WO2011008597A1

WO2011008597A1 - Dihydroimidazoisoquinoline derivatives useful as pde10 inhibitors

Info

Publication number: WO2011008597A1
Application number: PCT/US2010/041122
Authority: WO
Inventors: Ginny D. Ho; William M. Seganish; Deen B. Tulshian; Cornelis Marius Timmers; Rachel Deborah Van Rijn; Hubert Jan Jozef Loozen
Original assignee: Schering Corporation; N. V. Organon
Priority date: 2009-07-14
Filing date: 2010-07-07
Publication date: 2011-01-20

Abstract

The present invention relates to dihydroimidazoisoquinolines and derivatives thereof, the use of the compounds as phosphodiesterase 10 (PDE10) inhibitors for the treatment of PDE10-modulated disorders, to pharmaceutical compositions comprising the compounds.

Description

DIHYDROIMIDAZOISOQUINOLINE DERIVATIVES

USEFUL AS PDElO INHIBITORS Field of the Invention

The present invention relates to dihydroimidazoisoquinoline derivatives, to the use of the compounds as phosphodiesterase 10 (PDElO) inhibitors for the treatment of PDElO- modulated disorders, and to pharmaceutical compositions comprising the compounds. Background of the Invention

PDElO is known to be a dual cAMP/cGMP phosphodiesterase; see, for example, Kehler et al, "The potential therapeutic use of phosphodiesterase 10 inhibitors", Expert Opin. Ther. Patents (2007) 17(2): 147-158.

PDElO is expressed at high levels in all striatal medium spiny neurons (MSNs), but is expressed at much lower or undetectable levels elsewhere in the brain and periphery. By increasing cAMP and cGMP levels in all striatal MSNs, PDElO inhibition will mimic D2 dopamine receptor antagonism in the indirect striatopallidal output pathway and will increase the activity of the direct striatonigral output pathway, thus more fully normalizing the reduced striatal output that characterizes schizophrenia. By increasing corticostriatal transmission, PDElO inhibition should improve the cognitive dysfunction that characterizes schizophrenia. Furthermore, the discrete localization of PDElO should lead to an improved side effect profile: typical side effects include extrapyramidal syndrome, diabetes, weight gain, hyperprolactinemia, sedation and QT_C prolongation.

PDElO inhibitors have also been reported to be useful in treating in other CNS (central nervous system) disorders such as psychosis, cognitive disorders (such as

Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome.

Papaverine has been identified as a PDElO inhibitor, and has been shown to be effective in animal models of schizophrenia.

8-Substituted triazolopyridine phosphodiesterase 4 inhbitors useful in the treatment of skin diseases are disclosed in WO 2008/125111. 6,7-Di-aryl/heteroaryl-substituted triazolopyridines are disclosed in US 2006/0287324. 6-Aminomethyl-substituted

triazolopyridines and derivatives thereof are disclosed in WO 2007/113226. Imidazo- and triazolopyridine keratin dyeing compounds are disclosed in US 2005/0229333. Imidazo- and triazolopyridines useful in treating diseases associated with 11-beta-hydroxysteroid dehydrogenase type I are disclosed in WO 2006/135795. Imidazopyridines having phosphatidylinositol 3 kinase inhibitory activity are disclosed in EP 1277754.

Pharmaceutically useful imidazoisoquinolines are disclosed in US Patent 6,159,985 and WO 00/69860.

Summary of the Invention

In its several embodiments, the present invention provides a novel class of substituted dihydroimidazoisoquinoline PDElO inhibitor compounds and derivatives thereof represented by Formula I, below, pharmaceutical compositions comprising one or more of said compounds of Formula I, and methods of treating PDElO inhibitor mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome using said compounds of Formula I or pharmaceutical compositions comprising it.

Novel compounds of Formula I of the invention have the structural formula:

or a pharmaceutically acceptable salt thereof, wherein

R¹ is R¹²-Ci_₆alkyl, C_3-10 cycloalkyl, C_1-6alkoxyalkyl-, -CF₃ or -SF₅;

R² is H, OH, alkoxy, Ci_₆alkoxyalkoxy, -OCF₃, -OSF₅, -O- C₃-iocycloalkyl, or -O(CH₂)_nR;

or -OR¹ and -R² together are -O-(CH₂)_P-O-, wherein p is 1 or 2, and form a ring with the carbon atoms to which they are attached;

n is 0, 1 or 2;

R³ is H, R¹²-Ci_₆alkyl, Ci_₆alkoxy, C₃_iocycloalkyl, Ci_₆alkoxyalkoxy, OH, -CF₃, - OCF₃, -SF₅, -OSF₅, halo, -O- C₃_i₀cycloalkyl, benzyloxy, -N(R¹⁰XR¹¹) or CN;

R⁴, and R⁵, R⁶, R⁷ are independently selected from the group consisting of H, R¹²- Ci_ βalkyl, R¹³- Cβ-ioaryl and R¹³- C₅_ioheteroaryl; or R⁴ and R⁵, together with the carbon atom to which they are attached, form a 3-6 membered carbocyclic ring; or R⁶ and R⁷, together with the carbon atom to which they are attached, form a 3-6 membered carbocyclic ring;

R⁸ is H, R¹²- Ci_₆alkyl, C₃-i₀cycloalkyl, Ci_₆alkoxy, Ci_₆alkoxyalkoxy, OH, -CF₃, - OCF₃, -SF₅, -OSF₅, halo, -O- C₃_i₀cycloalkyl, benzyloxy, -N(R¹⁷)₂, CN, R¹³-C₆_i₀aryl or R¹³- C₅_ioheteroaryl;

R⁹ is R¹²-Ci_₆alkyl, R¹²-C₃_i₀cycloalkyl, R¹³-C₆-i₀aryl, R¹³-C₅_i₀heteroaryl or

-N(R¹⁰XR¹¹);

R is selected from the group consisting of

R¹⁰ and R¹¹ are independently selected from the group consisting of H,

R¹²-Ci_₆alkyl, C₃_i₀cycloalkyl, C₃_i₀heterocycloalkyl or benzyl;

or R¹⁰ and R¹¹, together with the nitrogen to which they are attached, form a 5 to 7 membered ring, wherein one carbon ring member not adjacent to the nitrogen can optionally be replaced by -O-, -S- or -NR¹⁴-;

R¹² is 1 or 2 substituents independently selected from the group consisting of H, OH,

Ci_₆alkoxy, Ci_₆alkyl, Ci_₆alkyl-S-, Ci_₆alkyl-SO₂-, C₆-ioaryl, C₆-ioaryl-S0₂-, C₅_ioheteroaryl, - C(O)O-R¹⁴ and -C(O)N(R¹⁴)₂;

R¹³ is 1 or 2 substituents selected from the group consisting of H, halo, Ci_6alkyl, C₂. galkenyl, OH, hydroxyalkyl, Ci_₆alkoxy, CN, -CF₃, -OCF₃, -SF₅, -OSF₅, -N(R¹⁷)₂,

-aminobenzyl, - Ci_6alkyl-N(R¹⁰)(R^π), -C(O)N(R¹⁰)(R^π), -0-SO₂- Ci_₆alkyl, C₃_i₀cycloalkyl, (CH₂)_nC₃_ioheterocycloalkylR¹⁶, (CH₂)_nC₆-i₀arylR¹⁶, C₆-ioarylalkyl- and

(CH₂)_nC₅_ioheteroarylR¹⁶ when R¹³ is attached to a ring carbon atom, and when R¹³ is attached to a ring nitrogen, it is H, C^alkyl or benzyl;

each R¹⁴ is independently selected from the group consisting of H, Ci_₆alkyl, C₃. iocycloalkyl and Cβ-ioarylalkyl;

R¹⁵ is 1 or 2 substituents independently selected from the group consisting of H, halo, Ci_₆alkyl, Ci_₆alkoxy, -CF₃, C₃_iocycloalkyl, Ci_₆alkoxyalkoxy, OH, hydroxyalkyl, -OCF₃, -O- C₃_iocycloalkyl, benzyloxy, -C(O)O C_halky!, -O- Ci_₆alkyl-CO₂H, -C(O)N(R¹⁰)₂, - N(R¹⁰)₂, - Ci_₆alkyl-N(R¹⁰)₂, -NR¹⁰-C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)O Ci_₆alkyl, -N(R¹⁰)SO₂- C₁. ealkyl, phenyl, CN, -SF₅, -OSF₅, -SO₂R¹⁰, -SR¹⁰ and trimethylsilyl;

R¹⁶ is H, Ci_₆alkyl, Ci_₆alkoxy; and

each R¹⁷ is independently selected from the group consisting of H, d_₆alkyl, C₃. _locycloalkyl, C₃_ioheterocycloalkyl and benzyl.

The present invention also relates to a pharmaceutical composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof in a

pharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a method of treating PDElO mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment. In another embodiment, the invention relates to a method of treating PDElO mediated disorders, for example CNS disorders such as schizophrenia, psychosis, cognitive disorders (such as Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes and metabolic syndrome comprising administering to a mammal in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Detailed Description

In one embodiment of Formula I, R¹ is alkyl, preferably methyl.

In one embodiment of Formula I, R² is H, OH, alkoxy (preferably methoxy or ethoxy) or -O(CH₂)_nR, preferably -O-CH₂-quinolyl. More preferably, R² is methoxy.

In one embodiment of Formula I, -OR¹ and R² together form -0-CH₂-O-.

In one embodiment of Formula I, R³ is H or alkoxy (preferably methyoxy). More preferably, R³ is H.

In one embodiment of Formula I, R⁴, R⁵, R⁶ and R⁷ are independently H or alkyl; preferably R⁴, R⁵, R⁶ and R⁷ are each H.

In one embodiment of Formula I, R⁸ is H, alkyl or aryl; preferably, R⁸ is H, alkyl (preferably methyl) or phenyl; more preferably, R⁸ is H or methyl. In one embodiment of Formula I, R⁹ is R¹²-cycloalkyl, R¹³- Cβ-ioaryl or R¹³- C₅-ioheteroaryl, preferably R¹³- Cβ-ioaryl or R¹³- Cs-ioheteroaryl. A preferred R¹²- cycloalkyl group is cyclohexyl. Preferred R¹³- Cβ-ioaryl groups are R¹³-phenyl, wherein R¹³ is H, 1 or 2 alkoxy groups (preferably methoxy), 1 or 2 halo atoms, -OCF₃, -O-SO₂-alkyl (preferably -O-SO₂-methyl), Cs-ioheterocycloalkyl, (preferably

— N O — N NR 14

o^r N— f , wherein R¹⁴ is H or methyl), -N(R¹⁷)₂ (preferably

Preferred R¹³-heteroaryl groups are those wherein the heteroaryl portion is thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidinyl or quinolyl; more preferred heteroaryl groups are thiazolyl and pyridyl.

Preferred R¹³ substituents on the carbon atoms of the heteroaryl groups are H, 1 or 2 halo atoms, 1 or 2 alkyl groups (preferably methyl or ethyl), alkoxy (preferably methoxy), cycloalkyl (preferably cyclopropyl), CN, alkenyl (preferably vinyl), hydroxyalkyl (preferably hydroxymethyl), aryl (preferably phenyl),-aminobenzyl, heterocycloalkyl (preferably morpholinyl, pyrrolidinyl or piperidinyl), -alkyl-N(R¹⁰)(R^π) (preferably -CH₂-morpholinyl or -CH₂-homomorpholinyl), -C(O)N(R¹^(R¹¹) (preferably -C(O)-N(alkyl)₂, -C(O)- morpholinyl,

heteroaryl (wherein heteroaryl is preferably pyridyl, imidazolyl, pyrimidinyl or indolyl). Preferred R¹³ substituents on the nitrogen atoms of the heteroaryl groups (e.g., imidazolyl) are H, methyl and benzyl, more preferably H.

When R⁹ is R¹³-thiazolyl, preferred R¹³ substituents are H, 1 or 2 halo atoms, hydroxyalkyl (preferably hydroxymethyl), aryl (preferably phenyl), C₃_ioheterocycloalkyl, (preferably morpholinyl), -alkyl-N(R¹⁰)(R^π) (preferably -CH₂-morpholinyl or -CH₂- homomorpholinyl), -C(O)N(R¹^(R¹¹) (preferably -C(O)-N(alkyl)₂, -C(O)-morpholinyl, - C(O)-homomorpholinyl, -C(O)NH-benzyl or

When R⁹ is R¹³-pyridyl, preferred R¹³ substituents are H, 1 or 2 halo atoms, 1 or 2 alkyl groups (preferably methyl or ethyl), alkoxy (preferably methoxy), cycloalkyl

(preferably cyclopropyl), CN, alkenyl (preferably vinyl), aryl (preferably phenyl), -aminobenzyl, heterocycloalkyl (preferably morpholinyl, pyrrolidinyl or piperidinyl), or R¹⁶-heteroaryl (wherein heteroaryl is preferably pyridyl, imidazolyl, pyrimidyl or indolyl).

In one embodiment of Formula I, R¹ is alkyl; R² is H, OH, alkoxy or

-O(CH₂)_nR, or -OR¹ and R² together form -0-CH₂-O-; R³ is H or alkoxy; R⁴, R⁵, R⁶ and R⁷ are independently H or alkyl; and R⁸ is H, alkyl or aryl.

In another embodiment of Formula I, R¹ is alkyl; R² is alkoxy; R³ is H; R⁴, R⁵, R⁶ and R⁷ are independently H or alkyl; and R⁸ is H or alkyl.

In one embodiment of Formula I, R¹ is alkyl, preferably methyl; R² is alkoxy

(preferably methoxy or ethoxy); R³ is H or alkoxy (preferably methoxy); R⁴, R⁵, R⁶ and R⁷ are independently H or alkyl, preferably H; and R⁸ is H or alkyl, preferably H or methyl. For compounds in this embodiment, R⁹ is preferably R¹³-phenyl; or R¹³-heteroaryl, wherein heteroaryl is preferably thiazolyl or pyridyl; preferred R¹³ substituents are H, 1 or 2 halo atoms, 1 or 2 alkyl groups (preferably methyl or ethyl), alkoxy (preferably methoxy), cycloalkyl (preferably cyclopropyl), CN, alkenyl (preferably vinyl), hydroxyalkyl (preferably hydroxymethyl), aryl (preferably phenyl), -aminobenzyl, heterocycloalkyl (preferably morpholinyl, pyrrolidinyl or piperidinyl), -alkyl-N(R¹⁰)(R^π) (preferably -CH₂-morpholinyl or -CH₂-homomorpholinyl), -C(O)N(R¹^(R¹¹) (preferably -C(O)-N(alkyl)₂, -C(O)- morpholinyl, -C(O)-homomorpholinyl, -C(O)NH-benzyl or

or R¹ - C₅- ioheteroaryl (wherein heteroaryl is preferably pyridyl, imidazolyl, pyrimidyl or indolyl).

Another embodiment of the invention is represented by compounds of Formula 1-1

wherein R¹ is methyl, R² is methoxy, R³ to R⁷ are H, R⁹ is shown by the structure, and R⁸ is as defined:

R⁸=H R⁸=H R⁸= H

R⁸=CH₃ R⁸=CH₃ R⁸=CH₃

R^B=H R⁸= H R^b=H R⁸= H R⁸=H R⁸=H R⁸=H

/ Ni _r-S n

R⁸=H Preferred compounds of Formula I are those in Examples IA, IB, ID, IE, IH, IN, IP, IQ, IR, IS, IU, IW, IY, IAA, ICC, IFF, IHH, HA, HC, HD, HE, HF, HG, HH, IU, HK, HL, HM, UN, HQ, HR, IIS, IIIA, IIIB, IUC, HID, HIE, IVA, IVB, IVC, IVD, VD, VIA, VIB, VIC, VID, VIE, VIF, VIIA, VIIB, VIIC, VIID, VIIE, VIIF, IX, X, XI, XII, XIV, XXII, XXIII, and XXIV.

More preferred compounds of Formula I are those in Examples ID, IP, IW, ICC, IFF, HD, HG, IU, HL, HQ, HR, IIIB, IUC, HID, IVD, VIA, VIB, VIC, VID, VIE, VIIA, VIIC, VIID, VIIE, XXII, and XXIV. As used herein, the following terms are as defined below unless otherwise indicated:

Mammal means humans and other mammalian animals.

The following definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Therefore, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl", "haloalkyl", "alkoxy", etc.

Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.

Hydroxyalkyl represents an alkyl group as defined substituted by 1 to 3 hydroxy groups. The bond to the parent is through the alkyl group.

Alkoxy means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

Halogen represents fluoro, chloro, bromo and iodo.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "isolated" or "in isolated form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 3 to about 7 carbon atoms. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantly and the like.

"Heterocycloalkyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocycloalkyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocycloalkyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any - NH in a heterocycloalkyls ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. The heterocycloalkyl ring can be joined to the parent moiety by a ring carbon atom or a ring nitrogen atom. Non-limiting examples of suitable monocyclic heterocycloalkyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl,

tetrahydrothiophenyl, lactam, lactone, and the like.

"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N- substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,

benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

When R⁴ and R⁵, or R⁶ and R⁷, together with the carbons to which they are attached form a 3-6 membered carbocyclic ring, the resultant spirocyclic rings are shown in the following partial structures:

It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl, halo, amino or thio groups on ring carbon atoms adjacent to a N, O or S. Thus, for example, in the ring:

there is no -OH, halo, amino or thio attached directly to carbons marked 2 and 5. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

When any variable (e.g., alkyl, halo, etc.) occurs more than one time in any constituent or in Formula I or II, its definition on each occurrence is independent of its definition at every other occurrence.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Prodrugs, solvates and co-crystals of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 1_4 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.

"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H₂O.

A co-crystal is a crystalline superstructure formed by combining an active

pharmaceutical intermediate with an inert molecule that produces crystallinity to the combined form. Co-crystals are often made between a dicarboxlyic acid such as fumaric acid, succinic acid etc. and a basic amine such as the one represented by compound I or II of this invention in different proportions depending on the nature of the co-crystal. (Rmenar, J. F. et. al. JAm. Chem. Soc. 2003, 125, 8456).

"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective as PDElO inhibitors and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,

benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,

methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry ( 1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen- containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Compounds of Formula I, and salts, solvates, co-crystals and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, co-crystals and prodrugs of the compounds as well as the salts and solvates, co-crystals of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected,

stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of Formula I. Isomers may also include geometric isomers, e.g., when a double bond is present.

Those skilled in the art will appreciate that for some of the compounds of Formula I, one isomer will show greater pharmacological activity than other isomers. Polymorphic forms of the compounds of Formula I, and of the salts, solvates, co- crystals and prodrugs of the compounds of Formula I, are intended to be included in the present invention.

In this specification, the term "at least one compound of Formula I" means that one to three different compounds of Formula I may be used in a pharmaceutical composition or method of treatment. Preferably one compound of Formula I is used.

The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formula I (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non- isotopically labelled reagent. Compounds of Formula I are prepared by methods known in the art. Typical procedures for preparing the compounds are shown in reaction Schemes 1 and 2; in the schemes, the exemplified compound of Formula I is that wherein R¹ is methyl, R² is methoxy, R³-R⁷ are H and R⁸ is H (Scheme 1) or methyl (Scheme 2). Scheme 1

Scheme 2

Compounds of Formula I can be converted into other compounds of Formula I using methods well known in the art. For examples, see preparative Examples III to XIII, wherein substituents on the R⁹ variable added or converted to different substituents.

In the scheme above and in the following preparative examples, the following abbreviations are used: RT - room temperature; Ac - acetyl; Me - methyl; Et - ethyl; Ph - phenyl; i-Pr - isopropyl; t-Bu - t-butyl; Ts - tosyl; t-Boc - N-tert-butoxycarbonyl; BINAP - 2,2 ' -bis(diphenylphosphino)- 1 , 1 'binaphthyl; m-CPBA - m-chloroperoxybenzoic acid; DEAD - diethyl azodicarboxylate; DBU - l,8-diazabicyclo[5.4.0]undec-7-ene; DMF - dimethylformamide; EDC - l-(3-dimethylaminopropyl)-3-ethylcarbodiimide; HOBT - 1- hydroxybenzotriazole hydrate; THF - tetrahydrofuran; TFA - trifluoroacetic acid; TLC - thin layer chromatography; DIPEA - diisopropylethylamine; KHMDS - potassium bis(trimethylsilyl)amide; MSA - methane sulfonic acid; HATU - O-(7-azabenzotriazol-l- yl)-Λ/,Λ/,Λf',Λf'-tetramethyluronium hexafluorophosphate; PPTS - pyridinium/?- toluenesulfonate; DCM - dichloromethane; DCE - 1,2-dichloroethane.

Where LC/MS data are presented, analyses were performed using an Applied Biosystems API-150 mass spectrometer and Shimadzu SCL-IOA LC system. Column: Phenomenex Gemini C 18, 5 micron, 50 mm x 4.6 mm ID; Gradient: From 90% water, 10% CH₃CN and 0.05%TFA, 5 min to 5% water, 95% CH₃CN, 0.05% TFA in 5 minutes. MS data were obtained using Agilent Technologies LC/MSD SL or 1100 series LC/MSD mass spectrometer. Retention times refer to Total Ion Current (TIC) unless uv is indicated.

Following are examples of the preparation of intermediates and compounds of Formula I.

Example I

1 2

2-(3,4-Dimethoxy-phenyl)-ethylamine (18 g) was dissolved in 150 mL of ethyl formate and heated to 70 ⁰C for 18 h. The reaction mixture was concentrated in vacuo to afford the desired formamide product 2 (21 g) which was used directly in the next step without further purification.

Formamide 2 (21 g) was dissolved in dry THF 140 (mL) and cooled to 0 ⁰C. Et₃N (70 mL) was added, followed by POCl₃ (10.2 mL in 25 mL of THF) dropwise over 10 min. The reaction was stirred at 0 ⁰C for 1 h. Ice water (500 mL) was added and the reaction was stirred for 10 min. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄) and evaporated. The oily residue was purified via column chromatography (25-50% EtOAc/hexanes) to give a colorless oil (17 g), which solidified on standing to a white solid. MS (ESI) 192 (M+H).

Step 3:

Ammonium formate (8.75 g), thiazole-5-carbaldehyde (5.23 g), and isonitrile 3 (12.0 g) were dissolved in MeOH (100 mL) and heated to reflux for 4 h. The solution was concentrated to approximately 20 mL of MeOH and EtOAc (200 mL) was added. The mixture was filtered and the solvent evaporated to yield a light brown solid. Trituration with ether provided a white solid (5.70 g), which was used without further purification in the following step. MS (ESI) 350 (M+H).

P2O5 (40.7 g) was added to a clear solution of MSA (160 mL). The mixture was heated to 75 ⁰C for 45 min, at which point most of the P2O5 had dissolved. Formamide 4 (5.56 g) was added as a solid in one portion. The resulting brown solution was stirred at 75 ⁰C for 1 h to consume all of the formamide. The solution was allowed to cool to ambient temperature and then slowly poured onto solid NaHCO₃ (400 g). Ice water was added and the aqueous suspension was extracted with EtOAc. The combined organic layers were dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-5% MeOH/DCM) to give I-A as a white solid (3.50 g). LCMS (ESI) 1.85 min (314, M+H).

The following compounds in Table I were prepared in a similar manner:

Example II

Ammonium acetate (3.01 g) and thiazole-5-carbaldehyde (1.59 g), were dissolved in 34 mL of trifluroethanol. The reaction was heated at 60 ⁰C for 30 min. Isonitrile 3 (3.35 g) was added in one portion, and the reaction was stirred at 60 ⁰C for 4 h. The solution was allowed to cool to ambient temperature, the solvent evaporated, and the residue dissolved in EtOAc and filtered. The EtOAc was removed in vacuo and the residue purified via column chromatography (0-50% acetone/hexane) to provide formamide 5 (1.10 g). MS (ESI) 364 (M+H).

Step 2:

P2O5 (5.5 g) was added to a clear solution of MSA (22 mL). The mixture was heated to 75 ⁰C for 30 min, at which point most of the P2O5 had dissolved. Formamide 5 (790 mg) was added as a solid in one portion. The resulting brown solution was stirred at 75 ⁰C for 3 h to consume all of the formamide. The solution was allowed to cool to ambient temperature and then slowly poured onto solid NaHCOs (65 g). Ice water was added and the aqueous suspension was extracted with EtOAc. The combined organic layers were dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-5% MeOH/DCM) to give H-A as a white solid (230 mg). LCMS (ESI) 2.06 min (328, M+H).

The following compounds in Table II were prepared in a similar manner:

Example III

I-A 6 6a

Compound I-A (100 mg) was dissolved in 3 niL of THF and cooled to -78 ⁰C. To this solution was added 200 μL of n-BuLi (2.5 M in hexanes). The reaction was stirred for 15 min at -78 ⁰C and was poured onto CO₂ pellets. After stirring for 10 min, the solvent was removed in vacuo to provide a mixture of 6 and 6a which was used without further purification in the next step.

Step 2:

Acid 6 from Step 1 (above) was dissolved in 5 mL of DMF. To this solution was added 100 μL of 4-ethylmorpholine, 130 μL of tert-hvXy\ methyl amine, 35 mg of HOBt and 120 mg of HATU. The reaction was stirred for 2 h at ambient temperature to consume all of the starting material (TLC). The reaction was diluted with water and extracted with EtOAc. The combined organic layers were dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-5% MeOH/DCM) to give IH-A (LCMS (ESI) 2.29 min (427, M+H)) and HIF (LCMS (ESI) 3.45 min (540, M+H)).

The following compounds in Table III were prepared in a similar manner:

Example IV

IV-A

IV-A

Bromide H-H (150 mg), and 3-pyridine boronic acid (92 mg) were dissolved in toluene (4 rnL) and MeOH (1.2 rnL). A 2 M aqueous solution OfK₂COs was added and the mixture was degassed with argon. Pd(PPtLs)₄ was added in one portion and the reaction was sealed and heated to 100 ⁰C for 4 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water. The solution was dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-5% MeOH- NHs/DCM) to give IV-A as a white solid (133 mg). LCMS (ESI) 2.35 min (399, M+H).

The following compounds in Table IV were prepared in a similar manner:

Example V

V-A

V-A

Bromide H-H (150 mg), Pd(OAc)₂ (8.4 mg) BINAP (14 mg) and ΦuONa (50 mg) were placed in a vial and purged with nitrogen. Toluene (2.5 rnL) was added, followed by pyrrolidine (48 μL). The reaction was sealed and heated to 100 ⁰C for 18 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water. The solution was dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-5% MeOH-NH₃/DCM) to give

V-A as a white solid (123 mg). LCMS (ESI) 2.11 min (391, M+H).

The following compounds in Table V were prepared in a similar manner:

Example VI

Example VI-A was prepared according to the procedure outlined for Example IV-A above except that bromide H-J was used in place of bromide H-H. The crude reaction residue was purified via column chromatography (0-5% MeOH-NH₃/DCM) to give VI-A as a white solid. LCMS (ESI) 2.75 min (399, M+H).

The following compounds in Table VI were prepared in a similar manner:

Example VII-A was prepared according to the procedure outlined for Example V-A above with the exception that bromide H-J was used in place of bromide H-H. The crude reaction residue was purified via column chromatography (0-5% Me0H-NH₃/DCM) to give VII-A as a white solid. LCMS (ESI) 1.48 min (391, M+H).

The following compounds in Table VII were prepared in the similar manner:

Example VIII

VIII

Bromide H-H (300 mg), Pd(PPh₃)₄ (87 mg), and Zn(CN)₂ (88 mg) were placed in a vial and purged with nitrogen. DMF (2.5 mL) was added and the reaction was sealed and heated to 80 ⁰C for 18 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water. The solution was dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-10% MeOH/DCM) to give VIII as a white solid (259 mg). LCMS (ESI) 2.99 min (347, M+H).

Example IX

IX

Example IX was prepared according to the procedure outlined for Example VIII above except that bromide H-J (300 mg) was used in place of bromide H-H. The crude reaction residue was purified via column chromatography (0-10% MeOH-NHs/DCM) to give IX as a white solid (240 mg). LCMS (ESI) 2.84 min (347, M+H).

Example X

Bromide H-H (200 mg) was placed in a vial and purged with nitrogen. DMF (2.5 mL) was added, followed by vinyl tributyltin (365 μL) and the solution was degassed with argon. Pd(PPtLs)₄ (58 mg) was added and the reaction was sealed and heated to 100 ⁰C for 5 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water. The solution was dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-5% MeOH/DCM) to give Example X as a white solid (139 mg). LCMS (ESI) 1.56 min (348, M+H).

Example XI

Xl

Example XI was prepared according to the procedure outlined for Example X above except that bromide H-J (200 mg) was used in place of bromide H-H. The crude reaction residue was purified via column chromatography (0-5% MeOH-NHs/DCM) to give XI as a white solid (140 mg). LCMS (ESI) 1.55 min (348, M+H).

Example XII

XII

Alkene X (50 mg) was dissolved in 5 mL of EtOH. Pd/C (10% Pd, 30 mg) was added and the reaction mixture was placed under a hydrogen atmosphere. Hydrogenation continued under balloon pressure for 12 h at ambient temperature. The mixture was filtered through celite and the solvent evaporated to give Example XII as a white solid (50 mg). LCMS (ESI) 1.95 min (350, M+H).

Example XIII

Xl XIII

Example XIII was prepared according to the procedure outlined for Example XII above except that alkene XI (50 mg) was used in place of alkene X. The reaction mixture was filtered through celite and the solvent evaporated to give Example XIII as a white solid (50 mg). LCMS (ESI) 2.55 min (350, M+H).

Example XIV

XIV

JV-Bromosuccinamide (NBS) (38 g) was added to a cool (0 ⁰C) solution of dimethoxyphenyl ethanol (7) (39 g) in DMF (800 mL). The red solution was allowed to warm to ambient temperature over 3 h. The solution was poured into water and extracted with EtOAc. The combined organic extracts were washed with sodium thiosulfate (aq), NaHCO₃ (aq), and brine. The organic solution was dried (MgSO₄) and evaporated to give bromide 8 (56 g) as an orange oil that was used without further purification in the next step.

Step 2:

Bromide 8 (56 g) was dissolved in DCM (250 mL). Dihydropyran (DHP) (29 mL) was added, followed by/?-toluene sulfonic acid (5.4 g). The solution was stirred at ambient temperature for 18 h. The solution was washed with water, NaHCO₃ (aq), and brine. The organic solution was dried (MgSO₄) and evaporated to give THP ether 9 (73 g) as a red oil that was used without further purification in the next step.

Step 3:

THP ether 9 (73 g) was dissolved in dry THF (700 mL). The solution was cooled to - 78 ⁰C and stirred at -78 ⁰C for 20 min. A solution of nBuLi in hexanes (2.5 M, 127 mL) was added slowly. After the addition was complete, the reaction was allowed to stir at -78 ⁰C for 30 min. B(OMe)₃ (35 mL) was added and the reaction was allowed to warm to ambient temperature over 2 h. IM HCl (600 mL) was added and the reaction vigorously stirred overnight. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were evaporated to a brown oil, and re-dissolved in DCM. The organic layer was extracted twice with 1 M NaOH. The combined aqueous layers were washed once with ether, and then acidified with concentrated HCl. The aqueous mixture was extracted with DCM. The combined organic extracts were dried (MgSO₄) and evaporated give boronic acid 10 as a light yellow solid (35 g). The boronic acid was used in Step 4 without any further purification.

Boronic acid 10 (33 g) and bromide 11 (28 g) were placed in a flask. Toluene (960 mL) and MeOH (280 mL) were added, followed by 96 mL of 2 M K₂CO₃ (aq). The solution was degassed with argon. Pd(PPh₃)₄ (5.6 g) was added and the reaction was refluxed for 18 h. After cooling to ambient temperature, the reaction mixture was extracted with EtOAc. The organic solution was dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-5% MeOH-NH₃ZDCM) to give imidazole-aryl 12 as a white solid (28 g). LCMS (ESI) 2.55 min (393, M+H).

Imidazole-aryl 12 (28 g) was dissolved in EtOH (100 mL). 4 M HCl (100 mL) was added and the reaction was heated to reflux for 18 h. The solvents were evaporated, and the residue dissolved in a 50/50 mixture of sat. NaHCO₃ (aq) and DCM. The aqueous layer was extracted with DCM, dried (MgSO₄), and evaporated to give compound 13 as a white solid (19 g). LCMS (ESI) 1.38 min (263, M+H).

Step 6:

Alcohol 13 (19 g) was dissolved in DCM (75 mL) and cooled to 0 ⁰C. Et₃N (28 mL) and DMAP (1.5 g) were added, followed by/?-toluenesulfonyl chloride (TsCl) (35 g). The reaction was allowed to slowly warm to RT over 2 h. The reaction was cooled to 0 ⁰C again and water (50 mL) was added and the reaction was vigorously stirred for 1 h at 0 ⁰C. The layers were separated, and the aqueous layer was extracted with DCM. The combine organic extracts were evaporated and dissolved in acetone (75 mL) and IM NaOH (100 mL) and stirred at ambient temperature overnight. The solution was extracted with DCM, the combined organic extracts were dried (MgSO₄), and evaporated. The residue was purified via column chromatography (0-5% MeOH-NH₃ZDCM) to give cyclized compound 14 as a white solid (11 g). LCMS (ESI) 2.89 min (245, M+H).

Step 7:

Cyclized compound 14 (11 g) was dissolved in DMF (250 niL) and cooled to 0 °C. NBS (8.8 g) was added in one portion and the reaction was stirred at 0 ⁰C for 2 h. The reaction was diluted with EtOAc and washed with water. The organic phase was dried (MgSO₄), and evaporated. The residue was purified via column chromatography (0-10% MeOH/DCM) to give bromide 15 as a white solid (14 g). LCMS (ESI) 2.78 min (338, M+H). Step 8:

XIV

Bromide 15 (90 mg), and 5-pyrmidine boronic acid (70 mg) were dissolved in toluene (4 mL) and MeOH (800 μL). A 2 M aqueous solution Of K₂CO₃ (300 μL) was added and the mixture was degassed with argon. Pd(PPtLs)₄ (32 mg) was added in one portion and the reaction was sealed and heated to 100 ⁰C for 4 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water. The solution was dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-10% MeOH/DCM) to give XIV as a white solid (63 mg). LCMS (ESI) 1.97 min (323, M+H).

Compound XV was synthesized using a similar procedure to Example XIV, except the substrate alcohol for Step 1 (above) was 2-(4-ethoxy-3-methoxy-phenyl)-ethanol instead of 2-(3,4-dimethoxy-phenyl)-ethanol (7). LCMS (ESI) 2.02 min (336, M+H).

Example XVI

Compound XV (20 mg) was dissolved in 150 μL of concentrated H₂SO₄. The red solution was heated to 65 ⁰C for 1 h to consume all of the starting material. After cooling to ambient temperature, the reaction mixture was poured into NaHCO₃ (aq) and extracted with DCM. The organic extracts were dried (MgSO₄) and evaporated to give XVI as a white solid (18 mg). LCMS (ESI) 2.59 min (308, M+H).

Example XVII

XVI XVI l

Compound XVI (35 mg), PPh₃ (30 mg), and quinolin-2-yl-methanol (18 mg) were placed in a vial and the vial was purged with nitrogen. THF (700 μL) was added and the reaction was cooled to 0 ⁰C. DEAD (20 mg) in 100 μL of THF was added dropwise and the reaction allowed to stir at ambient temperature for 18 h. The solvent was evaporated and the residue purified via column chromatography (0-10% MeOH-NH₃ZDCM) to give XVII as a white solid (34 mg). LCMS (ESI) 3.09 min (449, M+H).

Example XVIII

Example XVIII was prepared according to the general procedure outlined for Example II, except 3-(3-methoxy-phenyl)-propionitrile was used in place of 3-(3,4- dimethoxy-phenyl)-propionitrile (3). LCMS (ESI) 2.05 min (292, M+H).

Example XIX

Example XIX was prepared according to the general procedure outlined for Example II, except 3-benzo[l,3]dioxol-5-yl-propionitrile was used in place of 3-(3,4-dimethoxy- phenyl)-propionitrile (3). LCMS (ESI) 2.01 min (306, M+H).

Example XX

Benzyl imidazole H-B (327 mg) and ammonium formate (515 mg) were dissolved in MeOH. Pd/C (10% Pd, 20 mg) was added and the mixture heated at reflux for 2 h. After cooling to ambient temperature, the reaction mixture was filtered through celite. The solvent was evaporated, and the residue dissolved in DCM. The organic layer was washed with sat. NaHCO₃ (aq). The organic solution was dried (MgSO₄) and evaporated to give imidazole XX as a white solid (253 mg). LCMS (ESI) 0.96, 1.55 min (311, M+H).

Example XXI

XXI

Example XXI was prepared according to the general procedure outlined for Example II, except ammonium benzoate was used in place of ammonium acetate. LCMS (ESI) 2.47 min (384, M+H).

Example XXII and Example XXIII

Compound I-A (932 mg) was dissolved in dry THF (25 mL) and cooled to -78 ⁰C. A solution of n-BuLi in hexanes (1.49 mL, 2 M) was added dropwise and the reaction was stirred for 30 min. DMF (2.78 mL) was added dropwise and the reaction was allowed to warm to RT overnight. Ice water was added, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with sat. NH₄Cl, brine, and were dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-10% acetone/DCM) to give the desired aldehyde 21 which was used without further purification in the next step.

Step 2:

Aldehyde 21 (305 mg), morpholine (117 mg), and NaBH(OAc)₃ (492 mg) were placed into a flask and AcOH (76 μL) and DCE (7 mL) were added. The reaction was stirred at ambient temperature 18 h. The reaction mixture was diluted with DCM and washed with 10% Na₂CO₃ and brine. The organic solution was dried (MgSO₄) and evaporated. The residue was purified via column chromatography (0-60% acetone/DCM) to provide a mixture of Example XXII (LCMS (ESI) 0.93, 1.74 min (413, M+H)) and Example XXIII (LCMS (ESI) 1.07, 1.93 min (344, M+H)).

The following compound was prepared in a similar manner:

LCMS (ESI) 1.05, 1.75 min (427, M+H)

The amount and frequency of administration of the active compound employed and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient. A typical recommended dosage regimen can range from about 10 mg/dose to about 100 mg/dose, preferably about 10 to about 50 mg/dose, and more preferably about 20 to about 25 mg/dose.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and

suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of

pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), The Science and Practice of Pharmacy, 20^th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifϊers for oral solutions, suspensions and emulsions.

Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.

The activity of the compounds of Formula I can be determined by the following procedures.

In Vitro PDElO assay

PDElOAl activity was measured in white opaque 384-well Opti-Plates (Perkin Elmer

Life Sciences) using a scintillation proximity assay (GE Healthcare). Human recombinant PDElOAl was purchased from BPS Bioscience, Inc. The reaction mixture contained PDElOAl ( 0.02 nM), 10 nM [³H]cAMP ([5 ',8-³H] Adenosine 3 ',5 '-cyclic phosphate, ammonium salt], Amersham) and various concentrations of compound in 50 mM Tris-HCl, pH 7.5, 8.3 mM MgCl₂, 17 mM EGTA and 0.2% bovine serum albumen in a total volume of 30 1. The assay was initiated with the addition of substrate and was allowed to proceed for 30 minutes at room temperature before being stopped by the addition of 300 g yttrium SPA PDE beads. The reaction mixtures were thoroughly mixed, and the beads were allowed to settle for 30 minutes. The plates were then counted in a TopCount scintillation counter.

Under these conditions, less than 30% of the substrate was hydro lyzed in the absence of compound. Ki values were determined as described by Cheng and Prusoff (1973).

Using the test procedures described above, the following compounds of Formula I were found to have Ki values of less than 50 nM: Examples IA, IB, ID, IE, IH, IN, IP, IQ, IR,

IS, IU, IW, IY, IAA, ICC, IFF, IHH, HA, HC, HD, HE, HF, HG, HH, IU, HK, HL, HM, UN,

HQ, HR, IIS, IIIA, IIIB, IIIC, HID, HIE, IVA, IVB, IVC, IVD, VD, VIA, VIB, VIC, VID,

VIE, VIF, VIIA, VIIB, VIIC, VIID, VIIE, VIIF, IX, X, XI, XII, XIV, XXII, XXIII, and

XXIV.

The following compounds of Formula I were found to have Ki values of less than 10 nM: Examples ID, IP, IW, ICC, IFF, HD, HG, IU, HL, HQ, HR, IIIB, IIIC, HID, IVD, VIA,

VIB, VIC, VID, VIE, VIIA, VIIC, VIID, VIIE, XXII, and XXIV.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein

R¹ is R¹²-Ci_₆alkyl, C_3-1O cycloalkyl, Ci_₆alkoxyalkyl-, -CF₃ Or -SF₅;

R² is H, OH, alkoxy, C_1-6alkoxyalkoxy, -OCF₃, -OSF₅, -O- C₃_i₀cycloalkyl, or -0(CH₂)_nR;

or -OR¹ and -R² together are -0-(CH₂)_p-0-, wherein p is 1 or 2, and form a ring with the carbon atoms to which they are attached;

n is O, 1 or 2;

R⁸ is H, R¹²- Ci_₆alkyl, C₃_i₀cycloalkyl, C_1-6alkoxy, d_₆alkoxyalkoxy, OH, -CF₃, - OCF₃, -SF₅, -OSF₅, halo, -O- C₃_i₀cycloalkyl, benzyloxy, -N(R¹⁷)₂, CN, R¹³-C₆-i₀aryl or R¹³- C₅_ioheteroaryl;

-N(R¹⁰XR¹¹);

R is selected from the group consisting of

R¹⁰ and R¹¹ are independently selected from the group consisting of H, R¹²-Ci_₆alkyl, C₃-iocycloalkyl, C₃-ioheterocycloalkyl or benzyl;

R¹² is 1 or 2 substituents independently selected from the group consisting of H, OH, Ci_6alkoxy, Ci_6alkyl, Ci_6alkyl-S-, Ci_6alkyl-SO₂-, Cβ-ioaryl, C6-ioaryl-S0₂-, C₅_ioheteroaryl, - C(O)O-R¹⁴ and -C(O)N(R¹⁴)₂;

R¹³ is 1 or 2 substituents selected from the group consisting of H, halo, Ci-βalkyl, C₂- ealkenyl, OH, hydroxyalkyl, C_1-6alkoxy, CN, -CF₃, -OCF₃, -SF₅, -OSF₅, -N(R¹⁷)₂,

-aminobenzyl, - Ci_₆alkyl-N(R¹⁰)(R¹¹), -C(O)N(R¹^(R¹¹), -0-SO₂- C_1-6alkyl, C₃_i₀cycloalkyl, (CH₂)_nC₃_ioheterocycloalkylR¹⁶, (CH₂)_nC₆.i₀arylR¹⁶, C₆.i₀arylalkyl- and

(CH₂)_nC₅_ioheteroarylR¹⁶ when R¹³ is attached to a ring carbon atom, and when R¹³ is attached to a ring nitrogen, it is H, Ci_₆alkyl or benzyl;

R¹⁵ is 1 or 2 substituents independently selected from the group consisting of H, halo, Ci-βalkyl, Ci_₆alkoxy, -CF₃, C₃_iocycloalkyl, Ci_₆alkoxyalkoxy, OH, hydroxyalkyl, -OCF₃, -O- C₃_iocycloalkyl, benzyloxy, -C(O)O C_1-6alkyl, -O- C_1-6alkyl-CO₂H, -C(O)N(R¹⁰)₂, - N(R¹⁰)₂, - Ci_₆alkyl-N(R¹⁰)₂, -NR¹⁰-C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)O Ci_₆alkyl, -N(R¹⁰)SO₂- C₁. ₆alkyl, phenyl, CN, -SF₅, -OSF₅, -SO₂R¹⁰, -SR¹⁰ and trimethylsilyl;

R¹⁶ is H, Ci_6alkyl, Ci_6alkoxy; and

each R¹⁷ is independently selected from the group consisting of H, Ci_₆alkyl, C₃. iocycloalkyl, C₃_ioheterocycloalkyl and benzyl.

2. The compound of claim 1 wherein R¹ is alkyl; R² is H, OH, alkoxy or

-0(CH₂)_nR, or -OR¹ and R² together form -0-CH₂-O-; R³ is H or alkoxy; R⁴, R⁵, R⁶ and R⁷ are independently H or alkyl; and R⁸ is H, alkyl or aryl.

3. The compound of claim 1 wherein R¹ is alkyl; R² is alkoxy; R³ is H or methoxy; R⁴, R⁵, R⁶ and R⁷ are independently H or alkyl; and R⁸ is H or alkyl.

4. The compound of claim 1 wherein R is R 12 -cyc _~ilo _~a„1lk1 y 1l, τ R") 13 -aryl or

R¹³-heteroaryl.

5. The compound of claim 4 wherein R is R -phenyl, wherein R is H, 1 or 2 alkoxy groups, 1 or 2 halo atoms, -OCF₃, -0-S0₂-alkyl, heterocycloalkyl, -N(R 17\ )₂ or

R¹⁶-heteroaryl.

6. The compound of claim 5 wherein R¹³ is H, 1 or 2 methoxy groups, 1 or 2 halo atoms, -OCF₃, -0-SO₂-CH₃,

— N _.0 — N MR¹⁴ -HN-^ O

or >— f , wherein R¹⁴ is H or methyl

'

or R¹⁶-pyridyl.

7. The compound of claim 4 wherein R⁹ is R¹³-heteroaryl, wherein heteroaryl is thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidinyl or quinolyl and R¹³ is H 1 or 2 halo atoms, 1 or 2 alkyl groups, alkoxy, cycloalkyl, CN, alkenyl, hydroxyalkyl, aryl,

-aminobenzyl, heterocycloalkyl, -alkyl-N(R¹⁰)(R^π), -C(O)N(R¹⁰)(R^π) or R¹⁶-heteroaryl.

8. The compound of claim 7 wherein R¹³ is H, or 1 to 2 groups independently selected from halogen, methyl and ethyl, methoxy, cyclopropyl, CN, vinyl, hydroxymethyl, phenyl, - aminobenzyl, morpholinyl, pyrrolidinyl, piperidinyl, -CH₂-morpholinyl, -CH₂- homomorpholinyl),-C(O)-N(alkyl)₂, -C(O)-morpholinyl, -C(O)-homomorpholinyl, -

C(O)NH-benzy 1l,,

oorr RR¹⁶--lheteroaryl wherein heteroaryl is pyridyl, imidazolyl, pyrimidinyl or indolyl.

9. The compound of claim 7 wherein R is R -thiazolyl or R -pyridyl.

10. The compound of claim 8 wherein R⁹ is R¹³-thiazolyl or R¹³-pyridyl.

11. The compound of claim 1 wherein R¹ is alkyl; R² is H, OH, alkoxy or

-O(CH₂)_nR, or -OR¹ and R² together form -0-CH₂-O-; R³ is H or alkoxy; R⁴, R⁵, R⁶ and R⁷ are independently H or alkyl; R⁸ is H, alkyl or aryl; and R⁹ is R¹²-cycloalkyl, R¹³-aryl or R¹³-heteroaryl.

12. The compound of claim 1 wherein R¹ is alkyl; R² is alkoxy; R³ is H or methoxy; R⁴, R⁵, R⁶ and R⁷ are independently H or alkyl; R⁸ is H or alkyl; R⁹ is R¹³-phenyl, wherein R¹³ is H, 1 or 2 alkoxy groups, 1 or 2 halo atoms, -OCF₃, -0-S0₂-alkyl, heterocycloalkyl, - N(R¹⁷)2 or R¹⁶-heteroaryl; or R⁹ is R¹³-heteroaryl, wherein heteroaryl is thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidinyl or quinolyl and R¹³ is H 1 or 2 halo atoms, 1 or 2 alkyl groups, alkoxy, cycloalkyl, CN, alkenyl, hydroxyalkyl, aryl, -aminobenzyl, heterocycloalkyl, -alkyl-N(R¹⁰)(R^π), -C(O)N(R¹⁰)(R^π) or R¹⁶-heteroaryl.

13. A compound which is selected from the group consisting of Examples IA, Table I, Example II, Table II, Example III, Table III, Example IV, Table IV, Example V, Table V, Example VI, Table VI, Example VII, Table VII, Examples VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXII, XXIII, and XXIV, or a

pharmaceutically acceptable salt thereof.

14. The compound of claim 13 selected from the group consisting of Examples IA, IB, ID, IE, IH, IN, IP, IQ, IR, IS, IU, IW, IY, IAA, ICC, IFF, IHH, HA, IIC, HD, HE, HF, HG, IIH, IU, IIK, IIL, HM, IIN, HQ, HR, IIS, IIIA, IIIB, IIIC, HID, HIE, IVA, IVB, IVC, IVD, VD, VIA, VIB, VIC, VID, VIE, VIF, VIIA, VIIB, VIIC, VIID, VIIE, VIIF, IX, X, XI, XII, XIV, XXII, XXIII, and XXIV, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition for treating phosphodiesterase 10 modulated disorders comprising an effective amount of at least one compound of claim 1 in a pharmaceutically acceptable carrier.

16. A pharmaceutical composition for treating phosphodiesterase 10 modulated disorders comprising an effective amount of at least one compound of claim 13 in a pharmaceutically acceptable carrier.

17. A method of treating phosphodiesterase 10 modulated disorders comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1.