,l-dioxidothiomorpholin-3- yl}methoxy)acetic acid

The title compound was prepared according to general procedure K using tert-butyl ({(3i?)-4-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]- 1 , 1 -dioxidothiomorpholin-3-yl}methoxy)acetate (300 mg, 0.628 mmol) and 1 :9 TFA/DCM (5 mL). This afforded the title compound, which required no further purification. Yield: 220 mg, 93 %.

(3/?)-4-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]-3-({2-[4-(l-methylpiperidin-4-yl)piperazin- l-yl]-2-oxoethoxy}methyl)thiomorpholine 1,1-dioxide

The title compound was prepared according to general procedure K using ({(3i?)-4-[(4-Methoxy- 2,6-dimethylphenyl)sulfonyl]-l,l-dioxidothiomorpholin-3-yl}methoxy)acetic acid (100 mg, 0.24 mmol), CDI (47 mg, 0.29 mmol), l-(l-methylpiperidin-4-yl)piperazine (48 mg, 0.26 mmol) and DCE (2 mL). The crude product was purified using prep method 3. Yield: 16 mg, 11 %

Table 10

The preparation of 2,6-disubstituted piperidine derivatives

Scheme 11 describes the preparation of 2,6-disubstituted-piperidine-derived products

(R¹⁼Me, R²=R³=R⁴=R⁵=H; X¹⁼CH₂; X²=O; X³=various aromatic cycles; n=m=l; X⁴=NR¹⁹R^19a)

Cpd 150

Scheme 11

Ethyl cw-l-(diphenylmethyl)-6-methyl-l,2,3,6-tetrahydropyridine-2-carboxylate

To a stirred solution of ethyl [(diphenylmethyl)imino]ethanoate (5.00 g, 18.7 mmol) in TFE (50 mL) at -40 ⁰C was added TFA (1.4 mL, 18.7 mmol) dropwise. Then penta-l,3-diene (4.2 mL, 37.4 mmol) was added dropwise and the reaction mixture stirred at -40 ⁰C for 1 hour. The reaction mixture was allowed to warm to r.t, and concentrated in vacuo. The crude mixture was taken up in Et₂O (100 mL) and washed with saturated aqueous NaHCO₃ (3 x 100 mL), H₂O (100 mL), brine (100 mL) and dried over MgSO₄. The crude residue was purified by FCC eluting with 0-5% EtOAc in heptanes. Yield: 2.68 g, 43 %.

Ethyl cw-6-methylpiperidine-2-carboxylate

The title compound was prepared in a manner analogous to general procedure D using ethyl cis- 1 - (diphenylmethyl)-6-methyl-l,2,3,6-tetrahydropyridine-2-carboxylate (2.68 g, 7.99 mmol), EtOH (30 mL), 10 % Pd/C (cat., 268 mg) and hydrogen. The mixture was stirred overnight, and filtered through Celite. The filtrate was concentrated in vacuo, and the crude mixture taken up in 10% w/v aqueous citric acid (50 mL) and Et₂O (25 mL). The organic phase was separated off and the aqueous phase taken up to pH=l 1 using solid K₂CO3 and then extracted with Et₂O (3 x 50 mL). The organic phases were combined, dried over Na₂SO₄ and concentrated in vacuo to afford the title compound which required no further purification. Yield: 1.18 g, 86%

Ethyl cw-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]-6-methylpiperidine-2-carboxylate

To a stirred solution of 2,6-dimethyl-4-methoxybenzene-sulfonyl chloride (718 mg, 3.06 mmol) and TEA (1.7 mL, 3.06 mmol) in DCM (2 mL) was added a solution of ethyl cis-6- methylpiperidine-2-carboxylate (350 mg, 2.04 mmol) in DCM (1 mL). After the addition was complete the reaction mixture was stirred overnight at ambient temperature, then N₅N- dimethylethylene diamine (0.25 mL, 2.04 mmol) was added, and the reaction mixture stirred for 1 h. The reaction mixture was diluted with Et₂O (25 mL), washed with 1 M aqueous HCl (2 x 25 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified using FCC eluting with 0-10 % EtOAc in heptanes to afford the title compound. Yield: 342 mg, 45 % O^C H O

{cw-l-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-6-methylpiperidin-2-yl} methanol

The title compound was prepared according to general procedure T using ethyl cώ-l-[(4-methoxy- 2,6-dimethylphenyl)sulfonyl]-6-methylpiperidine-2-carboxylate (468 mg, 1.27 mmol), THF (4.5 mL) and 2.3 M solution Of LiAlH₄ in THF (1.1 mL, 2.53 mmol. The title compound was obtained as a clear oil. Yield: 237 mg, 57 %

¹H NMR (CDCl₃, 400 MHz): 6.65 (2H, s), 3.97 (2H, m), 3.83 (3H, s), 3.64-3.87 (2H, m), 2.64 (6H, s), 2.29 (IH, dd, J 4.1 Hz, 7.7 Hz), 1.46-1.78 (6 H, m), 1.38 (3H, d, J 7.0 Hz).

tert-Butyl ({cjs-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]-6-methylpiperidin-2- yl} methoxy)acetate

The title compound was prepared according to general procedure C using {cώ-l-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]-6-methylpiperidin-2-yl}methanol (240 mg, 733 μmol), TBAI (7 mg, 18.3 μmol), tert-butyl bromoacetate (162 μL, 1.10 mmol), DCM (2.5 mL) instead of toluene and 35 % w/v NaOH (2.5 mL). The crude product was purified using FCC eluting with 10-30 % EtOAc in heptanes to afford the title compound. Yield: 240 mg, 74 %

({cw-l-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-6-methylpiperidin-2-yl}methoxy)acetic acid

The title compound was prepared according to general procedure F using tert-butyl ({cis-l-[(4- methoxy-2,6-dimethylphenyl)sulfonyl]-6-methylpiperidin-2-yl}methoxy)acetate (240 mg, 543 μmol), DCM (2.2 mL) and TFA (0.20 mL). This afforded the title compound which required no further purification. Yield: 207 mg, 100 %

¹H NMR (CDCl₃, 400 MHz): 6.65 (2H, s), 4.43 (IH, m), 4.16 (2H, q, J 15.7 Hz, 86.5 Hz), 3.83 (3H, s), 3.79 (IH, t, J 9.5 Hz), 3.64 (IH, dd, J 6.3 Hz, 9.1 Hz), 3.57 (IH, m), 2.62 (6H, s), 1.40- 1.71 (6H, m), 1.38 (3H, d, 7.0 Hz).

l-[({cw-l-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-6-methylpiperidin-2- yl}methoxy)acetyl]-4-(l-methylpiperidin-4-yl)piperazine

The title compound was prepared according to general procedure K using ({cώ-l-[(4-methoxy- 2,6-dimethylphenyl)sulfonyl]-6-methylpiperidin-2-yl}methoxy)acetic acid (196 mg, 512 μmol), THF (2.5 mL), CDI (83 mg, 512 μmol) and l-(l-methylpiperidin-4-yl)piperazine (94 mg, 512 μmol) in. A portion of the crude mixture was purified using preparative HPLC using method 3.

{cw-l-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]-6-methylpiperidin-2-yl} methyl 4-(l- methylpiperidin-4-yl)piperazine-l-carboxylate

To a stirred solution of {cώ-l-[(4-methoxy-2,6-dimethylphenyl)sulfonyl]-6-methylpiperidin-2- yljmethanol (139 mg, 425 μmol) in MeCN (1.5 mL) was added DIPEA (0.15 mL, 850 μmol) and PNP chloro formate (86 mg, 425 μmol). The mixture was stirred for 1 h, and then a solution of 1- (l-methylpiperidin-4-yl)piperazine (78 mg, 425 μmol) in MeCN (1 mL) was added, and the mixture stirred overnight. The reaction mixture was concentrated in vacuo and the crude material was taken up in DCM (5 mL). The organic phase was washed with saturated aqueous NaHCC>3 (3 x 5 mL), dried over Na₂SO₄, and concentrated in vacuo. A portion of the crude mixture was purified using preparative HPLC using method 3. Table 11

Claims

Evotec Neurosciences GmbH 09. April 2008EVO64642PC IB/EBU/ihClaims

1. A compound of formula (I)

or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein

R¹ is H; methyl; ethyl; n-propyl; i-propyl; or cyclopropyl, wherein methyl; ethyl; n- propyl; i-propyl; and cyclopropyl are optionally substituted with one or more halogen, which are the same or different;

X¹ is CR⁶R^6a; O; S; S(O); or S(O)₂;

R⁶, R^6a are independently selected from the group consisting of H; and halogen;

X² is O; S; or N(R⁷);

R²; R³; R⁴; R⁵; R⁷ are independently selected from the group consisting of H; methyl; ethyl; n-propyl; i-propyl; and cyclopropyl, wherein methyl; ethyl; n-propyl; i-propyl; and cyclopropyl are optionally substituted with one or more halogen, which are the same or different;

Optionally R², R³ or R⁴, R⁵ are joined together with the carbon atom to which they are attached to give a cyclopropyl, which is optionally substituted with one or more halogen, which are the same or different; n is 1 or 2;

m is 0; 1 or 2;

X³ is phenyl or a 5- or 6-membered aromatic heterocycle, wherein X³ is substituted in 2-position relative to the sulfonamide group in formula (I) with R⁸ and is optionally substituted with one or more R⁹, which are the same or different;

R⁸; R⁹ are independently selected from the group consisting of halogen; CN; COOR¹⁰; OR¹⁰; C(O)N(R¹⁰R^10a); S(O)₂N(R¹⁰R^10a); S(O)N(R¹⁰R^10a); S(O)₂R¹⁰;

N(R¹⁰)S(O)₂N(R^10aR^10b); SR¹⁰; N(R¹⁰R^10a); NO₂; OC(O)R¹⁰; N(R¹⁰)C(O)R^10a;

N(R¹⁰)S(O)₂R^10a;N(R¹⁰)S(O)R^10a; N(R¹ °)C (O)N(R¹⁰V ^ob); N(R¹⁰)C(O)OR^10a;

OC(O)N(R¹⁰R^10a); C(O)R¹⁰; Ci_-6 alkyl; C₂-₆ alkenyl; C₂-₆ alkynyl; and T, wherein Ci_₆ alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R¹¹, which are the same or different;

Optionally, R⁸ and R⁹ in 2-position relative to R⁸ are joined together with the atoms to which they are attached to form benzo; or a 5- or 6-membered aromatic heterocyle; wherein benzo; and the 5- or 6-membered aromatic heterocyle; are optionally substituted with one or more R¹², which are the same or different;

Optionally, two adjacent R⁹ are joined together with the atoms to which they are attached to form benzo; or a 5- or 6-membered aromatic heterocyle; wherein benzo; and the 5- or 6-membered aromatic heterocyle; are optionally substituted with one or more R¹², which are the same or different;

R¹² is independently selected from the group consisting of halogen; CN; COOR¹⁰; OR¹⁰; C(O)N(R¹⁰R^10a); S(O)₂N(R¹⁰R^10a); S(O)N(R¹⁰R^10a); S(O)₂R¹⁰; N(R¹⁰)S(O)₂N(R^10aR^10b); SR¹⁰; N(R¹⁰R^10a); NO₂; OC(O)R¹⁰; N(R¹⁰)C(O)R^10a; N(R¹⁰)S(O)₂R^10a;N(R¹⁰)S(O)R^10a; N(R¹ °)C (O)N(R¹⁰¹¹R^{1 ob}); N(R¹⁰)C(O)OR^10a;

OC(O)N(R¹⁰R^10a); C(O)R¹⁰; Ci_-6 alkyl; C₂.₆ alkenyl; C₂.₆ alkynyl; and T, wherein Ci_-6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R¹¹, which are the same or different; R¹⁰, R^1Oa, R^10b are independently selected from the group consisting of H; T; Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R¹³, which are the same or different;

R¹¹, R¹³ are independently selected from the group consisting of halogen; C(O)R¹⁴;

CN; COOR¹⁴; OR¹⁴; C(O)N(R¹⁴R^14a); S(O)₂N(R¹⁴R^14a); S(O)N(R¹⁴R^14a); S(O)₂R¹⁴;

N(R¹⁴)S(O)₂N(R^14aR^14b); SR¹⁴; N(R¹⁴R^14a); NO₂; OC(O)R¹⁴; N(R¹⁴)C(O)R^14a;

N(R¹⁴)S(O)₂R^14a; N(R¹⁴)S(O)R^14a; N(R¹⁴)C(O)N(R^14aR^14b); N(R¹⁴)C(CO)OR^14a;

OC^N^V^ and T¹;

R¹⁴, R^14a, R^14b are independently selected from the group consisting of H; T¹; Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R¹⁵, which are independently selected from the group consisting of halogen; C(O)R¹⁶; CN; COOR¹⁶; OR¹⁶; C(O)N(R¹⁶R^16a); S(O)₂N(R¹⁶R^16a); S(O)N(R¹⁶R^16a); S(O)₂R¹⁶; N(R¹⁶)S(O)₂N(R^16aR^16b); SR¹⁶;

N(R¹⁶R^16a); NO₂; OC(O)R¹⁶; N(R¹⁶)C(0)R^16a; N(R¹⁶)S(O)₂R^16a; N(R¹⁶)S(O)R^16a;

N(R¹⁶)C(O)N(R^16aR^16b); N(R¹⁶)C(CO)OR^16a; and OC(O)N(R¹⁶R^16a);

R¹⁶, R^16a, R^16b are independently selected from the group consisting of H; Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

T, T¹ are independently selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; adamantyl; C₃_₇ cycloalkyl; 4 to 7 membered heterocyclyl; and 9 to 11 membered heterobicyclyl, wherein T, T¹ are optionally substituted with one or more R¹⁷, which are independently selected from the group consisting of halogen; CN; C(O)R¹⁸; COOR¹⁸; OR¹⁸; C(O)N(R¹⁸R^18a);

S(O)₂N(R¹⁸R^18a); S(O)N(R¹⁸R^18a); S(O)₂R¹⁸; N(R¹⁸)S(O)₂N(R^18aR^18b); SR¹⁸;

N(R¹⁸R^18a); NO₂; OC(O)R¹⁸; N(R¹⁸)C(O)R^18a; N(R¹⁸)S(O)₂R^18a; N(R¹⁸)S(O)R^18a; N(R¹⁸)C(O)N(R^18aR^18b); N(R¹⁸)C(O)OR^18a; OC(O)N(R¹⁸R^18a); oxo (=0), where the ring is at least partially saturated; Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci _

6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more halogen, which are the same or different; R¹⁸, R^18a, R^18b are independently selected from the group consisting of H; Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

X⁴ is OR¹⁹ or NR¹⁹R^19a;

R¹⁹, R^19a are independently selected from the group consisting of H; T²; Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R²⁰, which are the same or different;

Optionally R¹⁹, R^19a are joined together with the nitrogen to which they are attached to from a 4 to 7 membered heterocycle or 9 to 11 membered heterobicycle, wherein the 4 to 7 membered heterocycle or 9 to 11 membered heterobicycle is optionally substituted with one or more R²¹, which are the same or different;

T² is independently selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; adamantyl; C₃_₇ cycloalkyl; 4 to 7 membered heterocyclyl; and 9 to 11 membered heterobicyclyl, wherein T² is optionally substituted with one or more R²², which are the same or different;

R²¹, R²² are independently selected from the group consisting of halogen; CN; COOR²³; OR²³; C(O)N(R²³R^23a); S(O)₂N(R²³R^23a); S(O)N(R²³R^23a); S(O)₂R²³; N(R²³)S(O)₂N(R^23aR^23b); SR²³; N(R²³R^23a); NO₂; OC(O)R²³; N(R²³)C(O)R^23a; N(R²³)S(O)₂R^23a; N(R²³)S(O)R^23a; N(R²³)C(O)N(R^23aR^23b); N(R²³)C(O)OR^23a; OC(O)N(R²³R^23a); oxo (=0), where the ring is at least partially saturated; C(O)R²³;

C_1-10 alkyl; C_2-10 alkenyl; C_2-10 alkynyl; and T³, wherein C_1-10 alkyl; C_2-10 alkenyl; and C₂-₁0 alkynyl are optionally substituted with one or more R²⁴, which are the same or different;

R²³, R^23a, R^23b are independently selected from the group consisting of H; T³; Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R²⁵, which are the same or different; R²⁰ is independently selected from the group consisting of halogen; CN; C(O)R²⁶; COOR²⁶; OR²⁶; C(O)R²⁶; C(O)N(R²⁶R^26a); S(O)₂N(R²⁶R^26a); S(O)N(R²⁶R^26a); S(O)₂R²⁶; N(R²⁶)S(O)₂N(R^26aR^26b); SR²⁶; N(R²⁶R^26a); OC(O)R²⁶; N(R²⁶)C(O)R^26a; N(R²⁶)SO₂R^26a; N(R²⁶)S(O)R^26a; N(R²⁶)C(O)N(R^26aR^26b); N(R²⁶)C(O)OR^26a; OC(O)N(R²⁶R^26a); d_₆ alkyl; C₂-₆ alkenyl; C₂-₆ alkynyl and T², wherein Ci_-6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R²⁷, which are the same or different;

R²⁴, R²⁵ are independently selected from the group consisting of halogen; CN; C(O)R²⁶; COOR²⁶; OR²⁶; C(O)R²⁶; C(O)N(R²⁶R^26a); S(O)₂N(R²⁶R^26a);

S(O)N(R²⁶R^26a); S(O)₂R²⁶; N(R²⁶)S(O)₂N(R^26aR^26b); SR²⁶; N(R²⁶R^26a); OC(O)R²⁶;

N(R²⁶)C(O)R^26a; N(R²⁶)SO₂R^26a; N(R²⁶)S(O)R^26a; N(R²⁶)C(O)N(R^26aR^26b);

N(R²⁶)C(O)OR^26a; OC(O)N(R²⁶R^26a); d_₆ alkyl; C₂-₆ alkenyl; C₂-₆ alkynyl and T³, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_₆ alkynyl are optionally substituted with one or more R²⁷, which are the same or different;

R²⁶, R^26a, R^26b are independently selected from the group consisting of H; T³; Ci_₆ alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R²⁸, which are the same or different;

97 98

R , R are independently selected from the group consisting of halogen; CN; COOR²⁹; OR²⁹; C(O)R²⁹; C(O)N(R²⁹R^29a); S(O)₂N(R²⁹R^29a); S(O)N(R²⁹R^29a); S(O)₂R²⁹; N(R²⁹)S(O)₂N(R^29aR^29b); SR²⁹; N(R²⁹R^29a); NO₂; OC(O)R²⁹; N(R²⁹)C(O)R^29a; N(R²⁹)SO₂R^29a; N(R²⁹)S(O)R^29a; N(R²⁹)C(O)N(R^29aR^29b); N(R²⁹)C(O)OR^29a; OC(O)N(R²⁹R^29a); d_₆ alkyl; C₂.₆ alkenyl; C₂.₆ alkynyl; and T⁴, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_₆ alkynyl are optionally substituted with one or more R³⁰, which are the same or different;

R²⁹, R^29a, R^29b are independently selected from the group consisting of H; Ci_₆ alkyl; C₂_6 alkenyl; C₂_6 alkynyl; and T⁴ wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R³¹, which are the same or different;

T³; T⁴ are independently selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; adamantyl; C₃_₇ cycloalkyl; 4 to 7 membered heterocyclyl; and 9 to 11 membered heterobicyclyl, wherein T³, T⁴ are optionally substituted with one or more R³², which are the same or different;

R³² is independently selected from the group consisting of halogen; CN; COOR³³; OR³³; C(O)N(R³³R^33a); S(O)₂N(R³³R^33a); S(O)N(R³³R^33a); S(O)₂R³³;

N(R³³)S(O)₂N(R^33aR^33b); SR³³; N(R³³R^33a); NO₂; OC(O)R³³; N(R³³)C(O)R^33a;

N(R³³)S(O)₂R^33a; N(R³³)S(O)R^33a; N(R³³)C(O)N(R^33aR^33b); N(R³³)C(O)OR^33a;

OC(O)N(R³³R^33a); oxo (=0), where the ring is at least partially saturated; C(O)R³³; T⁵;

Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R³⁴, which are the same or different;

R³³, R^33a, R^33b are independently selected from the group consisting of H; Ci_₆ alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same of different;

T⁵ is phenyl; C3_7 cycloalkyl; or 4 to 7 membered heterocyclyl, wherein T⁵ is optionally substituted with one or more R³⁶, which are the same or different;

R³⁰; R³¹; R³⁴ are independently selected from the group consisting of halogen; CN;

COOR³⁵; OR³⁵; C(O)R³⁵; C(O)N(R³⁵R^35a); S(O)₂N(R³⁵R^35a); S(O)N(R³⁵R^35a);

S(O)₂R³⁵; N(R³⁵)S(O)₂N(R^35aR^35b); SR³⁵; N(R³⁵R^35a); NO₂; OC(O)R³⁵;

N(R³⁵)C(O)R^35a; N(R³⁵)SO₂R^35a; N(R³⁵)S(O)R^35a; N(R³⁵)C(O)N(R^35aR^35b);

N(R³⁵)C(O)OR^35a; OC(O)N(R³⁵R^35a); Ci_-6 alkyl; C₂-₆ alkenyl; C₂-₆ alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more one or more halogen, which are the same of different;

R³⁵, R^35a, R^35b are independently selected from the group consisting of H; Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same of different;

R³⁶ is independently selected from the group consisting of halogen; CN; COOR³⁷; OR³⁷; C(O)N(R³⁷R^37a); S(O)₂N(R³⁷R^37a); S(O)N(R³⁷R^37a); S(O)₂R³⁷; N(R³⁷)S(O)₂N(R^37aR^37b); SR³⁷; N(R³⁷R^37a); NO₂; OC(O)R³⁷; N(R³⁷)C(O)R^37a; N(R³⁷)S(O)₂R^37a; N(R³⁷)S(O)R^37a; N(R³⁷)C(O)N(R^37aR^37b); N(R³⁷)C(O)OR^37a; OC(O)N(R³⁷R^37a); oxo (=0), where the ring is at least partially saturated; C(O)R³⁷; Ci_6 alkyl; C₂_6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R³⁷, R^37a, R^37b are independently selected from the group consisting of H; Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same of different.

2. A compound according to claim 1 of formula (Ia)

or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein R¹ to R⁵ and X¹ to X⁴ have the meaning as indicated in claim 1.

3. A compound according to claim 1 or 2, wherein R¹ is H or methyl.

4. A compound according to claim 3, wherein R¹ is H.

5. A compound according to one of the claims 1 to 4, wherein X¹ is O; CH₂; or CF₂.

6. A compound according to one of the claims 1 to 5, wherein X² is O.

7. A compound according to one of the claims 1 to 6, wherein R², R³, R⁴, R⁵ are H.

8. A compound according to one of the claims 1 to 7, wherein n is 1.

9. A compound according to one of the claims 1 to 8, wherein m is 1 or 2.

10. A compound according to claim 9, wherein m is 1.

11. A compound according to one of the claims 1 to 10, wherein X³ is selected from the group consisting of

wherein X is substituted as indicated in claim 1.

12. A compound according to claim 11, wherein X is selected from the group consisting of

wherein R , r R> 9 and R , 12 have the meaning as indicated in claim 1.

13. A compound according to one of the claims 1 to 12, wherein R⁸, R⁹, R¹² are independently selected from the group consisting of halogen; CN; OR 10 ; NO₂; phenyl; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen; or phenyl and wherein R¹⁰ is H; or Ci_₆ alkyl, which is optionally substituted with phenyl or one or more halogen, which are the same or different.

14. A compound according to claim 13, wherein R⁸, R⁹, R¹² are independently selected from the group consisting of F; Cl; Br; I; CN; OCH₃; NO₂; CH₃; CH₂CH₃; CH(CH₃)₂; and CF₃.

15. A compound according to one of the claims 1 to 14, wherein X⁴ is NR¹⁹R^19a, wherein R¹⁹, R^19a have the meaning as indicated in claim 1.

16. A compound according to one of the claims 1 to 15, wherein R^19a is selected from the group consisting of H; and Ci_6 alkyl.

17. A compound according to one of the claims 1 to 16, wherein R¹⁹ is selected from the group consisting of T²; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more R²⁰ and wherein T² and R²⁰ have the meaning as indicated in claim 1.

18. A compound according to claim 17, wherein Ci_6 alkyl is substituted with one R²⁰ and wherein R²⁰ has the meaning as indicated in claim 1.

19. A compound according to one of the claims 1 to 18, wherein R¹⁹, R^19a are joined together with the nitrogen to which they are attached to form a piperazinyl; a homopiperazinyl; or a thiazolidinyl ring, wherein the ring is optionally substituted with one or more R²¹ and wherein R²¹ has the meaning as indicated in claim 1.

20. A compound according to claim 19, wherein the ring is substituted with one R²¹ and wherein R²¹ has the meaning as indicated in claim 1.

20 21. A compound according to one of the claims 1 to 20, wherein R is selected from the group consisting of T²; and N(R²⁶R^26a), wherein R²⁶, R^26a have the meaning as indicated in claim 1.

22. A compound according to claim 21, wherein R²⁶, R^26a are independently selected from the group consisting of H; and Ci_6 alkyl.

23. A compound according to one of the claims 1 to 22, wherein R²¹ is selected from the group consisting of C_1-10 alkyl; C_2-10 alkenyl; C_2-10 alkynyl; and T , wherein C_1-; alkyl; C_2-10 alkenyl; and C_2-10 alkynyl are optionally substituted with one or more R and wherein T³ and R²⁴ have the meaning as indicated in claim 1.

24. A compound according to claim 23, wherein C_1-10 alkyl; C_2-10 alkenyl; and C_2-10 alkynyl are optionally substituted with one R²⁴ and wherein R²⁴ has the meaning as indicated in claim 1.

25. A compound according to one of the claims 1 to 24, wherein R²⁴ is selected from the ggrroouupp ccoonnssiissttiinngg ooff TT³³;; CCNN;; NN((RR²²⁶⁶RR^2266aa));; and C(O)N(R²⁶R^26a) and wherein R²⁶, R^26a have the meaning as indicated in claim 1.

26. A compound according to one of the claims 1 to 25, wherein T² and T³ are independently selected from the group consisting of phenyl; cyclopentyl; cyclohexyl; tetralinyl; pyrrolidinyl; imidazolyl; piperidyl; pyridyl; mopholinyl; thiophenyl; and benzodioxolanyl, wherein T² is optionally substituted with one or more R²² and T³ is optionally substituted with one or more R³².

27. A compound according to one of the claims 1 to 26, wherein T² is optionally substituted with up to 3 R²², which are the same or different and T³ is optionally

32 substituted with up to 3 R , which are the same or different.

28. A compound according to one of the claims 1 to 27, wherein R²², R³² are independently selected from the group consisting of halogen; CN; OCi_6 alkyl; Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl.

29. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to one of the claims 1 to 28 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

30. A pharmaceutical composition according to claim 29, comprising one or more additional compounds or pharmaceutically acceptable salts thereof selected from the group consisting of compounds according to one of the claims 1 to 28 and not being the first compound; or other Bradykinin Bl antagonists.

31. A compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 28 for use as a medicament.

32. Use of a compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 28 for the manufacture of a medicament for the treatment or prophylaxis of pain and inflammation including visceral pain (like pancreatitis, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuropathic pain (including postherpetic neuralgia, acute zoster pain, nerve injury, the "dynias", including vulvodynia, phantom limb pain, root avulsions, radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, carpal tunnel syndrome, ulnar neuropathy, tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system including but not limited to stroke, multiple sclerosis, spinal cord injury), and postsurgical pain syndromes (including postmastectomy syndrome, postthoracotomy syndrome, stump pain)), bone and joint pain (osteoarthritis), spine pain (including acute and chronic low back pain, neck pain, spinal stenosis), shoulder pain, repetitive motion pain, dental pain, sore throat, cancer pain, burn pain, myofascial pain (muscular injury, fibromyalgia), postoperative, perioperative pain and preemptive analgesia (including but not limited to general surgery, orthopedic, and gynecological), chronic pain, dysmenorrhea (primary and secodnary), as well as pain associated with angina, and inflammatory pain of varied origins (including osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis and gout, ankylosing spondylitis, bursitis); hyperreactive airways and to treat inflammatory events associated with airways disease like asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy- infant syndrome"; chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis (seasonal and perennial), and vasomotor rhinitis; pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis; inflammatory bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders including psoriasis and eczema, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and angioedema (including hereditary angioedema and drug-induced angioedema including that caused by angiotensin converting enzyme (ACE) or ACE/neutral endopeptidase inhibitors like omepatrilat); diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion); spasm of the gastrointestinal tract or uterus; liver disease, multiple sclerosis, cardiovascular disease, including atherosclerosis, congestive heart failure, myocardial infarct; neurodegenerative diseases, including Parkinson's and Alzheimers disease, epilepsy, septic shock, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia, hyperactive bladder; and obesity.

33. Use according to claim 32 for the treatment or prophylaxis of pain and inflammation.

34. A method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment one or more conditions selected from the group consisting of pain and inflammation including visceral pain (like pancreatitis, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuropathic pain (like postherpetic neuralgia, acute zoster pain, nerve injury, the "dynias", including vulvodynia, phantom limb pain, root avulsions, radiculopathy, painful traumatic mononeuropathy, painful entrapment neuropathy, carpal tunnel syndrome, ulnar neuropathy, tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system including but not limited to stroke, multiple sclerosis, spinal cord injury), and postsurgical pain syndromes (including postmastectomy syndrome, postthoracotomy syndrome, stump pain)), bone and joint pain (osteoarthritis), spine pain (including acute and chronic low back pain, neck pain, spinal stenosis), shoulder pain, repetitive motion pain, dental pain, sore throat, cancer pain, burn pain, myofascial pain (muscular injury, fibromyalgia), postoperative, perioperative pain and preemptive analgesia (including but not limited to general surgery, orthopedic, and gynecological), chronic pain, dysmenorrhea (primary and secodnary), as well as pain associated with angina, and inflammatory pain of varied origins (including osteoarthritis, rheumatoid arthritis, rheumatic disease, teno-synovitis and gout, ankylosing spondylitis, bursitis); hyperreactive airways and to treat inflammatory events associated with airways disease like asthma including allergic asthma (atopic or non-atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral- or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy-infant syndrome"; chronic obstructive pulmonary disease including emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis (seasonal and perennial), and vasomotor rhinitis; pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis; inflammatory bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis, inflammatory skin disorders including psoriasis and eczema, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and angioedema (including hereditary angioedema and drug-induced angioedema including that caused by angiotensin converting enzyme (ACE) or ACE/neutral endopeptidase inhibitors like omepatrilat); diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance or diabetic symptoms associated with insulitis (e.g. hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion); spasm of the gastrointestinal tract or uterus; liver disease, multiple sclerosis, cardiovascular disease, including atherosclerosis, congestive heart failure, myocardial infarct; neurodegenerative diseases, including Parkinson's and Alzheimers disease, epilepsy, septic shock, headache including cluster headache, migraine including prophylactic and acute use, stroke, closed head trauma, cancer, sepsis, gingivitis, osteoporosis, benign prostatic hyperplasia, hyperactive bladder; and obesity.

35. A process for the preparation of a compound according to any of the claims 1 to 28, comprising the steps of

reacting an N-protected compound of formula (IV)

with bromo compound Br-(CR⁴R⁵)_mC(O)OC(CH₃)₃ to yield a compound of formula (III)

deprotecting compound of formula (III) at the nitrogen atom and reacting the resulting compound with Cl-S(O)₂X³ to yield a compound of formula (II)

(H)

deprotecting compound formula (II) and reacting the resulting compound with H- X⁴ to yield compound of formula (I).