NZ626199B2 - Thieno- and furo - pyrimidines and pyridines, useful as potassium channel inhibitors - Google Patents

Thieno- and furo - pyrimidines and pyridines, useful as potassium channel inhibitors Download PDF

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NZ626199B2
NZ626199B2 NZ626199A NZ62619912A NZ626199B2 NZ 626199 B2 NZ626199 B2 NZ 626199B2 NZ 626199 A NZ626199 A NZ 626199A NZ 62619912 A NZ62619912 A NZ 62619912A NZ 626199 B2 NZ626199 B2 NZ 626199B2
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optionally substituted
piperidy1
thieno
6alkyl
pyrimidin
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NZ626199A
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Richard Blunt
Lindsay Brown
Fiona Chan
Simon D Edwards
Basil Hartzoulakis
Derek Edward John
David Madge
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Xention Limited
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Priority claimed from GBGB1119703.5A external-priority patent/GB201119703D0/en
Priority claimed from GBGB1214250.1A external-priority patent/GB201214250D0/en
Application filed by Xention Limited filed Critical Xention Limited
Priority claimed from PCT/GB2012/052842 external-priority patent/WO2013072694A1/en
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Publication of NZ626199B2 publication Critical patent/NZ626199B2/en

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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract

Disclosed herein are thieno and furo pyridine and pyrimidine compounds of formula (I) wherein R3 is N(RaRb)J where Ra and Rb form a ring with the nitrogen to which they are attached and the remainder of the substituents are as are defined herein. The compounds are potassium channel inhibitors intended for use in treatment of diseases or conditions that are mediated by KI3.1 and/or Kir3.4 or any heteromultimers thereof, or that require inhibition of Kir3.1 and/or Kir3.4 or any heteromultimers thereof such as cardiovascular diseases. Also disclosed are pharmaceutical compositions comprising the compounds of formula (I). ed for use in treatment of diseases or conditions that are mediated by KI3.1 and/or Kir3.4 or any heteromultimers thereof, or that require inhibition of Kir3.1 and/or Kir3.4 or any heteromultimers thereof such as cardiovascular diseases. Also disclosed are pharmaceutical compositions comprising the compounds of formula (I).

Description

THIENO- AND FURO - PYRIMIDINES AND PYRIDINES, USEFUL AS POTASSIUM CHANNEL INHIBITORS TECHNICAL FIELD The present invention relates to compounds of a (I) which are potassium channel inhibitors. Pharmaceutical compositions comprising the compounds, their use in therapy and s of treatment employing the compounds are also provided.
BACKGROUND ART Ion channels are proteins that span the lipid bilayer of the cell membrane and provide an aqueous y through which specific ions such as Nal, Kl, Ca2+ and Cl" can pass (Hille er al., 1999). Potassium channels represent the t and most diverse sub-group of ion channels and they play a central role in regulating the membrane potential, cell volume, signal transduction lling cellular excitability (Armstrong & Hille, 1998). Potassium channels have been categorized into gene families based on their amino acid sequence and their biophysical properties (for nomenclature see (Gutman er al., 2003) and http://www.iuphar-db.org/DATABASE/ReceptorFamiliesForward?type=IC).
Compounds which te potassium channels have multiple therapeutic applications in a number of areas/disorders including vascular, neuronal, renal, metabolic, endocrine, auditory, pain, respiratory, immunological, inflammation, gastrointestinal, reproduction, cancer and cell proliferation, (for reviews see (Ehrlich, 2008;Wulff & Zhorov, 2008;Kobayashi & Ikeda, 2006;Mathie & Veale, 2007;Wulff er al., 2009;Camerino er al., 2008;Shieh er al., 2000;Ford er al., 2002;Geibel, 2005). More specifically potassium channels such as those formed by Kir3.x, Kv4.x, Kir2.x, Kir6.x, Kv11.x, Kv7.x, KCa, sz, and Kvl.x along with their ancillary subunit are involved in the risation phase of the action ial in cardiac myocytes (Tamargo er al., 2004). These potassium channels subtypes have been associated with vascular diseases and disorders including atrial arrhythmias, ventricular arrhythmias, cardiomyopathy, hypertrophy long QT syndrome, short QT syndrome, Brugada me; and all of which can cause cardiac failure and fatality n, 2002;Novelli er al., 2010;Tamargo er al., 2004).
Inwardly rectifying potassium channels are members of a large superfamily comprised of Kirl .x to Kir7.x. The Kir3.x subfamily are G-protein d inwardly rectifying potassium ion channels comprised of 4 mammalian subunit members Kir3.l to Kir3.4. These subunits form homo- or - tetrameric ion channels ed in potassium flux across the membrane. Kir3.x ion channels are expressed in the cardiovascular system (Kir3.1 and Kir3 .4), central nervous system (Kir3.1, Kir3.2, Kir3.3 > Kir3.4), gastrointestinal tract (Kir3.1 and Kir3.2) and have been implicated in a number of disease areas including cardiac arrhythmias, pain, Parkinson’s disease, Down’s Syndrome, epilepsy/seizure, addiction, depression and ataxia (Luscher & Slesinger, 2010;Tamargo er al., 2004) The human G-protein coupled ly-rectifying potassium channel subunits Kir3.1 and Kir3.4 are inantly expressed in the supraVentricular regions (including atria, nodal tissue, pulmonary sleeve) and conduction system of the heart and are believed to offer therapeutic opportunities for the management of atrial fibrillation for several ent reasons (see review of ch, 2008): (1) Kir3.1/3.4 underlies IKACh: There is eVidence that a eric assembly of Kir3.1 and/or Kir3.4 subunits underlies the cardiac acetylcholine/adenosine activated inwardly- rectifying potassium current o referred to as IKACh) in the heart due to similar biophysical (Kraininsky er al., 1995;Duprat et al., 1995;Corey & CLAPHAM, 1998;Corey er al., 1998) and pharmacological (Jin & Lu, 1998;Jin er al., 1999;Jin & Lu, rici er al., 2000;Cha er al., 2006;DobreV er al., oigt er al., 2010b) properties (for review see (Hibino er al., 2010;Be1ardinelli er al., 1995)). (2) IKACh is ed in AF: The Kir3.1 subunit cannot form a functional homotetramer or cannot traffic to the ne pson er al., 1995;Hedin er al., 1996;Woodward er al., 1997) and as such genetic knockout of Kir3.4 gene in the mouse results in the lack of a functional IKACh in the atria (Wickman et al., 1998). This genetic ablation of IKACh results in resistance to atrial fibrillation (Kovoor er al., 2001). These data support the notion of an ly of Kir3.1/3.4 and the importance of IKACh in the initiation and sustaining of AF. Furthermore, single nucleotide polymorphisms of Kir3.4 gene have been correlated with paroxysmal lone AF in a Chinese population (Zhang et al. no on has been ascribed to these polymorphisms. , 2009). However, (3) IKACh is an atrial-specific target: High levels of Kir3.1 and Kir3.4 gene expression (Gaborit et al., 2007b) and large IKACh are found in both the left and right human atria (DobreV er al., 2001;DobreV er al., 2005;Voigt er al., 2010b;Wettwer et al., 2004;Bosch er al., 1999;Voigt et al., 2010a). This contrasts with the human ventricle, where mRNA (Gaborit et al., 2007b) and current expression are considerable smaller, and the number of cells expressing IKACh and the ACh ivity is small compared to the atria (Koumi & Wasserstrom, 1994;Koumi et al., 1994). In conjunction with a lower density of parasympathetic innervations (Kent et al., 1974), this argues t a functional role of IKACh in human ventricles (Brodde & Michel, 1999;Be1ardinelli er al., 1995). This is further supported by the lack of effect of selective IKACh inhibitors on cular repolarisation in in vitro (Cha er al., 2006) and in viva dog studies (Hashimoto er al., 2006;Hashimoto er al., 2008;Machida er al., 2011). The predominant expression of IKACh in the atria cf. the ventricle provides a mechanism to modulate atrial risation without ering with ventricular repolarisation and potentially inducing fatal ventricular arrhythmia (Hashimoto er a1. , 2006). (4) Constitutive-activation of IKACh in chronic AF: The carbachol-induced IKACh recorded from atrial myocytes from ts with chronic AF is smaller than those from patients in sinus rhythm, a phenomenon initially thought to be due to decreased Kir3.4 mRNA and protein levels (Bosch er al., 1999;Brundel er al., 2001a;Brunde1 er al., 2001b;Dobrev er al., 2001). However, it was later demonstrated that the blunted response to carbachol is due to IKACh being constitutively active in the absence of agonist (Dobrev er al., 2005). Similar observations have also been reported in the atria and pulmonary vein in the tachypaced-dog model ofAF (Cha er al., 2006;Ehrlich er a1. 2004;Voigt er al., akary er al., 2011). Ionic remodeling (for review see (Schotten er al., 2011;Workman er al., 2008), including the constitutive —activation of IKACh, contributes to the shortening of action ial duration observed in chronic AF human patients (Dobrev er al., obrev et al., 2005;Bosch er al., 1999;Wettwer er al., 2004) and tachypaced dog atrial myocytes (Ehrlich er al., 2004;Ehrlich er al., 2007;Cha er al., 2006), which, in turn, causes a reduction in the atrial effective refractory period (Brundel er al., 2002b;Brundel er al., Workman er al., 2008) predisposing to the generation of arrhythmias. In on, the geneous distribution (Gaborit er al., 2007a;Lomax er al., 2003;Sarmast er al., 2003;Voigt er al., 2010b) of constitutively active IKACh (Dobrev er al., 2005;Cha er al., 2006;Ehrlich et al., 2004) across the atria is expected to increase the dispersion of atrial repolarization/refractoriness (Liu & Nattel, 1997;Kabell er al., 1994;Schauerte er al., 2000;Chiou er a1. , 1997) and in turn increase vulnerability to transient atrial arrhythmias (Liu & Nattel, 1997;Kabell er al., 1994). Pharmacological studies have shown that selective inhibition of IKACh has as a more pronounced prolonging effect on action potential on in the remodeled dog atria (Cha er al., 2006;Ehrlich er al., 2007).
Prolonging the action potential duration by inhibiting IKACh or the tutive IKACh could present safer pharmacological interventions for protecting against atrial arrhythmias such as chronic atrial fibrillation and atrial flutter ed to traditional class III antiarrhythmics by prolonging the atrial refractory period while leaving ventricular refractoriness red (Cha er al., 2006;Tanaka & oto, 2007;Hashimoto er al., 2007;Machida er al., 2011). (5) IKACh Inhibitors in AF: Class III antiarrhythmics have been widely reported as a red method for treating cardiac arrhythmias (Colatsky er al., 1990). Traditional and novel class III antiarrhythmic potassium channel blockers have been reported to have a mechanism of action that includes the direct tion of Kir3.1/3.4 or IKACh.
The known antiarrhythmics dronedarone (Altomare er al., 2000;Guillemare er al., 2000), rone (Watanabe et al., 1996;Guillemare et al., 2000), propafenone (Voigt er al., 2010a) and flecainide (Voigt er al., 2010a), ibutilide (Borchard er al., 2005) quinidine (Kurachi er al., 1987;Hara & , 2002), verapamil o er al., 2010), AVE0118 (Gogelein er al., 2004;Voigt er al., 2010a) NIP-142 (Matsuda er al., 2006;Hashimoto er al., 2007;Tanaka & Hashimoto, 2007), NIP-151 moto er al., 2008), NTC-801(Machida er al., 2011) have all been reported as potassium channel blockers of Kir3.1/3.4 or IKACh in atrial myocytes. A benzopyran derivative, NIP-142, preferentially blocks Kir3.1/3.4 with selectivity over other c channels, prolongs the atrial refractory period and terminates atrial fibrillation and flutter in in viva canine models (Nagasawa er al., 2002;Tanaka & Hashimoto, 2007). From the same chemical class, both NIP-151 and NTC-801 are highly selective IKACh inhibitors and have been shown to be effective in terminating AF in the vagal-induced and ine-induced canine models of AF moto er al., 2008;Machida er al., 2011). The latter, NTC- 801, has also been shown to prevent the induction of AF in an atrial-tachypacing dog model of persistent AF (AT-AF) (Machida er al., 2011) in which the atria exhibit electrical ling akin to chronic AF in man (Cha er al., hrlich er al., 2004;Voigt er al., 2008;Makary er al., 2011). The selective IKACh inhibitor peptide tertiapin (Jin & Lu, 1998;Drici er al., 2000) has also been shown to be effective in terminating AF in both vagal-induced and acontine-induced canine models of AF (Hashimoto er al., 2006). None of the agents were shown to affect ventricular repolarisation (QTc or VERP) at therapeutically relevant doses. These data support the utility of IKACh inhibitors for the cardioversion and prevention of recurrence of supraventricular arrhythmias such as AF and atrial flutter without effecting ventricular function. A combination of anti-arrhythmics with other ion channel modulating drugs may also provide greater gistic) benefit in the treatment of atrial arrhythmias as shown for the non-selective anti-arrhythmics drugs amiodarone/dronedarone and ranolozine (Burashnikov er al., 2010;Sicouri er al., 2009) and the combination of the IKr inhibitor sotalol with an IKur inhibitor BMS-394136 (Sun et al., 2010). As such, the combination of a selective IKACh inhibitor with other ion channel or ion ger modulating drugs could provide added clinical benefit. (6) IKACh inhibition in stroke tion in AF: Atrial fibrillation is associated with a 5-fold increased risk for stroke and in the United States approximately 15% to 25% of all strokes can be attributed to AF (Steinberg, 2004). Regardless of the ch to arrhythmias ent (rate, rhythm, ablation), the prevention of thromboembolism is a cornerstone of clinical treatment of atrial arrhythmias. Constitutive activation of IKACh has been reported to contribute to the contractile deficit associated with AF in the tachypaced-atrial dog model of AF. tion of IKACh could be a novel target to prevent hypocontractility-related thrombo-embolic complications (Koo er al., 2010).
IKACh inhibitors alone or in combination with other anti-platelet or anti-coagulant therapies may significant reduce the risk of stroke and thromboembolism in AF. (7) Role of autonomic system in AF: Clinical (Coumel, 1994;Coumel, 1996;Pappone et al., 2004;Tan er al., 2006;Yamashita er al., 1997;Huang er al., 1998) and experimental (Liu & Nattel, 1997;Ogawa er al., 2007;Sharifov er al., 2004;Jayachandran er al., cherlag er al., 2005;Horikawa—Tanami er al., 2007;Po er al., 2006) observations highlight the importance of the autonomic nervous system and in ular parasymthpathetic / vagal activation in AF. The electrophysiologic ate of AF is often latent until vagal activation which is sufficient to induce and maintain AF via IKACh activation. IKACh inhibitors are expected to be effective in the treatment of paroxysmal AF with a neurogenic (vagal) component. (8) Autonomic system in the initiation of AF: Ectopic activity arising from the pulmonary veins and sleeves (PV) has been shown to play a prominent role in the tion and maintenance of AF (Haissaguerre er al., 1998;Pappone er al., 2000). Pulmonary vein isolation is a procedure used frequently to ate the triggers g from the pulmonary veins. Electrical activity, originating from PV s following parasympathetic and/or sympathetic stimulation, has been proposed as a potential trigger in the initiation of AF (Burashnikov & Antzelevitch, 2006;Patterson er al., 2005;Patterson er al., 2006;Wongcharoen er al., 2007;Lo er al., 2007). Studies in animal models have shown an increase in the time-dependent IKACh in the pulmonary sleeve of the AT-AF dog (Ehrlich er al., 2004). Autonomic nerve stimulation reduces PV- sleeve action potential on and causes triggered PV firing that is suppressed by muscarinic cholinergic receptor blockade (Patterson er al., 2005). Fibrillatory cycle length shortening in response to vagal stimulation points to ACh effects on PV drivers (Takahashi er al. , 2006). Thus, inhibition of IKACH could remove vagally enhanced PV drivers that initiate and maintain AF. (9) Autonomic nervous system in atrial remodeling: Auto-antibodies to the muscarinic M2 receptor have been shown to increase sion of Kir3.1 and Kir3.4 mRNA and Kir3.4 protein in the rabbit heart, resulting in both ical and structural remodeling creating a substrate for AF (Hong et al., 2009). Increased vagal-nerve activity has been shown to promote atrial electrical remodeling in atrial tachypaced dogs; this effect was partially revered by atropine and fully reversed by a combination of cholinergic block and a vasoactive intestinal polypeptide (VIP) nist (Yang et al., 2011). Clinical studies have also shown that parasympathetic block may promote the recovery from AERP shortening associated with rapid atrial pacing (Miyauchi er al., 2004). Although the mechanism that underlies these observations is not fully elucidated, inhibition of IKACH alone or in combination with other agents could prevent or e atrial remodeling associated with AF.
Beyond use in the treatment of atrial arrhythmias, Kir3.1/3.4 inhibitors may have utility in a number of other indications: (1) IKACh and sinoatrial and atrioventricular node function: Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon stimulation of the vagus nerve. Negative tropic and ropic effects are cardiovascular features ated with ACh e upon mpathetic stimulation. In the mammalian heart, cholinergic parasympathetic fibres are extensively distributed to the sinus node, to the atria and to the atrioventricular (AV) node. Vagal stimulation produces a negative chronotropic and dromotropic effect on the heart and can induce or pose to atrial arrhythmias due to shortening of the atrial ERP. Vagal stimulation increases AV-ERP (ALANIS er al., 1958;ALANIS er al., 1959), prolongs atrial conduction time n, 1977) and es a negative dromotropic effect. Selective inhibition of IKACh with tertiapin has been shown to inhibit the dromotropic and blunts the chronotropic effects of ACh on the heart and relieve AV block (Drici et al., 2000). The nce of Kir3.1 and Kir3.4, is reported to be equal in the sinus node and atrial muscle (Tellez er al., 2006). Activation of IKACh causes decreased spontaneous activity, hyperpolarization of the maximum lic potential, and a decrease in the diastolic depolarization rate of the SA node contributing to the negative chronotropic effect of ACh (Dobrzynski et 2012/052842 al., 2007;Han & Bolter, 2011;Rodriguez-Martinez er al., 2011). Atrial fibrillation is associated with structure and ionic remodelling in the atria (for review see (Schotten et al., 2011;Workman er al., 2008) and damage to the SAN (Thery er al., 1977). al studies have shown that sick sinus syndrome is frequently associated with AF and atrial flutter (Ferrer, 1968;Gomes er al., 1981). Sinoatrial node dysfunction is a heterogeneous disorder of unknown etiology characterized by a variety of supraventricular arrhythmias with symptoms of persistent bradycardia, tachycardia, syncope, palpitations, and ess. The mechanism underlying the abnormal rhythm is incompletely understood.
However, ne, a muscarinic antagonist, is used in the treatment of sick sinus syndrome. However, side-effects preclude its long term use (1973). Taken together, these data highlight both the presence and functional importance of IKACh in the SAN and AVN and indicate the potential of an IKACh inhibitor to te AV conduction in setting of hypervagotony or early inferior myocardial infarctions (Drici er al., 2000) and provide a novel mechanism in the treatment of sinus node dysfunction. (2) Kir3.1/3.4 inhibitors and prevention of thromboembolism: Current ches to the prevention of thromboembolism e the use of anti-platelet therapy (6.g. aspirin) or anticoagulation y including the use vitamin K antagonist warfarin, and oral agents, ing direct thrombin inhibitors such as dabigatran, ximelagatran and factor Xa inhibitors such as apixaban, rivaroxaban, and an, betrixaban and YM150 (for review see (Ezekowitz er al., . d blood vessels, red blood cells and platelets release ADP and induce platelet aggregation. Pathological thrombosis formation can lead to vascular occlusion, resulting in ic insults. The et ADP receptor designated P2Y12, the target of the antithrombotic agents like clopidogrel, activates Kir3.x channels via Gi/o proteins (Hollopeter er al., 2001). Human platelets have been shown to express both Kir3.1 and Kir3.4 protein by Western blot (Shankar et al., 2004). Kir3.1/3.4 inhibitors, such as SCH23390 and ethosuximide, can inhibit ADP- and thrombin-mediated platelet aggregation (Shankar er al., 2004;Kobayashi er al., 2009). Therefore, Kir3.1/3.4 inhibitors may be effective for preventing thrombosis and thromboembolic diseases including stroke, myocardial tion and peripheral vascular diseases (Kobayashi & Ikeda, 2006). (3) Kir3.4 and atic function: Although predominantly expressed in the heart Kir3.4 has been cloned from the human pancreas (Chan et al., 1996) and has been detected in 0., B, 5 cells of the mouse pancreas (Yoshimoto er al., 1999;Ferrer er al., 1995;1wanir & Reuveny, 2008). Electrophysiological studies have shown that somatostatin and 0.2- adrenoceptor agonists activate sulfonylurea-insensitive K+ channels by a G protein- dependent mechanisms, and thereby inhibit activity of Kir3.4-expressing s (Rorsman er al., 1991), (Yoshimoto er al., 1999), suggesting that activation of Kir3 channels may inhibit insulin secretion. Additionally, somatostatin released from 5 cells activates Kir3 channels in glucagon-expressing or cells (Yoshimoto er al., 1999). The line-induced hyperpolarisation of mouse pancreatic cells has been shown to be a tertiapin-sensitive inwardly—rectifying potassium t (Iwanir & Reuveny, 2008).
Therefore, pancreatic Kir3.4 channels may be related to control of pancreatic hormone secretion and have utility in the treatment of diabetes mellitus alone or in combination with sulfonylureas and other oral agents (Kobayashi & Ikeda, 2006). (4) Kir3.1/3.4 in the central nervous system: In on to expression in the heart, Kir3.1 and Kir3.4 mRNA have been detected in the parts of the brain (Wickman er al., 2000;Mark & Herlitze, 2000;Hibino er al., 2010). A number of psychotropic and anti- depressant drugs have been shown to inhibit the Kir3.1/3.4 ls including paroxetine (Kobayashi et al., 2006), fluoxetine (Kobayashi et al., 2003), tine (Kobayashi et al., 2010), atomoxetine (Kobayashi et al., 2010), mipramine, desipramine, amitriptyline, nortriptyline, ramine, maprotiline, citalopram (Kobayashi et al., 2004), and ethosuximide (Kobayashi et al., 2009). This suggests that the Kir3.x inhibition may underlie some of the therapeutic effects related to the CNS.
As such, Kir3.1/3.4 inhibits may have utility in the treatment of neurological and neuropsychiatric ers es including pain, depression, anxiety, attention- deficit/hyperactivity disorder, and epilepsy. (5) Kir3.1/3.4 and pituitary function: Kir3.1 and Kir3.4 have been detected in the pituitary cells of the rat rson er al., 2001;Wu1fsen er al., 2000) where they potentially play a critical role in excitation-secretion coupling. As such, Kir3.1/3.4 inhibitors could be used to modulate neuro-endocrine function and the secretion of pituitary hormones. However, corroborative data in man is currently lacking. (6) Kir3.1/3.4 and cancer: In addition, other s have cloned Kir3.1 and Kir3.4 from human breast cancer cell line (Wagner er al. and suggest they may be ed in , 2010) cellular signaling and cancer (Dhar & Plummer, III, 2006;Plummer, III et al., 2004).
Although additional data are required to establish a causal link, ing Kir3.1/3.4 could be useful in the ent of breast cancer.
Nissan al Industries have reported a series of substituted yrans as atrial- specific antiarrythmics.
In WO 01/21610 Nissan discloses a series of benzopyran derivatives which are d to increase the functional refractory period in an ex vivo preparation of guinea pig atrial tissue with potential use as atrial-specific antiarrythmics.
In WO 02/064581, WO 03/000675 and Nissan discloses a series of 4- amino tuted benzopyran derivatives which are claimed to selectively prolong the atrial refractory period in an in vivo dog model of vagal-induced atrial fibrillation with potential use as atrial-specific antiarrythmics.
In Nissan discloses a series of fused tricyclic benzopyran derivatives which are claimed to selectively prolong the atrial refractory period in an in vivo dog model of vagal-induced atrial fibrillation with potential use as atrial-specific antiarrythmics.
The above Nissan patents do not specify a biological , but in subsequent publications (Hashimoto er al, 2008) compounds of these documents have been disclosed as blockers of the Kir3.l/3.4 channel and the IKACh c t. discloses a series of derivatives of the flavone acacetin which are claimed inter alia as blockers of the cardiac acetylcholine-activated current (IKACh) with potential use as atrial-specific antiarrythmics.
In WC 2009/104819 Otsuka Pharmaceuticals discloses a series of benzodiazepine derivatives which are claimed as blockers of the Kir3.l/3.4 channel with potential use as atrial-specific antiarrythmics. pyrimidines, pyrimidines and thienopyridines have been shown to modulate ligand-gated and voltage-gated ion channels as well as GPCRs.
U82005/0222175 and U82005/022176 disclose ridylamino substituted thieno[2,3- midines which te the 5-HT receptor, in particular, the 5-HT2b receptor for the treatment of pulmonary arterial hypertension, heart failure, and hypertension.
U82007/02877l7 (Vertex) discloses 2-phenyl substituted thieno[2,3-d] pyrimidines which modulate voltage-gated sodium and calcium channels for the treatment of various disorders including epilepsy and neuropathic pain.
U82009/0270405 and W02011/053292 disclose quinuclidine substituted thieno[2,3-d] pyrimidines which modulate the alphanicotinic acetylcholine receptor for the treatment of affective and neurodegenerative disorders.
W02004/11057 (Xention) discloses 4-alkylamino and 4-alkoxy thieno[2,3-d]pyrimidines as blockers of the KVl.5 voltage-gated potassium channel for the treatment of Atrial Fibrillation. /121149 (Xention) discloses furano[2,3-d]pyrimidines as blockers of the KVl.5 voltage-gated potassium l for the ent of Atrial Fibrillation. /066127 on) discloses 4-aminoalkyl and 4-alkoxy substituted thieno[3,2- c]pyridines as blockers of the KVl,5 voltage-gated potassium channel for the treatment of Atrial Fibrillation and also as blockers of the KVl .3 voltage-gated potassium l for the ent of autoimmune disorders.
W02006/06l642 (Xention) discloses 4-alkylamino tuted thieno[2,3-b]pyridines as blockers of the KVl,5 e-gated potassium channel for the treatment of Atrial Fibrillation and also as blockers of the Kvl.3 voltage-gated potassium channel for the treatment of autoimmune disorders.
Ramakrishna er al disclose fused thieno[2,3-d]pyrimidines and 4-alkoxythineo[2,3- d]pyrimidines which act as antagonists of the 5-HT6 receptor.
Modica er al (2004) disclose 4-piperazinyl thieno[2,3-d]pyrimidines which behave as competitive antagonists of the 5-HT3 receptor.
Thienopyrimidines have also been shown to be useful against other biological targets.
U82003/0153556 ses 4-piperazinyl and 4-homopiperazinyl substituted thieno[2,3- d]pyrimidines for the treatment of thrombosis.
W02006/0799l6, W02006/103555, /103545, W02006/103544, and / l 00591 acia and Upjohn) discose 2-aminopiperidyl substituted thieno[2,3-d]pyrimidines for the inhibition of ADP-mediated platelet ation.
USZOl 1/0166121 (LG Lifesciences) ses fused 4-piperidinyl and 4-piperazinyl thieno[2,3-d] pyrimidines for the inhibition of platelet aggregation. /029054 (University of Michigan) discloses 4-piperazinyl and 4-homopiperazinyl theino[2,3-d]pyrimidines which inhibit the interaction of menin with the oncogene Mixed Lineage Leukemia (MLL).
W02004/014850 (Predix ceuticals) discloses 4-(aminopiperidyl) substituted thieno[2,3-d]pyrimidines as Neurokinin antagonists.
W02004/06539l (Almirall Prodespharma) discloses 4-aminocarbonitrile substituted thieno[2,3-d]pyrimidines as tors of PDE7 for the treatment of T-cell mediated immune disorders. /03003l (Janssen/Addex) discloses 4-alkylamino substituted thieno[2,3- d]pyrimidines as positive allosteric modulators of the mGluR2 receptor.
W02006/07l988 (Memory Pharmaceuticals) discloses 4-alkoxy, 4-alkyl, and 4-aminoalkyl thieno[2,3-d]pyrimidines as inhibitors of PDE10.
W02009/007115 (Syngenta) discloses 4-tropanyl substituted thieno[2,3-d]pyrimidines that are claimed to have usefulness as pesticides.
Gorja er al (2011) disclose 4-alkynyl substituted tricyclic thieno[2,3-d]pyrimidines which were tested for cytotoxic activity against the chronic myelogenous leukemia (CML) cell line. 2012/052842 Jang er al (2010) disclose a series of 4-N—piperazinyl thieno[2,3-d]pyrimidines which were tested for immunosuppressive activity in a mixed lymphocyte reaction (MLR) assay.
Tasler er al (2010) disclose a series of 4-(4-aminopiperidyl) substituted thieno[2,3- d]pyrimidines which act as agonists for the BS-adrenoreceptor.
DISCLOSURE OF THE INVENTION A first aspect of the invention provides a compound of formula (I) R2 l I 2% (I) or a pharmaceutically able derivative thereof, wherein: A is O or S; X is N or CR3H; V is N or CR3 111; ZisNor CR31V; n one or two of V, X and Z are N; R1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R2 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally tuted alkoxy, , —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, — CONR4R5, , optionally substituted oxazolinyl, —SR14, —S(O)R14 and —S(O)2R14; R31 is selected from H, halo, —CN, trifluoromethyl, ally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, —NR6C(O)R7, — )2R7, —S(O)2NR4R5, —CONR4R5, —COZR7, —NR8R9, —CEC—J, optionally substituted cycloalkyl-J and —(NRaRb)—J; Each of R311, R3111, and R3“; is independently selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, —NR6C(O)R7, — NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, optionally substituted —alkylene—CONR4R5, — C02R7, —NR1°R“, —CEC—J, ally substituted cycloalkyl-J and —(NRcRd)—J, provided that R31 is —CEC—J, optionally tuted cycloalkyl-J or —(NRaRb)—J, and/or at least one of R311, R3111, and R3“; is present as —CEC—J, optionally substituted cycloalkyl-J or —(NRcRd)—J; wherein Ra and Rb are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1. zalkylene, —NR6—, —O—, or —S(O)Z—, wherein the optionally d, optionally substituted heterocycloalkyl ring is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, linyl, tetrahydro-l,3-oxazinyl, hexahydropyrimidinyl, l,4-thiazanyl, azepanyl, 1,4-oxaazepanyl, and l,4-thieazepanyl; wherein Rc and Rd are linked to form an optionally substituted 4 to 7 ed heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1. zalkylene, —NR6—, —0—, or —S(O)Z—; J is selected from H and —(CR12R13)q—L—M—W, wherein q is 0, 1 or 2; L is —O— or —N(G)—; and G is selected from hydrogen, optionally substituted alkyl and ally substituted cycloalkyl; M is —(CR12R13)t—; tis0,1,2or3; W is selected from the group consisting of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally tuted cycloalkyl, optionally substituted heterocycloalkyl, optionally tuted aryl, optionally substituted heteroaryl and —NR8R9, n when W is optionally substituted cycloalkyl it may optionally be bridged by a bond or optionally substituted C1_2alkylene, and wherein when W is optionally tuted heterocycloalkyl it may optionally be bridged by a bond, optionally substituted C1_2alkylene, —NR6—, —O—, or —S(O)Z—; atively, when L = —N(G)—, L, G, M and W may be linked to form an optionally substituted heterocycloalkyl, an ally substituted heterocycloalkenyl, or an optionally substituted heteroaryl; z is 0, l or 2; R4 and R5 are, at each instance, independently selected from H, optionally substituted alkyl, optionally tuted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl, or are linked to form an optionally substituted cycloalkyl; R6 and R7 are, at each instance, independently selected from H and optionally substituted alkyl, or are linked to form an optionally substituted heterocycloalkyl; R8 and R9 are, at each instance, independently ed from optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, ally substituted heteroaryl, and ally substituted cycloalkyl; R10 and R11 are, at each instance, independently ed from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted cycloalkyl; R12 and R13 are, at each instance, independently selected from H, hydroxy, and optionally substituted alkyl, or may be linked to form an optionally substituted cycloalkyl ring, or may together form =0; and R14 is ally substituted alkyl, wherein the optional substituents are independently selected from halo, omethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, -OH, -NOz, -CN, -COzH, -COZC1_ 6alkyl, -SO3H, -SOC1_6alkyl, -SOZC1_6alkyl, -NHSOZC1_6alkyl, -NC1_6alkylSOZC1_6alkyl, -SOzNH2, -SOzNHC1_6alkyl, -SOZN(C1_6alkyl)2, -NHSOZNH2, -NHSOZNHC1_6alkyl, -NHSOZN(C1_6alkyl)2, -NC1_6alkylSOzNH2, -NC1.6alkylSOZNHC1_6alkyl, -NC1_ 6alkylSOZN(C1_6alkyl)2, -C(=O)H, -C(=O)C1_6alkyl, -NHC(=O)C1_6alkyl, -NC1_ 6alkle(=O)C1_6alkyl, C1_6alkylenedioxy, =O, -N(C1_6alkyl)2, -C(=O)NH2, NHC1_6alkyl, -C(=O)N(C1_6alkyl)2, -NHC(=O)NH2, O)NHC1_6alkyl, -NHC(=O)N(C1_6alkyl)2, -NC1_6alkle(=O)NH2, -NC1-6alkle(=O)NHC1.6alkyl, -NC1_ 6alkle(=O)N(C1.6alkyl)2, -C(=NH)NH2, -C(=NH)NHC1_6alkyl, )N(C1_6alkyl)2, -C(=NC1_6alkyl)NH2, -C(=NC1-6alkyl)NHC1_6alkyl, -C(=NC1-6alkyl)N(C1_6alkyl)2, -C1_6alkyl, -C3_6cycloalkyl, -C3_6heterocycloalkyl, 2-imidazolidinonyl, l-C1-6alkylimidazolidinon- 3-yl, C1-6alkle3.6heterocycloalkyl, aryl, haloaryl, C1_6alkoxyaryl, -C1_6alkylene—NHSOZC1_ 6alkyl, -C1-6alkylene—NC1.6alkylSOZC1_6alkyl, -C1_6alkylene—SOZNH2, -C1_6alkylene— SOZNHC1_6alkyl, -C1-6alkylene—SOZN(C1.6alkyl)2, —ZtH, —Zt-C1_6alkyl, -C1_6alkylene—ZIH, — Zt-C3_6cycloalkyl, or -C(=O)NHC1_6alkylene—ZtH wherein Z1 is independently O, S, NH or N(C1_6alkyl).
In one embodiment, A is S, Z is N and V is CR3 111- In a further embodiment, X is N. In a further embodiment, R1 is phenyl. In a further embodiment, R2 is selected from H, trifluoromethyl, tuted alkyl, optionally substituted alkoxy, —NR4R5, O)R7, — S(O)2NR4R5, —CONR4R5, , optionally substituted oxazolinyl, —SR14, 14 and — S(O)2R14. In a further embodiment, R31 is selected from trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, — NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —COZR7, —NR8R9 optionally substituted cycloalkyl-J and —(NRaRb)—J. In a r embodiment, R3111, is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, — NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, optionally substituted —alkylene— CONR4R5, —C02R7, —NR1°R“, optionally substituted cycloalkyl-J and —(NRcRd)—J. In a further embodiment, R31 is —(NRaRb)—J. In a further embodiment, R31 is —(NRaRb)—J, V is CR3111 and R3111 is H or —(NRcRd)—J and, in at least one instance, I is—(CR12R13)q—L—M—W.
In a r embodiment, q is 0 or 1. In a further embodiment, q is 1. In a further embodiment, t is 0, l or 2. In a further embodiment, t is 2. In a further ment, L is O, or, in an alternative embodiment, L is —N(G)—. In a further embodiment, R12 and R13 are, at each ce, H. In a further embodiment, W is ally tuted heterocycloalkyl.
A second aspect of the invention provides a ceutical composition comprising at least one compound of formula (I) and, optionally, one or more pharmaceutically able excipients.
A third aspect of the invention provides a compound of formula (I) or a composition sing at least one compound of formula (I) for use in therapy.
A fourth aspect of the invention provides a method for the treatment of a disease or ion that is mediated by Kir3.l and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.l and/or Kir3.4 or any heteromultimers thereof, comprising administering to a subject an ive amount of at least one compound of formula (I) or ition comprising at least one compound of formula (I).
A fifth aspect of the invention provides a compound of formula (I) or a ition comprising at least one compound of formula (I) for use in a method for the treatment of a disease or condition that is mediated by Kir3.1 and/or Kir3.4 or any heteromultimers thereof, or that es inhibition of Kir3.1 and/or Kir3.4 or any heteromultimers thereof, comprising administering to a subject an effective amount of at least one compound of formula (I) or composition comprising at least one compound of formula (I).
A sixth aspect of the invention provides the use of a compound of formula (I) for the manufacture of a medicament for use in the treatment of a disease or condition that is mediated by Kir3.l and/or Kir3.4 or any multimers thereof, or that requires inhibition of Kir3.1 and/or Kir3.4 or any heteromultimers thereof In the first, second and third aspects of the invention, the compound of formula (I) is not: 2-Benzylmethylmorpholinyl-thieno [2, 3 -d] pyrimidinecarbonitrile, [l-(5-phenyl-thieno[2,3-d]pyrimidinyl)-piperidinyl]-carbamic acid tert-butyl ester, [l-(6-methylphenyl-thieno [2,3 -d]pyrimidinyl)-piperidinyl] -carbamic acid utyl ester, {1- [5-(4-bromo-phenyl)-thieno [2,3 -d]pyrimidinyl] -piperidinyl} -carbamic acid tert- butyl ester, [l-(5-p-tolyl-thieno[2,3-d]pyrimidinyl)-piperidinyl]-carbamic acid tert-butyl ester, [l-(5-methyl-thieno[2,3-d]pyrimidinyl)-piperidinyl]-carbamic acid tert-butyl ester, l-(5-phenyl-thieno[2,3-d]pyrimidineyl)-piperidinylamine, l-(6-methylphenyl-thieno[2,3-d]pyrimidineyl)-piperidinylamine, l-(5-(4-bromo-phenyl)-thieno[2,3-d]pyrimidineyl)-piperidinylamine, l-(5-p-tolyl-thieno[2,3-d]pyrimidineyl)-piperidinylamine, ethyl-thieno [2,3 -d]pyrimidineyl)-piperidinylamine, l-(5-phenyl-thieno[2,3-d]pyrimidinyl)-piperidinone, l-[5-(4-bromo-phenyl)-thieno[2,3-d]pyrimidinyl]-piperidinone, -tolyl-thieno[2,3-d]pyrimidinyl)-piperidinone, l-(6-methylphenyl-thieno[2,3-d]pyrimidinyl)-piperidinone, 2- { l - [5 -(4-bromo-phenyl)-thieno [2,3 -d]pyrimidinyl] -piperidinylamino} -cyclohexanol, 2- { l -(5 -p-tolyl-thieno [2,3 -d]pyrimidinyl)-piperidinylamino} -cyclohexanol, 2- { l thylphenyl-thieno [2,3 -d]pyrimidinyl)-piperidin-4ylamino} -cyclohexanol, l-benzyloxy—3-[ l enyl-thieno[2,3-d]pyrimidinyl)-piperidinylamino]-propanol, 2-[ l -(5-phenyl-thieno[2,3-d]pyrimidinyl)-piperidinylamino]-cyclohexanol, -methoxy {[ l -(5-phenyl-thieno[2,3-d]pyrimidinyl)-piperidinylamino]methyl} - phenol, bis-(2-fluoro-benzyl)-[ l enyl-thieno[2,3-d]pyrimidinyl)-piperidinyl]-amine, 2-fluoro {[l-(6-methylphenyl-thieno[2,3-d]pyrimidinyl)-piperidin ylamino]methyl} -phenol, 2-( { l -[5-(4-bromo-phenyl)-thieno[2,3-d]pyrimidinyl]-piperidinylamino}methyl) fluoro-phenol, 2-fluoro {[1-(5-p-tolyl-thieno [2,3 imidinyl)-piperidinylamino]methyl} -phenol (3 -Benzyloxyhydroxy-propyl)-[ l -(5-phenyl-thieno [2,3 -d]pyrimidinyl)-piperidinyl] - ammonium; chloride, 4- {4- [2-(4-Fluoro-phenoxymethyl-morpholinyl] -piperidin- l -yl} phenyl-thieno [2,3 - d]pyrimidine, 4- {4- [2-(Benzo[ l ,3 ] dioxolyloxymethyl)-morpholinyl] -piperidin- l -yl} phenyl- thieno[2,3-d]pyrimidine, or 6-(Benzo[ l ,3]dioxolyloxymethyl)[ l -(5-phenyl-thieno[2,3-d]pyrimidinyl)-piperidin- morpholinone.
As discussed above, inhibition of Kir3.l and/or Kir3.4 (or heteromultimers thereof) has implications in: 0 the diagnosis and ent of cardiovascular diseases, such as atrial ation (AF), atrial flutter (AFL), atrioventricular (AV) dysfunction and sinoatrial node (SAN) dysfunction; 0 the prevention of recurrence of supraventriclar arrhythmias including AF and AFL; 0 the maintenance of sinus rhythm; 0 the termination and cardioversion of supraventriclar arrhythmias; o the treatment of sinus node dysfunction; 0 the treatment of AV node ction, ing AV block; 0 the treatment of conduction dysfunction; 0 the tion or reversal of atrial structural and ionic remodeling; o the prevention of thrombosis, thromboembolism and thromboembolic diseases, such as stroke, dial infarction, and peripheral vascular diseases; 0 the improvement of cardiac contractility; o the treatment of metabolic diseases, such as diabetes mellitus; 0 the modulation of neuro-endocrine function; 0 the modulation of the secretion of pituitary hormones; 0 the treatment of neurological and neuropsychiatric ers, such as pain, depression, anxiety, attention deficit/hyperactivity disorder and epilepsy; and o the treatment of cancer, such as breast cancer.
DETAILED DESCRIPTION OF THE INVENTION At various places in the present specification, tuents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “CM alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
For compounds of the invention in which a variable appears more than once, each variable can be a different moiety selected from the h group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in ation in a single embodiment. sely, various es of the ion which are, for brevity, described in the context of a single embodiment, can also be ed separately or in any suitable subcombination.
However, combinations of es are sible only if such combinations result in stable compounds. Compounds of the invention are typically stable and isolatable at room temperature and pressure. A “stable” compound is sufficiently robust to e isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
In one embodiment, A is S. In another embodiment, A is O.
In one embodiment, Z is N. In another embodiment, X is N. In one embodiment, Z is N, and V is CR3 111- In another embodiment, Z is N, X is N, and V is CR3 111- In another embodiment, z is N, x is CR3H, and v is CR3HI.
In one ment, V is N, X is CR311, and Z is CR3IV. In another embodiment, X is N, V is CR3111, and Z is CR31V. In another embodiment, Z is N, V is N, and X is CR3 11- In another embodiment, V is N, X is N, and Z is CR31V.
In a specific embodiment, A is S, Z is N, X is N, and V is CR31H, i.e. the compounds are thienopyrimidines.
In one embodiment, R31 is —CEC—J or —(NRaRb)—J, and/or at least one of R311, R3111, and R3IV is t as —CEC—J or d)—J. In another embodiment, R31 is ally substituted cycloalkyl—J or —(NRaRb)—J, and/or at least one of R311, R3111, and R3 IV is present as optionally tuted cycloalkyl—J or —(NRcRd)—J. In another embodiment, R31 is —(NRaRb)—J and/or at least one of R311, R3111, and R3 IV is present as —(NRcRd)—J.
In one embodiment, R31 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —COZR7, —NR8R9, —CEC—J, optionally substituted cycloalkyl-J and —(NRaRb)—J.
In another embodiment, R31 is selected from trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, —NR6C(O)R7, — NR6S(O)2R7, NR4R5, —CONR4R5, —COZR7, —NR8R9, optionally substituted cycloalkyl-J and —(NRaRb)—J. In another embodiment, R31 is selected from H, —(NRaRb)—J, optionally substituted cycloalkyl-J and —CEC—J. In another embodiment, R31 is selected from b)—J, and —CEC—J. In another embodiment, R31 is selected from —(NRaRb)—J, and optionally substituted cycloalkyl-J. In another ment, R31 is —(NRaRb)—J. In another embodiment, R31 is —(NRaRb)—J and J is (CR12R13)q—L—M—W.
In one embodiment, each of R311, R3111, and R3IV is independently selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally tuted alkoxy, —NR6C(O)R7, — NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —COZR7, —NR1°R“, —CEC—J, optionally substituted cycloalkyl-J and d)—J. In another embodiment, each of R311, R3111, and R3IV is independently selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally tuted , optionally substituted heterocycloalkoxy, optionally substituted cycloalkylalkyl, O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, optionally substituted —alkylene—CONR4R5, —COZR7, —NR10R11, optionally substituted cycloalkyl-J and —(NRcRd)—J. In another embodiment, each of R311, R3111, and R3IV is independently selected from H, halo, —CN, trifluoromethyl, optionally substituted alkoxy, — NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —COZR7, —NR10R“, , optionally tuted cycloalkyl-J and —(NRcRd)—J. In another ment, each of R311, R3111, and R3 IV is independently selected from H, —NR10R11, —CEC—J, optionally tuted cycloalkyl-J and —(NRcRd)—J. In one embodiment, each of R311, R3111, and R3IV is independently selected from H, —NR10R“, —CEC—J and —(NRCRd)—J. In another WO 72694 embodiment, R311 and R3IV are H. In another embodiment, R311, R3111 and R31V, are independently selected from —CEC—J, optionally tuted cycloalkyl-J and —(NRCRd)—J.
In another embodiment, R3111 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted , optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, O)R7, —NR6S(O)2R7, —S(O)2NR4R5, — CONR4R5, optionally substituted —alkylene—CONR4R5, —COZR7, —NR1°R“, optionally substituted cycloalkyl-J and —(NRcRd)—J. In another embodiment, R3111 is independently ed from H, —NR1°R“, —CEC—J, ally substituted cycloalkyl-J and —(NRcRd)—J. In another embodiment, R3111 is selected from —CEC—J, optionally substituted cycloalkyl-J and — (NRcRd)—J. In another embodiment, R3111 is selected from optionally substituted cycloalkyl-J and —(NRcRd)—J. In another embodiment, R3111 is d)—J.
In one embodiment, R31 is —(NRaRb)—J, V is CR3 111 and R3111 is —(NRcRd)—J. In another embodiment, R31 is —(NRaRb)—J, V is CR3HI and R3111 is —(NRcRd)—J and, in at least one instance, I is R13 q—L—M—W. In another embodiment, R31 is —(NRaRb)—(CR12R13)q— L—M—W, V is CR3III and R3III is —(NRcRd)—H.
In one embodiment, ifX is N, then R31 is not —NR8R9. In another embodiment, ifX is CR3 11 and Z is N, then R31 is not H, halo or —NR8R9.
In one ment, each of R311, R3111, and R3“; is independently selected from — NR6S(O)2R7, —S(O)2NR4R5, —CEC—J, and optionally substituted cycloalkyl-J. In another embodiment, if V is N, then R311 and R3IV are independently selected from H, halo, —CN, trifluoromethyl, optionally tuted alkyl, optionally tuted , —NR6C(O)R7, — NR6S(O)2R7, NR4R5, —CONR4R5, —COZR7, —NR1°R“, —CEC—J, optionally substituted cycloalkyl-J and —(NRcRd)—J.
In one embodiment, R1 is selected from optionally substituted alkyl, optionally substituted aryl and optionally substituted aryl. In another embodiment, R1 is selected from optionally substituted alkyl and optionally substituted aryl. In another embodiment, R1 is selected from optionally substituted heteroaryl and optionally substituted aryl. In another embodiment, R1 is selected from optionally substituted alkyl and optionally substituted phenyl. In another embodiment, R1 is selected from optionally substituted methyl, optionally substituted ethyl, optionally substituted yl, and optionally substituted phenyl. In another embodiment, R1 is selected from methyl, ethyl, i-propyl, and phenyl, wherein phenyl is ally substituted by one or more of halo, —N02 and —SOZN(C1_ 6alkyl)2. In another embodiment, R1 is selected from methyl, ethyl, i-propyl, and phenyl, wherein phenyl is ally substituted by one or more of F, —N02 and —SOZNMe2. In another embodiment, R1 is optionally substituted . In r embodiment, R1 is phenyl. In another embodiment, R1 is substituted . In another embodiment, R1 is selected from methyl, ethyl and i-propyl. In embodiments in which R1 is substituted phenyl, it may be substituted at the 2-, 3-, 4-, 5- and/or 6- position(s). In one embodiment, R1 is 2- tuted phenyl and in a further embodiment, the 2-substituent is methoxy.
In one embodiment, R2 is ed from halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally tuted alkoxy, , —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, — CONR4R5, —COZR7, optionally tuted oxazolinyl,—SR14,—S(O)R14 and —S(O)2R14. In another embodiment, R2 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, —NR4R5, —NR6C(O)R7, —S(O)2NR4R5, — CONR4R5, —COZR7, optionally substituted oxazolinyl,—SR14,—S(O)R14 and —S(O)2R14. In another embodiment, R2 is selected from H, trifluoromethyl, substituted alkyl, optionally substituted alkoxy, —NR4R5, —NR6C(O)R7, —S(O)2NR4R5, —CONR4R5, —COZR7, optionally substituted oxazolinyl, —SR14, —S(O)R14 and —S(O)2R14. In another ment, R2 is selected from H, halo, —CN, optionally substituted alkyl, —NR4R5, —NR6C(O)R7, and — CONR4R5. In another embodiment, R2 is selected from H, halo, —CN, optionally substituted methyl, ethyl, and i-propyl, —NR4R5, O)R7, and —CONR4R5. In another embodiment, R2 is selected from H, bromo, —CN, methyl, ethyl, i-propyl, —NR4R5, — NR6C(O)R7, and —CONR4R5. In another embodiment, R2 is selected from H, —NR6C(O)R7, and —CONR4R5. In another embodiment, R2 is selected from H and —CONR4R5. In another ment, R2 is H. In one embodiment, optionally substituted oxazolinyl is optionally substituted 2-oxazolinyl.
In one embodiment, R2 is not —CN. In another ment, if R2 is —CN then R3111 is not substituted alkyl.
In a specific embodiment, R1 is phenyl and R2 is H.
In one embodiment, NRaRb forms an optionally bridged, ally substituted ring of formula (II): K j ) 11D\/ wherein n is 0, l or 2; D is selected from —CH2—, —CHJ—, and —O—.
In one embodiment, D is —CHJ—. In one embodiment, n is 0 or 1. In r embodiment, n is 1. In another embodiment, n is 0.
In one embodiment, NRaRb is optionally bridged by bond, CH2 C2H4 or CH] . In r embodiment, NRaRb is optionally bridged by bond, —CH2— or —CHJ—. In another embodiment, NRaRb is bridged by bond, CH2 CH] In another embodiment, , C2H4 or .
NRaRb is bridged by bond, —CH2— or —CHJ—. In another embodiment, NRaRb is not d.
In one embodiment, NRaRb is ed from optionally substituted pyrrolidinyl, optionally tuted piperidinyl, optionally substituted morpholinyl, optionally substituted azabicyclohexanyl, optionally substituted azabicycloheptanyl, and optionally substituted azabicyclooctanyl. In another embodiment, NRaRb is selected from optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, optionally substituted azabicyclo[3 . l .0]hexanyl, optionally substituted azabicyclo[2.2.l]heptanyl, and optionally substituted azabicyclo[3.2.l]octanyl. In another embodiment, NRaRb is selected from optionally substituted pyrrolidinyl, optionally tuted dinyl, optionally substituted morpholinyl, optionally substituted 3- azabicyclo[3.l.0]hexanyl, optionally substituted 2-azabicyclo[2.2.l]heptanyl, and optionally substituted 8-azabicyclo[3.2.l]octanyl. In r embodiment, NRaRb is selected from pyrrolidinyl, piperidinyl, and 3-azabicyclo[3.l.0]hexanyl. In another embodiment, NRaRb is selected from pyrrolidinyl, and piperidinyl. In one embodiment, NRaRb is pyrrolidinyl. In another embodiment, NRaRb is piperidinyl. 2012/052842 In one embodiment, if R31 is cycloalkyl—J or —(NRaRb)—J, wherein NRaRb is piperidinyl, q is 0, and L is —N(G)—, then R3111 is not H, ally substituted C1_4alkyl or optionally substituted cycloalkyl—J. In r embodiment, if R31 is —(NRaRb)—J, wherein NRaRb is piperidinyl, q is 0, and L is —N(G)—, then R3111 is not H, optionally substituted C1_4alkyl or optionally substituted cycloalkyl—J. In another embodiment, if R31 is —(NRaRb)—J, wherein NRaRb is piperidinyl, q is 0, and L is —N(G)—, then R3111 is not H. In another embodiment, if R31 is —(NRaRb)—J, wherein NRaRb is substituted piperidinyl and J is H, then R3111 is not H.
I may be attached to any atom on the ring or, if present, the bridge. In one embodiment, NRaRb is pyrrolidinyl and J is present at the 3-position. In another embodiment, NRaRb is piperidinyl and J is t at the 4-position.
Rc and Rd are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1_2alkylene, —NR6—, —O— or —. I may be attached to any atom on the ring or, if present, the bridge. In one embodiment, NRCRd forms an optionally bridged, optionally tuted heterocycloalkyl selected from the group ting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydro-l,3-oxazinyl, piperazinyl, hexahydropyrimidinyl, l,4-thiazanyl, azepanyl, 1,4- oxaazepanyl, l,4-thieazepanyl and 1,4-diazepanyl. In one embodiment, NRCRd forms an optionally bridged, optionally substituted ring of formula (II): K jlnD\/J ii... (I, wherein nis0, l or2; Dis selected from CH2 CHJ O and , , , N(H) N(J) .
In one embodiment, D is ed from —CHJ— and —N(J)—. In one ment, n is 0 or 1.
In one embodiment, n is 1. In another embodiment, n is 0.
In one embodiment, NRCRd is optionally bridged by bond, CH2 , C2H4 or CH] . In r embodiment, NRCRd is optionally d by bond, —CH2— or —CHJ—. In another embodiment, NRCRd is bridged by bond, CH2 CH] . In another embodiment, , C2H4 or NRCRd is bridged by bond, —CH2— or —CHJ—. In another embodiment, NRCRd is not bridged.
In one embodiment, NRCRd is ed from ally substituted pyrrolidinyl, optionally substituted dinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted azabicyclohexanyl, optionally substituted azabicycloheptanyl, and optionally substituted azabicyclooctanyl. In another embodiment, NRCRd is selected from optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted yclo[3.l.0]hexanyl, optionally substituted azabicyclo[2.2.l]heptanyl, and optionally substituted azabicyclo[3.2.l]octanyl. In another embodiment, NRCRd is selected from ally substituted pyrrolidinyl, optionally substituted piperidinyl, ally tuted morpholinyl, optionally substituted piperazinyl, optionally substituted 3- yclo[3.l.0]hexanyl, optionally substituted 2-azabicyclo[2.2.l]heptanyl, and optionally substituted icyclo[3.2.l]octanyl. In another embodiment, NRCRd is selected from optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and 3- azabicyclo[3.l.0]hexanyl. In another embodiment, NRCRd is selected from pyrrolidinyl, piperidinyl, piperazinyl, and 3-azabicyclo[3.l.0]hexanyl. In another embodiment, NRCRd is selected from pyrrolidinyl, piperidinyl, and zinyl. In another embodiment, NRCRd is selected from pyrrolidinyl and piperidinyl. In one embodiment, NRCRd is idinyl. In another embodiment, NRCRd is piperidinyl.
I may be attached to any atom on the ring or, if present, the . In one embodiment, NRCRd is pyrrolidinyl and J is present at the 3-position. In another embodiment, NRCRd is piperidinyl and J is present at the 4-position.
In one embodiment, J is —(CR12R13 q—L—M—W. In another embodiment, J is H. In another embodiment, if more than one I group is present, then, in at least one instance I is present as —(CR12R13 W.
In one embodiment, q is 0 or 1. In another embodiment, q is l or 2. In another embodiment, q is 0 or 2. In another embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is l or 2 and R12 and R13 are independently selected from H and alkyl. In another embodiment, q is l or 2 and R12 and R13 are both H.
In r embodiment, q is l and R12 and R13 are both H.
In one embodiment, L is O. In another embodiment, L is —N(G)—.
In one embodiment, L is —N(G)— and L, G, M and W may be linked to form an optionally substituted heterocycloalkyl. In one ment, L is —N(G)— and L, G, M and W are linked to form an optionally substituted heterocycloalkyl. In another ment, L is — N(G)— and L, G, M and W are linked to form optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl or optionally substituted morpholinyl. In another embodiment, L is —N(G)— and L, G, M and W are linked to form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl, wherein each of pyrrolidinyl, piperidinyl and linyl is optionally substituted by one or more groups selected from halo, trihalomethyl, -OH, lkyl, —O-C1_6alkyl, -N(C1_6alkyl)2, lkylene—OH, aryl, haloaryl, -C(=O)NH2 and -C3_6heterocycloalkyl. In another embodiment, L is —N(G)— and L, G, M and W are linked to form pyrrolidinyl, piperidinyl or morpholinyl substituted by one or more groups selected from pyrrolidinyl, OH, F, Me, OMe, CHZOH, —CF3, —NMe2, phenyl, F-phenyl, —CONH2.
In one embodiment, G is selected from hydrogen, and optionally substituted alkyl. In another embodiment, G is selected from H, optionally tuted methyl and optionally substituted ethyl. In another embodiment, G is selected from H, methyl and ethyl, wherein ethyl is optionally substituted by —OH or —O—C1_6alkyl. In another embodiment, G is selected from H, methyl and ethyl, wherein ethyl is optionally substituted by —OH or —0— Me. In another embodiment, G is selected from H and methyl.
In one embodiment, t is 0, l or 2. In another ment, t is 0. In another embodiment, t is 1. In another embodiment, t is 2. In another embodiment, t is 3. In another embodiment, M is selected from bond, (CH2) , (CH2)2 , (CH2)3 , cycloalkyl—, —CHOH—CH2—, — CH2—CHOH—,—CHz-C(alkyl)2 , (CH2) C(—O) In another embodiment, , C(—O) (CH2) .
M is ed from bond, (CH2) , (CH2)2 , (CH2)3 , entyl—, —CHOH—CH2—, — CH2-C(Me)2—, —(CH2)—C(=O)—. In another embodiment, M is selected from bond, —(CH2)—, 2— and —(CH2)3—.
In one embodiment, W is selected from the group consisting of substituted alkyl, alkoxy, alkenyl, cycloalkyl, optionally substituted heterocycloalkyl, aryl, heteroaryl. In another embodiment, W is selected from substituted alkyl, alkoxy, cyclopropyl, cyclobutyl, optionally substituted pyrrolidinyl, optionally substituted dinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, ydrofuran, furan, thiophene, phenyl, and pyridine. In another embodiment, W is selected from alkyl substituted by one or more groups ed from halo, -OH, -NH2, and -N(C1_6alkyl)2, alkoxy, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuran, furan, ene, , and pyridine, wherein each of pyrrolidinyl, piperidinyl, piperazinyl, and linyl is optionally substituted by one or more groups selected from halo, C1_6alkyl, -C(=O)C1_ , -COZC1_6alkyl, -N(C1_6alkyl)2, O)C1_6alkyl, -C(=O)NH2, and :0. In another embodiment, W is selected from alkyl substituted by one or more groups selected from -F, -OH, -NH2, and -N(Me)2, alkoxy, cyclopropyl, cyclobutyl, idinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuran, furan, ene, phenyl, and pyridine, wherein each of pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl is optionally substituted by one or more groups selected from -F, -Me, -Et, -iPr, -C(=O)Me, -COztBu, -NHC(=O)Me, -C(=O)NH2, and :0. In another embodiment, W is selected from ropyl, cyclobutyl, pyrrolidinyl, and piperidinyl, wherein each of pyrrolidinyl and piperidinyl is optionally substituted by one of -Me, -Et and -iPr. In another embodiment, W is selected from pyrrolidinyl, and piperidinyl, wherein each of pyrrolidinyl and piperidinyl is optionally substituted by one of -Me, -Et and —iPr. In one embodiment, W is l-methylpyrrolidinyl.
In one embodiment, z is 0. In another embodiment, z is 1. In another embodiment, z is 2.
In one embodiment, R4 and R5 are, at each instance, independently ed from H and ally substituted alkyl, or are linked to form an optionally substituted heterocycloalkyl.
In another embodiment, R4 and R5 are, at each ce, independently selected from H, optionally substituted methyl, optionally substituted ethyl, optionally substituted i-propyl, and optionally substituted pyrrolidinyl. In another embodiment, R4 and R5 are, at each instance, ndently selected from H, methyl, ethyl, yl, and pyrrolidinyl optionally substituted by :0.
R6 and R7 are, at each instance, independently selected from H and optionally substituted alkyl, or, in the groups —NR6C(O)R7, —NR6S(O)2R7, may be linked to form an optionally tuted heterocycloalkyl.
In one embodiment, R6 is, at each instance, independently selected from H and optionally substituted alkyl. In r embodiment, R6 is H.
In one embodiment, R7 is, at each ce, independently selected from H and optionally substituted alkyl. In another embodiment, R7 is alkyl. In another embodiment, R7 is methyl.
In one embodiment, R8 and R9 are, at each instance, ndently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl. In one embodiment, R8 and R9 are, at each instance, independently selected from optionally substituted alkyl, and optionally substituted cycloalkyl. In another embodiment, R8 and R9 are, at each instance, independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl.
In one ment, R10 and R11 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, ally substituted heteroaryl, and optionally substituted cycloalkyl. In one embodiment, R10 and R11 are, at each instance, independently selected from H, optionally substituted alkyl, and ally substituted cycloalkyl. In another embodiment, R10 and R11 are, at each instance, independently selected from H, optionally substituted methyl, ally substituted ethyl, and optionally substituted i-propyl. In another embodiment, R10 and R11 are, at each instance, independently selected from ally substituted methyl, optionally substituted ethyl, and optionally substituted yl. In another embodiment, R10 and R11 are, at each instance, independently selected from H, methyl, ethyl, and i-propyl, wherein each of methyl, ethyl, and yl is ally substituted by one or more of —OH, —O-C1_6alkyl, -C3_6cycloalkyl, -C3_6heterocycloalkyl and -C(=O)NH2. In another embodiment, R10 and R11 are, at each instance, independently selected from H, methyl, ethyl, and yl, wherein each of methyl, ethyl, and i-propyl is ally substituted by one or more of —OH, —OMe, cyclopropyl, pyrrolidinyl and -C(=O)NH2. In another embodiment, R10 and R11 are, at each instance, independently selected from H, methyl, ethyl, and i-propyl, wherein each of methyl, ethyl, and i-propyl is substituted by one or more of —OH, —OMe, ropyl, pyrrolidinyl and -C(=O)NH2. In one embodiment, R10 is H.
In one embodiment, R12 is H and R13 is, at each instance, independently selected from hydroxy, and optionally substituted alkyl, or R12 and R13 are linked to form an optionally substituted cycloalkyl ring, or together form :0. In another embodiment, R12 and R13 are, at each instance, independently ed from H, hydroxy, and optionally substituted alkyl. In another embodiment, R12 and R13 are, at each instance, independently selected from H, hydroxy, optionally substituted methyl, and optionally tuted ethyl. In another ment, R12 and R13 are, at each instance, H.
In one embodiment, R14 is alkyl. In another ment, R14 is methyl.
In one embodiment, the compound is not a compound of WO 2004/014850 or W02004/06539l.
In one embodiment, the compound is not NHZ NHBoc 6% N N RI R1 R] R2 l I //I R, /S 1 I) R2 J S S N N N or a hydrochloride salt thereof, or , , n R1 is optionally substituted aryl and R2 is H or optionally substituted alkyl.
Specific embodiments In one embodiment: A is S; X is N; V is CR3HI; Z is N; R1 is selected from optionally substituted alkyl, ally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R2 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, —NR4R5, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, — , —COZR7, ally substituted oxazolinyl, —SR14, —S(O)R14 and —S(O)2R14; R31 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, —NR6C(O)R7, — NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, , —NR8R9, —CEC—J, optionally substituted cycloalkyl-J and —(NRaRb)—J; R3111 is selected from H, halo, —CN, trifluoromethyl, ally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, R5, optionally substituted ene—CONR4R5, —COZR7, —NR1°R“, —CEC—J, optionally tuted cycloalkyl-J and —(NRCRd)—J, ed that R31 is —CEC—J, optionally substituted cycloalkyl-J or —(NRaRb)—J, and/or R3111 is —CEC—J, optionally substituted cycloalkyl-J or —(NRcRd)—J; wherein Ra and Rb are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1. zalkylene, —NR6—, —O—, or —S(O)Z—, wherein the optionally bridged, optionally substituted heterocycloalkyl ring is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydro-l,3-oxazinyl, hexahydropyrimidinyl, l,4-thiazanyl, azepanyl, 1,4-oxaazepanyl, and l,4-thieazepanyl; wherein Rc and Rd are linked to form an ally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally d by a bond, optionally substituted C1. ene, —NR6—, —0—, or —S(O)Z—; J is selected from H and —(CR12R13)q—L—M—W, n q is 0, 1 or 2; L is —O— or —N(G)—; and G is selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl; M is —(CR12R13)t—; tis0,1,20r3; W is ed from the group consisting of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally tuted cycloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and —NR8R9, wherein when W is optionally substituted cycloalkyl it may optionally be bridged by a bond or optionally substituted C1_2alkylene, and wherein when W is optionally substituted heterocycloalkyl it may optionally be bridged by a bond, optionally substituted C1_2alkylene, —NR6—, —O—, or —S(O)Z—; alternatively, when L = —N(G)—, L, G, M and W may be linked to form an optionally substituted heterocycloalkyl, an optionally substituted cycloalkenyl, or an optionally tuted heteroaryl; z is 0, l or 2; R4 and R5 are, at each instance, independently selected from H, ally tuted alkyl, optionally tuted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl, or are linked to form an optionally substituted heterocycloalkyl; R6 is, at each instance, independently selected from H and optionally substituted alkyl; R7 is, at each instance, ndently selected from H and optionally substituted alkyl; R8 and R9 are, at each instance, independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and ally substituted cycloalkyl; R10 and R11 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, ally substituted heteroaryl, and optionally substituted cycloalkyl; R12 and R13 are, at each instance, independently selected from H, hydroxy, and optionally substituted alkyl, or may be linked to form an ally substituted cycloalkyl ring, or may together form =0; and R14 is optionally substituted alkyl, wherein the optional substituents are independently selected from halo, trihalomethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, -OH, -NOZ, -CN, -COzH, -COZC1_6alkyl, -SO3H, -SOC1_6alkyl, -SOZC1_6alkyl, -NHSOZC1_6alkyl, -NC1_6alkylSOZC1_6alkyl, -SOZNH2, -SOzNHC1_6alkyl, -SOZN(C1_6alkyl)2, -NHSOZNH2, -NHSOZNHC1_6alkyl, -NHSOZN(C1_ )2, -NC1_6alkylSOZNH2, -NC1.6alkylSOZNHC1_6alkyl, -NC1.6alkylSOZN(C1_6alkyl)2, H, -C(=O)C1_6alkyl, -NHC(=O)C1_6alkyl, -NC1-6alkle(=O)C1_6alkyl, C1. enedioxy, =O, -N(C1_6alkyl)2, -C(=O)NH2, -C(=O)NHC1_6alkyl, -C(=O)N(C1_6alkyl)2, -NHC(=O)NH2, O)NHC1_6alkyl, -NHC(=O)N(C1_6alky1)2, -NC1_6alky1C(=O)NH2, -NC1.6alkle(=O)NHC1-6alkyl, -NC1-6alkle(=O)N(C1-6alkyl)2, -C(=NH)NH2, -C(=NH)NHC1_6alkyl, -C(=NH)N(C1_6alkyl)2, -C(=NC1_6alkyl)NH2, -C(=NC1.6alkyl)NHC1_6alkyl, -C(=NC1.6alkyl)N(C1_6alkyl)2, -C1_6alkyl, -C3_6cycloalkyl, -C3_6heterocycloalkyl, 2-imidazolidinon—3 -yl, l-C1-6alkylimidazolidinon-3 -yl, C1-6alkle3.6heterocycloalkyl, aryl, haloaryl, C1_6alkoxyaryl, —ZtH, —Zt-C1_6alkyl, -C1_ 6alkylene—ZtH, —Zt-C3_6cycloalkyl, or -C(=O)NHC1_6alkylene—ZtH wherein Z1 is independently O, S, NH or N(C1_6alkyl).
In one embodiment: A is S; X is N; V is CR3HI; Z is N; R1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R2 is selected from H, trifluoromethyl, substituted alkyl, ally substituted alkoxy, —NR4R5, —NR6C(O)R7, —S(O)2NR4R5, —CONR4R5, —COZR7, optionally substituted oxazolinyl, —SR14, —S(O)R14 and —S(O)2R14; R31 is ed from H, halo, —CN, romethyl, optionally substituted alkyl, optionally substituted , ally substituted heterocycloalkoxy, —NR6C(O)R7, — NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, —COZR7, —NR8R9, —CEC—J, optionally substituted cycloalkyl-J and b)—J; R3111 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, optionally substituted —alkylene—CONR4R5, —COZR7, “, , optionally tuted lkyl-J and —(NRCRd)—J, provided that R31 is —CEC—J, optionally substituted cycloalkyl-J or b)—J, and/or R3111 is —CEC—J, optionally substituted cycloalkyl-J or —(NRcRd)—J; wherein Ra and Rb are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1. zalkylene, —NR6—, —O—, or —S(O)Z—, wherein the optionally d, optionally substituted heterocycloalkyl ring is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydro-l,3-oxazinyl, hexahydropyrimidinyl, l,4-thiazanyl, azepanyl, 1,4-oxaazepanyl, and l,4-thieazepanyl; n Rc and Rd are linked to form an optionally tuted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1. zalkylene, —NR6—, —0—, or —S(O)Z—; J is selected from H and —(CR12R13)q—L—M—W, wherein q is 0, 1 or 2; L is —O— or —N(G)—; and G is selected from hydrogen, optionally substituted alkyl and optionally tuted cycloalkyl; M is —(CR12R13),—; ,2or3; W is selected from the group consisting of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and , wherein when W is optionally substituted cycloalkyl it may optionally be bridged by a bond or optionally substituted C1_2alkylene, and wherein when W is optionally substituted heterocycloalkyl it may optionally be bridged by a bond, optionally substituted C1_2alkylene, —NR6—, —O—, or —; alternatively, when L = —N(G)—, L, G, M and W may be linked to form an ally substituted cycloalkyl, an optionally tuted heterocycloalkenyl, or an ally tuted heteroaryl; z is 0, l or 2; R4 and R5 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl, or are linked to form an optionally substituted heterocycloalkyl; R6 is, at each instance, independently selected from H and optionally substituted alkyl; R7 is, at each instance, independently selected from H and optionally substituted alkyl; R8 and R9 are, at each instance, independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, ally substituted heteroaryl, and optionally substituted cycloalkyl; R10 and R11 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally tuted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted cycloalkyl; R12 and R13 are, at each instance, independently selected from H, hydroxy, and optionally tuted alkyl, or may be linked to form an optionally substituted cycloalkyl ring, or may together form :0; and R14 is optionally substituted alkyl, wherein the optional substituents are independently selected from halo, trihalomethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, -OH, -NOz, -CN, -COzH, -COZC1_6alkyl, -SO3H, -SOC1_6alkyl, -SOZC1_6alkyl, -NHSOZC1_6alkyl, -NC1_6alkylSOZC1_6alkyl, -SOzNH2, -SOzNHC1_6alkyl, -SOzN(C1_6alkyl)2, -NHSOzNH2, -NHSOzNHC1_6alkyl, -NHSOzN(C1_ )2, alkylSOZNH2, -NC1-6alkylSOZNHC1_6alkyl, alkylSOZN(C1_6alkyl)2, -C(=O)H, -C(=O)C1_6alkyl, -NHC(=O)C1_6alkyl, -NC1-6alkle(=O)C1_6alkyl, C1. 6alkylenedioxy, =O, 6alkyl)2, -C(=O)NH2, -C(=O)NHC1_6alkyl, -C(=O)N(C1_6alkyl)2, -NHC(=O)NH2, -NHC(=O)NHC1_6alkyl, -NHC(=O)N(C1_6alkyl)2, -NC1_6alkle(=O)NH2, -NC1-6alkle(=O)NHC1-6alkyl, -NC1_6alkle(=O)N(C1.6alkyl)2, -C(=NH)NH2, -C(=NH)NHC1_6alkyl, -C(=NH)N(C1_6alkyl)2, -C(=NC1_6alkyl)NH2, -C(=NC1.6alkyl)NHC1_6alkyl, -C(=NC1.6alkyl)N(C1_6alkyl)2, -C1_6alkyl, -C3_6cycloalkyl, -C3_6heterocycloalkyl, 2-imidazolidinon-3 -yl, l-C1-6alkylimidazolidinon-3 -yl, C1-6alkle3.6heterocycloalkyl, aryl, haloaryl, koxyaryl, —ZtH, —Zt-C1_6alkyl, -C1_ 6alkylene—ZtH, —Zt-C3_6cycloalkyl, or -C(=O)NHC1_6alkylene—ZtH wherein Z1 is independently O, S, NH or N(C1_6alkyl).
In one embodiment: A is S; X is N; V is CR3HI; Z is N; R1 is selected from optionally substituted alkyl, optionally tuted cycloalkyl, optionally substituted aryl, and ally substituted heteroaryl; R2 is selected from H, trifluoromethyl, substituted alkyl, optionally substituted alkoxy, —NR4R5, —NR6C(O)R7, —S(O)2NR4R5, —CONR4R5, —COZR7, optionally substituted oxazolinyl, —SR14, —S(O)R14 and —S(O)2R14; R31 is selected from trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, —NR6C(O)R7, —NR6S(O)2R7, — R4R5, —CONR4R5, —COZR7, —NR8R9, optionally substituted cycloalkyl-J and — (NRaRb—J; R3111 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted , ally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, —NR6C(O)R7, O)2R7, —S(O)2NR4R5, —CONR4R5, optionally substituted —alkylene—CONR4R5, —COZR7, —NR10R11, optionally substituted lkyl-J and d)—J, provided that R31 is optionally substituted cycloalkyl-J or —(NRaRb)—J, and/or R3111 is optionally substituted lkyl-J or —(NRcRd)—J; wherein Ra and Rb are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1. zalkylene, —NR6—, —O—, or —S(O)Z—, wherein the optionally bridged, optionally substituted cycloalkyl ring is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, ydro-l,3-oxazinyl, hexahydropyrimidinyl, l,4-thiazanyl, azepanyl, 1,4-oxaazepanyl, and l,4-thieazepanyl; wherein Rc and Rd are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1. zalkylene, —NR6—, —0—, or —S(O)Z—; J is selected from H and —(CR12R13)q—L—M—W, wherein q is 0 or 1; L is —O— or —N(G)—; and G is selected from hydrogen, optionally substituted alkyl and optionally tuted cycloalkyl; M is —(CR12R13)t—; t is 0, l, or 2; W is selected from the group consisting of optionally tuted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and —NR8R9, wherein when W is ally substituted cycloalkyl it may optionally be bridged by a bond or optionally substituted C1_2alkylene, and wherein when W is optionally substituted heterocycloalkyl it may optionally be bridged by a bond, optionally substituted C1_2alkylene, —NR6—, —O—, or —S(O)Z—; alternatively, when L = —N(G)—, L, G, M and W may be linked to form an optionally tuted heterocycloalkyl, an optionally substituted heterocycloalkenyl, or an optionally substituted heteroaryl; z is 0, l or 2; R4 and R5 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl, or are linked to form an optionally substituted heterocycloalkyl; R6 is, at each instance, independently selected from H and ally substituted alkyl; R7 is, at each instance, independently selected from H and ally substituted alkyl; R8 and R9 are, at each instance, independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted cycloalkyl; R10 and R11 are, at each instance, independently selected from H, optionally substituted alkyl, ally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and ally substituted cycloalkyl; R12 and R13 are, at each instance, independently selected from H, hydroxy, and ally tuted alkyl, or may be linked to form an optionally substituted cycloalkyl ring, or may together form =0; and R14 is optionally substituted alkyl, wherein the optional substituents are independently selected from halo, trihalomethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, -OH, -NOZ, -CN, -COzH, -COZC1_6alkyl, -SO3H, 6alkyl, -SOZC1_6alkyl, -NHSOZC1_6alkyl, -NC1_6alkylSOZC1_6alkyl, -SOZNH2, -SOzNHC1_6alkyl, -SOZN(C1_6alkyl)2, -NHSOZNH2, -NHSOZNHC1_6alkyl, -NHSOZN(C1_ )2, -NC1_6alkylSOZNH2, -NC1.6alkylSOZNHC1_6alkyl, alkylSOZN(C1_6alkyl)2, -C(=O)H, -C(=O)C1_6alkyl, O)C1_6alkyl, -NC1-6alkle(=O)C1_6alkyl, C1. 6alkylenedioxy, =O, 6alkyl)2, -C(=O)NH2, -C(=O)NHC1_6alkyl, -C(=O)N(C1_6alkyl)2, -NHC(=O)NH2, O)NHC1_6alkyl, O)N(C1_6alky1)2, -NC1_6alkle(=O)NH2, -NC1-6alkle(=O)NHC1.6alkyl, -NC1.6alkle(=O)N(C1.6alkyl)2, -C(=NH)NH2, -C(=NH)NHC1_6alkyl, -C(=NH)N(C1_6alkyl)2, -C(=NC1_6alkyl)NH2, -C(=NC1.6alkyl)NHC1_6alkyl, -C(=NC1.6alkyl)N(C1_6alkyl)2, -C1_6alkyl, ycloalkyl, -C3_6heterocycloalkyl, 2-imidazolidinon—3 -yl, l-C1-6alkylimidazolidinon-3 -yl, C1-6alkle3.6heterocycloalkyl, aryl, haloaryl, C1_6alkoxyaryl, —ZtH, —Zt-C1_6alkyl, -C1_ 6alkylene—ZtH, —Zt-C3_6cycloalkyl, or -C(=O)NHC1_6alkylene—ZtH wherein Z1 is independently O, S, NH or N(C1_6alkyl).
In one embodiment: A is S; X is N; V is CR3HI; Z is N; R1 is selected from ally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R2 is selected from H, trifluoromethyl, substituted alkyl, optionally substituted alkoxy, —NR4R5, —NR6C(O)R7, —S(O)2NR4R5, —CONR4R5, —COZR7, optionally substituted oxazolinyl, —SR14, —S(O)R14 and R14; R3I is —(NRaRb)—J; R3111 is selected from H, halo, —CN, trifluoromethyl, optionally tuted alkyl, ally substituted alkoxy, optionally tuted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, —NR6C(O)R7, —NR6S(O)2R7, —S(O)2NR4R5, —CONR4R5, optionally substituted —alkylene—CONR4R5, —COZR7, —NR10R11, optionally substituted cycloalkyl-J and —(NRcRd)—J, wherein Ra and Rb are linked to form an optionally tuted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, ally substituted C1. zalkylene, —NR6—, —O—, or —S(O)Z—, wherein the optionally bridged, optionally substituted heterocycloalkyl ring is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydro-l,3-oxazinyl, hexahydropyrimidinyl, l,4-thiazanyl, azepanyl, 1,4-oxaazepanyl, and l,4-thieazepanyl; wherein Rc and Rd are linked to form an optionally tuted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, ally substituted C1. zalkylene, —NR6—, —0—, or —S(O)Z—; J is selected from H and —(CR12R13 q—L—M—W, wherein q is 0 or 1; L is —O— or —N(G)—; and G is selected from hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl; M is —(CR12R13),—; t is 0, l, or 2; W is selected from the group ting of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, ally substituted aryl, optionally substituted heteroaryl and —NR8R9, wherein when W is optionally substituted cycloalkyl it may optionally be bridged by a bond or optionally substituted C1_2alkylene, and wherein when W is optionally substituted heterocycloalkyl it may optionally be d by a bond, optionally substituted C1_2alkylene, —NR6—, —O—, or —S(O)Z—; atively, when L = —N(G)—, L, G, M and W may be linked to form an optionally substituted heterocycloalkyl, an optionally tuted heterocycloalkenyl, or an optionally tuted heteroaryl; z is 0, l or 2; R4 and R5 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl, or are linked to form an optionally tuted heterocycloalkyl; R6 is, at each instance, ndently selected from H and optionally substituted alkyl; R7 is, at each instance, ndently selected from H and optionally substituted alkyl; R8 and R9 are, at each instance, independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally tuted aryl, and optionally substituted cycloalkyl; R10 and R11 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted cycloalkyl; 2012/052842 R12 and R13 are, at each instance, independently selected from H, hydroxy, and optionally substituted alkyl, or may be linked to form an optionally substituted cycloalkyl ring, or may together form =0; and R14 is optionally tuted alkyl, wherein the optional substituents are independently selected from halo, trihalomethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, -OH, -NOZ, -CN, -COzH, -COZC1_6alkyl, -SO3H, 6alkyl, -SOZC1_6alkyl, -NHSOZC1_6alkyl, alkylSOZC1_6alkyl, -SOZNH2, -SOzNHC1_6alkyl, -SOZN(C1_6alkyl)2, -NHSOZNH2, -NHSOzNHC1_6alkyl, -NHSOZN(C1_ 6alkyl)2, -NC1_6alkylSOZNH2, -NC1.6alkylSOZNHC1_6alkyl, -NC1-6alkylSOZN(C1_6alkyl)2, -C(=O)H, -C(=O)C1_6alkyl, -NHC(=O)C1_6alkyl, -NC1.6alkle(=O)C1_6alkyl, C1. 6alkylenedioxy, =O, -N(C1_6alkyl)2, -C(=O)NH2, -C(=O)NHC1_6alkyl, -C(=O)N(C1_6alkyl)2, O)NH2, -NHC(=O)NHC1_6alkyl, -NHC(=O)N(C1_6alkyl)2, -NC1_6alkle(=O)NH2, -NC1-6alkle(=O)NHC1.6alkyl, -NC1.6alkle(=O)N(C1-6alkyl)2, -C(=NH)NH2, -C(=NH)NHC1_6alkyl, -C(=NH)N(C1_6alkyl)2, -C(=NC1_6alkyl)NH2, 1-6alkyl)NHC1_6alkyl, -C(=NC1.6alkyl)N(C1_6alkyl)2, -C1_6alkyl, -C3_6cycloalkyl, -C3_6heterocycloalkyl, 2-imidazolidinon-3 -yl, l-C1-6alkylimidazolidinon-3 -yl, kle3.6heterocycloalkyl, aryl, haloaryl, C1_6alkoxyaryl, —ZtH, —Zt-C1_6alkyl, -C1_ 6alkylene—ZtH, —Zt-C3_6cycloalkyl, or -C(=O)NHC1_6alkylene—ZtH wherein Z1 is independently O, S, NH or N(C1_6alkyl).
In one ment: A is S; Z is N and V is CR3HI; R31 is selected from H, —(NRaRb)—J, optionally substituted cycloalkyl-J and —CEC—J; Each of R311, R3111, and R3 IV is independently selected from H, —NR10R11, —CEC—J, optionally substituted cycloalkyl-J and —(NRCRd)—J; R1 is selected from optionally substituted alkyl and optionally substituted phenyl; R2 is selected from H, halo, —CN, optionally substituted alkyl, —NR4R5, —NR6C(O)R7, — CONR4R5; NRaRb and NRCRd each form an optionally bridged, optionally substituted ring of formula (II): K j ) 11D\/ W (11) wherein n and D are defined in each case above; J is present in at least one instance as—(CR12R13)q—L—M—W; q is l or 2; G is selected from H, optionally substituted methyl and optionally substituted ethyl; M is selected from bond, (CH2) , (CH2)2 , (CH2)3 , cycloalkyl—, —CHOH—CH2—, — CHz—CHOH—, —CH2-C(alky1)2 , (CH2) C(—0) , C(—O) (CH2) ; W is selected from substituted alkyl, alkoxy, cyclopropyl, cyclobutyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, ally substituted piperazinyl, optionally tuted morpholinyl, tetrahydrofuran, furan, thiophene, , and pyridine; alternatively, when L = —N(G)—, L, G, M and W may be linked to form an ally substituted heterocycloalkyl; R4 and R5 are, at each instance, independently selected from H and optionally tuted alkyl, or are linked to form an optionally substituted heterocycloalkyl; R6 is H; R7 is alkyl; and R10 and R11 are, at each instance, independently selected from H, optionally substituted methyl, optionally substituted ethyl, and optionally substituted i-propyl, wherein the optional substituents are independently selected from halo, trihalomethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, -OH, -NOZ, -CN, -COzH, _6alkyl, -SO3H, -SOC1_6alkyl, -SOZC1_6alkyl, -NHSOZC1_6alkyl, -NC1_6alkylSOZC1_6alkyl, -SOZNH2, -SOzNHC1_6alkyl, C1_6alkyl)2, -NHSOZNH2, -NHSOZNHC1_6alkyl, -NHSOZN(C1_ 6alkyl)2, -NC1_6alkylSOZNH2, -NC1.6alkylSOZNHC1_6alkyl, -NC1.6alkylSOZN(C1_6alkyl)2, H, -C(=O)C1_6alkyl, O)C1_6alkyl, -NC1.6alkle(=O)C1_6alkyl, C1- 6alkylenedioxy, =O, -N(C1_6alkyl)2, NH2, -C(=O)NHC1_6alkyl, -C(=O)N(C1_6alkyl)2, -NHC(=O)NH2, -NHC(=O)NHC1_6alkyl, -NHC(=O)N(C1_6alkyl)2, -NC1_6alkle(=O)NH2, -NC1_6alkle(=O)NHC1.6alkyl, -NC1.6alkle(=O)N(C1-6alkyl)2, -C(=NH)NH2, -C(=NH)NHC1_6alkyl, -C(=NH)N(C1_6alkyl)2, -C(=NC1_6alkyl)NH2, 1_6alkyl)NHC1-6alkyl, -C(=NC1.6alkyl)N(C1_6alkyl)2, -C1_6alkyl, -C3_6cycloalkyl, -C3_6heterocycloalkyl, 2-imidazolidinonyl, l-C1-6alkylimidazolidinon—3-yl, WO 72694 C1-6alkle3.6heterocycloalkyl, aryl, haloaryl, C1_6alkoxyaryl, —ZtH, —Zt-C1_6alkyl, -C1_ 6alkylene—ZtH, —Zt-C3_6cycloalkyl, or -C(=O)NHC1_6alkylene—ZtH wherein Z1 is independently O, S, NH or N(C1_6alkyl).
In one embodiment: A is S; Z is N and V is CR3HI; R31 is selected from b)—J, and —CEC—J; R311 and R3IV are H; R3111 is ndently selected from H, —NR10R11, —CEC—J, optionally tuted cycloalkyl- J and —(NRcRd)—J; R1 is selected from methyl, ethyl, i-propyl, and phenyl, wherein phenyl is optionally substituted by one or more of halo, —N02 and —SOZN(C1_6alkyl)2; R2 is ed from H, bromo, —CN, methyl, ethyl, i-propyl, —NR4R5, —NR6C(O)R7, — CONR4R5; NRaRb is selected from optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, and 3- azabicyclo[3 . l .0]hexanyl; NRCRd is selected from optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and 3-azabicyclo[3 . l .0]hexanyl; J is present in at least one instance as—(CR12R13)q—L—M—W; q is l; G is selected from H, methyl and ethyl, wherein ethyl is ally substituted by —OH or — O—C1_6alkyl; M is ed from bond, (CH2) , (CH2)2 , (CH2)3 , cyclopentyl—, —CHOH—CH2—, — CHz-C(Me)2-, -(CH2)-C(=O)-; W is selected from alkyl substituted by one or more groups selected from halo, -OH, -NH2, and -N(C1_6alkyl)2, alkoxy, cyclopropyl, utyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, ydrofuran, furan, thiophene, phenyl, and pyridine, wherein each of pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl is optionally substituted by one or more groups selected from halo, C1_6alkyl, -C(=O)C1_6alkyl, -COZC1_6alkyl, -N(C1_6alkyl)2, O)C1_6alkyl, -C(=O)NH2, and :0; alternatively, when L is —N(G)—, L, G, M and W may be linked to form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl, wherein each of pyrrolidinyl, piperidinyl and morpholinyl is optionally substituted by one or more groups selected from halo, trihalomethyl, -OH, , -C1_6alkyl, —O-C1_6alkyl, -N(C1_6alkyl)2, -C1_6alkylene—OH, aryl, haloaryl, -C(=O)NH2 and -C3_6heterocycloalkyl; R4 and R5 are, at each instance, independently selected from H, methyl, ethyl, i-propyl, and pyrrolidinyl optionally substituted by :0; R6 is H; R7 is ; and R10 and R11 are, at each instance, independently selected from H, methyl, ethyl, and i-propyl, wherein each of , ethyl, and i-propyl is optionally substituted by one or more of —OH, —O-C1_6alkyl, -C3_6cycloalkyl, -C3_6heterocycloalkyl and -C(=O)NH2, wherein the optional substituents are independently selected from halo, trihalomethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, -OH, -NOZ, -CN, -COzH, -COZC1_6alkyl, -SO3H, -SOC1_6alkyl, _6alkyl, -NHSOZC1_6alkyl, alkylSOZC1_6alkyl, -SOZNH2, -SOzNHC1_6alkyl, -SOZN(C1_6alkyl)2, -NHSOZNH2, -NHSOZNHC1_6alkyl, -NHSOZN(C1_ 6alkyl)2, -NC1_6alkylSOZNH2, -NC1.6alkylSOZNHC1_6alkyl, -NC1.6alkylSOZN(C1_6alkyl)2, -C(=O)H, -C(=O)C1_6alkyl, O)C1_6alkyl, -NC1.6alkle(=O)C1_6alkyl, C1- 6alkylenedioxy, =O, 6alkyl)2, -C(=O)NH2, -C(=O)NHC1_6alkyl, -C(=O)N(C1_6alkyl)2, -NHC(=O)NH2, -NHC(=O)NHC1_6alkyl, -NHC(=O)N(C1_6alkyl)2, -NC1_6alkle(=O)NH2, -NC1_6alkle(=O)NHC1.6alkyl, -NC1-6alkle(=O)N(C1-6alkyl)2, -C(=NH)NH2, -C(=NH)NHC1_6alkyl, -C(=NH)N(C1_6alkyl)2, -C(=NC1_6alkyl)NH2, -C(=NC1_6alkyl)NHC1-6alkyl, -C(=NC1.6alkyl)N(C1_6alkyl)2, -C1_6alkyl, -C3_6cycloalkyl, -C3_6heterocycloalkyl, 2-imidazolidinon-3 -yl, l-C1-6alkylimidazolidinon-3 -yl, C1-6alkle3.6heterocycloalkyl, aryl, haloaryl, C1_6alkoxyaryl, —ZtH, —Zt-C1_6alkyl, -C1_ 6alkylene—ZtH, —Zt-C3_6cycloalkyl, or -C(=O)NHC1_6alkylene—ZtH wherein Z1 is independently O, S, NH or N(C1_6alkyl).
In one embodiment: A is S; dXisN; R3I is —(NRaRb)—J and J is 13)q—L—M—W; R311 and R3IV are H; R3III is —(NRcRd)—J; R1 is phenyl; R2 is H; NRaRb and NRCRd are each ed from pyrrolidinyl and piperidinyl; 2012/052842 J is present in at least one instance as—(CRIZR13 q—L—M—W; q is l; G is selected from H and methyl; M is ed from bond, (CH2) and , (CH2)2 (CH2)3 ; and W is selected from pyrrolidinyl, and piperidinyl, wherein each of pyrrolidinyl and piperidinyl is optionally substituted by one of -Me, -Et and —iPr; alternatively, when L is —N(G)—, L, G, M and W may be linked to form pyrrolidinyl, piperidinyl or morpholinyl substituted by one or more groups ed from idinyl, — OH, —F, —Me, —OMe, , —CF3, —NMe2, phenyl, F-phenyl, —CONH2.
In one embodiment, the nd of the invention is ed from: 4-[4-[2-(1-methylpyrrolidinyl)ethoxymethyl]-l-piperidyl]phenyl-thieno[2,3 - d]pyrimidine -methyl [4- [2-( l -methylpyrrolidinyl)ethoxymethyl] - l -piperidyl]thieno [2,3 - d]pyrimidine 4-[4-[2-(1-methylpyrrolidinyl)ethoxymethyl]-l-piperidyl]thieno[2,3 -d]pyrimidine ,6-dimethyl [4- [2-( l -methylpyrrolidinyl)ethoxymethyl] - l -piperidyl]thieno [2,3 - d]pyrimidine -phenyl [4-(2-pyrrolidin— l -ylethoxymethyl)- l -piperidyl]thieno [2,3 -d]pyrimidine 4- [2- [[ l -(5 -phenylthieno[2,3 -d]pyrimidinyl)piperidyl]methoxy] ethyl]morpholine 4- [4- [( l -methylpyrrolidinyl)methoxymethyl] - l -piperidyl] phenyl-thieno [2,3 - d]pyrimidine N,N—dimethyl-3 - [[ l -(5-phenylthieno [2,3 -d]pyrimidinyl)piperidyl] methoxy]propan- l - amine 4- [4-(cyclobutoxymethyl)- l -piperidyl] phenyl-thieno [2,3 -d]pyrimidine 4-[4-[2-(1-methylpiperidyl)ethoxymethyl]-l-piperidyl]phenyl-thieno[2,3 -d]pyrimidine methyl [[ l -(5-phenylthieno[2,3 -d]pyrimidinyl)piperidyl]methoxy]ethanamine 4- [4- [( l -methylpyrrolidin-3 -yl)oxymethyl] - l -piperidyl] phenyl-thieno [2,3 -d]pyrimidine 4- [4- [( l -methylpiperidyl)oxymethyl] - l -piperidyl] nyl-thieno [2,3 -d]pyrimidine l- [4- [4-(2-dimethylaminoethyloxymethyl)- l -piperidyl] phenyl-thieno [2,3 -d]pyrimidin yl]pyrrolidine-3 -carboxamide 4- [4-(isopropoxymethyl)- l -piperidyl] phenyl-thieno [2,3 -d]pyrimidine -phenyl [4-(tetrahydrofuran-3 -yloxymethyl)- l -piperidyl]thieno [2,3 -d]pyrimidine -(3 pheny1)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 - d]pyrimidine -ethy1methy1[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thieno[2,3 -d]pyrimidine 4-[2-[[1-(6-isopropy1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methoxy]ethy1]morpholine -(4-fluorophenyl)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 - d]pyrimidine 4- [2- [[ 1 - [5 -(4-fluor0pheny1)thieno[2,3 -d]pyrimidin—4-y1]—4- piperidy1]methoxy]ethyl]morpholine 4- [4- [2-(3 -fluor0pyrrolidin—1-y1)eth0xymethy1]—1-piperidyl]pheny1-thien0[2,3 - d]pyrimidine 4-[2-[[1-(5-ethy1methy1-thien0[2,3 -d]pyrimidiny1) piperidy1]methoxy]ethyl]morpholine -ethy1—6-methy1—4-[4-[2-(1-methy1pyrro1idiny1)ethoxymethy1]piperidy1]thien0[2,3 - d]pyrimidine 6-isopropy1[4-[2-(1-methy1piperidy1)ethoxymethyl]piperidy1]thieno[2,3 - d]pyrimidine 4- [4- [2-(3 ,3 -difluoropyrrolidiny1)eth0xymethy1]—1-piperidy1]pheny1—thien0[2,3 - d]pyrimidine -[2-[[1-(5-pheny1thieno[2,3 imidin—4-y1)piperidy1]methoxy] ethyl] —5 - azabicyc10[2.2. 1]heptane 4-[2-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methoxy] ethy1]piperazinone 1-[2-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methoxy] ethy1]pyrr01idine-3 - carboxamide N—[l-[2-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-yl)piperidy1]methoxy]ethy1]pyrrolidin-3 - y1]acetamide 1-[2-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methoxy] ethy1]pyrrolidine carboxamide 4- [4- [2- [(3R)-3 -fluoropyrrolidiny1]eth0xymethy1]—1-piperidyl]pheny1-thien0[2,3 - d]pyrimidine 4- [4- [2- [(3 S)-3 -fluoropyrrolidiny1]eth0xymethy1]— ridy1]pheny1—thien0[2,3 - d]pyrimidine -ethy1—6-methy1—4-[4-[2-(1-methy1—2-piperidyl)eth0xymethy1]piperidy1]thien0[2,3 - d]pyrimidine -(3 -flu0r0pheny1)[4-[2-(1-methylpyrr01idin—2-y1)eth0xymethy1]piperidyl]thien0[2,3 - d]pyrimidine -(3 -fluoropheny1)[4-[2-(1-methy1—2-piperidy1)eth0xymethyl]piperidy1]thien0[2,3 - d]pyrimidine -pheny1—4-[6-(2-pyrr01idin—1-yleth0xymethy1)azabicyc10[3. 1 .0]hexan—3-y1]thien0[2,3- d]pyrimidine 4-[2-[[3-(5-pheny1thien0[2,3-d]pyrimidin—4-yl)azabicyc10[3.1.0]hexan—6- yl]methoxy]ethy1]m0rpholine 4-[6-[2-(1-methy1pyrro1idin—2-y1)eth0xymethy1]azabicyc10[3.1 .0]hexan—3-y1]—5-pheny1- thieno[2,3-d]pyrimidine 4-[6-[2-[(3 S)flu0r0pyrrolidiny1]ethoxymethyl]azabicyc10[3.1.0]hexan—3-y1]—5- phenyl-thieno [2,3 -d]pyrimidine 2-[(3R)fluor0pyrrolidin—1-y1]eth0xymethy1]azabicyc10[3.1 .0]hexan—3-y1]—5- -thieno [2,3 -d]pyrimidine (2R)[2-[[3-(5-pheny1thien0[2,3-d]pyrimidin—4-y1)azabicyc10[3. 1 .0]hexan—6- y1]meth0xy]ethy1]pyrr01idinecarboxamide (2S)[2-[[3-(5-pheny1thien0[2,3-d]pyrimidinyl)azabicyc10[3.1.0]hexan—6- y1]meth0xy]ethy1]pyrr01idinecarboxamide N,N—dimethy1[4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 -d]pyrimidin— 5-y1]benzenesulfonamide (2R)[2-[[3-[5-(4-flu0r0pheny1)thieno[2,3-d]pyrimidin—4-y1]azabicyc10[3.1 .0]hexan—6- h0xy]ethy1]pyrr01idinecarboxamide itropheny1)[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 -d]pyrimidine -(4-flu0r0pheny1)[6-[2-[(3 S)flu0r0pyrr01idin— 1-y1]eth0xymethy1]—3- azabicyc10[3.1.0]hexan—3-y1]thien0[2,3-d]pyrimidine -[2-[[3-[5-(4-fluor0pheny1)thieno[2,3-d]pyrimidin—4-y1]azabicyc10[3.1.0]hexan—6- y1]meth0xy]ethyl] 0xa—5-azabicyc10 [2 .2. 1 ]heptane 1-cyc10pr0py1-N—[[ 1 -(5-pheny1thien0[2,3-d]pyrimidin—4-y1) piperidyl]methy1]methanamine 4- [4- [(3 -methy1pyrrolidin—1-y1)methy1]—1-piperidy1]pheny1—thieno[2,3 -d]pyrimidine N—[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methy1]pr0panamine fluor0-N—[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methyl]ethanamine 2-meth0xy-N—(2-methoxyethy1)-N—[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1) piperidy1]methy1]ethanamine WO 72694 [1-[[1-(5-pheny1thieno[2,3 imidin—4-y1) piperidyl]methy1amino]cyclopentyl]methanol 1- [[ 1 -(5 -pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methy1]piperidin-3 -01 2-pheny1—4-[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidyl]methy1]morpholine 3 -pheny1 [[ 1 -(5-pheny1thien0 [2,3 -d]pyrimidinyl)piperidy1]methylamino]pr0pan—1-01 2-(1 -methy1pyrr01idin—2-y1)-N-[[ 1 eny1thieno[2,3 -d]pyrimidiny1) piperidy1]methy1]ethanamine 2-methy1m0rpholin0-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1) piperidyl]methy1]propan— 1 -amine N,N—dimethy1—1-[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methyl]piperidin—3 - amine 1-(2-fury1)-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]methanamine N',N'-diisopr0py1—N— [[ 1 -(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]ethane- 1 ,2-diamine N'-[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methyl]ethane-1 mine N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]cyclobutanamine [1-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]pyrrolidin—2-yl]methanol N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl](2-pyridy1)methanamine (3 S ,4S)[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methy1] pyrr01idin— 1 -y1- pyrrolidin01 4- [4- [(3 -meth0xypyrrolidin—1-y1)methy1]—1-piperidy1]pheny1—thien0[2,3 -d]pyrimidine N—[[1-(5-pheny1thieno[2,3 imidin—4-y1)piperidy1]methyl](2-thieny1)methanamine 4- [4- [ [3 -(4-fluor0pheny1)pyrrolidin—1-y1]methy1]—1-piperidy1]pheny1—thien0[2,3 - d]pyrimidine N,N,N'-trimethy1-N'-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl] ethane- 1 ,2-diamine -trimethy1-N'-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methy1]pr0pane- 1 ,3 -diamine 4-[4-(azetidin—1-y1methy1)piperidy1]pheny1—thieno[2,3 -d]pyrimidine 3 0 N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]cyclopropanamine N,N—dimethy1—1-[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidyl]methy1]piperidin amine -pheny1 [4- [(3 -pyrr01idin—1-y1pyrr01idin—1-y1)methy1]—1-piperidy1]thieno[2,3 - d]pyrimidine 2012/052842 N— [[ 1 - [5-(4-flu0r0pheny1)thieno [2,3 -d]pyrimidin—4-y1]—4- piperidy1]methy1]cyclopropanamine N— [[ 1 - [5-(4-flu0r0pheny1)thieno [2,3 -d]pyrimidin—4-yl]piperidy1]methy1]cyclobutanamine 1- [[ 1 - [5 -(4-fluor0pheny1)thieno [2,3 -d]pyrimidin—4-y1] piperidy1]methy1] -N,N-dimethy1— piperidin—3 -amine 2-(1 -methy1—2-piperidy1)-N—[[ 1 -(5-pheny1thieno[2,3 imidin—4-y1) piperidy1]methy1]ethanamine (3R)-N,N—dimethy1—1-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1) piperidyl]methy1]pyrrolidinamine tert-butyl2-[2-[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1) piperidyl]methylamino]ethy1]pyrr01idinecarb0xylate N—methyl[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidy1] -N-(pyrr01idin—2- ylmethyl)methanamine N—[(1-methy1pyrro1idin—2-y1)methy1][1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1) piperidy1]methanamine N—[[1-(5-pheny1thieno[2,3 imidin—4-y1)piperidy1]methyl]pyrr01idin—2-y1— ethanamine N—methyl-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidy1]methyl]pyrr01idin—2- anamine 2-(1-ethy1pyrr01idin—2-y1)-N-methy1-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1) piperidy1]methy1]ethanamine 2-(1-is0pr0py1pyrrolidin—2-yl)-N-methy1—N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1) dy1]methy1]ethanamine 1-[2-[2-[methy1—[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1) piperidyl]methyl]amino] ethy1]pyrr01idiny1] ethanone (3 S)[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]piperidin—3-amine 1-methy1[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methylamino]pyrrolidin— 2-one 4- [4- [ [(3 S)-3 -flu0r0pyrrolidiny1]methy1]—1-piperidyl]pheny1-thieno[2,3 -d]pyrimidine 2-[methy1—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methy1]amino] idiny1-ethan0ne N—[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methy1]pr0penamine [1-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]pyrr01idin—3 -yl]methan01 N—[1-[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1] ethyl]cyclopropanamine 1-methy1—N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidyl]methy1]piperidin amine (2,5-dimethylpyrrolidiny1)methy1]—1-piperidy1]pheny1-thien0[2,3 -d]pyrimidine -pheny1—4-[4-[[4-(triflu0r0methy1)piperidy1]methy1]—1-piperidyl]thien0[2,3 imidine 2-[(2S)methy1pyrrolidin—2-yl]-N-[[1-(5-phenylthien0[2,3 -d]pyrimidin—4-y1) piperidy1]methy1]ethanamine y1(1-methy1pyrr01idin—2-y1)-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1) piperidy1]methy1]ethanamine N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidyl]methyl] tetrahydr0furan—2-y1- ethanamine 2-cyc10pr0py1—N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]ethanamine 2-(1-methy1pyrrolidin—3 -y1)-N-[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1) piperidy1]methy1]ethanamine 2-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methylamino]pyrr01idin—1-y1— ethanone (2S)[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidy1]methy1]pyrrolidine carboxamide 2-[2-hydr0xyethy1-[[1-[2-(4-methy1piperazin—1-y1)-5 -pheny1-thieno [2,3 -d]pyrimidiny1]—4- piperidyl]methyl]amino] ethanol 4-[4-[(isopropylamin0)methy1]piperidy1]pheny1—N—(2-pyrr01idin—1-ylethy1)thieno[2,3 - d]pyrimidin—2-amine 4-[4-[(2-methoxyethylamino)methy1]piperidy1]pheny1—N—(2-pyrr01idin— 1 - ylethy1)thien0[2,3 -d]pyrimidin—2-amine 4-[4-[[methy1—(1-methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]pheny1—N—(2- pyrrolidinylethy1)thieno[2,3 imidin—2-amine N,1-dimethy1—N—[[1-[2-(4-methy1piperazin—1-y1)pheny1—thieno[2,3 -d]pyrimidin—4-y1]—4- piperidyl]methy1]pyrrolidinamine N,1-dimethy1—N—[[1-(5-pheny1—2-piperazin—1-y1-thieno[2,3 -d]pyrimidiny1) piperidyl]methy1]pyrrolidinamine [1-[[1-[2-(4-methy1piperazin—1-y1)pheny1—thieno[2,3 -d]pyrimidiny1]—4- piperidyl]methy1amino]cyclopentyl]methanol [2-(4-methy1piperazin—1-y1)pheny1—thien0[2,3 -d]pyrimidiny1]—4- piperidy1]methyl] ( 1 -methylpyrr01idin—2-y1)ethanamine 2012/052842 N,N—dimethy1—1-[[1-[2-(4-methy1piperazin—1-y1)pheny1—thieno[2,3 -d]pyrimidin—4-y1]—4- piperidyl]methyl]piperidin—3-amine N—[[1-[2-(4-methy1piperazin—1-y1)pheny1—thien0[2,3 -d]pyrimidiny1]—4- piperidyl]methyl]cyclobutanamine 4- [4- [ [3 -(dimethy1amin0)piperidy1]methy1] piperidy1] pheny1-N—(2-pyrrolidin ylethy1)thien0[2,3 -d]pyrimidin—2-amine N—(2-methoxyethy1) [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]—5- phenyl-thieno [2,3 -d]pyrimidin—2-amine N—(cyclopropylmethy1)[4-[[methy1—(1-methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]— 5-pheny1-thieno [2,3 -d]pyrimidinamine 1- [4- [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]pheny1—thieno[2,3 - d]pyrimidin—2-y1]pyrrolidinecarb0xamide 2-[methyl-[4-[4-[[methy1—(1-methy1pyrr01idin—3 -y1)amino] methyl] piperidy1] pheny1- thieno [2,3 imidin—2-y1] amino] acetamide [2-[4-(2-methoxyethyl)piperazin—1-y1]pheny1-thieno[2,3 -d]pyrimidiny1]—4- piperidy1]methyl] -N, 1 -dimethy1—pyrrolidin—3 -amine 1- [4- [4- [ [3 -(dimethy1amino)piperidy1]methy1]—1-piperidy1]pheny1—thieno[2,3 - d]pyrimidin—2-y1]pyrrolidinecarb0xamide 4- [4- [ [3 -(dimethy1amin0)piperidy1]methy1] piperidy1] -N-(2-methoxyethy1)pheny1- thieno [2,3 imidin—2-amine 4-[4-[4-[(cyclobutylamino)methy1]piperidy1]pheny1-thien0[2,3 -d]pyrimidin—2- yl]piperazin—2-one 4-[4-[(cyclobutylamino)methyl]piperidy1]-N-(2-meth0xyethy1)pheny1—thieno[2,3 - d]pyrimidin—2-amine 4-[4-[(cyclobutylamin0)methyl]piperidy1]pheny1—N—(2-pyrrolidin—1-ylethy1)thieno[2,3 - d]pyrimidin—2-amine 4-[(cyclobutylamin0)methyl]piperidy1]pheny1—thieno[2,3 -d]pyrimidin—2- y1]pyrr01idine-3 -carb0xamide 1- [4- [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]pheny1—thieno[2,3 - midin—2-y1]piperidinecarboxamide 1- [4- [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]pheny1—thieno[2,3 - d]pyrimidin—2-y1]pyrrolidinecarb0xamide N—methy1 [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1] piperidy1] pheny1- thieno [2,3 -d]pyrimidinecarboxamide N—isopropy1 [4- [ [methyl-( 1 -methy1pyrrolidin-3 ino]methy1] piperidy1] pheny1- thieno [2,3 -d]pyrimidinecarboxamide -isopropyl-N,N—dimethy1—4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 - d]pyrimidinecarboxamide r0py1—N—methy1—4-[4-(2-pyrrolidinylethoxymethy1)piperidy1]thieno[2,3 - d]pyrimidinecarboxamide N,N—dimethy1phenyl[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thieno[2,3 - d]pyrimidinecarboxamide N,N—dimethy1—4-[4-[[methy1-(1-methy1pyrr01idiny1)amino]methy1] piperidy1] pheny1— thieno [2,3 -d]pyrimidinecarboxamide -(3 -flu0r0pheny1)-N—isopropy1[4-(2-pyrr01idin— 1 -yleth0xymethy1) piperidy1]thien0 [2,3 -d]pyrimidinecarboxamide -(3 pheny1)-N,N—dimethy1[4-(2-pyrr01idin— 1-ylethoxymethyl) piperidy1]thien0 [2,3 -d]pyrimidinecarboxamide [5-pheny1—4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 -d]pyrimidin—6-y1]— pyrrolidiny1—methanone N—isopropyl-S-pheny1[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 - d]pyrimidinecarboxamide N—methyl-S-pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidyl]thien0[2,3 - d]pyrimidinecarboxamide 3 -pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -b]pyridine 0pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -b]pyridine 3 -pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -b]pyridine carbonitrile 5-pheny1—2-[4-(2-pyrr01idin—1-ylethy1)piperaziny1]thien0[2,3 -d]pyrimidine 2-(1-methy1pyrro1idin—2-y1)-N—[[1-(5-phenylthien0[2,3 imidiny1) piperidy1]methy1]ethanamine (2R)[2-[4-(5-pheny1thieno[2,3 -d]pyrimidin—2-y1)piperazin— 1 -y1] ethy1]pyrr01idine carboxamide 5-pheny1[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thien0[2,3 -d]pyrimidine -pheny1 [3 -(2-pyrr01idin—1-ylethoxymethy1)pyrr0lidiny1]thien0[2,3 -d]pyrimidine (3R)[2-[4-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperazin—1-y1]ethy1]pyrr01idine-3 - carboxamide 2- [4- [2- [(3R)-3 -fluoropyrrolidiny1]eth0xymethy1]—1-piperidyl]pheny1—thien0[2,3 - d]pyrimidine -(4-fluorophenyl)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 - d]pyrimidine 1-[2-[[1-(5-pheny1thien0[2,3 imidin—2-y1)piperidy1]methoxy] pyrr01idine-3 - carboxamide -[2-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—2-y1)piperidy1]methoxy] ethyl] 0xa—5 - azabicyclo [2 .2. 1]heptane N—[5-pheny1—2- [4-(2-pyrr01idin— 1 -yleth0xymethy1)piperidy1]thieno [2,3 -d]pyrimidin—6- y1]acetamide 1-[5-pheny1—2-[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 -d]pyrimidin—6- yl]pyrr01idin—2-0ne -isopr0py1—2-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -d]pyrimidine 1-[5-pheny1—2-[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 -d]pyrimidin—6- yl]pyrr01idin—2-0ne -isopr0py1—2-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -d]pyrimidine 4- [3 -[(1 1pyrr01idin—3 -y1)methoxy]propyny1]pheny1—thien0[2,3 -d]pyrimidine -pheny1—4- [3 -(2-pyrr01idin—1-yleth0xy)pr0pyny1]thien0[2,3 -d]pyrimidine N—[5-pheny1—4- [4-(2-pyrr01idin— 1 -yleth0xymethy1)piperidy1]thieno [2,3 -d]pyrimidin—6- y1]acetamide 1-[5-pheny1—4-[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 imidin—6- yl]pyrr01idin—2-0ne -pheny1—4- [(1 S ,5R)-3 -(2-pyrr01idin—1-yleth0xymethy1)azabicyclo[3.2.1]0ctan—8- y1]thieno[2,3 -d]pyrimidine [8-(4-m0rph01inopheny1—thieno [2,3 -d]pyrimidin—2-y1)azabicyclo [3 .2. 1] octan—3 - y1]methan01 1-methy1pyrro1idin—2-y1)ethyl](5-pheny1thien0[2,3 -d]pyrimidiny1)piperidine carboxamide -pheny1—4-[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thien0[2,3 -d]pyrimidine carbonitrile N—benzyl-S-pheny1[4-(2-pyrr01idinyleth0xymethy1)piperidy1]thien0[2,3 - d]pyrimidin—6-amine N,N—dimethy1—1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidin—4-amine 1-(2-ethy1—5-pheny1—thien0 [2,3 -d]pyrimidin—4-y1)-N,N-dimethy1—piperidin—4-amine 2012/052842 2-[ l - [5-(4-fluorophenyl)(2-hydroxyethylamino)thieno [2,3 -d]pyrimidin—4-yl] piperidyl] ethanol 4- [4-(methoxymethyl)- l idyl] phenyl-thieno [2,3 -d]pyrimidine 4-(methoxymethyl)- l -piperidyl] phenyl-thieno [2,3 -d]pyrimidinyl] -N',N'- dimethyl-ethane- l ,2-diamine 4- [4-(methoxymethyl)- l idyl] (4-methylpiperazin— l -yl)phenyl-thieno [2,3 - d]pyrimidine 4- [4-(methoxymethyl)- l -piperidyl] phenyl-N-(2-pyrrolidin- l -ylethyl)thieno [2,3 - d]pyrimidin—2-amine 4- [4-(4-methoxyphenyl)- l -piperidyl] phenyl-thieno [2,3 -d]pyrimidine -cyclohexyl [4-(methoxymethyl)- l -piperidyl] -N- [2-( l -methylpyrrolidin—2- yl)ethyl]thieno [2,3 -d]pyrimidin—2-amine 4-(3 -benzyloxypyrrolidin— l -yl)phenyl-thieno [2,3 -d]pyrimidine 4- [4-(dimethylamino)- l -piperidyl] phenyl-N-(2-pyrrolidin- l -ylethyl)thieno [2,3 - d]pyrimidin—2-amine -phenyl [4-(3 -pyridyloxymethyl)- l -piperidyl]thieno [2,3 -d]pyrimidine -phenyl [3 -( l -piperidyl)pyrrolidin— l -yl]thieno[2,3 imidine 2- [4- [4-(methoxymethyl)- l idyl] phenyl-thieno [2,3 -d]pyrimidinyl] -N-(2- pyrrolidin- l -ylethyl)acetamide 2- [4- [4-(methoxymethyl)- l -piperidyl] phenyl-thieno [2,3 -d]pyrimidinyl] - l -pyrrolidin— l - yl-ethanone -(4-fluorophenyl)[4-(methoxymethyl)- l -piperidyl] (2-pyrrolidin- l -ylethyl)thieno [2,3 - d]pyrimidine 2- [ [4- [4-(methoxymethyl)- l -piperidyl] phenyl-thieno [2,3 -d]pyrimidinyl] -(2-pyrrolidin— l -ylethyl)amino] ethanol 2- [2-hydroxyethyl- [[ l -(5-phenylthieno [2,3 imidin—4-yl) piperidyl]methyl]amino] ethanol N— [[ l -(5-phenylthieno [2,3 -d]pyrimidin—4-yl)piperidyl]methyl]propan—2-amine l- [4- [4-(dimethylamino)- l -piperidyl] phenyl-thieno [2,3 imidinyl]pyrrolidin—3 -ol 1- [5 -phenyl(2-pyrrolidin— l -ylethylamino)thieno [2,3 -d]pyrimidinyl]pyrrolidin—3 -ol (3 S)- l - [[ l -(5 lthieno [2,3 -d]pyrimidin—4-yl)piperidyl]methyl]pyrrolidin-3 -ol [1- [4- [4-(methoxymethyl)- l -piperidyl] phenyl-thieno [2,3 -d]pyrimidinyl] piperidyl]methanol 2-meth0xy-N—[[1-[4-[4-(meth0xymethy1)piperidy1]pheny1-thien0[2,3 -d]pyrimidin piperidy1]methy1]ethanamine 4-[4-(meth0xymethy1)piperidy1]—N—methy1—N—(1-methy1pyrr01idin-3 -y1)pheny1- thieno [2,3 -d]pyrimidin—2-amine -cyc10hexy1[4-(meth0xymethy1)piperidy1]—2-piperazin—1-y1-thien0[2,3 -d]pyrimidine 1-(5-pheny1thien0[2,3 -d]pyrimidinyl)(pyrr01idin—1-y1methy1)piperidin—4-01 N—[[1-(5-cyclohexy1thien0[2,3 -d]pyrimidin—4-yl)piperidyl]methyl]pr0pan—2-amine 4-[[1-(5-cyc10hexy1thieno[2,3 -d]pyrimidin—4-y1)piperidyl]methyl] imethy1— morpholine 4- [4- [(3 1pyrrolidiny1)methy1]pheny1-pyrr01idiny1]pheny1-thien0[2,3 - d]pyrimidine 2- [5-(4-fluoropheny1)(2-pheny1pyrr01idin— 1 -y1)thien0 [2,3 -d]pyrimidin—2-y1]—N—(2- pyrrolidiny1ethy1)acetamide 1-[[1-(5-cyc10hexy1thien0[2,3 -d]pyrimidin—4-y1)piperidyl]methyl]pyrr01idin—3 -01 2-[[1-(5-cyc10hexy1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl-(2- hydroxyethy1)amino]ethanol N,1-dimethy1—N—[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidyl]methyl]pyrr01idin—3 - amine N—methyl-N— [[ 1 -(5-pheny1thien0[2,3 imidiny1)piperidy1]methyl]tetrahydrofuran— 3 -amine 2-(1-methy1pyrro1idiny1)-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)pyrr01idin—3 - y1]methy1]ethanamine N,1-dimethy1—N—[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)pyrr01idin-3 - y1]methy1]pyrrolidinamine N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]pyrr01idin—1-y1- ethanamine N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-yl)-3 -piperidy1]methy1]cyclobutanamine N,N—dimethy1—1-[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)-3 idy1]methyl]piperidin—3 - amine N— [ [5-methyl(5-pheny1thien0 [2,3 imidiny1)pyrr01idin—3 -y1]methyl] ( 1 - methylpyrro1idiny1)ethanamine 2-(1-methy1pyrr01idiny1)-N—[[1-(5-methy1thien0[2,3 -d]pyrimidiny1)pheny1— pyrrolidin-3 -y1]methy1] ethanamine 1-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methy1]piperidinamine y1 [4- [ [3 -(triflu0r0methy1)piperidy1]methy1]—1-piperidy1]thieno[2,3 imidine 4-[[1-(5-pheny1thien0[2,3 imidin—4-y1)piperidy1]methy1]piperazinone 4-[4-[(4-methylpiperaziny1)methy1]—1-piperidy1]—5 -pheny1-thieno [2,3 -d]pyrimidine (3 S)-N,N—dimethyl[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1) piperidyl]methyl]piperidin—3-amine (3R)-N,N—dimethy1—1-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1) piperidyl]methyl]piperidin—3-amine N',N'-dimethy1-N— [[ 1 -(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidy1]methy1]propane- 1 ,3 -diamine 5-pheny1 [4- [ [3 -(1-piperidy1)pyrrolidiny1]methy1]—1-piperidy1]thien0[2,3 -d]pyrimidine 2-(1-methy1pyrro1idin—2-y1)-N—[[1-(5-phenylthien0[2,3 -d]pyrimidiny1)azetidin—3 - y1]methy1]ethanamine N—[[1-(5 ,6-dimethy1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl] ( 1 -methy1pyrr01idin— thanamine 2-(1-methy1imidazoly1)-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1) piperidy1]methy1]ethanamine N,N—dimethy1—1-[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidyl]piperidin—4-amine 1-methy1—N—[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidyl]piperidinamine N—[2-(1-methy1pyrro1idin—2-y1)ethyl](5-pheny1thien0[2,3 -d]pyrimidiny1)piperidine carboxamide 1-[4-[4-[[2-dimethylaminoethy1(methy1)amin0]methy1]piperidyl]pheny1-thieno[2,3 - d]pyrimidin—2-y1]pyrrolidinecarb0xamide N—[1-[4-[4-[[methy1—(1-methy1pyrrolidin-3 -y1)amin0]methy1] piperidy1] pheny1- thieno [2,3 imidin—2-y1]pyrro1idin—3 -y1] acetamide N—methyl[4-[4-[[methy1—(1-methy1pyrrolidin-3 -y1)amino]methy1] piperidy1] pheny1- thieno [2,3 -d]pyrimidin—2-y1]piperidine-3 -carb0xamide N,N—diethy1—1-[4-[4-[[methy1-(1-methylpyrrolidin-3 -y1)amin0]methy1]—1-piperidy1]—5- phenyl-thieno [2,3 -d]pyrimidin—2-y1]piperidine-3 xamide (2R)[4-[4-[[methy1—(1-methy1pyrr01idin—3 -y1)amino]methy1] piperidy1] pheny1- 3 0 thieno [2,3 -d]pyrimidin—2-y1]pyrrolidinecarboxamide 4-[4-(4-methy1piperazin—1-y1)piperidy1]pheny1-thieno[2,3 imidine N—methyl-N—( 1 -methy1pyrrolidin-3 -y1)(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidin—4- amine N—[[1-(5 ,6-dimethy1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]methy1-piperidin—4- amine N—[[1-(5 ,6-dimethy1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl](1-methy1 piperidyl)ethanamine 1-[[1-(5 ,6-dimethy1thieno[2,3 -d]pyrimidin—4-y1)piperidyl]methyl] -N,N-dimethy1— piperidin—3 -amine 1-[4-[4-[[4-(dimethy1amino)piperidy1]methy1]—1-piperidy1]pheny1-thien0[2,3 - midin—2-y1]pyrrolidinecarb0xamide 1- [4- [4- [ [(3R)-3 -(dimethylamin0)pyrrolidiny1]methy1]—1-piperidy1]pheny1—thien0[2,3 - d]pyrimidin—2-y1]pyrr01idinecarb0xamide 1- [4- [4- [ [methyl-( 1 -methy1pyrr01idin—3 in0]methy1]—1-piperidy1]pheny1—thieno[2,3 - d]pyrimidin—2-y1]azetidinecarb0xamide 1- [4- [4- [ l-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]pheny1—thieno[2,3 - d]pyrimidin—2-y1]piperidinecarb0xamide 1- [4- [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]pheny1—thieno[2,3 - d]pyrimidin—2-y1]piperidinecarboxamide 1- [5 ,6-dimethy1—4-[4-[[2-(1-methy1piperidy1)ethylamin0]methyl]piperidy1]thieno[2,3 - d]pyrimidin—2-y1]pyrrolidinecarb0xamide N—methyl-N—[1-[4-[4-[[methy1—(1-methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]—5thieno[2,3-d]pyrimidin—2-yl]piperidy1]acetamide N—[[1-(5-isopropy1thieno[2,3 -d]pyrimidiny1)piperidy1]methyl](1 -methy1pyrr01idin— 2-y1)ethanamine 2-(1-methy1pyrro1idin—2-y1)-N—[[1-(5-methy1thieno[2,3 -d]pyrimidiny1) piperidy1]methy1]ethanamine 1-[[4-[4-[[methy1—(1-methy1pyrr01idin—3 -y1)amino]methy1] piperidy1] pheny1-thieno [2,3 - d]pyrimidin—2-y1]methy1]pyrrolidin0ne 1- [5 -is 0pr0py1—4- [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amino]methy1] piperidy1]thien0 [2,3 -d]pyrimidin—2-y1]pyrrolidine-3 -carb0xamide ethy1[[1-(5-phenylthien0[2,3 -d]pyrimidiny1)piperidy1]methy1]piperidine-3 - 3 0 carboxamide 1- [[ 1 -(5 -pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]pyrrolidinecarb0xamide N—methyl-N—[ 1 - [[ 1 -(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidyl]methyl]pyrr01idin—3 - y1]acetamide N—methyl-N—( 1 -methy1pyrrolidin-3 -y1)(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidine carboxamide 1-methy1[methy1—[[1-(5-phenylthien0[2,3 -d]pyrimidin—4-y1) dy1]methy1]amino]pyrrolidin—2-0ne N—methyl-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidy1]methyl]cyclobutanamine 2-[cyc10buty1-[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidyl]methyl]amino] -N- methyl-acetamide N—[l-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidyl]methyl]pyrr01idin—3 - y1]acetamide (2S)-N,N—dimethy1 [[ 1 -(5-pheny1thien0 [2,3 -d]pyrimidin—4-y1) piperidy1]methoxy]propan— 1 -amine 4-[2-(1-methy1pyrro1idin—2-y1)ethoxymethyl]piperidy1]pheny1—thieno[2,3 - d]pyrimidin—2-y1]pyrrolidinecarb0xamide 1- [5-pheny1 [4-(2-pyrr01idin— 1 -yleth0xymethy1)piperidy1]thieno [2,3 imidin—2- y1]pyrr01idine-3 -carb0xamide -pheny1—4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidyl]thien0[2,3 -d]pyrimidin—2- y1]pyrr01idin-3 -y1] acetamide 1-[4-[4-(2-m0rph01inoeth0xymethy1)piperidy1]pheny1—thieno[2,3 -d]pyrimidin—2- y1]pyrr01idine-3 -carb0xamide N—[ 1 -[4-[4-(2-m0rph01inoethoxymethy1)piperidy1] pheny1—thieno[2,3 -d]pyrimidin y1]pyrr01idin-3 -y1] acetamide N—methyl-l-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1) piperidyl]methy1amino]cyclobutanecarboxamide 1- [4- [2- [[ 1 -(5 -pheny1thien0 [2,3 -d]pyrimidiny1)piperidy1]methoxy]ethyl]piperazin—1- yl] ethanone -pheny1 [(3R)-3 -(2-pyrr01idin—1-ylethoxymethy1)pyrr01idiny1]thien0[2,3 imidine y1 [(3 S)-3 -(2-pyrr01idin—1-ylethoxymethy1)pyrr01idiny1]thien0[2,3 -d]pyrimidine isopropy1—4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -d]pyrimidine- 6-carboxamide 5-isopropy1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -d]pyrimidine N—[[1-(6-brom0pheny1—thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl] -N, 1 -dimethy1— pyrrolidin-3 -amine 1-(5-pheny1thien0 [2,3 -d]pyrimidiny1)-N—(2-pyrrolidin— 1 -ylethy1)piperidine carboxamide 1-(5-pheny1thien0[2,3 -d]pyrimidiny1)-N—(2-pyrr01idin—1-ylethy1)piperidine-3 - carboxamide -pheny1 [3 rr01idin—1-ylethoxy)pyrrolidiny1]thieno[2,3 -d]pyrimidine 1-(5-pheny1thien0[2,3 -d]pyrimidiny1)-N—(2-pyrrolidin— 1 -ylethy1)pyrrolidine-3 - carboxamide -pheny1[4-(2-pyrr01idin—1-yleth0xy)piperidy1]thien0[2,3 -d]pyrimidine -pheny1 [3 -(2-pyrr01idin—1-yleth0xy)piperidy1]thien0[2,3 -d]pyrimidine -pheny1 [3 rr01idin—1-yleth0xymethy1)azetidin—1-y1]thien0[2,3 -d]pyrimidine heny1—2-[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 -d]pyrimidin—4- y1]pyrr01idine-3 -carb0xamide N,N-dimethy1pheny1[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thieno[2,3 - d]pyrimidin—4-amine 4-[5-pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 -d]pyrimidin—4- yl]m0rph01ine (2S) [2- [ [3 - [5 -(4-flu0r0pheny1)thieno [2,3 -d]pyrimidin—4-y1]—3 -azabicyc10 [3 . 1 an—6- y1]meth0xy]ethy1]pyrr01idinecarboxamide -(4-fluoropheny1) [6- [2- [(3R)-3 -fluor0pyrr01idin— 1 -y1]eth0xymethy1]—3 - azabicyc10[3.1.0]hexan—3-y1]thien0[2,3-d]pyrimidine 2-ch10r0—5-(4-fluoropheny1) [4-(2-pyrr01idinyleth0xymethy1)piperidy1]thieno [2,3 - d]pyrimidine N—(2-hydroxyethy1)pheny1[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thieno[2,3 - d]pyrimidinecarboxamide [5-pheny1—4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 -d]pyrimidin—6- han01 N—methyl-N—( 1 -methy1pyrrolidin-3 -y1)(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidine-3 - carboxamide -cyc10hexy1[4-(2-pyrr01idin—1-yleth0xymethy1)-1 -piperidy1]thieno [2,3 -d]pyrimidine -pheny1 [5-(2-pyrr01idin— 1 -yleth0xy)azabicyclo [2 .2. 1 n—2-y1]thieno[2,3 - d]pyrimidine N—(2-m0rpholinoethy1)(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidinecarb0xamide y1 [3 -(2-pyrr01idin—1-yleth0xymethy1)azabicyclo[3.2. 1]0ctan—8-y1]thien0[2,3 - d]pyrimidine -is 0pr0py1—4- [3 -(2-pyrr01idin— 1 -yleth0xymethy1)azabicyc10 [3 .2. 1 ]0ctan—8-y1]thieno[2,3 - d]pyrimidine 2012/052842 -isopropy1[5-(2-pyrr01idin—1-yleth0xy)azabicyclo[2.2.1]heptan—2-y1]thien0[2,3- midine y1[3-(2-pyrr01idin—1-yleth0xy)azabicyclo[3.2.1]0ctan—8-y1]thieno[2,3- d]pyrimidine 1-[2-[[2-(5-pheny1thien0[2,3-d]pyrimidin—4-y1)azabicyclo[2.2. 1]heptan—5- yl] oxy] ethy1]pyrr01idine-3 -carb0xamide 4-[5-[2-[(3 S)flu0r0pyrrolidiny1]ethoxy]azabicyc10[2.2.1]heptan—2-y1]—5-pheny1— thieno[2,3-d]pyrimidine -[2-[[2-(5-isopropy1thien0 [2,3-d]pyrimidin—4-y1)azabicyclo[2.2. 1]heptan—5 - yl] oxy] ethyl] 0xa—5-azabicyc10 [2 .2. 1 ]heptane (2R)[2-[[2-(5-pheny1thieno[2,3-d]pyrimidin—4-y1)azabicyclo[2.2.1]heptan—5- yl]oxy]ethy1]pyrr0lidinecarb0xamide 4-[5-[2-[(3 S)flu0ropyrrolidiny1]ethoxy]azabicyc10[2.2. 1]heptan—2-y1]isopr0py1- thieno[2,3-d]pyrimidine 4-[5-[2-[(3R)fluor0pyrrolidin—1-y1]ethoxy]azabicyclo[2.2.1]heptan—2-y1]isopr0py1— thieno[2,3-d]pyrimidine -pheny1 [4-(3 -pyrr01idin—1-y1pr0p0xy)piperidy1]thien0[2,3 -d]pyrimidine -isopr0py1—4-[3-(2-pyrr01idin—1-yleth0xy)azabicyclo[3.2.1]0ctan—8-y1]thien0[2,3- d]pyrimidine [8-(4-m0rph01in0pheny1-thien0[2,3-d]pyrimidin—2-y1)azabicyclo[3.2.1]0ctan—3- y1]methan01 8-[4-[4-(meth0xymethy1)- 1 idy1]pheny1-thieno[2,3-d]pyrimidiny1]—8- azabicyclo[3.2.1]0ctan—3-01 4-[2-[3-(meth0xymethy1)azabicyc10[3.2.1]0ctan—8-y1]pheny1-thieno[2,3-d]pyrimidin—4- yl]m0rph01ine 8-[2-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 -d]pyrimidin—4-y1]—3 -0xa azabicyclo[3.2.1]0ctane 3 -methy1—N— [5-pheny1—2- [4-(2-pyrr01idin— 1 -yleth0xymethy1)piperidy1]thieno [2,3 - d]pyrimidin—6-y1]butanamide 2-methy1—N—[5-pheny1—2-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 - d]pyrimidiny1]pr0panamide 4-[5-pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 imidin—4- yl]morpholinecarboxamide 1-(4-m0rph01inopheny1-thieno[2,3-d]pyrimidiny1)pyrr01idinecarb0xamide 2-(2-azabicyc10[2.2.1]heptan—5-y10xy)[4-(methoxymethy1)piperidy1]—5-pheny1- thieno [2,3 -d]pyrimidine -pheny1—4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]fur0[2,3 -d]pyrimidine 1- [4-(2-oxaazabicyc10 [2 .2. 1 ]heptan—5-y1)pheny1—thieno [2,3 -d]pyrimidin y1]pyrr01idine-3 -carb0xamide 1- [4- [3 -(hydroxymethy1)azabicyclo [3 .2. 1 ]0ctan—8 -y1] pheny1-thieno [2,3 -d]pyrimidin—2- y1]pyrr01idine-3 -carb0xamide -(4-pyridy1)[4-(2-pyrr01idin—1-yleth0xymethy1)-1 -piperidy1]thieno [2,3 -d]pyrimidine -(3 -meth0xypheny1)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 - d]pyrimidine 4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]—5-[3 - (trifluoromethoxy)phenyl]thieno [2,3 -d]pyrimidine y1[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thien0[2,3 imidin—2-amine -(3 -fury1)[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thien0[2,3 -d]pyrimidine 5-(2-meth0xy—3 -pyridy1)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 - d]pyrimidine 4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]—5-(3 -thieny1)thien0 [2,3 -d]pyrimidine N—tert-butylmethy1—4-(5-pheny1thien0 [2,3 -d]pyrimidin—4-y1)but-3 -ynamine -(1 ,3 di0x01—5-y1)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 - d]pyrimidine -(2-pyridy1)[4-(2-pyrr01idin—1-yleth0xymethy1)-1 -piperidy1]thieno [2,3 -d]pyrimidine N—cyclobutyl(2-cyc10pr0py1—5-pheny1—thieno[2,3 imidin—4-yl) azabicyc10[3.2.1]0ctan—3-amine 4- [3 -(azetidin—1-y1)azabicyclo[3.2. n—8-y1]cyc10pr0py1—5-pheny1—thieno[2,3 - d]pyrimidine N—[[8-(5-pheny1thien0 [2,3 -d]pyrimidin—4-y1)azabicyclo[3.2.1]0ctan—3 - y1]methy1]cyclobutanamine -(3 -pyridy1)[4-(2-pyrr01idin—1-yleth0xymethy1)-1 -piperidy1]thieno [2,3 -d]pyrimidine N—cyclobutyl-S-(S-pheny1thieno [2,3 imidin—4-y1)azabicyclo [3 .2. 1 ]octan—3 -amine 4- [3 -(azetidin—1-y1)azabicyclo[3.2. 1]0ctan—8-y1]—5 -pheny1-thieno [2,3 -d]pyrimidine N—isopropy1(5-pheny1thien0 [2,3 -d]pyrimidin—4-y1)azabicyc10[3.2.1]0ctan—3-amine -(2-isopropoxy-3 -pyridy1)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 - d]pyrimidine -(2-meth0xypheny1)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 - d]pyrimidine N,N—dimethy1[4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 -d]pyrimidin— -y1]benzamide th0xy-3 -pyridy1)[4-(2-pyrr01idinyleth0xymethyl)piperidy1]thieno[2,3 - midine N,N—dimethy1[4-[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thieno[2,3 -d]pyrimidin— -y1]benzamide 2-methy1-N—[[8-(5-pheny1thien0[2,3-d]pyrimidin—4-y1)azabicyclo[3 .2. 1 —3- yl]methy1]propan—2-amine N—[[8-(5-pheny1thieno[2,3-d]pyrimidin—4-yl)azabicyc10[3.2. 1]octan—3-y1]methy1]propan— 2-amine -pheny1—4-[3-(pyrr01idiny1methy1)azabicyclo[3.2. 1]0ctan—8-y1]thieno[2,3- d]pyrimidine 4- ny1—2-(trifluor0methy1)thieno [2,3 -d]pyrimidin—4-y1]morpholine 1-[4-[3-(cyc10butylamin0)azabicyclo[3.2.1]octany1]pheny1-thieno[2,3-d]pyrimidin- 2-y1]pyrr01idinecarb0xamide 4-[3-(cyc10butylamin0)azabicyclo[3.2.1]0ctan—8-y1]pheny1—thien0[2,3-d]pyrimidine carbonitrile 4-[3-(cyc10buty1amino)azabicyclo[3.2. 1]0ctan—8-y1]-N,N-dimethy1pheny1—thieno[2,3- d]pyrimidinecarboxamide -pheny1—4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidyl](trifluor0methy1)thien0[2,3 - d]pyrimidine N—cyclobutyl-S- [5 - [2-(trifluoromethoxy)pheny1]thieno [2,3 -d]pyrimidiny1]—8- azabicyc10[3.2.1]0ctan—3-amine N—cyclobutyl[5-(2-meth0xyphenyl)thien0[2,3-d]pyrimidin—4-y1]—8- azabicyc10[3.2.1]0ctan—3-amine 4-[3-(cyc10butylamin0)azabicyclo[3.2. 1]octan—8-y1]-N-methy1—5-pheny1—thieno[2,3- d]pyrimidinecarboxamide N—cyclobutyl-S-[5-(0-t01y1)thieno[2,3-d]pyrimidiny1]azabicyclo[3.2.1]0ctan—3-amine N—cyclobutyl[5-(2-meth0xypyridy1)thien0[2,3-d]pyrimidin—4-y1]—8- azabicyc10[3.2.1]0ctan—3-amine N—cyclobutyl-S-[5-(5-fluor0methoxypyridy1)thieno[2,3-d]pyrimidin—4-yl]—8- azabicyc10[3.2.1]0ctan—3-amine 4- [3 - [cyclobutyl(methy1)amin0] azabicyclo [3 .2. 1 ]0ctan—8-y1] imethy1—5-pheny1- thieno[2,3-d]pyrimidinecarboxamide 2-(2-azabicyc10[2.2.1]heptan—5-yloxy)[3-meth0xyazabicyc10[3.2.1]0ctan—8-y1]—5- phenyl-thieno [2,3 -d]pyrimidine 8-[2-(2-azabicyc10[2.2.1]heptan—5-y10xy)pheny1-thieno[2,3-d]pyrimidin—4-yl]0xa azabicyclo[3.2.1]0ctane N—cyclobutyl[5-(2-methoxypheny1)thieno[2,3-d]pyrimidin—4-yl]-N-methy1 azabicyc10[3.2.1]0ctan—3-amine N—cyclobutyl-S- [5-(2-meth0xy-3 -pyridy1)thieno [2,3 -d]pyrimidin—4-y1]-N-methy1—8- azabicyc10[3.2.1]0ctan—3-amine 2-(2-azabicyc10[2.2.1]heptan—5-yloxy)[3-(meth0xymethy1)azabicyclo[3.2.1]0ctan—8- yl] pheny1-thieno [2,3 imidine N,N—dimethy1—5-pheny1—4-[3-pyrr01idin—1-y1azabicyc10[3.2.1]0ctan—8-yl]thien0[2,3- d]pyrimidinecarboxamide N—isopropyl-S-pheny1[3-pyrr01idin—1-y1azabicyclo[3.2. 1]0ctan—8-y1]thieno[2,3- d]pyrimidinecarboxamide N—isopropyl-S-pheny1[3-pyrr01idin—1-y1azabicyclo[3.2. 1]0ctan—8-y1]thieno[2,3- midinecarboxamide N,N—dimethy1—5-pheny1—4-[3-(2-pyrr01idin—1-yleth0xymethy1)azabicyclo[3.2. n—8- y1]thieno[2,3-d]pyrimidinecarb0xamide N—isopropyl-S-pheny1[3-(2-pyrr01idin—1-ylethoxymethyl)azabicyclo[3.2.1]0ctan—8- y1]thieno[2,3-d]pyrimidinecarb0xamide 2-cyc10pr0py1—5-(2-meth0xypheny1)[4-(2-pyrr01idin—1-yleth0xymethy1) piperidy1]thien0[2,3-d]pyrimidine N—cyclobutyl-S- [5-pheny1—2-(trifluor0methy1)thien0 [2,3 -d]pyrimidiny1]—8- azabicyc10[3.2.1]0ctan—3-amine 2-cyc10propy1pheny1—4- [4-(2-pyrr01idin— 1 -yleth0xymethy1)piperidy1]thieno [2,3 - d]pyrimidine N—methyl-S-pheny1[3-(2-pyrr01idin—1-yleth0xymethy1)azabicyclo[3.2.1]0ctan—8- y1]thieno[2,3-d]pyrimidinecarb0xamide -(2-meth0xypheny1)[3-(2-pyrr01idin—1-yleth0xymethy1)azabicyclo[3.2.1]0ctan—8- eno[2,3 -d]pyrimidine -(2-meth0xypyridy1)[3-(2-pyrr01idin—1-yleth0xymethy1)azabicyclo[3.2.1]0ctan—8- y1]thieno[2,3 -d]pyrimidine WO 72694 N,N—dimethyl [4- [3 -(2-pyrr01idin—1-yleth0xymethy1)azabicyclo[3.2. 1]0ctan—8- y1]thieno[2,3 -d]pyrimidiny1]benzamide (2-methoxypyridy1)thieno[2,3-d]pyrimidin—4-y1]azabicyclo[3.2.1]0ctan—3- y1]methan01 2-(2-azabicyc10[2.2.1]heptan—5-yloxy)[3-(meth0xymethy1)azabicyclo[3.2.1]0ctan—8- yl] -N,N-dimethy1—5-pheny1-thien0 [2,3 imidinecarboxamide N—[[8-[5-(2-meth0xypheny1)thieno[2,3-d]pyrimidin—4-y1]azabicyclo[3.2. 1]0ctan—3- y1]methy1]cyclobutanamine 1-[5-pheny1—4-[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 -d]pyrimidin—6- yl]imidazolidin—2-0ne 2-[5-pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 -d]pyrimidin—6-y1]— 1,2-thiazolidine 1,1-di0xide 1-(2-ethy1—5-pheny1-thien0 [2,3 -d]pyrimidin—4-y1)-N,N-dimethy1-piperidin—4-amine [8-[4-(3-methoxyazabicyclo[3.2.1]octany1)(2-methoxypheny1)thien0[2,3- d]pyrimidin—2-y1]azabicyclo[3.2. 1]0ctan—3-y1]methan01 8-[4-[3-(meth0xymethy1)azabicyclo[3.2.1]0ctan—8-y1](2-methoxypheny1)thien0[2,3- d]pyrimidin—2-yl]azabicyc10[3.2.1]0ctan—3-01 1-[5-(2-chlor0pheny1)(3-meth0xyazabicyclo[3.2.1]0ctan—8-y1)thien0[2,3-d]pyrimidin— 2-y1]piperidinecarb0xamide 1-[5-(2-chlor0pheny1)(3-meth0xyazabicyclo[3.2.1]0ctan—8-y1)thien0[2,3-d]pyrimidin— 4-y1]piperidinecarb0xamide 8-[5-(2-ch10r0pheny1)(3-meth0xyazabicyclo[3.2.1]octan—8-y1)thieno[2,3-d]pyrimidin— 2-y1]azabicyclo[3.2.1]0ctan—3-01 1-[4-[3-(meth0xymethy1)azabicyclo[3 .2. 1 ]0ctan—8-y1](2-meth0xypheny1)thien0[2,3- d]pyrimidin—2-y1]pyrrolidinecarb0xamide 8-[4-(3-meth0xyazabicyclo[3.2.1]octany1)(2-meth0xypheny1)thien0[2,3- d]pyrimidin—2-y1]azabicyclo[3.2. 1]0ctan—3-01 4-[4-[3-(methoxymethy1)azabicyclo[3 .2. 1 ]0ctan—8-y1](2-meth0xypheny1)thien0[2,3- d]pyrimidin—2-y1]piperazin—2-one 3-meth0xyazabicyclo[3.2.1]octany1)(2-meth0xypheny1)thien0[2,3- d]pyrimidin—2-y1]0xaazabicyclo[3 .2. 1]0ctane 4-[4-(3-methoxyazabicyclo[3.2.1]octan—8-y1)(2-meth0xypheny1)thien0[2,3- d]pyrimidin—2-y1]piperazin—2-one WO 72694 3-methoxyazabicyclo[3.2.1]octany1)(2-meth0xypheny1)thieno[2,3- d]pyrimidin—Z-yl]piperidinecarb0xamide 4-[5-(2-chlor0pheny1)(3-meth0xyazabicyclo[3.2. 1]0ctan—8-y1)thien0[2,3-d]pyrimidin— 2-y1]piperazin—2-0ne 4-[5-(2-chlor0pheny1)(3-meth0xyazabicyclo[3.2. 1]0ctan—8-y1)thien0[2,3-d]pyrimidin— 2-y1]piperazine-Z-carboxamide 1-[5-(2-chlor0pheny1)[3-(hydr0xymethy1)azabicyc10[3.2. 1]0ctan—8-y1]thieno[2,3- d]pyrimidin—4-y1]piperidinecarb0xamide 4-[4-(3-methoxyazabicyclo[3.2.1]octan—8-y1)(2-meth0xypheny1)thien0[2,3- d]pyrimidin—Z-yl]piperazine-Z-carboxamide 8- [2- [3 -(meth0xymethy1)azabicyclo [3 .2. 1 ]0ctan—8 -y1] (2-meth0xypheny1)thien0 [2,3 - d]pyrimidin—4-y1]0xaazabicyclo[3 .2. 1]0ctane 1-[4-(3-methoxyazabicyclo[3.2.1]octany1)(2-meth0xypheny1)thieno[2,3- midin—Z-y1]pyrr01idinecarb0xamide 8-[2-(3-meth0xyazabicyclo[3.2. 1]octany1)(2-meth0xypheny1)thien0[2,3- d]pyrimidin—4-y1]0xaazabicyclo[3 .2. 1]0ctane 4-[5-(2-meth0xypheny1)(3-0xaazabicyclo[3 .2. 1 ]octan—8-y1)thien0[2,3-d]pyrimidin—2- y1]piperazine-Z-carboxamide 1-[5-(2-meth0xypheny1)(3-oxaazabicyclo[3.2. n—8-y1)thieno[2,3-d]pyrimidin—2- y1]piperidinecarb0xamide 8-[5-(2-methoxypheny1)(3-oxaazabicyclo[3 .2. 1 ]octan—8-y1)thien0[2,3-d]pyrimidin—2- yl azabicyclo[3.2.1]0ctan—3-01 2-meth0xypheny1)(3-oxaazabicyclo[3.2. 1]octan—8-y1)thieno[2,3-d]pyrimidin—2- yl]pyrr01idinecarb0xamide 8-[5-(2-methoxypheny1)(3-oxaazabicyclo[3 .2. 1 ]octan—8-y1)thien0[2,3-d]pyrimidin—4- yl]oxaazabicyclo[3.2.1]0ctane 4-[5-(2-meth0xypheny1)(3-0xaazabicyclo[3.2.1]0ctan—8-y1)thieno[2,3-d]pyrimidin—2- yl]piperazin—2-one 1-[5-(2-meth0xypheny1)(3-oxaazabicyclo[3.2. 1]octan—8-y1)thieno[2,3-d]pyrimidin—2- yl]pyrr01idin—3-01 4-(3 -meth0xyazabicyclo [3 .2. 1 ]0ctan—8-y1)(2-methoxypheny1)thieno[2,3 -d]pyrimidine- 2-carb0nitrile 4- [3 -(meth0xymethy1)azabicyclo [3 .2. 1 ]0ctan—8-yl] (2-methoxypheny1)thieno [2,3 - d]pyrimidine-Z-carbonitrile 2,4-bis(3-meth0xyazabicyclo[3.2.1]octany1)(2-methoxypheny1)thien0[2,3- d]pyrimidine 4-[5-(2-chloropheny1)(3-meth0xyazabicyclo[3.2. 1]0ctan—8-y1)thien0[2,3-d]pyrimidin— 2-y1]morpholine-Z-carboxamide 4-[4-(3-methoxyazabicyclo[3.2.1]octan—8-y1)(2-meth0xypheny1)thien0[2,3- d]pyrimidin—Z-yl]morpholine-Z-carboxamide 1-[5-(2-chloropheny1)(3-0xaazabicyclo[3.2. 1]octan—8-y1)thieno[2,3-d]pyrimidin—2- y1]piperidinecarb0xamide 1-[5-(2-chloropheny1)(3-0xaazabicyclo[3.2. 1]octan—8-y1)thieno[2,3-d]pyrimidin—4- y1]piperidinecarb0xamide 2-chloropheny1)(3-hydr0xyazabicyclo[3.2. 1]0ctan—8-y1)thien0[2,3-d]pyrimidin— 4-y1]pyrr01idinecarb0xamide 4-[2-[3-(hydr0xymethy1)azabicyclo[3.2.1]0ctan—8-y1](2-meth0xypheny1)thieno[2,3- d]pyrimidin—4-y1]piperazin—2-one 1-[2-(3-hydr0xyazabicyclo[3.2.1]octany1)(2-meth0xypheny1)thien0[2,3- d]pyrimidin—4-y1]pyrrolidinecarb0xamide 1-[5-(2-chloropheny1)(3-0xaazabicyclo[3.2. 1]octan—8-y1)thieno[2,3-d]pyrimidin—4- y1]pyrr01idine-3 -carb0xamide 4-[5-(2-chlor0pheny1)(3-0xaazabicyclo[3.2.1]0ctan—8-y1)thien0[2,3-d]pyrimidin—2- yl]piperazine-Z-carboxamide 4-[5-(2-chlor0pheny1)(3-0xaazabicyclo[3.2.1]0ctan—8-y1)thien0[2,3-d]pyrimidin—4- yl]piperazine-Z-carboxamide 2-meth0xypheny1)(3-0xaazabicyclo[3 .2. 1 ]octan—8-y1)thien0[2,3-d]pyrimidin—2- '~<1]morpholine-Z-carboxamide 2-methoxypheny1)(3-0xaazabicyclo[3 .2. 1 —8-y1)thien0[2,3-d]pyrimidin—4- '~<1]morpholine-Z-carboxamide 4-[5-(2-chlor0pheny1)(3-0xaazabicyclo[3.2.1]0ctan—8-y1)thien0[2,3-d]pyrimidin—2- '~<1]morpholine-Z-carboxamide 8-[5-(2-ch10r0pheny1)(3-oxaazabicyclo[3 .2. 1 ]octan—8-y1)thieno[2,3-d]pyrimidin—2-y1]— 8-azabicyclo[3.2.1]0ctan—3-01 1-[5-(2-chloropheny1)(3-0xaazabicyclo[3.2. 1]octan—8-y1)thieno[2,3-d]pyrimidin—2- yl]pyrr01idinecarb0xamide 8-[5-(2-ch10r0pheny1)(3-0xaazabicyclo[3.2.1]0ctan—8-yl)thien0[2,3-d]pyrimidin—4-y1]— 3-oxaazabicyclo[3.2.1]0ctane WO 72694 4-[5-(2-chloropheny1)(3-oxaazabicyclo[3.2.1]octany1)thieno[2,3-d]pyrimidin y1]piperazinone 8-[5-(2-chloropheny1)morpholino-thieno[2,3-d]pyrimidiny1]oxa azabicyclo[3.2.1]octane, 1-[5-(2-chloropheny1)(3-oxaazabicyclo[3.2.1]octany1)thieno[2,3-d]pyrimidin yl]pyrrolidin—3-ol, N-[[8-[5-(2-methoxypyridy1)thieno[2,3-d]pyrimidiny1]azabicyclo[3.2.1]octan yl]methyl] cyclobutanamine.
In one embodiment, the compound of the invention is not 2-[5-pheny1[4-(2-pyrrolidin ylethoxymethy1)piperidy1]thieno[2,3 -d]pyrimidiny1] - 1 ,2-thiazolidine 1 ,1-dioxide or 1-(2-ethy1pheny1-thieno [2,3 -d]pyrimidin—4-y1)-N,N-dimethy1-piperidin—4-amine.
In one ment, the compound of the invention is selected from: 4-[4-[2-(1-methy1pyrro1idiny1)ethoxymethy1]piperidy1]pheny1-thieno[2,3 - d]pyrimidine -methy1[4-[2-(1-methy1pyrro1idiny1)ethoxymethy1]piperidy1]thieno[2,3 - d]pyrimidine 4-[4-[2-(1-methy1pyrrolidin—2-y1)ethoxymethyl]piperidy1]thieno[2,3 -d]pyrimidine 5 ,6-dimethy1[4-[2-(1-methy1pyrro1idiny1)ethoxymethy1]piperidy1]thieno[2,3 - d]pyrimidine -pheny1[4-(2-pyrrolidin—1-y1ethoxymethy1)piperidy1]thieno[2,3 -d]pyrimidine 4-[2-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methoxy] ethy1]morpholine 4-[4-[(1-methy1pyrrolidin—2-y1)methoxymethy1]piperidy1]pheny1-thieno[2,3 - d]pyrimidine N,N—dimethy1[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methoxy]propan— 1 - amine 4-[4-(cyclobutoxymethy1)piperidy1]pheny1-thieno[2,3 -d]pyrimidine 4-[4-[2-(1-methy1piperidy1)ethoxymethy1]piperidy1]pheny1-thieno[2,3 -d]pyrimidine 3 0 methy1[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methoxy]ethanamine 4-[4-[(1-methy1pyrrolidin—3 -y1)oxymethy1]—1-piperidy1]pheny1-thieno[2,3 -d]pyrimidine 4-[4-[(1-methy1piperidyl)oxymethy1]piperidy1]pheny1-thieno[2,3 -d]pyrimidine 1 -(2-dimethy1aminoethyloxymethy1)piperidy1]pheny1-thieno[2,3 -d]pyrimidin y1]pyrrolidinecarboxamide 4- [4-(isopr0p0xymethy1)piperidy1] pheny1-thieno [2,3 -d]pyrimidine -pheny1 [4-(tetrahydr0furan—3 methy1)piperidy1]thieno[2,3 -d]pyrimidine -(3 -fluoropheny1)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 - midine -ethy1methy1[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thieno[2,3 -d]pyrimidine 4-[2-[[1-(6-isopropy1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methoxy]ethy1]m0rpholine -(4-fluorophenyl)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 - d]pyrimidine 4- [2- [[ 1 - [5 -(4-fluor0pheny1)thieno[2,3 -d]pyrimidin—4-y1]—4- piperidy1]methoxy]ethyl]morpholine 4- [4- [2-(3 -fluor0pyrrolidin—1-y1)eth0xymethy1]—1-piperidyl]pheny1-thien0[2,3 - d]pyrimidine 4-[2-[[1-(5-ethy1methy1-thien0[2,3 -d]pyrimidiny1) piperidy1]methoxy]ethyl]morpholine 5-ethy1—6-methy1—4-[4-[2-(1-methy1pyrro1idiny1)ethoxymethy1]piperidy1]thien0[2,3 - d]pyrimidine 6-isopropy1[4-[2-(1-methy1piperidy1)eth0xymethyl]piperidy1]thieno[2,3 - d]pyrimidine 4- [4- [2-(3 ,3 r0pyrrolidin—1-y1)eth0xymethy1]—1-piperidy1]pheny1—thien0[2,3 - d]pyrimidine -[2-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methoxy] ethyl] 0xa—5 - azabicyc10[2.2. 1]heptane 4-[2-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methoxy] ethyl]piperazin—2-one 1-[2-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methoxy] ethy1]pyrr01idine-3 - carboxamide N—[l-[2-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-yl)piperidyl]meth0xy] ethy1]pyrr01idin-3 - y1]acetamide 1-[2-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methoxy] pyrrolidine amide 4- [4- [2- [(3R)-3 -fluoropyrrolidiny1]eth0xymethy1]—1-piperidyl]pheny1-thien0[2,3 - d]pyrimidine 4- [4- [2- [(3 S)-3 -fluor0pyrrolidiny1]eth0xymethy1]— 1-piperidy1]pheny1—thien0[2,3 - d]pyrimidine -ethy1—6-methy1—4-[4-[2-(1-methy1—2-piperidyl)eth0xymethy1]piperidy1]thien0[2,3 - d]pyrimidine -(3 pheny1)[4-[2-(1-methylpyrr01idin—2-y1)eth0xymethy1]piperidyl]thien0[2,3 - d]pyrimidine -(3 -fluoropheny1)[4-[2-(1-methy1—2-piperidy1)eth0xymethyl]piperidy1]thien0[2,3 - d]pyrimidine -pheny1—4-[6-(2-pyrr01idin—1-yleth0xymethy1)azabicyc10[3. 1 .0]hexan—3-y1]thien0[2,3- d]pyrimidine 4-[2-[[3-(5-pheny1thien0[2,3-d]pyrimidin—4-yl)azabicyc10[3.1.0]hexan—6- yl]methoxy]ethy1]m0rpholine 4-[6-[2-(1-methy1pyrro1idin—2-y1)eth0xymethy1]azabicyc10[3.1 .0]hexan—3-y1]—5-pheny1- thieno[2,3-d]pyrimidine 4-[6-[2-[(3 S)flu0r0pyrrolidiny1]ethoxymethyl]azabicyc10[3.1.0]hexan—3-y1]—5- phenyl-thieno [2,3 -d]pyrimidine 4-[6-[2-[(3R)fluor0pyrrolidin—1-y1]eth0xymethy1]azabicyc10[3.1 .0]hexan—3-y1]—5- phenyl-thieno [2,3 -d]pyrimidine (2R)[2-[[3-(5-pheny1thien0[2,3-d]pyrimidin—4-y1)azabicyc10[3. 1 .0]hexan—6- h0xy]ethy1]pyrr01idinecarboxamide (2S)[2-[[3-(5-pheny1thien0[2,3-d]pyrimidinyl)azabicyc10[3.1.0]hexan—6- y1]meth0xy]ethy1]pyrr01idinecarboxamide N,N—dimethy1[4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 -d]pyrimidin— -y1]benzenesulfonamide (2R)[2-[[3-[5-(4-flu0r0pheny1)thieno[2,3-d]pyrimidin—4-y1]azabicyc10[3.1 .0]hexan—6- h0xy]ethy1]pyrr01idinecarboxamide 5-(4-nitropheny1)[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 -d]pyrimidine u0r0pheny1)[6-[2-[(3 S)fluor0pyrr01idin— th0xymethy1]—3- azabicyc10[3.1.0]hexan—3-y1]thien0[2,3-d]pyrimidine -[2-[[3-[5-(4-fluor0pheny1)thieno[2,3-d]pyrimidin—4-y1]azabicyc10[3.1.0]hexan—6- y1]meth0xy]ethyl] 0xa—5-azabicyc10 [2 .2. 1 ]heptane 1-cyc10pr0py1-N—[[ 1 -(5-pheny1thieno[2,3-d]pyrimidin—4-y1) piperidyl]methy1]methanamine 4- [4- [(3 -methy1pyrrolidin—1-y1)methy1]—1-piperidy1]pheny1—thieno[2,3 -d]pyrimidine N—[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methy1]pr0panamine 2,2-difluor0-N—[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methyl]ethanamine 2-meth0xy-N—(2-meth0xyethy1)-N—[[ 1 -(5-pheny1thieno[2,3 -d]pyrimidiny1) dy1]methy1]ethanamine [1-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1) piperidyl]methy1amino]cyclopentyl]methanol 1- [[ 1 -(5 -pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methy1]piperidin-3 -01 2-pheny1—4-[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidyl]methy1]morpholine 3 -pheny1 [[ 1 -(5-pheny1thien0 [2,3 -d]pyrimidinyl)piperidy1]methylamino]pr0pan—1-01 2-(1-methy1pyrro1idin—2-y1)-N—[[1-(5-phenylthien0[2,3 -d]pyrimidiny1) piperidy1]methy1]ethanamine 2-methy1m0rpholin0-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1) piperidyl]methy1]propan— 1 -amine N,N—dimethy1—1-[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methy1]piperidin-3 - amine 1-(2-fury1)-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]methanamine N',N'-diisopr0py1—N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]ethane- 1 ,2-diamine N'-[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methyl]ethane-1 ,2-diamine (5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]cyclobutanamine [1-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]pyrrolidin—2-yl]methanol N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl](2-pyridy1)methanamine (3 S ,4S)[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methy1] r01idin— 1 -y1- pyrrolidin-3 -01 4- [4- [(3 xypyrrolidin—1-y1)methy1]—1-piperidy1]pheny1—thien0[2,3 -d]pyrimidine (5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl](2-thieny1)methanamine 4- [4- [ [3 -(4-flu0r0pheny1)pyrrolidin—1-y1]methy1]—1-piperidy1]pheny1—thien0[2,3 - d]pyrimidine N,N,N'-trimethy1-N'-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl] ethane- 1 mine N,N,N'-trimethy1-N'-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methy1]pr0pane- 1,3-diamine 4-[4-(azetidin—1-y1methy1)piperidy1]pheny1—thieno[2,3 -d]pyrimidine N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]cyclopropanamine N,N—dimethy1—1-[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidyl]methyl]piperidin—4- amine -pheny1 [4- [(3 -pyrr01idin—1-y1pyrr01idin—1-y1)methy1]—1-piperidy1]thieno[2,3 - d]pyrimidine N— [[ 1 - [5-(4-flu0r0pheny1)thieno [2,3 -d]pyrimidin—4-y1]—4- piperidy1]methy1]cyclopropanamine N— [[ 1 - [5-(4-flu0r0pheny1)thieno [2,3 -d]pyrimidin—4-yl]piperidy1]methy1]cyclobutanamine 1- [[ 1 - [5 -(4-fluor0pheny1)thieno [2,3 -d]pyrimidin—4-y1] piperidy1]methy1] -N,N-dimethy1— piperidin—3 -amine 2-(1 -methy1—2-piperidy1)-N—[[ 1 -(5-pheny1thieno[2,3 -d]pyrimidin—4-y1) piperidy1]methy1]ethanamine (3R)-N,N—dimethy1—1-[[1-(5-pheny1thieno[2,3 imidin—4-y1) piperidyl]methy1]pyrrolidinamine tert-butyl2-[2-[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1) piperidyl]methylamino]ethy1]pyrr01idinecarb0xylate N—methyl[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidy1] -N-(pyrr01idin—2- ylmethyl)methanamine N—[(1-methy1pyrro1idin—2-y1)methy1][1-(5-pheny1thien0[2,3 imidin—4-y1) dy1]methanamine N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]pyrr01idin—2-y1— ethanamine N—methyl-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidy1]methyl]pyrr01idin—2- anamine 2-(1-ethy1pyrr01idin—2-y1)-N-methy1-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1) piperidy1]methy1]ethanamine 2-(1-is0pr0py1pyrrolidin—2-yl)-N-methy1—N—[[1-(5-pheny1thieno[2,3 imidin—4-y1) piperidy1]methy1]ethanamine 1-[2-[2-[methy1—[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1) piperidyl]methyl]amino] pyrr01idiny1] ethanone (3 S)[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]piperidin—3-amine 1-methy1[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methylamino]pyrrolidin— 2-one 4- [4- [ [(3 S)-3 -flu0r0pyrrolidiny1]methy1]—1-piperidyl]pheny1-thieno[2,3 -d]pyrimidine 2-[methy1—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methy1]amino] pyrrolidiny1-ethan0ne N—[[1-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperidy1]methy1]pr0penamine WO 72694 [1-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]pyrr01idin—3 -y1]methan01 N—[1-[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1] cyclopropanamine 1-methy1—N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidyl]methy1]piperidin amine (2,5-dimethy1pyrr01idin— 1 -y1)methy1]— 1 -piperidy1]pheny1—thieno[2,3 -d]pyrimidine -pheny1—4-[4-[[4-(triflu0r0methy1)piperidy1]methy1]—1-piperidyl]thien0[2,3 -d]pyrimidine 2-[(2S)methy1pyrrolidin—2-y1]-N-[[1-(5-phenylthien0[2,3 -d]pyrimidin—4-y1) piperidy1]methy1]ethanamine N—methy1(1-methy1pyrr01idin—2-y1)-N—[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1) piperidy1]methy1]ethanamine N—[[1-(5-pheny1thieno[2,3 -d]pyrimidin—4-y1)piperidyl]methyl] tetrahydr0furan—2-y1- ethanamine 2-cyc10pr0py1—N—[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methyl]ethanamine 2-(1-methy1pyrrolidin—3 -y1)-N-[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1) piperidy1]methy1]ethanamine 2-[[1-(5-pheny1thien0[2,3 -d]pyrimidin—4-y1)piperidy1]methylamino]pyrr01idin—1-y1— ethanone (2S)[[1-(5-pheny1thien0[2,3 -d]pyrimidiny1)piperidy1]methy1]pyrrolidine carboxamide 2-[2-hydr0xyethy1-[[1-[2-(4-methy1piperazin—1-y1)-5 -pheny1-thieno [2,3 -d]pyrimidiny1]—4- dyl]methy1]amino] ethanol 4-[4-[(isopropylamin0)methy1]piperidy1]pheny1—N—(2-pyrr01idin—1-y1ethy1)thien0[2,3 - d]pyrimidin—2-amine 4- [4- [(2-meth0xyethylamino)methy1] piperidy1] pheny1-N—(2-pyrr01idin— 1 - ylethy1)thien0[2,3 -d]pyrimidin—2-amine 4-[4-[[methy1—(1-methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]pheny1—N—(2- pyrrolidiny1ethy1)thien0[2,3 -d]pyrimidin—2-amine N,1-dimethy1—N—[[1-[2-(4-methy1piperazin—1-y1)pheny1—thien0[2,3 -d]pyrimidin—4-y1]—4- piperidyl]methy1]pyrrolidinamine N,1-dimethy1—N—[[1-(5-pheny1—2-piperazin—1-y1-thieno[2,3 -d]pyrimidiny1) piperidyl]methy1]pyrrolidinamine -[2-(4-methy1piperazin—1-y1)pheny1—thien0[2,3 -d]pyrimidiny1]—4- piperidy1]methy1amin0]cyclopentyl]methanol N—[[1-[2-(4-methy1piperazin—1-y1)pheny1—thien0[2,3 -d]pyrimidiny1]—4- dy1]methyl] ( 1 -methylpyrr01idin—2-y1)ethanamine methy1—1-[[1-[2-(4-methy1piperazin—1-y1)pheny1—thieno[2,3 -d]pyrimidin—4-y1]—4- piperidyl]methyl]piperidin—3-amine N—[[1-[2-(4-methy1piperazin—1-y1)pheny1—thien0[2,3 -d]pyrimidiny1]—4- piperidyl]methyl]cyclobutanamine 4- [4- [ [3 -(dimethy1amin0)piperidy1]methy1] - 1 idy1] pheny1—N—(2-pyrrolidin ylethy1)thien0[2,3 -d]pyrimidin—2-amine ethoxyethy1) [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]—5- phenyl-thieno [2,3 -d]pyrimidin—2-amine N—(cyclopropylmethy1)[4-[[methy1—(1-methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]— -pheny1-thieno [2,3 -d]pyrimidinamine 1- [4- [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]pheny1—thieno[2,3 - d]pyrimidin—2-y1]pyrrolidinecarb0xamide 2-[methyl-[4-[4-[[methy1—(1-methy1pyrr01idin—3 -y1)amin0]methy1] piperidy1] pheny1- thieno [2,3 -d]pyrimidin—2-y1] amino] acetamide N—[[1-[2-[4-(2-methoxyethyl)piperazin—1-y1]pheny1-thieno[2,3 -d]pyrimidiny1]—4- piperidy1]methyl] -N, 1 -dimethy1—pyrrolidin—3 -amine 1- [4- [4- [ [3 -(dimethy1amino)- 1 idy1]methy1] piperidy1] pheny1-thien0 [2,3 - d]pyrimidin—2-y1]pyrrolidinecarb0xamide 4- [4- [ [3 thy1amin0)piperidy1]methy1] piperidy1] -N-(2-methoxyethy1)pheny1- thieno [2,3 -d]pyrimidin—2-amine 4-[4-[4-[(cyclobutylamino)methy1]piperidy1]pheny1-thieno[2,3 -d]pyrimidin—2- yl]piperazin—2-one 4-[4-[(cyclobutylamino)methyl]piperidy1]-N-(2-meth0xyethy1)pheny1—thieno[2,3 - d]pyrimidin—2-amine 4-[4-[(cyclobutylamin0)methyl]piperidy1]pheny1—N—(2-pyrrolidin—1-ylethy1)thieno[2,3 - d]pyrimidin—2-amine 1-[4-[4-[(cyclobutylamin0)methyl]piperidy1]pheny1—thieno[2,3 imidin—2- y1]pyrr01idine-3 -carb0xamide 1- [4- [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]pheny1—thieno[2,3 - d]pyrimidin—2-y1]piperidinecarboxamide 1- [4- [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1]—1-piperidy1]pheny1—thieno[2,3 - d]pyrimidin—2-y1]pyrrolidinecarb0xamide N—methy1 [4- [ [methyl-( 1 -methy1pyrr01idin—3 -y1)amin0]methy1] piperidy1] pheny1- thieno [2,3 -d]pyrimidinecarboxamide N—isopropy1 [4- [ [methyl-( 1 -methy1pyrrolidin-3 -y1)amino]methy1] piperidy1] ny1- thieno [2,3 -d]pyrimidinecarboxamide -isopropyl-N,N—dimethy1—4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 - d]pyrimidinecarboxamide -isopr0py1—N—methy1—4-[4-(2-pyrrolidinylethoxymethy1)piperidy1]thieno[2,3 - d]pyrimidinecarboxamide N,N—dimethy1phenyl[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thieno[2,3 - d]pyrimidinecarboxamide N,N—dimethy1—4-[4-[[methy1-(1-methy1pyrr01idiny1)amino]methy1] piperidy1] pheny1— thieno [2,3 -d]pyrimidinecarboxamide -(3 -flu0r0pheny1)-N—isopropy1[4-(2-pyrr01idin— 1 -yleth0xymethy1) piperidy1]thien0 [2,3 -d]pyrimidinecarboxamide 5-(3 -flu0r0pheny1)-N,N—dimethy1[4-(2-pyrr01idin— 1-ylethoxymethyl) piperidy1]thien0 [2,3 imidinecarboxamide [5-pheny1—4-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 -d]pyrimidin—6-y1]— pyrrolidiny1—methanone N—isopropyl-S-pheny1[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 - d]pyrimidinecarboxamide N—methyl-S-pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidyl]thien0[2,3 - d]pyrimidinecarboxamide 3 -pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -b]pyridine 2-brom0pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -b]pyridine 3 -pheny1[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -b]pyridine carbonitrile -pheny1—2-[4-(2-pyrr01idin—1-ylethy1)piperaziny1]thien0[2,3 imidine 2-(1-methy1pyrro1idin—2-y1)-N—[[1-(5-phenylthien0[2,3 -d]pyrimidiny1) piperidy1]methy1]ethanamine (2R)[2-[4-(5-pheny1thieno[2,3 imidin—2-y1)piperazin— 1 -y1] ethy1]pyrr01idine amide -pheny1[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thien0[2,3 imidine -pheny1 [3 -(2-pyrr01idin—1-ylethoxymethy1)pyrr0lidiny1]thien0[2,3 -d]pyrimidine (3R)[2-[4-(5-pheny1thieno[2,3 -d]pyrimidiny1)piperazin—1-y1]ethy1]pyrrolidine-3 - carboxamide 2- [4- [2- [(3R)-3 -fluoropyrrolidiny1]eth0xymethy1]—1-piperidyl]pheny1—thien0[2,3 - d]pyrimidine -(4-fluorophenyl)[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thieno[2,3 - d]pyrimidine [1-(5-pheny1thien0[2,3 -d]pyrimidin—2-y1)piperidy1]methoxy] ethy1]pyrr01idine-3 - carboxamide -[2-[[1-(5-pheny1thieno[2,3 -d]pyrimidin—2-y1)piperidy1]methoxy] ethyl] 0xa—5 - yc10[2.2. 1]heptane N—[5-pheny1—2- [4-(2-pyrr01idin— 1 -yleth0xymethy1)piperidy1]thien0[2,3 -d]pyrimidin—6- y1]acetamide heny1—2-[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 -d]pyrimidin—6- yl]pyrr01idin—2-0ne 5-isopr0py1—2-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -d]pyrimidine 1- [5-pheny1—2- [4-(2-pyrr01idin— 1 -yleth0xymethy1)piperidy1]thieno [2,3 -d]pyrimidin—6- yl]pyrr01idin—2-0ne -isopr0py1—2-[4-(2-pyrr01idin—1-yleth0xymethy1)piperidy1]thien0[2,3 -d]pyrimidine 4- [3 -[(1-methy1pyrrolidin—3 -y1)methoxy]propyny1]pheny1—thien0[2,3 -d]pyrimidine 5-pheny1—4- [3 -(2-pyrr01idin—1-yleth0xy)pr0pyny1]thien0[2,3 -d]pyrimidine N—[5-pheny1—4- [4-(2-pyrr01idin— 1 -yleth0xymethy1)- 1 idy1]thieno [2,3 -d]pyrimidin—6- tamide 1-[5-pheny1—4-[4-(2-pyrr01idin—1-ylethoxymethy1)piperidy1]thieno[2,3 -d]pyrimidin—6- yl]pyrr01idin—2-0ne 5-pheny1—4- [(1 S ,5R)-3 -(2-pyrr01idin—1-yleth0xymethy1)azabicyclo[3.2.1]0ctan—8- y1]thieno[2,3 -d]pyrimidine [8-(4-m0rph01inopheny1—thieno [2,3 -d]pyrimidin—2-y1)azabicyclo [3 .2. 1] octan—3 - y1]methan01 1-methy1pyrro1idin—2-y1)ethy1](5-pheny1thien0[2,3 -d]pyrimidiny1)piperidine carboxamide -pheny1—4-[4-(2-pyrr01idin—1-yleth0xymethyl)piperidy1]thien0[2,3 -d]pyrimidine carbonitrile and N—benzyl-S-pheny1[4-(2-pyrr01idinyleth0xymethy1)piperidy1]thien0[2,3 - d]pyrimidin—6-amine.
In one embodiment, there is a compound of formula (I) A Z? (I) ? or a pharmaceutically acceptable derivative thereof, wherein: A is 0 or S; X is N or CR31i; V is N or CR31I1; Z is N or CR3w; ? wherein one or two of V, X and Z are N; R' is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R2 is selected from H, halo, —CN, trifluoromethyl, optionally substituted alkyl, optionally substituted alkoxy, , —NR6C(0)R7, —NR6S(0)2R7, —S(0)2NR4R5, —CONR4R5, —0O2127, ? optionally substituted oxazolinyl, —SR14, —S(0)R14 and —S(0)2R14; R31 is —(NRaRb)—J; Each of R311, R3111, and R31V is independently selected from H, halo, —CN, oromethyl, optionally tuted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkoxy, optionally substituted heterocycloalkylalkyl, —NR6C(0)R7, —NR6S(0)2R7, — ? S(0)2NR4R5, —CONR4R5, ally substituted ene—CONR4R5, —CO2R7, —NRI°RI —CE-C— J, optionally substituted cycloalkyl-J and td)_J, wherein Ra and Rb are linked to form an optionally substituted 4 to 7 ed heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C i lene, — NR6—, —0—, or —S(0),—, wherein the optionally bridged, optionally substituted heterocycloalkyl ? ring is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, ydro-1,3-oxazinyl, hexahydropyrimidinyl, 1,4-thiazanyl, azepanyl, 1,4-oxaazepanyl, and 1,4- thieazepanyl; wherein Rc and Rd are linked to form an optionally substituted 4 to 7 membered heterocycloalkyl ring, which is optionally bridged by a bond, optionally substituted C1 _2alkylene, — NR6—, —0—, or —S(0)z--; J is —(CR12R13)q—L—M—W, wherein q is 0, 1 or 2; L is —0—; and M is —(CR12R13)t—; t is 0, 1,2 or 3; ? W is selected from the group ting of optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and —NR8R9, wherein when W is optionally substituted cycloalkyl it may optionally be bridged by a bond or optionally substituted Ci _2alkylene, and ? wherein when W is optionally substituted heterocycloalkyl it may optionally be bridged by a bond, optionally substituted Ci_2alkylene, —NR6—, —0—, or —S(0)z—; z is 0, 1 or 2; R4 and R5 are, at each instance, independently ed from H, optionally substituted alkyl, optionally substituted aryl, ally tuted heteroaryl, and optionally substituted ? cycloalkyl, or are linked to form an optionally substituted heterocycloalkyl; R6 and R7 are, at each instance, independently selected from H and optionally substituted alkyl, or are linked to form an optionally substituted heterocycloalkyl; R8 and R9 are, at each instance, independently ed from ally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted ? heteroaryl, and optionally substituted cycloalkyl; R1° and R11 are, at each instance, independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally tuted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted cycloalkyl; R12 and R13 are, at each instance, independently ed from H, hydroxy, and optionally ? substituted alkyl, or may be linked to form an optionally substituted cycloalkyl ring, or may together form =0; and R14 is optionally substituted alkyl, n the al substituents are independently ed from halo, trihalomethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, -OH, -NO2, -CN, -CO2H, -CO2C1- HArbOnterwoven WRPortbl \DCC\IIBR \75887321.doc.x-23/03/2015 6alkyl,? -SO3H,? -SOC1 _6a1kyl,? -S02C1 _6alkyl,? -NHSO2C _6alkyl,? -NC1 _6alkylSO2C _ 6alkyl, -SO2NH2, -SO2NHC1 _6alkyl, -SO2N(C1 _6alky1)2, -NHSO2NH2, -NHSO2NHC1 _ 6alkyl, -NHSO2N(C1 _6alky1)2, -NC1_6alkylSO2N142, -NCI_6alkylSO2NHCi _6alkyl, -NCI _ 6alkylSO2N(Ci 1)2, -C(=0)H, C1 _6alkyl, -NHC(=0)C1 _6alkyl, -NC1 lC(=0)Ci _ 6alkyl,? Ci _6alkylenedioxy,? =0,? -N(Ci _ 6alkyl)2, -C(=0)NH2, -C(=0)NHC1 _6alkyl, -C(=0)N(Ci _6alky1)2, -NHC(=O)NH2, -NHC(=0)NHCI _ 6alkyl, -NHC(=0)N(C1 _6alky1)2, -NC1 _6alkylC(=0)NH2, -NC1 _6alkylC(=0)NHC1 l, -NC 6alkylC(=0)N(C1 _ )2, -C(=NH)NH2, -C(=NH)NHCi _6alkyl, -C(=NH)N(C1 _6alky1)2, -C(=NC1 _6alkyl)NH2, -C(=N ? C1 _6alkyONHC1 _6alkyl, -C(=NC1 _6alkyl)N(C1 _6alky1)2, -C1 _6alkyl, -C3_6cycloalkyl, -C3_6heterocycloa lkyl, 2-imidazolidinonyl, 1-C1 _6alky1imidazolidinonyl, C1 _6alky1C3_6heterocycloalkyl, aryl, yl, CI _6alkoxyaryl, -C1 _6alkylene-NHSO2C1 _6alkyl, -C1 _6alkylene-NC1.6alkylS02C1- 6alkyl, -C1 _6alkylene-SO2NH2, -C1 lene-SO2NHC1 _6alkyl, -Ci_6alkylene-SO2N(C1 _6alkyl)2, - ZtH,? -Ci _6alkylene-ZtH, -Zt-C3_6cycloalkyl, or -C(=0)NHC1 _6alkylene-ZH wherein ? Zt is independently 0, S, NH or N(C1 _6alkyl).
Chemical Groups Halo The term en” (or “halo”) includes fluorine, chlorine, bromine and iodine (or , , bromo, and iodo).
Alkyl, ne, l, alkynyl, cycloalkyl etc.
The terms “alkyl”, “alkylene99 SE or “alkynyl” are used herein to refer to both , alkenyl”, straight and branched chain acyclic forms. Cyclic analogues thereof are referred to as cycloalkyl, etc.
The term “alkyl” includes monoyalent, straight or branched, saturated, acyclic hydrocarbyl groups. Alkyl may be C1_1oalkyl, or C1_6alkyl, or C1_4alkyl. Examples e methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
The term “cycloalkyl” includes monovalent, saturated, cyclic hydrocarbyl .
Cycloalkyl may be C3_10cycloalkyl, or C3_6cycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. A cycloalkyl may optionally be “bridged”, which occurs when ring carbon atoms are further linked by a bond, or by one or more carbon atoms. Typical bridges are one or two carbon atoms, e.g. methylene or ethylene groups.
When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
The term “alkoxy” means alkyl-O-. Examples include methoxy, , n-propoxy, i- propoxy, n-butoxy, s-butoxy, xy, n-pentoxy, and oxy.
The term “alkenyl” includes monoyalent, straight or branched, unsaturated, acyclic hydrocarbyl groups haVing at least one carbon-carbon double bond at any point along the carbon chain and, optionally, no carbon-carbon triple bonds. l may be C2_1oalkenyl, or C2_6alkenyl, or C2_4alkenyl. es include l and propenyl.
The term “cycloalkenyl” includes monoyalent, lly unsaturated, cyclic hydrocarbyl groups haVing at least one carbon-carbon double bond and, optionally, no carbon-carbon triple bonds. Cycloalkenyl may be C3_10cycloalkenyl, or C5_10cycloalkenyl. Examples include cyclohexenyl and benzocyclohexyl.
The term “alkynyl” includes monoyalent, straight or branched, unsaturated, acyclic hydrocarbyl groups haVing at least one carbon-carbon triple bond at any point along the carbon chain and, optionally, no carbon-carbon double bonds. Alkynyl may be C2_10alkynyl, or C2_6alkynyl, or C2_4alkynyl. Examples include ethynyl and propynyl.
The term ene” includes divalent, straight or branched, saturated, acyclic hydrocarbyl groups. Alkylene may be C1_1oalkylene, or C1_6alkylene, or C1_4alkylene, such as methylene, ethylene, n-propylene, i-propylene or t-butylene groups.
The term “alkenylene” es divalent, straight or branched, unsaturated, acyclic hydrocarbyl groups having at least one carbon-carbon double bond and, optionally, no carbon-carbon triple bonds. Alkenylene may be C2_1oalkenylene, or kenylene, or C2_4alkenylene.
Heteroalkyl etc.
The term “heteroalkyl” es alkyl groups in which up to three carbon atoms, or up to two carbon atoms, or one carbon atom, are each replaced independently by O, S(O)Z (z = 0, l or 2) or N, provided at least one of the alkyl carbon atoms remains. The alkyl group may be C-linked or -linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through 0, S(O)Z or N.
The term “heterocycloalkyl” includes cycloalkyl groups in which up to three carbon atoms, or up to two carbon atoms, or one carbon atom, are each replaced independently by O, S(O)Z or N, provided at least one of the cycloalkyl carbon atoms remains. Examples of heterocycloalkyl groups include oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, ydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, l,4-dioxanyl, 1,4-oxathianyl, morpholinyl, ydro- l,3-oxazinyl, l,4-dithianyl, piperazinyl, dropyrimidinyl, l,4-thiazanyl, oxepanyl, thiepanyl, azepanyl, l,4-dioxepanyl, athiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl and 1,4-diazepanyl. The cycloalkyl group may be C-linked or N- linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through a nitrogen atom. A heterocycloalkyl may optionally be “bridged”, which occurs when ring carbon or en atoms are further linked by a bond or one or more atoms (6.g.
C, O, N, or S). Typical s include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. A cycloalkyl bridged by one or more atoms including a heteroatom (lie. 0, N, or S) may be viewed as a heterocycloalkyl with a carbon bridge. Examples of bridged heterocycloalkyl groups include azabicyclohexanyl, (e.g. 3-azabicyclo[3.l.0]hexanyl), azabicycloheptanyl (e.g. 2- azabicyclo[2.2.l]heptanyl), azabicyclooctanyl (e.g. 8-azabicyclo[3.2.l]octanyl), and 2-oxa— -azabicyclo[2.2.l]heptane (or 5-aza—2-oxabicyclo[2.2.l]heptane). The values given herein in terms such as “4 to 7 membered heterocycloalkyl ring” refer specifically to the number of atoms present in the ring; any ing” atoms are counted separately.
The term “heteroalkenyl” includes alkenyl groups in which up to three carbon atoms, or up to two carbon atoms, or one carbon atom, are each replaced independently by O, S(O)Z or N, provided at least one of the l carbon atoms remains. The alkenyl group may be C-linked or hetero-linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through 0, S(O)Z or N.
The term “heterocycloalkenyl” es cycloalkenyl groups in which up to three carbon atoms, or up to two carbon atoms, or one carbon atom, are each replaced independently by O, S(O)Z or N, provided at least one of the cycloalkenyl carbon atoms remains. Examples of heterocycloalkenyl groups include 3,4-dihydro-2H-pyranyl, 5dihydro-2H-pyranyl, 2H- pyranyl, l,2,3,4-tetrahydropyridinyl and 1,2,5 rahydropyridinyl. The heterocycloalkenyl group may be C-linked or N-linked, i.e. it may be linked to the remainder of the molecule h a carbon atom or through a nitrogen atom.
The term “heteroalkynyl” includes alkynyl groups in which up to three carbon atoms, or up to two carbon atoms, or one carbon atom, are each replaced independently by O, S(O)Z or N, provided at least one of the alkynyl carbon atoms remains. The heteroalkynyl group may be C-linked or hetero-linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through 0, S(O)Z or N.
The term oalkylene” includes alkylene groups in which up to three carbon atoms, or up to two carbon atoms, or one carbon atom, are each replaced independently by O, S(O)Z or N, provided at least one of the alkylene carbon atoms s.
The term “heteroalkenylene” includes alkenylene groups in which up to three carbon atoms, or up to two carbon atoms, or one carbon atom, are each replaced independently by O, S(O)Z or N, provided at least one of the alkenylene carbon atoms s.
The term “heterocycloalkoxy” means heterocycloalkyl-O-.
The term “heterocycloalkylalkyl” means alkyl substituted with a heterocycloalkyl group.
Aryl The term “aryl” includes monoyalent, aromatic, cyclic hydrocarbyl groups, such as phenyl or naphthyl (e. g. l-naphthyl or 2-naphthyl). In general, the aryl groups may be monocyclic or polycyclic fused ring aromatic groups. Preferred aryl groups are C6-C14aryl.
Other examples of aryl groups are monoyalent derivatives of aceanthrylene, acenaphthylene, acephenanthrylene, cene, azulene, chrysene, coronene, thene, fluorene, as- 2012/052842 indacene, s-indacene, indene, alene, ovalene, perylene, ene, phenanthrene, picene, pleiadene, pyrene, pyranthrene and rubicene.
The term “arylalkyl” means alkyl substituted with an aryl group, 6.g. benzyl.
Heteroaryl The term “heteroaryl” includes monoyalent, heteroaromatic, cyclic arbyl groups additionally ning one or more heteroatoms independently selected from O, S, N and NRN, where RN is selected from H, alkyl (6.g. C1_6alkyl) and cycloalkyl (e.g. C3_6cycloalkyl).
In l, the heteroaryl groups are monocyclic or polycyclic (e.g. bicyclic) fused ring heteroaromatic groups. A heteroaryl groups may contain 5-13 ring members (preferably 5-10 members) and 1, 2, 3 or 4 ring heteroatoms independently selected from O, S, N and NRN, or may be a 5, 6, 9 or 10 membered, e. g. 5-membered monocyclic, 6-membered clic, 9- membered fused-ring bicyclic or 10-membered fused-ring bicyclic.
Monocyclic aromatic groups include heteroaromatic groups containing 5-6 ring members and 1, 2, 3 or 4 atoms selected from O, S, N or NRN.
Examples of 5-membered monocyclic aryl groups are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, lyl, 1,2,3 triazolyl, 1,2,4 triazolyl, 1,2,3 oxadiazolyl, 1,2,4 oxadiazolyl, 1,2,5 oxadiazolyl, 1,3,4 oxadiazolyl, 1,3,4 thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5 triazinyl, 1,2,4 triazinyl, 1,2,3 triazinyl and tetrazolyl.
Examples of 6-membered monocyclic heteroaryl groups are pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.
Bicyclic heteroaromatic groups include fused-ring heteroaromatic groups containing 9-13 ring s and 1, 2, 3, 4 or more heteroatoms selected from O, S, N or NRN.
Examples of 9-membered fused-ring bicyclic heteroaryl groups are uranyl, hiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5- b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, indazolyl, purinyl, indolininyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,2-a]pyridinyl, pyrrolo[1 ,2-b]pyridazinyl and imidazo[ 1 ,2-c]pyrimidinyl.
Examples of bered fused-ring bicyclic heteroaryl groups are quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7- yridinyl, 1 ,8-naphthyridinyl, 1 ,5 -naphthyridinyl, 2,6-naphthyridinyl, 2,7- naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4- d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, [3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl and pyrimido[4,5-d]pyrimidinyl.
The term “heteroarylalkyl” means alkyl substituted with a heteroaryl group.
General Unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e. g. arylalkyl, the last mentioned group contains the atom by which the moiety is ed to the rest of the molecule.
Where reference is made to a carbon atom of an alkyl group or other group being replaced by O, S(O)Z or N, what is ed is that: —CH— —N— I 1s replaced by —CH= is replaced by —N=; EC-H is replaced by EN; or —CH2- is replaced by —0—, —S(O)Z— or —NRN-.
By way of clarification, in relation to the above mentioned heteroatom containing groups (such as heteroalkyl etc.), where a numerical of carbon atoms is given, for instance C3. 6heteroalkyl, what is intended is a group based on C3_6alkyl in which one of more of the 3-6 chain carbon atoms is replaced by O, S(O)Z or N. Accordingly, a C3_6heteroalkyl group, for example, will contain less than 3-6 chain carbon atoms.
Substitution Groups of the compounds of the invention (e. g. alkyl, cycloalkyl, , alkenyl, cycloalkenyl, alkynyl, alkylene, alkenylene, heteroalkyl, heterocycloalkyl, heteroalkenyl, cycloalkenyl, heteroalkynyl, heteroalkylene, heteroalkenylene, heterocycloalkoxy, heterocycloalkylalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl or heteroarylheteroalkyl groups etc.) may be substituted or unsubstituted. Typically, substitution involves the notional replacement of one or more hydrogen atoms on a designated atom (e.g. a carbon atom or a nitrogen atom) with one or more substituent groups (provided that the designated atom’s normal valency is not exceeded), or two en atoms in the case of substitution by :0. Alternatively, in the case of bivalent substituent groups such as kylenedioxy, tution involves the notional replacement of a hydrogen atom on a designated atom and a en atom on an adjacent atom with the substituent group.
Where an “optionally tuted” group is indeed substituted, there will generally be 1 to 5 substituents on the group, or 1 to 3 substituents, or 1 or 2 tuents, or 1 substituent. The substituents are independently selected from halo, trihalomethyl, trihaloethyl, omethoxy, trihaloethoxy, -OH, -NOZ, -CN, -COzH, _6alkyl, -SO3H, -SOC1_ 6alkyl, -SOZC1_6alkyl, C1_6alkyl, alkylSOZC1_6alkyl, -SOZNH2, -SOZNHC1_ 6alkyl, -SOZN(C1_6alkyl)2, -NHSOZNH2, -NHSOZNHC1_6alkyl, -NHSOZN(C1_6alkyl)2, -NC1_ 6alkylSOZNH2, -NC1_6alkylSOZNHC1.6alkyl, -NC1.6alkylSOZN(C1_6alkyl)2, -C(=O)H, -C(=O)C1_6alkyl, -NHC(=O)C1_6alkyl, -NC1.6alkle(=O)C1_6alkyl, C1_6alkylenedioxy , =O, -N(C1_6alkyl)2, -C(=O)NH2, -C(=O)NHC1_6alkyl, -C(=O)N(C1_6alkyl)2, -NHC(=O)NH2, -NHC(=O)NHC1_6alkyl, -NHC(=O)N(C1_6alkyl)2, -NC1_6alkle(=O)NH2, -NC1_ 6alkle(=O)NHC1_6alkyl, -NC1_6alkle(=O)N(C1.6alkyl)2, -C(=NH)NH2, -C(=NH)NHC1_6alkyl, -C(=NH)N(C1_6alkyl)2, -C(=NC1_6alkyl)NH2, -C(=NC1.6alkyl)NHC1_6alkyl, 1.6alkyl)N(C1_6alkyl)2, -C1_6alkyl, -C3_6cycloalkyl, eterocycloalkyl, 2-imidazolidinon—3 -yl, l-C1-6alkylimidazolidinon-3 -yl, C1-6alkle3.6heterocycloalkyl, aryl, haloaryl, C1_6alkoxyaryl, -C1-6alkylene—NHSOZC1-6alkyl, -C1-6alkylene—NC1.6alkylSOZC1_6alkyl, -C1_6alkylene—SOZNH2, lkylene—SOZNHC1_ 6alkyl, -C1-6alkylene—SOZN(C1.6alkyl)2, —ZtH, —Zt-C1_6alkyl, -C1_6alkylene—ZIH, — Zt-C3_6cycloalkyl, or NHC1_6alkylene—ZtH wherein Z1 is independently O, S, NH or N(C1_6alkyl). lkyl” and “C1_6alkylene” in the above substituents may optionally be replaced by “C1_6heteroalkyl” and “C1_6heteroalkylene” respectively.
In one embodiment, the tuents are independently selected from halo, trihalomethyl, trihaloethyl, trihalomethoxy, trihaloethoxy, -OH, -NOZ, -CN, -COzH, -COZC1_6alkyl, -SO3H, -SOC1_6alkyl, -SOZC1_6alkyl, -NHSOZC1_6alkyl, -NC1_6alkylSOZC1_6alkyl, -SOZNH2, -SOZNHC1_6alkyl, -SOZN(C1_6alkyl)2, NH2, -NHSOZNHC1_6alkyl, -NHSOZN(C1_ 6alkyl)2, -NC1_6alkylSOZNH2, -NC1.6alkylSOZNHC1_6alkyl, -NC1_6alkylSOZN(C1.6alkyl)2, -C(=O)H, -C(=O)C1_6alkyl, -NHC(=O)C1_6alkyl, -NC1_6alkle(=O)C1.6alkyl, C1- 6alkylenedioxy , =O, -N(C1_6alkyl)2, -C(=O)NH2, -C(=O)NHC1_6alkyl, -C(=O)N(C1_6alkyl)2, -NHC(=O)NH2, -NHC(=O)NHC1_6alkyl, -NHC(=O)N(C1_6alkyl)2, -NC1_6alkle(=O)NH2, -NC1-6alkle(=O)NHC1.6alkyl, alkle(=O)N(C1.6alkyl)2, -C(=NH)NH2, -C(=NH)NHC1_6alkyl, -C(=NH)N(C1_6alkyl)2, -C(=NC1_6alkyl)NH2, -C(=NC1.6alkyl)NHC1_6alkyl, -C(=NC1.6alkyl)N(C1_6alkyl)2, -C1_6alkyl, -C3_6cycloalkyl, eterocycloalkyl, 2-imidazolidinon—3 -yl, l-C1-6alkylimidazolidinon-3 -yl, C1-6alkle3.6heterocycloalkyl, aryl, haloaryl, C1_6alkoxyaryl, —ZtH, —Zt-C1_6alkyl, -C1_ 6alkylene—ZtH, —Zt-C3_6cycloalkyl, or -C(=O)NHC1_6alkylene—ZtH wherein Z1 is independently O, S, NH or N(C1_6alkyl). “C1_6alkyl” and “C1_6alkylene” in the above substituents may optionally be replaced by “C1_6heteroalkyl” and “C1_6heteroalkylene” respectively.
In another embodiment, the substituents are independently selected from halo, trihalomethyl, trihaloethyl, -OH, -NOZ, -CN, -COZH, -COZC1_6alkyl, -SO3H, -SOC1_6alkyl, -SOZC1_6alkyl, -NHSOZC1_6alkyl, -SOZNH2, -SOZNHC1_6alkyl, C1_6alkyl)2, -C(=O)H, C1_ 6alkyl, O)C1_6alkyl, -NC1-6alkle(=O)C1_6alkyl, =O, -N(C1_6alkyl)2, -C(=O)NH2, -C(=O)NHC1_6alkyl, -C(=O)N(C1_6alkyl)2, -C1_6alkyl, -C3_6cycloalkyl, -C3_6heterocycloalkyl, aryl, haloaryl, —ZtH, —Zt-C1_6alkyl, -C1_6alkylene—ZIH or _6cycloalkyl, wherein Z1 is independently O, S, NH or N(C1_6alkyl).
Where a group has at least 2 ons which may be tuted, the group may be substituted by both ends of an alkylene or heteroalkylene chain to form a cyclic moiety.
The molecular weight of the nds of the invention may, optionally, be less than 1000 g/mole, or less than 950 g/mole, or less than 900 g/mole, or less than 850 g/mole, or less than 800 g/mole, or less than 750 , or less than 700 g/mole, or less than 650 g/mole, or less than 600 g/mole, or less than 550 g/mole, or less than 500 g/mole.
The compounds of the invention may include any isotopes of the atoms comprised in the compounds. Examples include 2H and 3H, and 13C and 14C.
Pharmaceutically acceptable derivatives The term “pharmaceutically acceptable derivative” includes any pharmaceutically acceptable salt, solvate, hydrate or prodrug of a compound of the invention. In one embodiment, the pharmaceutically acceptable derivatives are pharmaceutically acceptable salts, solvates or hydrates of a compound of the invention.
The term "pharmaceutically able" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, tion, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts The term “pharmaceutically acceptable salt” includes a derivative of a compound of the invention that is a salt prepared from pharmaceutically acceptable xic acids or bases including inorganic or c acids and bases.
Compounds of the invention which contain basic, e. g. amino, groups are capable of forming pharmaceutically acceptable salts with acids. Pharmaceutically able acid addition salts of the compounds of the invention may include, but are not limited to, those of inorganic acids such as hydrohalic acids (6.g. hydrochloric, hydrobromic and hydroiodic acid), sulfuric acid, sulfamic acid, nitric acid, and phosphoric acid. Pharmaceutically acceptable acid addition salts of the nds of the invention may include, but are not limited to, those of organic acids such as aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which include: aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid or c acid; aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid; oxylic acids such as oxalic acid, maleic acid, hydroxymaleic acid, fumaric acid or succinic acid; aromatic carboxylic acids such as benzoic acid, p- chlorobenzoic acid, 2-acetoxybenzoic acid, phenylacetic acid, ylacetic acid or triphenylacetic acid; aromatic hydroxyl acids such as o-hydroxybenzoic acid, p- hydroxybenzoic acid, l-hydroxynaphthalenecarboxylic acid or 3 hydroxynaphthalene carboxylic acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, onic acid, benzenesulfonic acid, toluenesulfonic acid. Other pharmaceutically acceptable acid addition salts of the compounds of the invention include, but are not limited to, those of ascorbic acid, glycolic acid, onic acid, furoic acid, glutamic acid, anthranilic acid, salicylic acid, mandelic acid, embonic c) acid, pantothenic acid, stearic acid, sulfanilic acid, algenic acid, and galacturonic acid.
Compounds of the invention which contain acidic, e.g. carboxyl, groups are capable of forming pharmaceutically acceptable salts with bases. In one embodiment, pharmaceutically acceptable basic salts of the nds of the invention include, but are not limited to, metal salts such as alkali metal or alkaline earth metal salts (e. g. , potassium, magnesium or calcium salts) and zinc or aluminium salts. In one embodiment, pharmaceutically acceptable basic salts of the compounds of the invention include, but are not limited to, salts formed with ammonia or ceutically acceptable organic amines or heterocyclic bases such as ethanolamines (e.g. diethanolamine), benzylamines, N—methyl- glucamine, amino acids (6.g. lysine) or pyridine. lts of acids and bases may also be formed, 6.g. hemisulphate salts.
Pharmaceutically acceptable salts of compounds of the invention may be prepared by methods well-known in the art. For instance, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an c solvent, or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. For a review of ceutically acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, im, Germany, 2002).
Solvates & hydrates The compounds of the invention may exist in both unsolvated and solyated forms. The term “solvate” includes molecular complexes (6. g. crystals) comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules such as water or C1_6 alcohols, e. g. ethanol. The term “hydrate” means a “solvate” where the t is water.
Prodrugs The invention es prodrugs of the compounds of the invention. Prodrugs are tives of compounds of the invention (which may have little or no pharmacological activity themselves), which can, when administered in vivo, be converted into compounds of the invention.
Prodrugs can, for example, be produced by replacing functionalities present in the compounds of the invention with riate moieties which are metabolized in vivo to form a compound of the ion. The design of prodrugs is well-known in the art, as discussed in Bundgaard, Design of Prodrugs 1985 (Elsevier), The Practice of Medicinal Chemistry 2003, 2nd Ed, 561-585 and Leinweber, Drug Metab. Res. 1987, 18: 379.
Examples of prodrugs of compounds of the invention are esters and amides of the nds of the invention. For example, where the compound of the invention contains a ylic acid group ), the hydrogen atom of the carboxylic acid group may be replaced to form an ester (6.g. the hydrogen atom may be replaced by lkyl). Where the compound of the invention contains an alcohol group (-OH), the en atom of the alcohol group may be replaced in order to form an ester (6. g. the hydrogen atom may be replaced by —C(O)C1_6alkyl. Where the compound of the invention contains a primary or secondary amino group, one or more hydrogen atoms of the amino group may be replaced in order to form an amide (e.g. one or more hydrogen atoms may be replaced by -C(O)C1_ 6alkyl).
Amorphous & crystallineforms The compounds of the invention may exist in solid states from amorphous h to crystalline forms. "Amorphous" refers to a solid form of a molecule, atom, and/or ions that is not crystalline. Different crystalline forms (“polymorphs”) have the same chemical composition but different spatial ements of the molecules, atoms, and/or ions forming the crystal. All such solid forms are included within the invention.
Purity The compounds of the invention may, subsequent to their ation, be ed and d to obtain a composition containing an amount by weight equal to or greater than 99% of said nd ("substantially pure" compound), which is then used or formulated as described .
Isomericforms Compounds of the invention may exist in one or more geometrical, optical, omeric, diastereomeric and tautomeric forms, including but not limited to cis- and trans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. All such isomeric forms are included within the invention. The isomeric forms may be in isomerically pure or enriched form (6.g. one enantiomer may be present in excess, also known as a scalemic mixture), as well as in mixtures of isomers (e.g. racemic or diastereomeric mixtures).
If one enantiomer is present in a greater amount that its corresponding enantiomer, the enantiomeric excess may be expressed as a percentage of the whole. For instance, a 98:2 e of one enantiomer to another has a 96 % enantiomeric excess of the first omer.
The enantiomeric excess may be at least 5 %, 10 %, 15 %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 % or up to 100 % (Le. omerically pure, up to the detection limit of purity).
The invention therefore provides: ° stereoisomeric mixtures of compounds of the invention; 0 a diastereomerically enriched or diastereomerically pure isomer of a compound of the invention; or ° an enantiomerically enriched or enantiomerically pure isomer of a compound of the invention.
The ses for preparation can utilize racemates, enantiomers, or diastereomers as starting materials. Where appropriate, isomers can be prepared by the application or adaptation of known methods (6. g. asymmetric synthesis). When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization. ic labeling The invention includes pharmaceutically acceptable isotopically—labelled compounds of the invention n one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 1251, en, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32F, and sulphur, such as 358. Certain isotopically—labelled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The ctive isotopes 3H and 14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with r isotopes such as 2H may afford certain therapeutic advantages resulting from r metabolic stability, for example, increase in viva half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with on emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in on Emission Topography (PET) studies for examining ate receptor occupancy.
Isotopically-labelled compounds of the invention can lly be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
Treatment ofDiseases and Conditions nds of the invention are inhibitors of Kir3.1 and/or Kir3.4.
The invention provides a compound of the invention for use in therapy. The invention further provides a pharmaceutical composition comprising a compound of the invention in combination with a pharmaceutically acceptable excipient.
The invention further provides a method for the treatment of a disease or condition mediated by Kir3.1 and/or Kir3.4 or any heteromultimers thereof, or that es inhibition of Kir3.l and/or Kir3.4 or any heteromultimers thereof, comprising the step of administering a therapeutically effective amount of a compound of the invention to a patient. The invention also provides the use of a compound of the ion for the manufacture of a medicament for the treatment of a disease or condition mediated by Kir3.l and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.l and/or Kir3.4 or any multimers thereof The invention also provides a compound of the invention for use in a method for the ent of a disease or condition ed by Kir3.1 and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.l and/or Kir3.4 or any heteromultimers thereof Preferred compounds of the invention have an IC50 in the Kir3.l/3.4 Electrophysiology Method (described below) of<100 uM, <10 uM, <3 uM, <l uM, < 100 nM, or <10 nM.
Diseases and conditions mediated by Kiri] and/or 4 or heteromultimers thereof / requiring inhibition ofKiri] and/or [(173.4 or heteromultimers thereof The invention is useful for the treatment of a disease or condition mediated by Kir3.1 and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.l and/or Kir3.4 or any heteromultimers thereof In particular, the heteromultimer may be the heterotetramer /3.4. The invention therefore has use in: 0 the treatment of cardiovascular diseases, such as atrial fibrillation (AF), atrial flutter (AFL), entricular (AV) dysfunction and rial node (SAN) ction; 0 the prevention of recurrence of supraventriclar arrhythmias including AF and AFL; 0 the maintenance of sinus rhythm; 0 the termination and version of supraventriclar arrhythmias; o the treatment of sinus node dysfunction; 0 the treatment ofAV node dysfunction, including AV block; 0 the treatment of conduction dysfunction; 0 the tion or reversal of atrial structural and ionic remodeling; o the prevention of thrombosis, oembolism and thromboembolic es, such as stroke, myocardial infarction, and peripheral vascular diseases; 0 the improvement of cardiac contractility; o the treatment of metabolic diseases, such as diabetes mellitus; 0 the modulation of neuro-endocrine function; 0 the modulation of the secretion of pituitary hormones; 0 the treatment of neurological and neuropsychiatric disorders, such as pain, depression, anxiety, attention deficit/hyperactivity disorder and epilepsy; and o the treatment of cancer, such as breast cancer. eutic definitions As used herein, ment” includes curative, modulative (i. e. arresting the pment of a disease state) and prophylactic treatment. As used , a “patient” means an animal, such as a mammal, such as a human, in need of treatment.
The amount of the compound of the invention administered should be a therapeutically effective amount Where the compound or derivative is used for the treatment of a disease or condition, or its modulation, and a prophylactically effective amount where the compound or derivative is used for the prevention of a disease or condition.
The term “therapeutically ive amount” used herein refers to the amount of compound needed to treat or rate a targeted disease or condition. The term ylactically effective amount” used herein refers to the amount of compound needed to prevent a targeted disease or condition. The exact dosage will generally be dependent on the patient’s status at the time of administration. s that may be taken into consideration when determining dosage include the severity of the e state in the patient, the general health of the patient, the age, weight, gender, diet, time, frequency and route of administration, drug ations, reaction sensitivities and the patient’s tolerance or response to therapy.
The precise amount can be determined by routine experimentation, but may ultimately lie with the judgement of the clinician. Generally, an effective dose will be from 0.01 mg/kg/day (mass of drug compared to mass of patient) to 1000 day, e.g. 1 mg/kg/day to 100 day.
Compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. The daily oral dosage of the active ingredient may be between 3 and 600 mg either administered once daily or in divided doses administered twice daily. Alternatively, the active ingredient may be administered in doses of 10-20 mg stered twice daily or 40 to 100 mg administered once daily. Alternatively, the active ingredient may be administered a dose of 12.5 mg twice a day or 75 mg once a day. Alternatively, the active ingredient may be stered in doses of 3, 10, 30, 100, 300, and 600 mg administered either once or twice a day.
Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones. stration & Formulation General For pharmaceutical use, the compounds of the invention may be administered as a medicament by enteral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), oral, intranasal, , vaginal and topical (including buccal and sublingual) administration. The compounds of the invention should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.
The compounds of the invention may be administered as crystalline or amorphous products.
The compounds of the ion may be administered alone or in combination with one or more other compounds of the invention or in ation with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more ceutically acceptable excipients. The term ient” includes any ingredient other than the compound(s) of the invention which may impart either a functional (6. g. drug release rate controlling) and/or a non-functional (e. g. processing aid or diluent) characteristic to the formulations. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and ity, and the nature of the dosage form.
Typical pharmaceutically acceptable excipients include: ° diluents, e. g. lactose, dextrose, sucrose, ol, sorbitol, cellulose and/or glycine; ° lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; ° binders, e.g. ium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; ° disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or 0 absorbants, colorants, flavors and/or sweeteners.
A gh sion of pharmaceutically acceptable excipients is available in Gennaro, Remington: The Science and Practice of Pharmacy 2000, 20th edition (ISBN: 0683306472). ingly, the present invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
Compounds of the invention can also be administered in the form of me ry systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the invention may also be d with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, droxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or hyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) may contain from about 1 milligram to about 500 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will typically be present in an amount of about 05-95% by weight based on the total weight of the composition.
Oral stration The compounds of the invention may be administered . Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration e solid plugs, solid microparticulates, olid and liquid (including le phases or dispersed s) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids (e. g. aqueous solutions, or solutions in a digestible oil, such as soybean oil, cottonseed oil or olive oil), emulsions or powders; lozenges (including liquid-filled); chews; gels; fast sing dosage forms; powders; granules; films; ovules; sprays; and buccal/mucoadhesive patches.
Formulations suitable for oral administration may also be designed to deliver the compounds of the invention in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic y of the said compounds.
Means to deliver compounds in a rate-sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to l their release.
Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to e the said compounds by diffusion or a combination of diffusion and polymer erosion. Examples of rate-sustaining polymers include hydroxypropyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium ymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, m gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
Liquid (including multiple phases and dispersed systems) formulations include emulsions, suspensions, solutions, , tinctures and elixirs. Such formulations may be presented as fillers in soft or hard es (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically se a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
The compounds of the invention may also be used in issolving, fast-disintegrating dosage forms such as those bed in Liang and Chen, Expert Opinion in Therapeutic Patents 2001, 11(6): 981-986.
The formulation of tablets is discussed in H. man and L. Lachman, Pharmaceutical Dosage Forms: Tablets 1980, vol. 1 (Marcel Dekker, New York).
Parenteral administration The compounds of the ion can be administered parenterally.
The compounds of the invention may be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ. Suitable means for administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral ations are typically aqueous or oily solutions and may include, as carriers, water, a le oil, saline, aqueous dextrose (glucose) and related sugar solutions, and/or glycols such as propylene glycol or hylene glycols. Where the solution is aqueous, excipients such as sugars (including but restricted to glucose, mannitol, sorbitol, etc.) salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a le vehicle such as sterile, pyrogen-free water (WFI).
Solutions for parenteral stration may contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulflte, sodium sulfite, or ic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium de, methyl- or propylparaben, and butanol. eral formulations may include implants d from degradable polymers such as polyesters (i. e. polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into the subcutaneous , muscular tissue or directly into specific .
The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation ques, such as the oration of co-solvents and/or solubility-enhancing agents such as surfactants, micelle structures and cyclodextrins.
Inhalation & intranasal administration The compounds of the invention can be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with olipids, such as phosphatidylcholine) from a dry powder r, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an er using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable lant, such as l,l,l,2-tetrafluoroethane or l,l,l,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for e, chitosan or cyclodextrin.
The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for e, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as e or starch and a performance er such as l leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, ably the . Other suitable excipients include n, glucose, maltose, sorbitol, l, fructose, sucrose and trehalose.
Formulations for d/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, ned-, pulsed-, controlled-, targeted and programmed release.
Transa’ermal administration Suitable formulations for transdermal application include a therapeutically effective amount of a compound of the invention with carrier. Advantageous rs include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir ning the nd optionally with rs, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and ermined rate over a prolonged period of time, and means to secure the device to the skin.
Combination Therapy A compound of the invention may be administered alone, or may be administered in combination with another therapeutic agent (i. e. a different agent to the compound of the invention). The nd of the invention and the other therapeutic agent may be administered in a therapeutically effective amount.
The compound of the t invention may be administered either simultaneously with, or before or after, the other eutic agent. The compound of the present ion and the other therapeutic agent may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition.
In one embodiment, the invention provides a product comprising a compound of the invention and another therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by Kir3.l and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.l and/or Kir3.4 or any heteromultimers f Products provided as a combined preparation include a composition comprising the compound of the invention and the other therapeutic agent together in the same pharmaceutical composition, or the compound of the invention and the other therapeutic agent in separate form, 6. g. in the form of a kit.
The invention es a ceutical composition comprising a compound of the invention and another therapeutic agent. Optionally, the pharmaceutical composition may WO 72694 comprise a pharmaceutically acceptable excipient, as described above in “Administration & Formulation”.
The invention es a kit comprising two or more te pharmaceutical itions, at least one of which contains a compound the invention. The kit may comprise means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An e of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
The kit of the invention may be used for stering different dosage forms, for example, oral and parenteral, for stering the te compositions at different dosage intervals, or for titrating the separate compositions t one another. To assist compliance, the kit of the invention typically comprises directions for stration.
In the combination ies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before stration; (iii) in the patient themselves, 6. g. during sequential administration of the compound of the invention and the other therapeutic agent.
The compound of the invention and the other therapeutic agent may be combined in a single dosage unit. Optionally, they may be formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the intestinal tract such that one of these components is not released in the stomach but rather is released in the ines. One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the ed active ingredients.
Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still r approach can involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active ents.
The polymer coating serves to form an additional barrier to interaction with the other component.
Accordingly, the invention es the use of a compound of the invention in the manufacture of a medicament for treating a disease or condition mediated by Kir3.l and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.l and/or Kir3.4 or any heteromultimers thereof, n the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent in the manufacture of medicament for treating a disease or ion mediated by Kir3.1 and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.l and/or Kir3.4 or any heteromultimers thereof, wherein the medicament is prepared for administration with a compound of the ion.
The ion also provides a compound of the invention for use in a method of treating a e or condition mediated by Kir3.1 and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.l and/or Kir3.4 or any heteromultimers thereof, wherein the compound of the ion is prepared for administration with another therapeutic agent.
The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by Kir3.1 and/or Kir3.4 or any multimers thereof, or that requires inhibition of Kir3.1 and/or Kir3.4 or any heteromultimers thereof, wherein the other therapeutic agent is prepared for administration with a compound of the ion. The invention also provides a compound of the invention for use in a method of treating a disease or condition mediated by Kir3.l and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.l and/or Kir3.4 or any multimers thereof, wherein the compound of the invention is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by Kir3.l and/or Kir3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.1 and/or Kir3.4 or any heteromultimers thereof, wherein the other eutic agent is administered with a compound of the invention.
The invention also provides the use of a compound of the invention in the cture of a medicament for treating a disease or condition mediated by Kir3.l and/or Kir3.4 or any heteromultimers thereof, or that es inhibition of Kir3.l and/or Kir3.4 or any heteromultimers thereof, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent in the manufacture of a ment for treating a e or condition mediated by Kir3.1 and/or K,r3.4 or any heteromultimers thereof, or that requires inhibition of Kir3.1 and/or Kir3.4 or any heteromultimers thereof, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of the invention.
In one embodiment, the other therapeutic agent is selected from other antiarrhythmic , such ? as n-Williams class 1, class II, class III, or class IV agents, or from other cardiovascular The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior ation (or information derived from it) or known matter ? forms part of the common general dge in the field of endeavour to which this specification relates.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of ? any other integer or step or group of rs or steps.
Synthesis Compounds of formula (1) may be prepared by conventional routes, for example those set out in Schemes 1 to 21 shown below.
SCHEME 1 >,)n nds of formula (ii) where R31 is NR8R9, —(NRaRb)—J (e.g.? *? ), -CN, or alkoxy and where R', R2, R8, R9, n, D and J are as defined above may be prepared ing to scheme 1 from compounds of formula (i) via displacement of the 4-chloro substituent by a suitable nucleophilic s. Typically, this reaction is performed in the presence of a base, for example, ? triethylamine or potassium carbonate, ing standard methods familiar to those skilled in the art such as reaction in solvents such as tetrahydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or via microwave irradiation.
SCHEME 2 R1 R31 R1 R3I / x / x R2 / | ——> R2 / l Z C1 A \Z R3111 (iii) (iv) Compounds of formula (iv) Where 11311115 NRloR“, —(NRcRd)—J (e.g. >x< ), -CN, or alkoxy and where R1, R2, R31, R10, R“, n, D and J are as defined above may be prepared according to scheme 2 from compounds of formula (iii) via displacement of the 2-chloro substituent by a suitable nucleophilic species. Typically, this reaction is med in the presence of a base, for example, triethylamine or potassium carbonate, utilising standard methods familiar to those skilled in the art such as reaction in solvents such as ydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux ature or via microwave irradiation.
SCHEME 3 D (a D (a | | )n “f )n R1 N HN—G R1 N (vii) / / R2 / j\ R24% A \Z R3 A III \Z R3 (vi) nds of a (vi) may be prepared according to scheme 3 by reaction of compounds of formula (v) Where L* is defined as a suitable leaving group, for example, bromine, chlorine, iodine, tosylate, or mesylate. Typically, this reaction is performed in the presence of a base, for e, triethylamine or ium carbonate, utilising standard methods familiar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, acetonitrile or dichloromethane at a range of atures from ambient to reflux temperature or via microwave irradiation. Compounds of formula (vii) are known compounds or may be prepared by standard published methods familiar to those skilled in the art.
SCHEME 4 1 N M/W / / x R2 k ( q A I Z R3111 (viii) )n R1 N | / / x HN—G R2 O I // .. \ (V11) A Z R3HI (Vi) R1 N (1X) Compounds of formula (vi) where q is 0 or 1 may also be prepared from the corresponding aldehyde (viii) or ketone (ix) according to scheme 4 via a ive amination. The reaction may be performed in a one pot procedure with in situ formation and reduction of the imine or via a two stage s where the imine is isolated and purified prior to reduction. Imine formation is performed under acid catalysis, suitable catalysts include acetic acid. The ion may be performed using standard methods such as reaction in solvent such as tetrahydrofuran, itrile, dichloromethane or toluene at a range of temperatures from - °C to reflux temperature with a suitable reductant such as sodium triacetoxyborohydride or sodium cyanoborohydride, the reduction may also be performed using catalytic hydrogenation or in the presence of phenylsilane and dibutyltin dichloride. Compounds of formula (vii) are known compounds or may be prepared by standard published methods familiar to those skilled in the art.
SCHEME 5 D K/ R1 N / / x D (Fq/ I I )n Z R3111 R1 N (viii) oxidation //0 / / x A R1 N Z R3111 (1X) Compounds such as (viii) and (ix) may be prepared from the corresponding alcohols (x) according to scheme 5 via an oxidation. Typically, this reaction is performed in the presence of an t, for e, pyridinium chlorochromate or Dess-Martin inane, utilising standard methods ar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, acetonitrile or dichloromethane at a range of temperatures from -10°C to reflux temperature or via ave irradiation.
SCHEME 6 U (L ( q ( q D D | | )n T )n R1 N OH R1 N (Xi) / ifimfl—> / / x R2 R2 A xR3111 (xii) Compounds of formula (xii) may be prepared according to scheme 6 by reaction of compounds of a (V) Where L* is defined as a suitable leaving group, for example, bromine, chlorine, iodine, te, or te. It is understood that the reverse case also holds true in that (V) may bear the hydroxyl and (xi) the g group. Typically, this reaction is performed in the presence of a base, for example, sodium hydride, sodium hydroxide or potassium carbonate, utilising standard methods familiar to those d in the art such as reaction in solvent such as tetrahydrofuran, toluene, acetonitrile or dimethylformamide, or a mixture of solvents such as toluene/water in the presence of a phase-transfer catalyst such as tetrabutyl ammonium bromide, at a range of temperatures from ambient to reflux temperature or via microwave irradiation. Compounds of formula (xi) are known compounds or may be prepared by standard published methods familiar to those skilled in the art.
SCHEME 7 OH L* \ Dr )n )n R1 N R1 N . / A l A \zrR3111 Compounds of formula (V) where L* is a halogen may be prepared according to scheme 7 from compounds of formula (x) Via reaction with a suitable nating agent. For example, when L* is bromine, suitable reagents include phosphorous tribromide or orous oxybromide or when L* is chlorine, le ts include phosphorous pentachloride, phosphorous oxychloride or l chloride. The halogenation reaction may also be performed using Appel (Appel R, 1975) conditions in the presence of carbontetrabromide and triphenylphosphine when L* is bromine, or carbontetrachloride and triphenylphosphine when L* is chlorine. The halogenation may be performed in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or e, or in neat t, at a range of temperatures from -10°C to reflux temperature.
Compounds of formula (V) where L* is an O-alkyl, or O-aryl sulfonyl leaVing group may be synthesized from compounds of formula (x). Typically, this reaction is performed in the presence of a suitable sulfonylchloride such as tolunesulfonyl chloride or methanesulfonyl chloride and in the presence of base such as triethylamine or ium carbonate utilising standard methods familiar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, toluene, acetonitrile or dichloromethane at a range of temperatures from - °C to reflux temperature. 2012/052842 SCHEME 8 OH OH ( q R1 i j)n K / (xiv) R2 / R2 l A \zj\ —> \k R3III A (xii) Compounds of formula (x) may be prepared according to scheme 8 from compounds of formula (xii). Typically, this reaction is performed in the presence of a base, for example, triethylamine or potassium carbonate, utilising standard methods familiar to those skilled in the art such as reaction in solvent such as ydrofuran, toluene, itrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or Via microwave irradiation. Compounds of formula (xiv) are known compounds or may be prepared by standard published methods ar to those skilled in the art.
SCHEME 9 R1 R3I Br / ‘ z R3Ill (xviii) R1 R3I / / Ix Alkyl '0 A \zAR3111 (XVI) y NHRARS NHR4R5 / / x \ J\ R3131 HO A z R3 (XV) Compounds of formula (xvii) may be prepared according to scheme 9 via the reaction of compounds of formula (xv) with amines of formula NHR4R5. lly, this reaction is carried out using a coupling reagent such as l-ethyl(3-dimethylaminopropyl)- carbodiimide (EDC) or 2-(7-aza—lH—benztriazole-l-yl)-l,l,3,3-tetramethyluronium orophosphate (HATU) utilising standard methods familiar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at a range of temperatures from ambient to reflux temperature.
Compounds of formula (xv) may be prepared according to scheme 9 via hydrolysis of an alkyl ester. Typically, this reaction is carried out using s acid or base, at a range of temperatures from ambient to reflux temperature. Suitable acids e hydrochloric acid and suitable bases include sodium hydroxide or lithium hydroxide.
Compounds of formula (xvii) may also be sised directly from compounds of formula (xvi) and amines of formula NHR4R5. Typically this reaction is carried out using hylaluminium utilising standard methods familiar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or via microwave irradiation.
Compounds of formula (xvi) may be synthesised from compounds of a (xviii) via reaction with an organolithium base and reaction of the resulting anion derived from bromine/lithium ge with a chlorocarbonate, preferably methyl chloroformate.
Compounds of formula (xviii) may be synthesised by adapting procedures found in W02004/111057.
SCHEME 10 1 RI / / Buchwald ion X \N / | ——> 0 \ k A 3 3 O:< 7 (XX) (XIX) Compounds of formula (xx) may be prepared according to scheme 10 via the reaction of compounds of formula (xviii) and amides of form HNC(O)R7 using the procedure of Buchwald er al. Typically, this on is carried out using a palladium coupling reagent such as tris(dibenzylideneacetone) dipalladium utilising standard methods familiar to those d in the art, such as reaction in solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at a range of temperatures from ambient to reflux temperature or via microwave irradiation.
SCHEME 11 R1 R1 Zinc / / x R2 :Zj\Cl—> R2 \ZJ\CI (xxi) (XXll) R2 / I Z R3111 (xxiii) Compounds of formula (xxiii) where R3III is NRIOR“, —(NRcRd)—J (e.g * ), — CN, or alkoxy and where R1, R2, R10, R11 D and J are as defined above may be prepared , n, according to scheme 11 from compounds of formula (xxi) via cement of the 2-chloro substituent by a suitable nucleophilic species. Typically, this on is performed in the presence of a base, for example, triethylamine or potassium carbonate, utilising standard s familiar to those skilled in the art such as reaction in solvents such as tetrahydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux ature or via microwave irradiation.
Compounds of formula (xxii) may be prepared according to scheme 11 from compounds of formula (xxi) via selective reduction of the 4-chloro position. Typically, this reaction is performed in the ce of reducing metal, for example, Zinc, utilising standard methods familiar to those skilled in the art such as on in solvents such as ethanol in the ce of aqueous ammonia, at a range of temperatures from ambient to reflux temperature or via microwave irradiation. 2012/052842 SCHEME 12 1\|/I/ W L | ( q ( q Cl ‘ ‘ R1 R1 (XXV) R2 / I R2 / | \ \ A A Z R3111 Z R3111 (XXiV) (XXVi) nds of formula (XXVi) may be prepared according to scheme 12 via reaction of compounds of formula (xxiv) with ene compounds of formula (XXV) using the method of Sonogashira coupling (Chinchilla er al, 2007; Berg er al, 2006). Typically, this reaction is carried out using a palladium coupling reagent such as tris(dibenzylideneacetone) dipalladium utilising standard methods familiar to those skilled in the art, such as reaction in solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at a range of temperatures from ambient to reflux temperature or via microwave irradiation.
SCHEME 13 W W M/ M/ OH W O O (l/61 WK ( q ( q D L* D D (xxviii) (xxx) 11 —> n ' ’ n N N N I H PG PG (xxvii) (XXiX) W 1 c1 “I“ R O / x R2 / D S \zlR3111 (xxxi) (xxxn)..
R1 N / / x R2 | Z R3111 nds of formula (xxxii) may be prepared according to scheme 13 via reaction of compounds of formula (xxx) with compounds of formula (xxxi). Typically, this reaction is performed in the presence of a base, for example, triethylamine or potassium carbonate, utilising standard methods familiar to those skilled in the art such as reaction in solvents such as tetrahydrofuran, e, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or via microwave irradiation.
Compounds of formula (xxx) may be prepared ing to scheme 13 via the deprotection of nitrogen compounds of a (xxix). Suitable nitrogen protecting groups (PG) are familiar to those skilled in the art and may e those removed by hydrogenation such as benzyl, and oxycarbonyl (CBZ) or those removed by ent with acid such as tert- butoxy carbonyl (BOC). A list of suitable protecting groups may be found in Greene et al (1999).
Compounds of formula (xxix) may be prepared according to scheme 13 by reaction of compounds of formula (xxvii) with compounds of formula (xxviii) where L* is defined as a suitable leaving group, for example, bromine, chlorine, iodine, tosylate, or mesylate. It is understood that the reverse case also holds true in that (xxviii) may bear the hydroxyl and (xxvii) the leaving group. Typically, this reaction is performed in the presence of a base, for example, sodium hydride, sodium hydroxide or potassium carbonate, utilising standard methods familiar to those skilled in the art such as reaction in solvent such as ydrofuran, toluene, acetonitrile or ylformamide, or a mixture of solvents such as toluene/water in the presence of a phase-transfer catalyst such as tetrabutyl ammonium bromide, at a range of temperatures from ambient to reflux temperature or via ave irradiation. Compounds of a (xxviii) are known compounds or may be prepared by standard hed methods familiar to those skilled in the art.
SCHEME 14 RI Br R? R1 R13 / / X LDA / / X R—D* Br I 1 / X —> —>/ \ | I A \ Z R3 A 3 \ Z R A Z R3 (XXXV) (XXXiV) i) Compounds of formula (xxiii) where R1 is aryl or heteroaryl may be prepared from compounds of formula (xxxiv) via an organometallic cross-coupling reaction. Suitable reactions for this transformation may include Suzuki couplings, where D* is a boronic acid, boronic acid ester, or borate salt; or Stille couplings where D* is a trialkyl tin moiety.
Typically, the reaction is performed under catalysis in the presence of a palladium coupling reagent, for example tetrakis(triphenylphosphine) Palladium(0) and utilising standard methods ar to those skilled in the art, such as on in solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at a range of temperatures from ambient to reflux temperature or via microwave ation.
Compounds of formula (xxxiv) may be prepared from compounds of formula (xxxv) via a base-catalysed migration of a bromine atom using the method cited in W02004/ 111057.
Suitable bases include organolithium compounds such as m ropyl amide in a t such as diethyl ether or tetrahydrofuran. The reaction may be performed at a range of temperatures from -78°C to 0°C.
SCHEME 15 R R1 / / X Alkyl—O A z R1311 (XV!) \ hydmlySis R1 RI R o / / / X |)< 4R5 m \ X RLN \ A 3 HO A 3 (XV) Compounds of formula (xvii) may be ed according to scheme 15 via the reaction of compounds of formula (xv) with amines of formula NHR4R5. Typically, this reaction is d out using a coupling reagent such as 1-ethyl(3-dimethylaminopropyl)- carbodiimide (EDC) or 2-(7-aza—lH—benztriazole-l-yl)-l,1,3,3-tetramethyluronium hexafluorophosphate (HATU) utilising standard methods familiar to those d in the art such as reaction in t such as tetrahydrofuran, acetonitrile or dimethylformamide at a range of temperatures from ambient to reflux temperature in the presenceof an organic base, for example, N,N—diisopropylethylamine. nds of formula (xv) may be prepared according to scheme 15 via hydrolysis of an alkyl ester. Typically, this reaction is carried out using aqueous acid or base, at a range of temperatures from ambient to reflux temperature. Suitable acids include hydrochloric acid and suitable bases include sodium hydroxide or lithium hydroxide. In the case where R3111 is a substituted alkoxy group and the substitution described in scheme 2 is performed under ly basic conditions concomitant hydrolysis of the r may also occur to give (xv) directly. Compounds of formula (xvii) may also be synthesised ly from compounds of formula (xvi) and amines of formula NHR4R5. Typically this reaction is carried out using trimethylaluminium utilising standard methods familiar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, toluene, acetonitrile or dimethylformamide, at a range of atures from ambient to reflux temperature or via microwave ation.
Compounds of formula (xvi) may be prepared from compounds of formula (xxxVi) using the methods described in s 1 and 2.
Compounds of formula (xxxVi) may be prepared from compounds of formula (xxxvii) via treatment with an organlithium base, for example, lithium diisopropylamide in a solvent, for example, ydrofuran at a range of temperature from -78°C to 0°C and quenching of the resulting anion with a chlorocarbonate typically methyl chloroformate. Compounds of formula (xxxvii) may be prepared according to the methods ofW02004/111057.
SCHEME 16 (xxxviii) Xa R111 1 H2N(xli) —> / Compounds of formula (xliii) where R3III is NR10R11,—(NRCRd)—J(e.g >x< ), -CN, or alkoxy and where R1, R2, R31, R10, R“, n, D and J are as defined above may be prepared according to scheme 16 from compounds of formula (i) or (xlii) via displacement of a suitable leaving-group such as a ro or 4-trifluorosulfonate substituent by a suitable nucleophilic species. Typically, this reaction is performed in the ce of a base, for example, triethylamine or potassium carbonate, utilising standard methods familiar to those skilled in the art such as reaction in solvents such as tetrahydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or via microwave irradiation.
Compounds of formula (xlii) may be prepared via the reaction of compounds of formula (xl) with trifluoromethanesulfonic ide in a solvent for example, dichloromethane or ydrofuran and in the presence of a base, for example, pyridine. Compounds of formula (i)(a) may be prepared via the reaction of compounds of a (xl) with a suitable nating agent for example, phosphorous oxychloride or diphenylphosphoryl chloride.
Typically, this reaction is performed in a neat on of the chlorinating reagent at temperatures ranging from 50°C to reflux temperature.
Compounds of formula (xl) may be prepared via cyclisation of nds of formula (xxxviii) with an amidate of formula (xxxix). Typically, the on is performed in a suitable solvent, for example ethanol and at reflux temperature of the t.
Compounds of formula (i) may be prepared via cyclisation of nds of formula ii) with primary amides of formula (xli) in the presence of a chlorinating agent for example, phosphorous trichloride. Typically, this reaction is performed in a solvent, for example toluene at temperatures ranging from 60°C to reflux temperature.
SCHEME 17 Compounds of formula (xlvi) where R3111 is NRIOR“, —(NRcRd)—J (e.g * ), -CN, or alkoxy and where R1, R2, R31, R10, R“, n, D and J are as defined above may be prepared according to scheme 17 from compounds of formula (xlv) via displacement of a suitable leaving-group (L*) for example, an alkyl sulfone, by a suitable nucleophilic species. lly, this reaction is performed in the presence of a base, for example, triethylamine or potassium carbonate, utilising rd methods familiar to those skilled in the art such as reaction in solvents such as ydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or via microwave ation. nds of formula (xlvii) may be prepared from compounds of formula (xliv) via treatment of compounds of formula (xlv) with a suitable reductant, for example, sodium borohydride in a solvent, for example, ethanol. Typically, this reaction is performed at a range of temperatures from 0°C to 25°C. 2012/052842 Compounds of formula (xlv) Where R31 is NRSRQ, —(NRaRb)—J (e.g. * ), -CN, or alkoxy and where R1, R2, R8, R9, n, D and J are as defined above may be prepared according to scheme l7from compounds of formula (xliv) via displacement of a suitable leaving-group (L) for example, and alkyl sulfone by a suitable philic species. Typically, this reaction is performed in the presence of a base, for e, triethylamine or potassium carbonate, utilising standard methods familiar to those skilled in the art such as reaction in solvents such as ydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or via microwave irradiation. Compounds of formula (xliv) may be prepared according to the methods of W02005/121 149.
SCHEME 18 1 Cl 3 R R1 RI / / IN 0 R2 2 / N o R / \ UL s /Alkyl —* I N__ o S \N O/Alkyl (X11111) (liii) 1 Cl i R1 R13 R / / N O \ J\/\ R2 / N 0H (xl1x) \M N OH l (liv) R1 R13 i / / R1 \ / N o NJ\/\ OH R2 / (lii) Compounds of formula (lii) may be prepared according to scheme 18 from compounds of a (li) via displacement of a le leaving-group L* for example, a methansulfonyl, toluenesulfonyl, iodo, bromo or chloro group by a suitable nucleophile Nuc-H, for e, an amino or alkoxy group. Typically, this reaction is performed in the presence of a base, for example, triethylamine or potassium carbonate, utilising standard methods familiar to those skilled in the art such as reaction in solvents such as tetrahydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or Via microwave irradiation. Compounds of formula (li) where L* is defined as a suitable g group, for example, methansulfonyl, esulfonyl, iodo, bromo, or chloro, may be prepared from compounds of formula (1) using standard methods familiar to those skilled in the art, for example reaction with a sulfonyl chloride or a suitable halogenating agent such as thionyl chloride or phosphorous tribromide.
Compounds of formula (1) where R31 is NRSRQ, —(NRaRb)—J (e.g., >x< ), -CN, or alkoxy and where R1, R2, R8, R9, n, D and J are as defined above may be prepared according to scheme 18 from compounds of formula (xlix) via displacement of a suitable leaving- group, for example, an alkyl sulfone, by a suitable nucleophilic species. Typically, this reaction is performed in the presence of a base, for example, triethylamine or potassium carbonate, utilising standard methods ar to those skilled in the art such as reaction in solvents such as tetrahydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or via ave irradiation. Compounds of a (xlix) may be prepared via ion of compounds of formula (xlviii). Suitable reductants include m aluminium hydride in anhydrous solvent, typically tetrahydrofuran or diethyl ether at a range of temperatures from -78°C to 0°C. Compounds of a (xlviii) may be prepared according to the methods ofW02004/111057.
Compounds of formula (IV) may be prepared from compounds of formula (liv) via an amide formation. lly, this may be performed by conversion of compounds of formula (liv) to their corresponding acid chloride tives by treatment with a le chlorinating agent sucgh as thionyl chloride or oxalyl chloride, optionally in the presence of a solvent for example dichloromethane. The acid chloride is then treated with an amine in the presence of base, typically pyridine, optionallyin the presence of solvent, for e dichloromethane to give the amide (1v). atively, compounds of formula (IV) may be prepared via the on of compounds of formula (liv) with amines of formula NHR4R5. Typically, this reaction is carried out using a coupling reagent such as l-ethyl(3-dimethylaminopropyl)- carbodiimide (EDC) or 2-(7-aza—lH—benztriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU) utilising standard methods ar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at a range of temperatures from ambient to reflux temperature in the presenceof an organic base, for example, N,N—diisopropylethylamine.
Compounds of formula (liv) may be ed according to scheme 18 via hydrolysis of an alkyl ester (liii). Typically, this reaction is carried out using aqueous acid or base, at a range of temperatures from ambient to reflux temperature. Suitable acids include hloric acid and suitable bases include sodium hydroxide or lithium hydroxide.
Compounds of formula (liii) where R3I is NRSRQ, —(NRaRb)—J (e.g >x< ), -CN, or alkoxy and where R1, R2, R8, R9, n, D and J are as defined above may be ed according to scheme x from compounds of formula (xlviii) via displacement of a suitable leaving- group for example, a 4-chloro, by a suitable nucleophilic species. Typically, this reaction is performed in the presence of a base, for example, triethylamine or potassium carbonate, ing standard methods familiar to those skilled in the art such as reaction in ts such as tetrahydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or via microwave irradiation.
SCHEME 19 R1 R1 R1 R1 Buchwald amination / / X 4—» R1 / / X Br I R\ N l \ IllH( ')5 x1x R4/ \ Z R1311 R A z R1311 Compounds of formula (lvii) may be prepared according to scheme 19 via the reaction of nds of formula (lxvi) and amines of form NHR4R5 using the procedure of ld er al. Typically, this on is carried out in the presence of a palladium coupling reagent and using standard methods familiar to those skilled in the art, such as reaction in solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at a range of temperatures from ambient to reflux temperature or via microwave irradiation.
SCHEME 20 Cl Nuc (lviii) Compounds of formula ) may be prepared according to scheme 20 from compounds of formula (lvix) via displacement of a suitable g-group for example, a chloro group, by a suitable nucleophile Nuc-H, for example, a substituted amino or alkoxy group. lly, this reaction is performed in the presence of a base, for example, triethylamine or potassium carbonate, ing standard methods familiar to those skilled in the art such as reaction in solvents such as tetrahydrofuran, toluene, acetonitrile or dimethylformamide, at a range of temperatures from ambient to reflux temperature or via microwave irradiation.
SCHEME 21 (1X) Compounds of formula (lx) may be ed from compounds of formula (lvi)(a) via the introduction of a cyano group under catalytic conditions. Typically, the source of the cyanide group is zinc cyanide and the catalyst is formed from a palladium complex, for e, that formed from the combination of tris(dibenzylideneacetone) dipalladium with diphenylphosphino ferrocene. The reaction is med in a solvent, preferably dimethylformamide at a range of temperatures from ambient to reflux ature or via microwave irradiation.
General The term “comprising” encompasses “including” as well as “consisting” e. g. a composition “comprising” X may consist exclusively ofX or may include ing additional e.g. X + The word “substantially” does not exclude “completely” 6. g. a ition which is “substantially free” from Y may be tely free from Y. Where ary, the word “substantially” may be omitted from the definition of the invention.
The term “about” in relation to a numerical value x means, for example, xi10%.
MODES FOR CARRYING OUT THE INVENTION Experimental Section Many of the starting materials referred to in the reactions described below are available from commercial sources or can be made by methods cited in the literature references. Synthetic methods can also be found in reviews; [2,3-d]pyrimidines for example, can be found in references cited in WO2004/111057 and reference such as Han et al (2010).
Synthetic s for thieno[2,3-d]pyridines may be found in WO2006/06l642 and references such as Gewald et al (1979) Munchof et al (2004), Barker et al (1985), Charvat et al (1995) and articles cited therein.
The following starting materials were synthesized using the ures described in WO2004/111057: 4-Chloro-5—phenyl—thien0[2, 3-07pyrimidine 4-Chlor0(3-flu0r0phenyl)-thien0[2,3-d]pyrimidine 4-Chlor0(4-flu0r0phenyl)-thien0[2,3-d]pyrimidine 2, 4-Dichl0r0phenyl—thien0[2, rimidine Methyl 4-ch10r0phenyl-thien0[2,3-d]pyrimidine-(S—carboxylate 6-Br0m0ch10r0phenyl—thien0[2, 3-d]pyrimidine 4-ch10r0isopropyl—thien0[2, 3-07pyrimidine 4-Chl0r0-5, 6-dimethyl—thien0[2, 3-07pyrimidine 2, 4-dichlor0-5—cyclohexyl—thien0[2, 3-07pyrimidine 4-Chl0r0ethylphenyl—thien0[2, 3-07pyrimidine 4-Chl0r0cyclohexyl-thien0[2, 3-07pyrimidine l 16 WO 72694 2, 4-dichlor0-5—(4-flu0r0phenyl)thien0[2, 3-07pyrimidine methyl 2—[4-chl0r0-5—(4-flu0r0phenyl)thien0[2,3-d]pyrimidin-2—yl]acerate The ing starting materials were synthesized using the procedures described in W02006/06l642: r0phenyl-thien0[2, 3-1)]pyridine The following starting materials were synthesized using the ures described in W02005/121149: 2, 4-Bz'smethylsulph0nyl)phenyl—fur0[2, 3-61]-pyrimidine Analytical methods HPLC analysis was conducted using the following s: AGILENT 61 10/1200 LCMS system Solvent : [HZO-0.l% HCOZH : MeCN—0.05% HCOZH : HZO-0.l% , 10-95% gradient 3min, 95% 3-5min, 5.5-5.8min 95%-20% gradient; 6min 5%; Column: Phenomenex Gemini 50x4.6 mm id, 3 micronC18 e phase; Flow rate: 0.75mL/min.
UV detection 220/254nm, MS Electrospray (+ve and —ve mode).
Preparative HPLC purification was conducted in the following manner: Solvent : [MeCN—0.05% HCOZH : HZO-0.l% HCOZH], 5-95% gradient 12min, 95% 3min; Waters X-Bridge 100x19 mm id. C18 reverse phase; Flow rate: l6mL/min unless otherwise indicated.
HPLC: Agilent HPLC with Waters XBridge C18, 5 um, 100 mm x 19 mm id. column and a flow rate of l6ml/minute. With two Gl36lA prep pumps, a G2258A duel loop auto sampler, a G1315 diode array detector and a G3064B prep fraction collector. Analysed by ChemStation 3. Solvents, (acidic method) water with 0.01% formic acid and acetonitrile with 0.05% formic acid or (basic ) water with 0.1% ammonia and acetonitrile.
Method a: Time minutes 0 12 15 15 .5 itrile concentration % 5 95 95 5 Method b: Time minutes 0 1.5 13.5 14 15 15.5 16 Acetonitrile concentration % 5 40 65 98 98 5 5 Method c: Time minutes 0 1.5 14 14.5 15 15.5 Acetonitrile concentration % 5 50 75 95 95 5 Method d: Time minutes 0 1.5 14 14.5 15 15.5 Acetonitrile concentration % 5 50 65 95 95 5 Method e: Time s 0 1 1 12 15 15 Acetonitrile concentration % 5 35 95 95 5 Method f: Time minutes 0 1.5 12 15 15 .5 Acetonitrile concentration % 5 50 95 95 5 Method g: Time minutes 0 1 1 1 1.5 14.5 15 Acetonitrile concentration % 5 55 95 95 5 HPLC: Agilent HPLC with Phenomenex Gemini-NX, 5 um, 100 mm x 30mm i.d. column and a flow rate of 40m1/minute. With two G1361A prep pumps, a G2258A duel loop auto sampler, a G1315 diode array detector and a G3064B prep fraction collector. ed by ChemStation 3. Solvents, (acidic method) water with 0.01% formic acid and acetonitrile with 0.05% formic acid or (basic method) water with 0.1% ammonia and acetonitrile.
Method 1: Time s 0 12 15 15 .5 Acetonitrile concentration % 5 95 95 5 Method 2: Time minutes 0 1.5 13.5 14 15 15.5 16 Acetonitrile tration % 40 65 98 98 5 5 Method 3: Time minutes 1.5 14 14.5 15 15.5 Acetonitrile tration % 50 75 95 95 5 Method 4: Time minutes 1.5 14 14.5 15 15.5 Acetonitrile concentration % 50 65 95 95 5 Method 5: Time minutes ll 12 15 15 Acetonitrile concentration % 35 95 95 Method 6: Time minutes 1.5 12 15 15.5 Acetonitrile concentration % 50 95 95 Method 7: Time s ll 11.5 14.5 15 Acetonitrile concentration % 55 95 95 Proton and carbon NMR were acquired on a Bruker Advance 300 at 300 and 75 mHz respectively.
Method A Synthesis of 2-(I-methylpyrrolidin-Z-yl)-N—[[I-(5-phenylthien0[2,3-d]pyrimidin-4—yl)-4— piperidyUmethyUethanamine (Example 58) i) [4-(5-Phenyl-thieno[2,3-d]pyrimidinyl)-piperidinyl]-methanol 4-Chlorophenyl-thieno[2,3-d]pyrimidine (l g, 4.05 mmol) was dissolved in ethanol (15 ml) to give a yellow solution. To this was added triethylamine (1.7 ml, 12.2 mmol) and 4- dinemethanol (0.58 g, 5 mmol). The reaction mixture was heated to 50 °C and stirred for 1.5 hours until no 4-chlorophenyl-thieno[2,3-d]pyrimidine was present by TLC. The reaction mixture was allowed to cool to room temperature before being poured over ice water (50:50 mix). The resultant precipitate was collected by filtration to give the product as a pale yellow solid (1.23 g, yield 90%). LCMS: RT = 4.05 min, M+1 = 326.
The following compounds were synthesised according to the method described using the appropriate ng materials: (4-flu0r0phenyl)thien0[2, 3-07pyrimidinyl]azabicyclo[3. I . 0]hexan-6—yl]methanol [I-[5-(4-nitr0pheny0thien0[2, 3-07pyrimidinyl]piperidyl]methanol [3-(5—phenylthien0[2, 3-d]pyrimidinyDazabicycl0[3. I. 0]hexan-6—yl]methan0l [I-[5-(3-flu0r0phenyl)thien0[2, 3-07pyrimidinyl]piperidyl]methanol [I-(5-ethylmethyl—thien0[2, 3-07pyrimidinyDpzperidyl]methanol [I-(6-is0pr0pylthien0[2, 3-07pyrimidinyDpzperidyl]methanol [I-(5—methylthien0[2, 3-d]pyrimidinyDpzperidyl]methanol [I-(5—phenylthien0[2, 3-d]pyrimidiny0azetidinyl]methanol [I-(5—phenylthien0[2, 3-d]pyrimidinpryrrolidinyl]methanol [I-(5—phenylthien0[2, 3-d]pyrimidinyDpzperidyl]methanol [5-phenyl—I-(5—phenylthien0[2, 3-d]pyrimidinpryrrolidinyl]methanol [5-methyl—I-(5—phenylthien0[2, 3-d]pyrimidinpryrrolidinyl]methanol [I-(5, 6-dimethylthien0[2, 3-07pyrimidinyDpzperidyl]methanol is0pr0pylthien0[2, 3-07pyrimidinyDpzperidyl]methanol [8-(5—phenylthien0[2, 3-d]pyrimidinyD-8—azabicycl0[3. 2. I]octanyl]methanol I-(5—phenylthien0[2, 3-d]pyrimidin-4—yl)pzperidin0Z I-(5—phenylthien0[2, 3-d]pyrimidin-4—yl)pzperidin0Z I-(5—phenylthien0[2, rimidiny0pyrr0lidin0l [3-[5-(4-flu0r0phenyl)thien0[2, 3-07pyrimidinyl]azabicyclo[3. I . 0]hexan-6—yl]methanol [(3R)-I-(5—phenylthien0[2, 3-d]pyrimidinpryrrolidinyl]methanol 2—(5—phenylthien0[2, 3-d]pyrimidinyD-2—azabicycl0[2. 2. I]heptan-5—01 yclohexylthien0[2, 3-d]pyrimidin-4—yl)-2—azabicyclo[2. 2. I]heptan-5—01 [(SS)-I-(5—phenylthien0[2, 3-d]pyrimidinyl)pyrrolidinyl]methanol [I-(5—methylthien0[2, 3-d]pyrimidinpryrrolidinyl]methanol ii) 4-(4-Bromomethyl-piperidin- l -yl)phenyl-thieno [2,3 -d]pyrimidine [4-(5-Phenyl-thieno[2,3-d]pyrimidinyl)-piperidinyl]-methanol (8 g, 24.6 mmol) and tetrabromomethane (12.2 g, 36.9 mmol) were dissolved in dry dichloromethane (40 ml) at 0 °C to give a yellow solution. To this was added nylphosphine (0.089 g, 0.338 mmol) in ns. The reaction mixture was cooled with ice before the brown solution was left to stir for 2.5 hours. After this there was no [4-(5-phenyl-thieno[2,3-d]pyrimidinyl)-piperidin WO 72694 yl]-methanol present by LCMS or TLC. The reaction mixture was d through silica before solvent was removed in vacuo to give a crude e (14.24 g). This was purified through a plug of silica, eluted with l ether before further purification by flash chromatography. The product was collected and concentrated to give a cream solid (7.63 g, yield 80%). LCMS: RT = 5.3min, M+1: 389.8.
The following compounds were synthesised according to the method described using the appropriate starting materials: 4—[3-(bromomethyD-I-piperidyl]-5—phenyl—thien0[2, 3-07pyrimidine 4—[3-(bromomethpryrrolidin-I-yl]-5—phenyl—thien0[2, 3-61]pyrimidine 4—[3-(bromomethyDazetidin-I-yl]-5—phenyl—thien0[2, 3-07pyrimidine 4—[4—(bromomethyl)-2—phenyl—pyrr0lidin-I-yl]-5—phenyl—thien0[2, 3-07pyrimidine 4—[4—(bromomethyD-I-piperidyl]-5, 6-dimethyl—thien0[2, 3-61]pyrimidine 4—[4—(bromomethyD-I-piperidyl]-5—is0pr0pyl—thien0[2, 3-61]pyrimidine 4—[3-(brom0methy0-8—azabicycl0[3. 2. I]octanyl]-5—phenyl—thien0[2, 3-07pyrimidine 4—[4—(bromomethyD-I-piperidyl]-5—methyl—thien0[2, 3-07pyrimidine 4—[3-(bromomethpryrrolidin-I-yl]-5—methyl—thien0[2, 3-61]pyrimidine iii) 2-(1-methylpyrrolidinyl)-N-[[l-(5-phenylthieno[2,3 -d]pyrimidinyl)piperidyl] methyl]ethanamine (Example 58) 4-[4-(Bromomethyl)-l-piperidyl]phenyl-thieno[2,3-d]pyrimidine (13.8 g, 35.5 mmol), 2- (1-methylpyrrolidin—2-yl)ethanamine (5.47 g, 42.6 mmol) and potassium ate (7.37 g, 53.3 mmol) were heated in acetonitrile (100 mL) in the microwave at 150°C for 30 s in 8 x 20 mL microwave vials. The reaction mixtures were combined and diluted with DCM (250 mL). The organic was washed with water (250 mL) and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of DCM to 1 DCM / MeOH / NH40H to afford the target nd (4.0 g) and mixed fractions. LCMS [M+H]+ = 436.0 Other compounds prepared by Method A as described for example (iii) using the appropriate starting materials are listed in TABLE 1.
Method B Synthesis of I-[4—[4—[[methyl-(I-methylpyrrolidin-S-yl)amin0]methyl]-I-piperidyl]-5— phenyl—thien0[2, 3-d]pyrimidin-Z-yl]pyrrolidinecarb0xamide (Example 120) i) [1-(2-chlorophenyl-thieno [2,3 -d]pyrimidinyl)piperidyl]methanol 4-Piperidinemethanol (987 mg, 8.57 mmol) was added to a stirred suspension of 2,4- dichlorophenyl-thieno[2,3-d]pyrimidine (2 g, 7.14 mmol) and ylamine (2.18 ml, .7 mmol) in dry ethanol (15 ml) at room temperature. Reaction was warmed to 40 0C and the resulting solution d for ~2h. Reaction was allowed to cool to room ature and poured onto ice/water (50 ml). The resulting suspension was d and the solid dried in a vacuum oven at 40 0C. The desired compound was obtained as a pale yellow solid (2.4 g, 93%). LCMS: (M+1) 360, RT = 4.69 min.
The following compounds were synthesised according to the method described using the appropriate starting materials: [I-(2—chlor0-5, 6-dimethyl—thien0[2, 3-07pyrimidin-4—yDpzperidyl]methanol [I-(2—chlor0-5—isopropyl—thien0[2, 3-07pyrimidin-4—y0-4—p1peridyl]methanol ii) 1-(2-chlorophenyl-thieno[2,3-d]pyrimidinyl)piperidinecarbaldehyde Pyridinium chlorochromate (898 mg, 4.17 mmol) was added to a stirred solution of [1-(2- chlorophenyl-thieno[2,3-d]pyrimidinyl)piperidyl]methanol (1 g, 2.78 mmol) in dry dichloromethane (15ml) at room temperature. The ing mixture was stirred for 2h and then eluted through a pad of silica (eluting ethyl acetate). The solvent was evaporated to give the 1-(2-chlorophenyl-thieno[2,3-d]pyrimidinyl)piperidinecarbaldehyde as a pale yellow solid (1 g, quantitative yield). Product was used in the subsequent reaction t further purification. LCMS: (M + H)+ 358, RT = 4.98 min.
The following compounds were synthesised according to the method described using the appropriate ng als: I—(2-ch10r0is0pr0pyl—thien0[2, 3-d]pyrl'midiny0pzperidinecarbaldehyde I—(2-ch10r0-5, 6-dimethyl—thien0[2, 3-d]pyrl'midiny0piperidinecarbaldehyde iii) N— [[ l -(2-chlorophenyl-thieno [2,3 -d]pyrimidinyl)piperidyl]methyl] -N, l - dimethyl-pyrrolidinamine Sodium triacetoxyborohydride (1.54 g, 7.28 mmol) was added to a stirred solution of l-(2- phenyl-thieno[2,3-d]pyrimidinyl)piperidinecarbaldehyde (1.3 g, 3.64 mmol), N, N’-dimethylaminopyrrolidine (519 ul, 4.00 mmol) and acetic acid (240 ul, 4.00 mmol) in dry dichloromethane (20 ml) at room temperature. The solution was stirred for ~2h, after which time the reaction had reached completion. Water (20 ml) was added and the organic layer separated, the aqueous phase was extracted with dichloromethane (x3) and the combined organics washed with brine, then dried (MgSO4) and ated. The crude residue was purified by flash column chromatography (0 to 5% 7.0M OH in dichloromethane). N— [[ l -(2-chloro-5 -phenyl-thieno [2,3 -d]pyrimidinyl) piperidyl]methyl] -N, l -dimethyl-pyrrolidin-3 -amine was isolated as a pale yellow oil (1.25 g, 76%). LCMS: (M + H)+ 456.2, RT = 2.99.
The following compounds were synthesised according to the method described using the appropriate starting als: [I-[[I-(Z-Chloro-5—phenyl—thien0[2, 3-d]pyrimidin-4—yl)-4— piperidyUmethylamin0]cyclopentyl]methanol N—[[I-(Z-Chloro-5—phenyl—thien0[2, 3-d]pyrimidin-4—yDpzperidyUmethyU-Z-(I- methylpyrrolidin-Z-yl)ethanamine N—[[I-(2—chlor0-5—phenyl—thien0[2, 3-07pyrimidin-4—yDpzperidyl]methyl]cyclobutanamine I-[[I-(Z-Chloro-5—phenyl—thien0[2, 3-d]pyrimidin-4—yl)-4—piperidyl]methyU-N,N—dimethyl— piperidin-S-amine iv) 1- [4- [4- [ l-( 1 -methylpyrrolidin-3 -yl)amino]methyl] - l idyl] phenyl- thieno[2,3-d]pyrimidinyl]pyrrolidinecarboxamide (Example 120) N— [[ l -(2-chlorophenyl-thieno [2,3 -d]pyrimidinyl)piperidyl]methyl] -N, l -dimethyl- pyrrolidinamine (100 mg, 0.219 mmol) and pyrrolidinecarboxamide (300 mg, 2.63 mmol) were stirred in dry acetonitrile (1.5 ml) and heated in a ave at 1400C for 0.5h.
The solvent was evaporated and the crude residue purified by flash column chromatography (0 to 5% 7.0M NH3/MCOH in dichloromethane) to give l-[4-[4-[[methyl-(l- methylpyrrolidin-3 -yl)amino]methyl] - l idyl] phenyl-thieno [2,3 -d]pyrimidin yl]pyrrolidinecarboxamide as an off white solid (25 mg, 21%). m/z (M + H)+ 534.3, RT = 2.69 min.
Other nds prepared by Method B as described for example (iV) using the appropriate starting materials are listed in TABLE 1.
Method C sis of N,N—dimethyl-5—phenyl—4—[4—(Z-pyrrolidih-I-yleth0xymethyl)cycl0hexyl] thieh0[2,3-d]pyrimidihecarb0xamide (Example 135) i) Methyl 5-phenyl [4-(2-pyrrolidin- l -ylethoxymethyl)- l -piperidyl]thieno [2,3 - d]pyrimidinecarboxylate To a stirred solution of methyl 4-chlorophenyl-thieno[2,3-d]pyrimidinecarboxylate (0.850 g, 2.80 mmol) in THF (50 mL), was added diisopropylethylamine (0.73 mL, 4.20 mmol) and 4-(2-pyrrolidin—l-ylethoxymethyl)piperidine (0.890 g, 4.20 mmol) in one portion, and the reaction left to stir at room temperature for 2 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The on was dried over sodium sulphate, d and concentrated under reduced pressure. The crude material was purified by column chromatography using DCM: MeOH (0-25%) as eluent to afford the named product (1.012 g, 75%). m/z [M+H]+ 481; RT = 3.03min.
The following compounds were synthesised according to the method described using the riate starting materials: methyl 5-is0pr0pyl—4—[4—(Z-pyrrolidih-I-ylethoxymethyl)-I-piperidyl]thieh0[2, 3-d] pyrimidine-(S-carboxylate methyl 5-phehyl[3- (Z-pyrrolidih-I-yleth0xymethyl)-8—azabicycl0[3. 2. hyl] thieho[2, 3-d]pyrimidihecarb0xylate methyl 5-phehyl[3- (Z-pyrrolidih-I-ylethoxymethyl)-8—azabicycl0[3. 2. I]octahyl] thieho[2, 3-d]pyrimidihecarb0xylate ii) N,N—dimethylphenyl [4-(2-pyrrolidin- l -ylethoxymethyl)cyclohexyl] thieno[2,3 - d]pyrimidinecarboxamide (Example 13 5) l 24 WO 72694 To a stirred on of methyl 5-phenyl[4-(2-pyrrolidin-l-ylethoxymethyl)-l- piperidyl]thieno[2,3-d]pyrimidinecarboxylate (0.200 g, 0.42 mmol) in DCM (4 mL) was added trimethylaluminium (0.63 mL, 1.26 mmol, 2M solution in hexane) and the reaction stirred at room temperature for 15 minutes. Dimethylamine (0.63 mL, 1.26 mmol, 2M solution in THF) was added and the reaction heated in a microwave at 100 0C for 2 hours.
The reaction was diluted with DCM (20 mL) and water (20 mL) and the organic phase separated. The aqueous phase was further extracted with DCM (2 x 10 mL) and the combined extracts dried over sodium te, filtered and concentrated under reduced pressure. The crude material was purified by high performance liquid chromatography and the pure fractions combined and evaporated under reduced pressure to afford the named product (0.044 g, 22%). m/z [M+H]+ 494; RT = 2.62 min.
Other compounds prepared by Method C as described for example (ii) using the appropriate starting materials are listed in TABLE 1.
Method D Synthesis of N—isopropyl—5—phenyl—4—[4— rolidin-I-ylethoxymethyD-I-piperidyl] thien0[2,3-d]pyrimidine—(S—carboxamide (Example 139) i) 5-phenyl [4-(2-pyrrolidin— l -ylethoxymethyl)- l -piperidyl]thieno [2,3 -d]pyrimidine- 6-carboxylic acid Lithium hydroxide monohydrate (0.08 g, 1.9 mmol) was added to a stirred solution of methyl 5-phenyl [4-(2-pyrrolidin- l -ylethoxymethyl)- l idyl]thieno [2,3 imidine- 6-carboxylate (0.44 g, 0.91 mmol) in THF (10 mL) and water (10 mL). The mixture was d for 2 hr. The organic t was evaporated and the remaining aqueous mixture was extracted with EtOAc (3 x 10 mL). The aqueous layer was ied (to pH 3) with concentrated hydrochloric acid and then extracted with DCM / MeOH 4:1 (3 x 25 mL). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give the target compound (0.08 g) as a light orange solid. m/z [M+H]+ 467.0. Retention time 2.80 min (LCMS method +ve 6 min).
The aqueous layer was evaporated to dryness. The residue was mixed with DCM and MeOH (l:l), sonicated and filtered. The filtrate was evaporated to give the target compound (424 mg) as a yellow solid.
The following compounds were synthesised according to the method described using the appropriate starting materials: -is0pr0pyl—4—[4—(Z-pyrrolidin-I-ylethoxymethyD-I-piperidylfihienop, 3-d]pyrimidine-6— ylic acid -phenyl—4—[3-(Z-pyrrolidin-I-yleth0xymethyD-8—azabicyclo[3. 2. I]octanyl]thien0[2, 3- midine-6—carb0xylic acid ii) N—isopropylphenyl [4-(2-pyrrolidin- l -ylethoxymethyl)- l -piperidyl] thieno [2,3 - d]pyrimidinecarboxamide (Example 139) A mixture of 5-phenyl[4-(2-pyrrolidin-l-ylethoxymethyl)-l-piperidyl]thieno[2,3- d]pyrimidinecarboxylic acid (70 mg, 0.15 mmol), HATU (l 14 mg, 0.30 mmol), isopropylamine (30 uL, 0.35 mmol) and triethylamine (63 uL, 0.45 mmol) in DMF (5 mL) was stirred at room temperature for 3 nights. The t was evaporated. The residue was ved in EtOAc (5 mL) and water (5 mL). The layers were separated and the aqueous was extracted with EtOAc (2 x 5 mL). The ed organic layers were dried (magnesium sulfate), filtered and evaporated to give a brown solid. This was d by preparative HPLC. ons containing target compound were combined and evaporated to give the target compound (24.3 mg) as a brown solid. m/z [M+H]+ 508; RT = 2.94 min.
Other compounds prepared by Method D as described for example (ii) using the appropriate starting materials are listed in TABLE 1.
Method E Synthesis of N—[5—phenyl—4-[4-(Z-pyrrolidin-I-ylethoxymethyD-I-piperidylfihienop, 3- d]pyrimidin-6—yl]acetamide (Example I 62) i) 6-bromophenyl [4-(2-pyrrolidin— l -ylethoxymethyl)- l -piperidyl]thieno [2,3 - d]pyrimidine To a stirred solution of 6-bromochlorophenyl-thieno[2,3-d]pyrimidine (0.820 g, 2.52 mmol) in THF (50 mL), was added diisopropylethylamine (0.65 mL, 3.78 mmol) and 4-(2-pyrrolidin—1-ylethoxymethyl)piperidine (0.801 g, 3.78 mmol) in one portion, and the reaction left to stir at room temperature overnight. The on was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The reaction was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using DCM: MeOH (0-25%) as eluent to afford the named product (0.828 g, 66%). ii) N—[5-phenyl pyrrolidinylethoxymethyl)piperidyl]thieno [2,3 - d]pyrimidinyl]acetamide (Example 162) To a stirred mixture of 6-bromophenyl[4-(2-pyrrolidinylethoxymethyl) piperidy1]thieno[2,3-d]pyrimidine (0.075 g, 0.15 mmol), cesium carbonate (0.102 g, 0.30 mmol), ide (0.019 g, 0.23 mmol), xantphos (0.014 g, 0.023 mmol) and tris(dibenzylideneacetone) dipalladium (0.007 g, 0.008 mmol) sealed in a microwave tube under an atmosphere of nitrogen, was added acetonitrile (2 mL) and 1,4-dioxane (2 mL).
The reaction was placed in a microwave reactor at 150 0C for 1 hour. The reaction was concentrated under reduced re, diluted with ethyl acetate (20 mL) and water (20 mL), the organic layer washed with brine, dried over sodium sulphate, filtered and concentrated under d pressure. The crude material was purified by high performance liquid chromatography and the pure fractions combined and evaporated under d pressure to afford the named product (0.012 g, 17%). LCMS [M+H]+ = 480; RT = 2.82 min.
Other nds prepared by Method E as described for example (ii) using the appropriate starting materials are listed in TABLE 1.
Method F 1) Synthesis of 5-phenyl—4—[4-(Z-pyrrolidin-I-ylethoxymethyD-I-pz'peridyUthienop,3- midine (Example 5) i) 5-phenyl [4-(2-pyrrolidin— 1 -ylethoxymethyl)piperidyl]thieno [2,3 -d]pyrimidine (Example 5) [1-(5-Phenylthieno[2,3-d]pyrimidinyl)piperidyl]methanol (100 mg, 0.31 mmol) was dissolved in ous DMF (2 mL) under a nitrogen atmosphere. Sodium hydride (50 mg, 1.25 mmol, 60% w/w dispersion in mineral oil) was added and the mixture was stirred for 5 min. 1-(2-Chloroethy1)-pyrrolidine hydrochloride (105 mg, 0.62 mmol) was added and the mixture was stirred for two nights. Further ns of sodium hydride (50 mg, 1.25 mmol, 60% w/w dispersion in mineral oil) and 1-(2-chloroethyl)-pyrrolidine hydrochloride (105 mg, 0.62 mmol) were added and the mixture was d overnight. It was d with MeOH and then concentrated. The residue was dissolved in EtOAc (5 mL) and water (5 mL). The layers were separated and the aqueous was extracted with EtOAc (2 x 5 mL). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give a brown oil. This was purified by LCUV (basic method F). Collected fractions were analysed by LCMS and fractions containing the target compound were combined and evaporated to give the target compound (62 mg) as a white solid. m/z [M+H]+ 423.0. RT = 3.20 min . 1H NMR (CDC13): 5 = 0.64 (2H, qd), 1.38 (2H, d), 1.44 - 1.80 (5H, m), 2.38 - 2.53 (6H, m), 2.57 (2H, t), 3.04 (2H, d), 3.42 (2H, t), 3.75 (2H, d), 7.14 (1H, s), 7.25 - 7.42 (5H, m), 8.51 (1H, s) Other compounds prepared by Method F as described for example (i) using the appropriate starting materials are listed in TABLE 1. 2) Synthesis 0f5-[2-[[2-(5-is0pr0pylthien0[2,3-d]pyrimidinyZ) azabicyclo[2.2. anyl]0xy]ethyl]0xaazabicyclo[2.2.1]heptane (Example 292) i) tert—butyl 5-(2-tetrahydropyranyloxyethoxy)azabicyclo[2.2.1]heptane carboxylate Tert-butylhydroxyazabicyclo[2.2.1]heptanecarboxylate (1.5 g, 7.0 mmol) and utylammonium bromide (0.35 g, 0.70 mmol) were stirred in sodium hydroxide (10 M) (30 mL, 1600 mmol) / toluene (30 mL) and heated to 60 °C. 2-(2- Bromoethoxy)tetrahydropyran (4.4 g, 21 mmol) was added in 4 portions over 2 hours and heating continued overnight. Further 2-(2-bromoethoxy)tetrahydropyran (1 eq) was added and the reaction heated for a further 3 hours. The reaction mixture was diluted with DCM, washed with water, dried over NaZSO4 and concentrated in vacuo to afford a yellow oil. The reaction e was purified by flash chromatography, g with DCM then 90/10 DCM/MeOH to afford tert-butyl(2-tetrahydropyranyloxyethoxy) azabicyclo[2.2.1]heptanecarboxylate (1.08 g). ii) 2-(2-azabicyclo[2.2.1]heptanyloxy)ethanol Tert-butyl(2-tetrahydropyranyloxyethoxy)azabicyclo [2 .2. 1]heptanecarboxylate (1.08 g, 3.16 mmol) was stirred overnight in 5 M hydrochloric acid (30 mL, 990 mmol) / THF (30 mL) . The reaction mixture was basified with NaOH and washed with DCM. The c was dried over NaZSO4 and concentrated in vacuo to afford 2-(2- azabicyclo[2.2.1]heptan—5-yloxy)ethanol (350 mg). LCMS RT = 0.57 min. M+1 = 158. iii) 2- [ [2-(5-isopropylthieno [2,3 -d]pyrimidinyl)azabicyclo [2 .2. 1 ]heptan—5 - yl]oxy] ethanol 4-Chloroisopropyl-thieno[2,3-d]pyrimidine (0.35 g, 1.6 mmol), 2-(2- azabicyclo[2.2.1]heptanyloxy)ethanol (0.39 g, 2.5 mmol), triethylamine (0.50 g, 0.70 mL, 4.9 mmol) and ethanol (3.95 g, 5 mL, 85.6 mmol) were combined and heated to 50 °C overnight. The reaction mixture was trated in vacuo. The resulting residue was taken up in DCM, washed with water, dried over NaZSO4 and concentrated in vacuo to afford 2- [ [2-(5-isopropylthieno [2,3 -d]pyrimidinyl)azabicyclo [2 .2. 1 ]heptan—5 - yl]oxy]ethanol (562 mg). LCMS RT: 3.47 min. M+1 = 334. iv) 2- [ [2-(5-isopropylthieno [2,3 -d]pyrimidinyl)azabicyclo [2 .2. 1 ]heptan—5 - yl]oxy] ethyl esulfonate 2-[[2-(5-Isopropylthieno[2,3-d]pyrimidinyl)azabicyclo[2.2. 1]heptanyl]oxy] l (0.56 g, 1.7 mmol) was stirred in DCM (13.25 g, 10 mL, 156.0 mmol) at 0°C. Triethylamine (0.52 g, 0.71 mL, 5.0 mmol) was added. Methanesulfonyl chloride (0.29 g, 0.20 mL, 2.5 mmol) was added dropwise and the reaction allowed to warm slowly to room temperature and stirred for 1 hour. The reaction mixture was diluted with DCM, washed with water, dried over NaZSO4 and concentrated in vacuo to afford 2-[[2-(5-isopropylthieno[2,3- d]pyrimidinyl)azabicyclo[2.2.l]heptanyl]oxy]ethyl methanesulfonate (0.747 g).
LCMS RT = 3.94 min. M+l = 412. (v) [2—(5-is0pr0pylthien0[2, 3-d]pyrimidin-4—yl)-2—azabicyclo[2. 2. I]heptan-5— yl]0xy]ethyl]-2—0xaazabicyclo[2.2. ne (Example 292) 2-[[2-(5-Isopropylthieno[2,3-d]pyrimidinyl)azabicyclo[2.2. l]heptanyl]oxy] ethyl methanesulfonate (0.11 g, 0.27 mmol), 2-oxaazabicyclo[2.2.l]heptane hydrochloride (0.072 g, 0.53 mmol) and potassium carbonate (0.11 g, 0.80 mmol) were combined in methyl ethyl ketone (2 mL) / DMF (1 mL, 12.8) and heated in the microwave for 30 minutes at 180 °C. The reaction mixture was diluted with DCM, washed with water, dried over NaZSO4 and concentrated at d pressure. The resulting residue was purified by basic prep HPLC (method 2) to afford 5-[2-[[2-(5-isopropylthieno[2,3-d]pyrimidinyl) azabicyclo[2.2.l]heptanyl]oxy]ethyl]oxa—5-azabicyclo[2.2.l]heptane as a colourless gum (20 mg). LCMS RT = 4.33 min. M+l = 415.
Other compounds prepared by Method F as described for example (V) using the appropriate ng materials are listed in TABLE 1.
Method G Synthesis 0f5—phenyl—2—[4— (Z-pyrrolidin-I-ylethoxymethyD-I-pz'peridyUthienop, 3- d]pyrimidine (Example 148) i) rophenyl-thieno[2,3-d]pyrimidine 2,4-Dichlorophenyl-thieno[2,3-d]pyrimidine (l g, 3.56 mmol) and zinc dust (2.34 g, 35.6 mmol) were combined and stirred in ethanol (10 mL). NH4OH (1 mL) was added and the on heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (50 mL) and filtered through celite. The filtrate was washed with water (100 mL), dried over NaZSO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of petroleum ether to
NZ626199A 2011-11-15 2012-11-15 Thieno- and furo - pyrimidines and pyridines, useful as potassium channel inhibitors NZ626199B2 (en)

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NZ626199B2 true NZ626199B2 (en) 2015-07-28

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