EA044379B1 - 5,7-DIHYDROPYRROLOPYRIDINE DERIVATIVES - Google Patents

Description

Field of invention

The present invention generally relates to novel 5,7-dihydropyrrolopyridine derivatives which are M4 muscarinic receptor activators, salts thereof, pharmaceutical compositions thereof and their use for the treatment of M4-mediated diseases and disorders such as schizophrenia, Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and associated memory and executive dysfunction, agitation and associated psychosis.

Prerequisites for creating the invention

Patients with schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression and various other neurological/neurodegenerative diseases often suffer from behavioral and cognitive impairments, resulting in debilitating disruptions in their daily lives. Over the years, many pharmacological treatments have been discovered that provide some improvement in behavior and cognitive function. However, improvement is modest at best and, as is often the case, underlying dose-limiting side effects are associated with these treatments, including extrapyramidal and metabolic side effects that lead to partial response and noncompliance.

In an effort to discover new and improved pharmacological treatments, researchers have begun to look at the muscarinic acetylcholine receptor (mAChR) as a mechanism of action. There are five mAChR subtypes (M1-M5) that have been identified and are part of the G protein-coupled receptor (GPCR) superfamily. These subtypes are widely distributed throughout the peripheral and central nervous system, with subtypes M1 and M4 predominantly expressed in the CNS.

Since then, researchers have focused on identifying subtypes of selective activators of the M4 acetylcholine muscarinic receptor. For example, positive allosteric modulators (PAMs) of the M4 acetylcholine muscarinic receptor have received attention as an adjunctive treatment for behavioral disturbances associated with schizophrenia and other neuropsychiatric disorders such as Alzheimer's disease. [Cm. Bubser, Michael, et al., Selective Activation of M4 Muscarinic Acetylcholine Receptors reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents, American Chemical Society, Chemical Neuroscience (2014); and Bynum, Nellie E., et al., Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100, Neuropsychopharmacology (2014) 1-16]. Although the etiology of schizophrenia is unclear, an imbalance in the dopaminergic system is thought to play a major role. mAChR receptors are known to regulate dopamine levels in critical brain regions associated with psychosis, with M4 being the major subtype for dopamine regulation. (See Chan, W.Y., et al., Allosteric Modulation of the Muscarinic M4 receptor as an Approach to Treating Schizophrenia, PNAS, August 2008, Vol. 105 No. 31 p. 10978; and Byun, Nellie, et al., Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100, Neuropsychopharmacology (2014) 1-16). Another hypothesis for M4 in schizophrenia is its ability to influence hippocampal interneuronal connectivity (Shirley, Jana K., et al., An allosteric potentiator of M4 mACHR modulates hippocampal synaptic transmission, Nature Chemical Biology, Vol. 4, No. 1, January 2008; and Dasari, Sameera, et. al., M1 and M4 Receptors Modulate Hippocampal Pyramidal Neurons, J. Neurophysiology 105: 779–792, 2011) due to modulation of the trisynaptic pathway in the hippocampus, which is reported to be dysregulated in patients with schizophrenia ((Tamminga, Carol A., et. al., Glutamate Dysfunction in Hippocampus: Relevance of Dentate Gyms and CA3 Signaling, Schizophrenia Bulletin Vol. 38, no.5, pp. 927-935, 2012), Alzheimer's disease ( Quiroz et al 2010 Ann Neurol, Filipini et al., 2009 PNAS) and aMCI (Bakker, A., et. al., Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance , Neuromalge: Clinical 7 (2015) 688-698). Hyperactivity in the trisynaptic pathway in the hippocampus has been proposed as a likely cause of psychosis in subjects with schizophrenia. (Tamminga, et al.).

Vanderbilt University has published several international patent applications directed at positive allosteric modulators (PAMs) of the M4 acetylcholine muscarinic receptor, some of which include: WO 2013/126856 A1 (substituted analogues of 5-aminothieno[2,3C]pyridazine-6-carboxamide); WO 2014/035829 A1 (substituted analogues of 3-aminothieno[2,3-C]pyridine2-carboxamide); WO 2015/027204 A1 (substituted analogues of thieno[2,3-B]pyridine-2-carboxamide); and WO 2015/027214 A1 (substituted analogues of thieno[2,3-C]pyridazine-6-carboxamide).

WO 2006/047124 A1 (Lilly) discloses thienopyridines as allosteric potentiators of the M4 muscarinic receptor.

New or improved activators, including positive allosteric modulators, of M4 muscarinic receptors are needed to provide new and improved therapies for the treatment of M4-mediated diseases and disorders such as schizophrenia, Alzheimer's disease and others described herein.

- 1 044379

The essence of the invention

The present invention provides, in part, a compound of formula I

(I) or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein each R ¹ is independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, (C ₁ -C ₆ )alkoxy, wherein (C ₁ -C ₆ )alkyl is optionally substituted with 1-2 halogens or hydroxy, (C ₁ -C ₆ )alkylthio and (C ₁ -C ₆ )alkoxy is optional substituted with 1-2 halogens;

a is an integer selected from 0, 1, 2 and 3;

each R ² when present is (C ₁ -C ₆ )alkyl;

b is an integer selected from 0 and 1;

L is selected from -(CH ₂ ) _m -, -O-, or -NH-, where m is an integer selected from 1 and 2;

A is absent or selected from the group consisting of (C ₃ -C ₆ )cycloalkyl and (4-6 membered) heterocycloalkyl, wherein heterocycloalkyl contains 1 nitrogen atom, with the proviso that when L is -NH-, A is (C ₃ -C ₆ )cycloalkyl or (4-6-membered) heterocycloalkyl;

E is selected from (C ₃ -C ₁₀ )cycloalkyl, (C ₆ -C ₁₀ )aryl and (5-10 membered) heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein said cycloalkyl, aryl and heteroaryl is substituted with 0 to 3 substituents, which are independently selected from the group consisting of halogen, cyano, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, (C ₁ -C ₆ )alkoxy, ( C ₃ -C ₆ )cycloalkyl, methyloxetanyl, -N(R ³ )(R ⁴ ) and -C(=O)N(R ³ )(R ⁴ ), wherein (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, (C ₁ -C ₆ )alkoxy and (C ₃ -C ₆ )cycloalkyl are optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, cyano and (C ₃ -C ₆ ) cycloalkyl, with the proviso that when L is -NH-, E is (5-10 membered) heteroaryl; And

R ³ and R ⁴ are in each case independently selected from hydrogen or (C ₁ -C ₆ )alkyl.

In some embodiments, the invention also provides one or more compounds or an N-oxide thereof, or a pharmaceutically acceptable salt of a compound or N-oxide described in Examples 1-78.

The compounds of formula I are suitable for the treatment or prevention of M4-mediated diseases and/or disorders, such as schizophrenia, Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and associated memory and executive dysfunction, agitation, and behavioral and cognitive impairments related to the above, as well as pain, trauma, cardiac, thrombotic, metabolic, autoimmune and inflammatory diseases or disorders, as well as disorders associated with increased endothelial activity/impaired endothelial barrier function.

The present invention is also directed to the use of the compounds described herein, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, in the preparation of a medicament for the treatment or prevention of a condition susceptible to activation (eg, modulation of the allosteric binding site) of acetylcholine M4 muscarinic receptor (mAChR).

The present invention is also directed to pharmaceutically acceptable preparations containing a mixture of the compound(s) of the present invention or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, and at least one excipient formulated in a pharmaceutical dosage form. Examples of such dosage forms include tablets, capsules, suppositories, gels, creams, ointments, lotions, injection solutions/suspensions (eg, depots), inhalation aerosols, and oral solutions/suspensions.

Detailed description of the invention

Headings in this document are used only to expedite the reader's review of the document. They are not to be construed as limiting the invention or claims in any way.

Definitions and illustrative examples.

As used throughout this application, including the claims, the following terms have the meanings defined below unless specifically stated otherwise. Plural and singular should be treated as interchangeable except for the indication of number.

As used herein, the term M4 muscarinic receptor activator(s) means that the compounds of the present invention are: i) agonists, where the compound induces an effect at the M4 receptor in the absence of the presence of a native ligand (eg, acetylcholine); ii) a positive allosteric modulator (PAM), wherein the compound induces

- 2 044379 effect on the receptor in the presence of a suboptimal concentration of the native ligand; or iii) compounds of the present invention having both agonist and PAM activity.

As used herein, the term n-membered, where n is an integer, generally describes the number of ring-forming atoms in a fragment, the number of ring-forming atoms being n. For example, pyridine is an example of a 6-membered heteroaryl ring, and thiophene is an example of a 5-membered heteroaryl ring.

At various places throughout the present specification, substituents of the compounds of the invention are disclosed in groups or ranges. The invention is specifically intended to include each and every specific combination of members of such groups and ranges. For example, the term C1-C6 alkyl is specifically intended to include C1 alkyl (methyl), C2 alkyl (ethyl), _C3 alkyl, _C4 alkyl, _C5 alkyl, and _C6 alkyl. For another example, the term 5-10 membered heteroaryl group is specifically intended to include any 5-, 6-, 7-, 8-, 9-, and 10-membered heteroaryl group.

The term (C ₁ -C ₆ )alkyl, as used herein, refers to a saturated branched or straight chain alkyl group containing from 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, npentyl, isopentyl, neopentyl, and n-hexyl.

The term optionally substituted (C ₁ -C ₆ )alkyl, as used herein, refers to (C ₁ -C ₆ )alkyl, as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, -(C ₁ -C ₆ )alkoxy, -N(R ³ )(R ⁴ ), -N(R ³ )(C(=O)R ⁴ ), - N(R ³ )C(=O)OR ⁴ , -C(=O)N(R ³ )(R ⁴ ), -OC(=O)N(R ³ )(R ⁴ ), -C(=O )R ³ , -C(=O)OR ³ , and optionally substituted (C3-C6)cycloalkyl, wherein each R ³ and R ⁴ are independently selected from hydrogen and optionally substituted (C1-C ₆ )αalkyl. For example, the (C ₁ -C ₆ )alkyl moiety may be replaced by one or more halogen atoms to form a (C1 -C ₆ )alkyl halogen. Illustrative examples of halogen(C ₁ -C ₆ )alkyl include, but are not limited to, fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, and pentafluoroethyl. Other examples of optionally substituted (C ₁ -C ₆ )alkyl include, but are not limited to, methanol and methoxymethyl.

The term (C ₂ -C ₆ )alkenyl refers to an aliphatic hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon double bond, including straight chain or branched chain groups having at least one double bond carbon-carbon. Illustrative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. When the compounds of the invention contain a (C ₂ -C ₆ )alkenyl group, the compound may exist as a pure E (entgegen) form, a pure Z (zusammen) form, or any mixture thereof.

The term optionally substituted (C ₂ -C ₆ )alkenyl refers to (C ₂ -C ₆ )alkenyl, as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, - SF ₅ , nitro, -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkoxy, N(R ³ )(R ⁴ ), -N(R ³ )(C(=O)R ⁴ ) , -N(R ³ )C(=O)OR ⁴ , -C(=O)N(R ³ )(R ⁴ ), -OC(=O)N(R ³ )(R ⁴ ), -C( =O)R ³ , -C(=O)OR ³ , and optionally substituted (C3-C6)cycloalkyl, wherein R ³ and R ⁴ are each independently selected from hydrogen and optionally substituted (C1-C ₆ )alkyl.

The term (C ₂ -C ₆ )alkynyl refers to an aliphatic hydrocarbon having from two to six carbon atoms and at least one carbon-carbon triple bond, including straight chain and branched chain groups that have at least one carbon triple bond -carbon. Illustrative examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl and hexynyl.

The term optionally substituted (C ₂ -C ₆ )alkynyl refers to (C ₂ -C ₆ )alkynyl, as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, - SF ₅ , nitro, -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkoxy, N(R ³ )(R ⁴ ), -N(R ³ )(C(=O)R ⁴ ) , -N(R ³ )C(=O)OR ⁴ , -C(=O)N(R ³ )(R ⁴ ), -OC(=O)N(R ³ )(R ⁴ ), -C( =O)R ³ , -C(=O)OR ³ , and optionally substituted (C3-C6)cycloalkyl, wherein each R ³ and R ⁴ are independently selected from hydrogen and optionally substituted (C1-C ₆ )alkyl.

The term (C ₁ -C ₆ )alkoxy, as used herein, refers to a (C ₁ -C ₆ )alkyl group, as defined above, attached to a generic molecular moiety via an oxygen atom. Illustrative examples of (C ₁ -C ₆ )alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy and hexyloxy.

The term optionally substituted (C ₁ -C ₆ )alkoxy, as used herein, refers to a (C ₁ -C ₆ )alkoxy group, as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SF ₅ , nitro, -(C1-C6)alkyl, -(C1-C6)alkoxy, -N( ^R3 )( ^R4 ), -N( ^R3 )(C(=O )R ⁴ ), -N(R ³ )C(=O)OR ⁴ , -C(=O)N(R ³ )(R ⁴ ), -OC(=O)N(R ³ )(R ⁴ ) , -C(=O)R ³ , -C(=O)OR ³ , and optionally substituted (C3-C6)cycloalkyl, wherein each R ³ and R ⁴ are independently selected from hydrogen and optionally substituted (C1-C ₆ ) alkyl For example, (C1- _C6 )alkoxy may be replaced by one or more halogen atoms to form halogen( _C1 - _C6 )alkoxy. Illustrative examples of halogen(C ₁ -C ₆ )alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, 2-fluoroethoxy, trifluoromethoxy and pentafluoroethoxy.

The term (C ₁ -C ₆ )alkylthio, as used herein, refers to a (C ₁ -C ₆ )alkyl group, as defined above, attached to a generic molecular moiety via a sulfur atom. Illustrative examples of (C ₁ -C ₆ )alkylthio include, but are not limited to, methylthio, ethylthio, propylthio and the like.

The term optionally substituted (C ₁ -C ₆ )alkylthio, as used herein, refers to a (C ₁ -C ₆ )alkylthio group, as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SF5, nitro, -(C1-Cb)alkyl, -(C1-C6)alkoxy, -N(R ³ )(R ⁴ ), -N(R ³ )(C(=O) R ⁴ ), -N(R ³ )C(=O)OR ⁴ , -C(=O)N(R ³ )(R ⁴ ), -OC(=O)N(R ³ )(R ⁴ ), -C(=O)R ³ , -C(=O)OR ³ , and optionally substituted (C3-C6)cycloalkyl, wherein each R ³ and R ⁴ are independently selected from hydrogen and optionally substituted (C1-C ₆ )alkyl .

As used herein, the term (C ₃ -C ₁₂ )cycloalkyl refers to a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molecule where the cyclic structure has from 3 to 12 carbon atoms. (C ₃ -C ₆ )cycloalkyl refers to a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molecule having from 3 to 8 carbon atoms. (C ₃ -C ₆ )cycloalkyl refers to a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molecule having from 3 to 6 carbon atoms. Cycloalkyl may be a monocyclic ring, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Also included within the definition of cycloalkyl are unsaturated, non-aromatic cycloalkyls such as, but not limited to, cyclohexenyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl, and cyclooctenyl. Alternatively, cycloalkyl may contain more than one ring, such as (C ₄ -C ₈ )bicycloalkyl. The term (C ₄ -C ₈ )bicycloalkyl refers to a bicyclic ring system containing from 4 to 8 carbon atoms. The bicycloalkyl may be anelated, such as bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, and bicyclo[ 3.3.0]octanyl. The term bicycloalkyl also includes bridged bicycloalkyl systems such as, but not limited to, bicyclo[2.2.1]heptanyl and bicyclo[1.1.1]pentanyl. Other bicyclic cycloalkyl ring systems include (C ₃ -C ₁₂ )cycloalkyls, in which a 3-, 4-, 5-, or 6-carbon cycloalkyl ring is annealed together with another ring, such as another cycloalkyl ring or an aromatic ring. For example, the dihydroindenyl ring is a cycloalkyl ring, with the cyclopentyl ring annelated along with the phenyl ring.

The term optionally substituted (C ₃ -C ₆ )cycloalkyl or optionally substituted (C ₃ -C ₆ )cycloalkyl refers to a (C ₃ -C ₆ )cycloalkyl or (C ₃ -C ₆ )cycloalkyl as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SF5, nitro, -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkoxy, N(R ³ )( R ⁴ ), -N(R ³ )(C(=O)R ⁴ ), -N(R ³ )C(=O)OR ⁴ , -C(=O)N(R ³ )(R ⁴ ), -OC(=O)N(R ³ )(R ⁴ ), -C(=O)R ³ , -C(=O)OR ³ , and optionally substituted (C3-C6)cycloalkyl, in which each R ³ and R ⁴ is independently selected from hydrogen and optionally substituted (C1-C ₆ )alkyl.

The term -O-(C ₃ -C ₆ )cycloalkyl refers to a (C ₃ -C ₆ )cycloalkyl, as described above, attached to the generic molecular moiety via an oxygen atom. Illustrative examples of -O-(C ₃ C ₆ )cycloalkyl include, but are not limited to, cyclopropoxy, cyclobutoxy and the like.

The term optionally substituted -O-(C ₃ -C ₆ )cycloalkyl refers to -O-(C ₃ -C ₆ )cycloalkyl, as described above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo , cyano, hydroxy, -SF5, nitro, -(C ₁ -C ₆ )alkyl, -(C ₁ -C ₆ )alkoxy, N(R ³ )(R ⁴ ), -N(R ³ )(C(= O)R ⁴ ), -N(R ³ )C(=O)OR ⁴ , -C(=O)N(R ³ )(R ⁴ ), -OC(=O)N(R ³ )(R ⁴ ), -C(=O)R ³ , -C(=O)OR ³ , and optionally substituted (C3-C6)cycloalkyl, wherein each R ³ and R ⁴ are independently selected from hydrogen and optionally substituted (C1-C ₆ )alkyl.

Heterocycloalkyl, as used herein, refers to a cycloalkyl, as defined above, in which at least one of the ring carbon atoms is replaced by a heteroatom selected from nitrogen, oxygen or sulfur. The term (4-6 membered) heterocycloalkyl means a heterocycloalkyl substituent that contains a total of 4 to 6 ring atoms, at least one of which is a heteroatom. The term (4-8 membered) heterocycloalkyl means a heterocycloalkyl substituent that contains a total of 4 to 8 ring atoms, at least one of which is a heteroatom. (4-10 membered) heterocycloalkyl means a heterocycloalkyl substituent that contains a total of 4 to 10 ring atoms. (6-membered) heterocycloalkyl means a heterocycloalkyl substituent that contains a total of 6 ring atoms, at least one of which is a heteroatom. (5-membered) heterocycloalkyl means a heterocycloalkyl substituent that contains a total of 5 ring atoms, at least one of which is a heteroatom. The heterocycloalkyl may be a single ring with up to 10 members. Alternatively, heterocycloalkyl, as defined above, may contain 2 or 3 rings fused together, at least one such ring containing a heteroatom as a ring atom (ie, nitrogen, oxygen or sulfur). The heterocycloalkyl substituent may be attached to the dihydropyrrolopyridine ring of the compound of the present invention via a nitrogen atom having the appropriate valence or via any ring carbon atom. The heterocycloalkyl moiety may optionally be substituted with one or more substituents on a nitrogen atom having the appropriate valency or on any available carbon atom.

Also included within the definition of heterocycloalkyl are heterocycloalkyls that are annealed to a phenyl or naphthyl ring or to a heteroaryl ring such as, but not limited to, a pyridinyl ring or a pyrimidinyl ring.

Examples of heterocycloalkyl rings include, but are not limited to, azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octaohydrobenzo thiazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydrooxazolyl, morpholinyl, oxetanil, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidinyl, chromanil, isochromanil, dihydrobenzodioxinil, benzodioxolyl, benzoxazinil, indolinyl, dihydrobenzofuranyl, those trahydroquinolyl, isochromyl, dihydro-III-isoindolyl, 2-azabicyclo[2.2. 1]heptanonyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and the like. Additional examples of heterocycloalkyl rings include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3 -yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, 1,3-oxazolidin-3-yl, 1 ,4-oxazepan-1-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl , 1,2-tetrahydrodiazin2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl, oxazolidinonyl, 2-oxopiperidinyl (for example, 2oxopiperidin-1-yl) and the like.

The term optionally substituted heterocycloalkyl [e.g., optionally substituted (410-membered) heterocycloalkyl] refers to heterocycloalkyl, as defined above, in which one or more hydrogen atoms, where chemically permissible, are replaced by a substituent selected from the group consisting of halogen, oxo, cyano , hydroxy, -SF5, nitro, -(C ₁ -C ₆ )alkyl, -(C1-C ₆ )alkoxy, -N(R ³ )(R ⁴ ), -N(R ³ )(C(=O) R ⁴ ), -N(R ³ )C(=O)OR ⁴ , -C(=O)N(R ³ )(R ⁴ ), -OC(=O)N(R ³ )(R ⁴ ), -C(=O)R ³ , -C(=O)OR ³ , and optionally substituted (C3-C6)cycloalkyl, wherein R ³ and R ⁴ are each independently hydrogen or optionally substituted (C1-C ₆ )alkyl .

(C ₆ -C ₁₀ )aryl refers to an all-carbon monocyclic or annelated ring polycyclic aromatic group having a conjugated pi-electron system containing from 6 to 10 carbon atoms, such as phenyl or naphthyl.

The term optionally substituted (C ₆ -C ₁₀ )aryl refers to (C ₆ -C ₁₀ )aryl, as defined above, in which one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, - SF5, nitro, -(C1-C ₆ )alkyl, -(C1-C ₆ )alkoxy, -N(R ³ )(R ⁴ ), -N(R ³ )(C(=O)R ⁴ ), - N(R ³ )C(=O)OR ⁴ , -C(=O)N(R ³ )(R ⁴ ), -OC(=O)N(R ³ )(R ⁴ ), -C(=O )R ³ , -C(=O)OR ³ , and optionally substituted (C3-C6)cycloalkyl, wherein each R ³ and R ⁴ are independently selected from hydrogen and optionally substituted (C1-C ₆ )alkyl.

As used herein, the term heteroaryl refers to monocyclic or annelated ring polycyclic aromatic heterocyclic groups with one or more heteroatom ring members (ring-forming atoms), each independently selected from oxygen (O), sulfur (s) and nitrogen (N ) in at least one ring. The (5-14 membered) heteroaryl ring touches a heteroaryl ring having from 5 to 14 ring atoms, in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen or sulfur), the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. The (5-10 membered) heteroaryl ring touches a heteroaryl ring having from 5 to 10 ring atoms, in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen or sulfur), the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. A (5-10 membered) nitrogen-containing heteroaryl ring touches a heteroaryl ring having from 5 to 10 ring atoms, in which at least one of the ring atoms is nitrogen, the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen. (5-6 membered) heteroaryl refers to a heteroaryl ring having from 5 to 6 ring atoms, in which at least one of the ring atoms is a heteroatom (i.e. oxygen, nitrogen or sulfur), the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. A (5-6 membered) nitrogen-containing heteroaryl ring touches a heteroaryl ring having 5 to 6 ring atoms, in which one of the heteroatoms in the ring is nitrogen. A (6-membered) nitrogen-containing heteroaryl touches a heteroaryl ring having 6 ring atoms, in which one of the heteroatoms in the ring is nitrogen. (5-membered) nitrogen soder

- 5 044379 the constricting heteroaryl refers to a heteroaryl ring having 5 ring atoms, in which one of the heteroatoms in the ring is nitrogen. Heteroaryl may be a single ring or 2 or 3 annealed rings. Examples of heteroaryls include, but are not limited to, 6-membered ring substituents such as pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl; 5-membered heteroaryls such as thiazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, and pyrazolyl; 6/5-membered ring substituents such as indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, furanopyridinyl, purinyl, imidazopyridinyl, imidazopyrimidinyl , pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, thienopyridinyl , triazolopyrimidinyl, triazolopyridinyl (eg, [1,2,4]triazolo[1,5-a]pyridin-2-yl), and anthranilyl; and 6/6-membered ring substituents such as quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, oxochromanyl and 1,4-benzoxazinyl.

It should be understood that heteroaryl may optionally be annealed to a cycloalkyl group, or to a heterocycloalkyl group, as defined herein.

The heteroaryl substituent may be attached to the dihydropyrrolopyridine ring of the compounds of the present invention via a nitrogen atom having the appropriate valence or via a carbon atom. The heteroaryl moiety may be optionally substituted with one or more substituents on a nitrogen atom having the appropriate valence or on any available carbon atom.

The terms optionally substituted (5-10 membered) heteroaryl, optionally substituted (56 membered) heteroaryl and optionally substituted (5-6 membered) nitrogen-containing heteroaryl refer to (5-14 membered) heteroaryl, (5-6 membered) heteroaryl and a (5-6 membered) nitrogen-containing heteroaryl as defined above, in which one or more hydrogen atoms are replaced, where chemically possible, by a substituent selected from the group consisting of halogen, oxo, cyano, hydroxy, -SF5, nitro, -(C1-C ₆ )alkyl, -(C1-C ₆ )alkoxy, -N(R ³ )(R ⁴ ), -N(R ³ )(C(=O)R ⁴ ), -N(R ³ )C(=O)OR ⁴ , -C(=O)N(R ³ )(R ⁴ ), -OC(=O)N(R ³ )(R ⁴ ), -C(=O)R ³ , -C(=O)OR ³ , and optionally substituted (C3-C6)cycloalkyl, wherein each R ³ and R ⁴ are independently selected from hydrogen and optionally substituted (C1-C ₆ )alkyl.

The substituent may be attached to the heteroaryl moiety through any accessible carbon atom or through a heteroatom when the heteroatom is nitrogen having the appropriate valence.

A halogen or halogen atom as used herein refers to a chlorine, fluorine, bromine or iodine atom.

Hydroxy or hydroxyl as used herein means an -OH group.

Cyano, as used herein, means the -CN group, which may also be represented by |--C=N as ’

Nitro, as used herein, means the -NO ₂ group. Oxo, as used herein, means =O fragment. When oxo is a substituent on a carbon atom, together they form a carbonyl moiety [-C(=O)-]. When oxo is a substituent on a sulfur atom, together they form a sulfoxide moiety [-S(=O)-]; when two oxo groups are substituents on a sulfur atom, then together they form a sulfonyl fragment [-S(=O) ₂ -].

Optionally substituted, as used herein, means that the substitution is optional and thus includes both unsubstituted and substituted atoms and moieties. A substituted atom or fragment indicates that any hydrogen on a particular atom or fragment can be replaced by a substituent selected from a specified group (up to and including that each hydrogen atom on a particular atom or fragment is substituted by a selected from a specified group substituent), provided that the normal valency of the particular atom or moiety is not exceeded and that the substitution results in a stable compound. For example, if a methyl group (ie -CH3) is optionally substituted, then up to 3 hydrogen atoms on a carbon atom may be replaced by a group of substituents.

The patient touches warm-blooded animals such as, for example, pigs, cows, chickens, horses, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees and humans.

Pharmaceutically acceptable indicates that the substance or composition must be compatible, chemically and/or toxicologically, with the other ingredients contained in the preparation and/or with the mammal being treated with it.

A therapeutically effective amount refers to that amount of a compound, administered, that will relieve to some extent one or more symptoms of the disorder being treated.

The term therapeutically effective amount as used herein refers to that amount of a compound (including its N-oxide or pharmaceutically acceptable salt of the compound

- 6 044379 or N-oxide) that is administered that will reduce some of the severity of one or more of the symptoms of the disorder being treated. When applied to the treatment of an M4-mediated disorder (e.g., Alzheimer's disease or schizophrenia), a therapeutically effective amount refers to that amount that has the effect of reducing some of the severity of (or, e.g., eliminating) one or more symptoms associated with the M4-mediated disorder (e.g., positive , a negative or cognitive symptom of schizophrenia; or a psychotic symptom of Alzheimer's disease).

The term treatment, as used herein, unless otherwise specified, means the reversal, alleviation, inhibition of development or prevention of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term treatment, as used herein, unless otherwise specified, refers to the effect of treatment as treatment is defined herein. The term treatment also includes adjuvant and neo-adjuvant treatment of a subject.

Isoform means any of several different forms of the same protein.

Isoenzyme or isoenzyme means a closely related variant of an enzyme that differs in amino acid sequence but catalyzes the same chemical reaction.

Isomer means stereoisomer and geometric isomer, as defined below.

Stereoisomer refers to compounds having one or more chiral centers, each of which can exist in the R or S configuration. Stereoisomers include all diastereomeric, enentiomeric and epimeric forms, as well as racemates and mixtures thereof.

Geometric isomer refers to compounds that can exist in cis, trans, anti, entgegen (E), and zusammen (Z) forms, as well as mixtures of these.

As used herein, unless otherwise indicated, the point of attachment of the substituent may be at any suitable position of the substituent. For example, pyridinyl (or pyridyl) may be 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

When the bond to a substituent is shown to cross a bond that connects two atoms in a ring, then the substituent may be bonded to any ring-forming atoms on that ring that may be substituted (i.e., bonded to one or several hydrogen atoms) unless otherwise indicated or unless the context clearly indicates otherwise. For example, as shown in Formula I below, one R ¹ (where a is 1, 2 or 3) can be bonded to any one of the ring carbon atoms of a 5-membered ring, as shown below:

When a substituted or optionally substituted moiety is described without specifying the atom by which such moiety is linked to a substituent, the substituent may be linked through any corresponding atom in such moiety. For example, in an optionally substituted (5-10 membered) heteroaryl, the substituent on the heteroaryl may be bonded to any carbon atom in the heteroaryl moiety or to a heteroatom of the heteroaryl if valence permits. Combinations of substituents and/or variables are permitted only if such combinations result in stable compounds.

This description uses the terms substituent, radical, and group interchangeably.

If substituents are described as being independently selected from a group, then each example of substituent is selected independently of any other. Each substituent, as a result, may be identical or different from the other substituent(s).

As used herein, the terms formula I, formula Ia and formula Ib may be referred to hereinafter as the compound(s) of the invention. Such terms are further defined to include all forms of the compounds of the invention, including, but not limited to, their hydrates, solvates, isomers (including, for example, rotational stereoisomers), crystalline and non-crystalline forms, isomorphs, polymorphs, metabolites, prodrugs . For example, the compounds of the invention, or pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry that is independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will depend on wet and dry conditions. In such cases, a non-stoichiometric ratio will be the norm. In general, solvated forms

- 7 044379 are considered equivalent to non-solvated forms for the purposes of the present invention.

The compounds of this invention may exist as clathrates or other complexes (eg, cocrystals). Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes, where the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the compounds of the invention that contain two or more organic and/or inorganic components, which may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Sci., 64(8), 1269-1288, Haleblian (August 1975). Cocrystals are generally defined as crystalline complexes of neutral molecular components that are associated with each other through non-covalent interactions, but can also be a complex of a neutral molecule with a salt. Cocrystals can be prepared by melt crystallization, recrystallization from solvents, or by physically grinding the components together; see O. Almarsson and M.J. Zaworotko, Chem. Commun. 2004, 17, 1889-1896. Looking forward to a general overview of multicomponent complexes, see J.K. Haleblian, J. Pharm. Sci. 1975, 64, 1269-1288.

The compounds of this invention may exist as geometric isomers, where the compounds have asymmetric carbon atoms, and thus may exist as two or more stereoisomeric forms. The present invention includes all individual stereoisomers and geometric isomers of the compounds of this invention, and mixtures thereof. Individual enantiomers can be obtained by chiral resolution or by using the corresponding enantiomers in synthesis. The carbon-carbon bonds of compounds of formula I can be depicted herein using a solid line (---), a solid wedge line (- ^- )' or a dotted wedge line (............ /

The use of a solid line to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers (eg, specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge line to depict bonds to an asymmetric carbon atom is intended to indicate that the stereoisomer shown is present. When present in racemic compounds, the solid and dotted wedge line is used to determine relative stereochemistry rather than absolute stereochemistry. Racemic compounds having this specified relative stereochemistry are designated (±). For example, unless otherwise indicated, it is intended that the compounds of this invention may exist as stereoisomers, which include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers and their mixtures. The compounds of this invention may exhibit more than one type of isomerism. Also included are acid addition or basic addition salts in which the counterion is optically active, such as D-lactate or L-lysine, or racemic, such as DL-tartrate or DL-arginine.

In some embodiments, the compounds of the present invention may exist and/or be isolated as atropisomers (eg, one or more atropeneantiomers). Those skilled in the art will appreciate that atropoisomerism can exist in a compound that has two or more aromatic rings (eg, two aromatic rings linked through a single bond). See, for example, Freedman, T.V. et al., Absolute Configuration Determination of Chiral Molecules in the Solution State Using Vibrational Circular Dichroism. Chirality 2003, 15, 743-758; and Bringmann, G. et al., Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angew. Chem., Int. Ed. 2005, 44, 5384-5427.

When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) mentioned above, where the resultant is one homogeneous crystal form containing both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate, where the resulting two crystal forms are in equimolar amounts, each containing one enantiomer.

The compounds of the present invention may also exist in the form of its N-oxide or a pharmaceutically acceptable salt of the compound or N-oxide.

As is known to one skilled in the art, amine compounds (ie, those containing one or more nitrogen atoms), such as tertiary amines, can form N-oxides (also known as amine oxides or amine N-oxides). The N-oxide has the formula (r ¹⁰⁰ r ²⁰⁰ r ³⁰⁰ )N ⁺ -O ^_ , where the parent amine (R ¹⁰⁰ R2 ⁰⁰ R ³⁰⁰ )N may be, for example, a tertiary amine (for example, each of R ¹⁰⁰ , R ²⁰⁰ , R ³⁰⁰ is independently an alkyl, arylalkyl, aryl, heteroaryl, or the like), heterocyclic or heteroaromatic amine [e.g., (r ¹⁰⁰ r ²⁰⁰ r ³⁰⁰ )N together forms 1-alkylpiperidine, 1-alkylpyrrolidine, 1-benzylpyrrolidine, or pyri - 8 044379 din]. For example, an imine nitrogen, especially a heterocyclic or heteroaromatic imine nitrogen, or a pyridine-type nitrogen atom (% ^N ) [such as the nitrogen atom in pyridine, pyridazine, or pyrazine], can be N-oxidized to form an N-oxide containing a group (*/ such Thus, a compound according to the present invention containing one or more nitrogen atoms (for example, an imine nitrogen atom) may be capable of forming its N-oxide (for example, moho-N-oxides, bis-K-oxides or multi-N-oxides). oxides, or mixtures thereof depending on the number of nitrogen atoms suitable for the formation of stable N-oxides).

As used herein, the term ''N-oxide(s)'' refers to all possible, and in particular all stable, N-oxide forms of the amine compounds (e.g., compounds containing one or more imine nitrogen atoms) described herein, such as mono-N-oxides (including various isomers where more than one nitrogen atom of the amine compound may form a monoA-oxide) or multi-N-oxides (eg, bis-K-oxides), or mixtures thereof in any ratio.

As defined above, the compounds of the invention (or their N-oxides) may exist in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. Depending on the particular compound, the salts of the compound may be preferred due to one or more of the physical properties of the salts, such as increased pharmaceutical stability at various temperatures and humidity, or desired solubility in water or oil. In some cases, the salt of the compound may also be used as an auxiliary in the isolation, purification and/or separation of the compounds.

When it is meant that the salt is administered to a patient (compared to, for example, that used in an in vitro context), the salt is advantageously pharmaceutically acceptable. The term pharmaceutically acceptable salt refers to a salt prepared by combining a compound of the present invention with an acid whose anion, or base, whose cation is generally considered acceptable for human consumption. Pharmaceutically acceptable salts are useful as products of the methods of the present invention due to their higher solubility in water relative to the parent compound.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention, when possible, include those derived from inorganic acids such as, but not limited to, hydrochloride, hydrobromide, hydrofluoride, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic and sulfuric acid and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric and trifluoroacetic acids. Suitable organic acids generally include, but are not limited to, the aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids.

Specific examples of suitable organic acid salts include, but are not limited to, acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronic, maleate, fumarate, pyruvate, aspartate, gluta obscene , benzoate, anthranilate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, alginate , β-hydroxybutyrate, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecyl sulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalsulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, th cyanate and undecanoate salt.

Moreover, when the compounds of the invention carry an acid moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example sodium or potassium salts; alkaline earth metal salts, for example calcium or magnesium salts; and salts formed with suitable organic ligands, for example quaternary ammonium salts. In another embodiment, the basic salts are formed from bases that form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.

Organic salts can be derived from secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Groups containing basic nitrogen can be quaternized with agents such as lower alkyl (C1- _C6 ) halides (e.g. methyl,

- 9 044379 ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (i.e. dimethyl, diethyl, dibutyl and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), arylalkyl halides (for example, benzyl and phenethyl bromides) and others.

In one embodiment, hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.

For a review of acceptable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to one skilled in the art.

The compounds of the invention may exist on a continuum of solid states ranging from completely amorphous to completely crystalline. The term amorphous refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, can exhibit the physical properties of a solid or a liquid. Typically such materials do not produce characteristic X-ray diffraction patterns and, although they exhibit solid-state properties, are more formally described as a liquid. When heated, a transition occurs from a visible solid to a material with the properties of a liquid, which is characterized by a change of state, usually of the second order (glass transition). The term crystalline refers to a solid phase in which the material has an ordered internal structure at the molecular level and produces a characteristic x-ray pattern with defined peaks. Such materials, when heated sufficiently, will also exhibit the properties of a liquid, but the transition from solid to liquid is characterized by a phase change, usually of the first order (melting point).

The compounds of the invention can also exist in a mesomorphic state (mesophase or liquid crystal) when exposed to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism resulting from a change in temperature is described as thermotropic, while mesomorphism resulting from the addition of a second component such as water or another solvent is described as lyotropic. Compounds that can form lyotropic mesophases are described as amphiphilic and consist of molecules that are ionic (such as -COO ^- Na ⁺ , -COO-K + , or -SO3 ^- Na ⁺ ) or nonionic (such as -N ^- N ⁺ (CH3) ₃ ) polar head group. For more information, see Crystals and the Polarizing Microscope by N.H. Hartshorne and A. Stuart, ^4th Edition (Edward Arnold, 1970).

The invention also concerns prodrug compounds according to the present invention. Thus, certain derivative compounds of the invention, which may have little or no pharmacological activity of their own, can, when administered to or on the body, be converted into compounds of formula I that have the desired activity, for example, by hydrolytic cleavage. Such derivatives are called prodrugs. Additional information regarding the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs according to the invention can, for example, be prepared by replacing the corresponding functionality present in the compounds of the invention with certain fragments known to one skilled in the art as pro-fragments as described, for example, in Design of Prodrugs by H. Bundgaard ( Elsevier, 1985), or in Prodrugs: Challenges and Reward, 2007 edition, edited by Valentino Stella, Ronald Borchardt, Michael Hageman, Reza Oliyai, Hans Maag, Jefferson Tilley, pages 134-175 (Springer, 2007).

In addition, some of the compounds of the invention may themselves act as prodrugs of other compounds of the invention.

The present invention also covers compounds of the invention containing protecting groups. Those skilled in the art will appreciate that the compounds of the invention can also be formulated with certain protecting groups which are useful for purification and storage and can be removed before administration to a patient. The introduction of protecting groups and the removal of protecting groups from functional groups are described in Protective Groups in Organic Chemistry, edited by JWF McOmie, Plenum Press (1973) and Protective Groups in Organic Synthesis, ^3rd edition, TW Greene and PGM Wuts, Wiley-Interscience (1999) ).

Also included within the scope of the invention are the metabolites of the compounds according to the invention, that is, the compounds formed in vivo upon administration of the drug.

The present invention also includes all pharmaceutically acceptable isotopically labeled compounds identical to those presented herein, in which one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number, which is commonly found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen such as ^2H , ^3H ; carbon, such as 10 044379 ^PS , ¹³ C, and ¹⁴ C; chlorine, such as ³⁶ Cl; fluoride such as ¹⁸ F; iodine, such as ¹²³ I and ¹²⁵ I; nitrogen, such as ¹³ N and ¹⁵ N; oxygen such as ¹⁵ O, ¹⁷ O, and ¹⁸ O; phosphorus, such as ³² R; and sulfur, such as ³⁵ S. Certain isotopically labeled compounds of the present invention, eg those incorporated with radioactive isotopes, are useful in drug and/or substrate tissue distribution studies (eg, assays). Radioactive isotopes of tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C are particularly preferred for this purpose from the point of view of their ease of preparation and ability to be detected. Substitution with heavier isotopes such as deuterium, i.e. ^2H may provide certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some situations. Substitution with positron-emitting isotopes such as ^PS , ¹⁵ F, ¹⁸ F, ¹⁵ O and ¹³ N can be useful in positron emission tomography (PET) studies to study receptor substrate occupancy. The isotope-labeled compounds of the present invention can generally be prepared using conventional methods known to one skilled in the art, or using methods similar to those described in the accompanying diagrams and/or in the examples and preparations using the appropriate isotope-labeled compound. labeled reagent instead of the unlabeled reagent that was used previously. Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvents may be isotopically substituted, for example, D ₂ O, acetone-d ₆ , or DMSO-d ₆ . The compounds of the invention, which include the compounds illustrated in Examples 1-67 described below, include isotopically labeled versions of these compounds, such as, but not limited to, deuterated and tritiated isotopes and all other isotopes discussed above.

In some embodiments, the present invention is directed to novel selective radiolabeled M4 positive allosteric modulators that are useful for imaging and quantifying the distribution of M4 compounds in tissues (eg, brain) using positron emission tomography (PET).

Connections.

The compounds of formula I, as described above, contain a 5,7-dihydropyrrolopyridine ring, the ring being optionally substituted on the pyridine ring by up to three R ¹ ; optionally substituted on the pyrrole ring with up to four R ² ; and L, A, and E are as defined above and hereinafter.

In one embodiment, in Formula I as described above, each R ¹ , when present, is selected from the group consisting of halogen, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₁ -C ₆ )alkoxy, and -N(R ³ )(R ⁴ ); and a is an integer selected from 1, 2 and 3.

In certain embodiments, R ¹ is halogen, and the halogen is selected from chlorine and fluorine.

In certain embodiments, R ¹ is optionally substituted (C ₁ -C ₆ )alkyl, and (C ₁ -C ₆ )alkyl is selected from methyl and ethyl. Examples of optionally substituted (C ₁ -C ₆ )alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methanol and methoxymethyl.

In certain embodiments, R ¹ is optionally substituted (C ₁ -C ₆ )alkoxy, and (C ₁ -C ₆ )alkoxy is selected from methoxy and ethoxy. Examples of optionally substituted (C ₁ -C ₆ )alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy and trifluoroethoxy.

In certain embodiments, R ¹ is -N(R ³ )(R ⁴ ), wherein each R ³ and R ⁴ are independently selected from hydrogen and (C1-C6)alkyl, wherein (C1-C6)alkyl is selected from methyl, ethyl and drank it away. In certain embodiments, one of R ³ and R ⁴ is hydrogen and the other is (C1-C ₆ )alkyl. In another embodiment, both R ³ and R ⁴ may be hydrogen. In yet another embodiment, both R ³ and R ⁴ may be (C1-C6)alkyl. For example, when R ³ and R ⁴ are each (C1- _C6 )alkyl, ( _C1 - _C6 )alkyl is methyl.

It should be understood that any of the above subgenera (embodiments) of R ¹ can be combined together with any of the subgenera for R ² , L, A, and E, as described above and hereinafter.

In certain other embodiments, in Formula I as described above, each R ² , when present, is (C ₁ -C ₆ )alkyl; and b is an integer selected from 0 and 1.

In certain embodiments, b is 1 and (C ₁ -C ₆ )alkyl is methyl.

In certain embodiments, b is equal to 0 (ie, there is no R ² ).

It should be understood that any of the above-mentioned subgenera (embodiments) of R ² can be combined together with any of the subgenera for R ¹ , L, A, and E, as described above and hereinafter.

In certain other embodiments, in Formula I as described above, L is

- 11 044379 is oxygen.

In certain other embodiments, in Formula I as described above, L is -NH-.

In certain embodiments, L is -(CH ₂ ) _m and m is an integer selected from 1 and 2.

In certain embodiments, L is -(CH ₂ ) _m - and m is 2.

In certain embodiments, L is -(CH ₂ ) _m - and m is 1.

It should be understood that any of the above-mentioned subgenera (embodiments) of L may be combined together with any of the subgenera for R ¹ , R ² , A and E, as described above and hereinafter.

In certain other embodiments, in Formula I as described above, A is (C ₃ -C ₆ )cycloalkyl, which is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, A is cyclopropyl.

In certain other embodiments, A is a (4-6 membered) heterocycloalkyl, which is selected from the group consisting of azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, imidazolidinyl, pyrrolidinyl, piper idinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydrooxazolyl, oxetanil, dioxetanil, dioxolanil, dioxanil, oxazinyl and oxathiazinyl.

In certain embodiments, A is (4-6 membered) heterocycloalkyl, and heterocycloalkyl is azetidinyl.

It should be understood that any of the above-mentioned subgenera (embodiments) A may be combined together with any of the subgenera for R ¹ , R ² , L, and E, as described above and hereinafter.

In certain embodiments, in Formula I, as described above, E is a (510-membered) heteroaryl, which is selected from the group consisting of triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2, 4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indonyl, indazonyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl, furanopyridinyl, purinyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl, anthranilyl, quinolinyl, isoquinolinyl , cinolinyl, quinazolinyl, oxochromanyl, and 1,4-benzoxazinyl, said heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ )alkyl and optionally substituted (C ₁ -C ₆ )alkoxy.

In certain other embodiments, E is a (5-6 membered) nitrogen heteroaryl selected from the group consisting of triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl, wherein said nitrogen heteroaryl is optionally substituted from one to three substituents that are independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ )alkyl and optionally substituted (C ₁ -C ₆ )alkoxy.

In certain other embodiments, E is pyridinyl, optionally substituted with one to two substituents independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₁ -C ₆ )alkoxy.

In certain other embodiments, E is pyrimidinyl, optionally substituted with one to two substituents independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₁ -C ₆ )alkoxy.

It should be understood that any of the above-mentioned subgenera (embodiments) of E may be combined together with any of the subgenera for R ¹ , R ² , L, and A, as described above and hereinafter.

In certain other embodiments, the present invention is a compound of Formula Ia

- 12 044379 or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein each R ¹ , when present, is independently selected from the group consisting of halogen, optionally

optionally substituted (C ₁ -C ₆ )alkyl and optionally substituted (C ₁ -C ₆ )alkoxy;

a is an integer selected from 1, 2 and 3;

R ² when present is optionally substituted (C ₁ -C ₆ )alkyl;

b is an integer selected from 0 and 1;

E is a (5-6 membered) heteroaryl, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₁ -C ₆ )alkoxy, and -N(R ³ )(R ⁴ ), wherein R ³ and R ⁴ are in each case independently selected from hydrogen and optionally substituted (C ₁ -C ₆ )alkyl.

In another embodiment, in Formula Ia as described above, b is 1 and R ² is methyl.

In another embodiment, b is 0 (ie, there is no R ² ).

In another embodiment, in Formula Ia as described above, E is a (5-6 membered) nitrogen heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl and pyrazinyl, wherein said nitrogen heteroaryl is optionally substituted from one up to three substituents which are independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ )alkyl and optionally substituted (O ₁ -C ₆ )alkoxy.

In certain other embodiments, E is pyridinyl, optionally substituted with one to two substituents independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₁ -C ₆ )alkoxy.

In certain other embodiments, E is pyrimidinyl, optionally substituted with one to two substituents independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₁ -C ₆ )alkoxy.

In certain other embodiments, the present invention is a compound of Formula Ib

or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein each R ¹ , when present, is independently selected from the group consisting of halogen, optionally substituted (C ₁ -C ₆ )alkyl, and optionally substituted (C ₁ - C ₆ )alkoxy;

a is an integer selected from 1, 2 and 3;

R ² when present is optionally substituted (C ₁ -C ₆ )alkyl;

b is an integer selected from 0 and 1;

E is a (5-6 membered) heteroaryl, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₁ -C ₆ )alkoxy, and -N(R ³ )(R ⁴ ), wherein in each case R ³ and R ⁴ are each independently selected from hydrogen and optionally substituted (C ₁ -C ₆ )alkyl.

In another embodiment, in Formula Ib as described above, b is 1 and R ² is methyl.

In another embodiment, b is 0 (ie, there is no R ² ).

In another embodiment, in Formula Ib as described above, E is a (5-6 membered) nitrogen heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl and pyrazinyl, wherein said nitrogen heteroaryl is optionally substituted from one up to three substituents, which are independently selected from

- 13 044379 group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C1-C ₆ )alkyl and optionally substituted (C ₁ -C ₆ )alkoxy.

In certain other embodiments, E is pyridinyl, optionally substituted with one to two substituents independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₁ -C ₆ )αalkoxy.

In certain other embodiments, E is pyrimidinyl, optionally substituted with one to two substituents independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ ) alkyl and optionally substituted (C ₁ -C ₆ )alkoxy.

In certain other embodiments, the present invention is directed to a compound that is selected from the group consisting of

1-(2,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[1-(pyridin-3yl)azetidin-3-yl]ethanone,

2-{1-[2-(difluoromethyl)pyridin-4-yl]azetidin-3-yl}-1-(2,4-Dimethyl-5,7dihydro-6H-pyrrolo[3,4-b]pyridin-6 -yl)ethanone,

1-(2,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[1(pyrimidin-4-yl)azetidin-3-yl]ethanone ,

2-{1-[2-(difluoromethoxy)pyridin-4-yl]azetidin-3-yl}-1-(2,4-Dimethyl-5,7dihydro-6/-/-pyrrolo[3,4-b] pyridin-6-yl)ethanone,

2-[1 -(1,2,4-thiadiazol-5-yl)azetidin-3-yl]-1 -(2,3,4-trimethyl-5,7-dihydro-6Hpyrrolo[3,4-b] pyridin-6-yl)ethanone,

1-[2-(difluoromethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2{1-[2-(trifluoromethyl)pyridin-4- yl]azetidin-3-yl}ethanone,

1-[2-(methoxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2{1-[2-(trifluoromethyl)pyridin-4- yl]azetidin-3-yl}ethanone,

2-{1-[2-(difluoromethoxy)pyridin-4-yl]azetidin-3-yl}-1-[2-(methoxymethyl)-4methyl-5,7-dihydro-6H-pyrrolo[3,4-b ]pyridin-6-yl]ethanone,

1-[2-(hydroxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]2-[1-(pyridin-3-yl)azetidin-3 -il]ethanone,

2-{1-[2-(difluoromethoxy)pyridin-4-yl]azetidin-3-yl}-1-[2-(difluoromethyl)3,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3, 4-b]pyridin-6-yl]ethanone,

1-(2,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2(trifluoromethyl)pyridin-4-yl]azetidin- 3-yl}ethanone,

1-(3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2(difluoromethyl)pyridin-4- yl]azetidin-3-yl}ethanone,

1-(3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[1(pyridin-3-yl)azetidin-3 -il]ethanone,

2-[1-(pyridin-3-yl)azetidin-3-yl]-1-(2,4,5-trimethyl-5,7-dihydro-6Hpyrrolo[3,4-b]pyridin-6-yl) ethanone, ENT-1,

2-[1-(pyridin-3-yl)azetidin-3-yl]-1-(2LAtrimethyl-5,7-dihydro-6/-/pyrrolo[3A]pyridin-6-yl)ethanone, ENT-2,

1-(2Adimethyl-57-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[(18,2E)-2-(6methylpyridin-3-yl)cyclopropyl]ethanone,

- 14 044379

1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[(1 R,2S)-2-(6methylpyridin-3-yl )cyclopropyl]ethanone,

1-[2-(difluoromethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2[(1H,28)-2-(6-methylpyridine -3-yl)cyclopropyl]ethanone,

2,4-dimethyl-M-[1-(pyridin-3-yl)azetidin-3-yl]-57-dihydro-6H-pyrrolo[3,4 b]pyridin-6-carboxamide,

1-(pyridin-3-yl)azetidin-3-yl 2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4b]pyridin-6-carboxylate,

1-(2-methoxy-4-methyl-57-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2-[1(pyridin-3-yl)azetidin-3-yl ]ethanone,

1-(3-chloro-2-methoxy-4-methyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2[1-(pyridin-3-yl )azetidin-3-yl]ethanone,

2-[1-(pyridin-3-yl)azetidin-3-yl]-1-(2,3,4-trimethyl-5,7-dihydro-6/7pyrrolo[3,4-b]pyridin-6- yl)ethanone,

1-[2-(hydroxymethyl)-4-methyl-57-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]2-[1-(pyrimidin-4-yl)azetidin-3-yl ]ethanone,

2-{1-[2-(difluoromethoxy)pyridin-4-yl]azetidin-3-yl}-1-[2-(difluoromethyl)-4methyl-57-dihydro-6H-pyrrolo[3,4-b]pyridine -6-yl]ethanone,

1-(3-chloro-2-methoxy-4-methyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2[1-(pyrimidin-5-yl )azetidin-3-yl]ethanone,

1-[2-(methoxymethyl)-4-methyl-57-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2[1-(pyridin-3-yl)azetidin-3-yl ]ethanone,

1-(2-methoxy-3,4-dimethyl-57-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2-[1(pyridin-3-yl)azetidin-3 -il]ethanone,

1-(2-methoxy-3,4-dimethyl-57-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2-[1(pyrimidin-5-yl)azetidin-3 -il]ethanone,

1-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2-[1(pyridazin-4-yl)azetidin-3-yl ]ethanone,

1-[2-(methoxymethyl)-4-methyl-57-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl]-2[1-(pyrimidin-5-yl)azetidin-3 -il]ethanone,

1-[3-chloro-2-(difluoromethoxy)-4-methyl-5,7-dihydro-6/7-pyrrolo[3,4b]pyridin-6-yl]-2-[1-(pyrimidin-5- yl)azetidin-3-yl]ethanone,

- 15 044379

1-[2-(hydroxymethyl)-4-methyl-57-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]2-{1-[2-(trifluoromethyl)pyridin-4-yl] azetidin-3-yl}ethanone,

1-[2-(difluoromethyl)-4-methyl-57-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl]-2[1-(pyrimidin-5-yl)azetidin- 3-yl]ethanone, 2-[1-(pyrimidin-4-yl)azetidin-3-yl]-1-(2D4-trimethyl-5,7-dihydro-6/-/pyrrolo[3,4-b] pyridin-6-yl)ethanone,

1-(pyridin-3-yl)azetidin-3-yl 2,3,4-trimethyl-5,7-dihydro-6/-/-pyrrolo[3,4b]pyridin-6-carboxylate,

2-[trans-2-(pyridin-3-yl)cyclopropyl]-1-(2D4-trimethyl-5,7-dihydro-6/-/pyrrolo[3,4-b]pyridin-6-yl)ethanone, ENT-1,

2-[trans-2-(pyridin-3-yl)cyclopropyl]-1-(2D4-trimethyl-5,7-dihydro-6/-/pyrrolo[3,4-b]pyridin-6-yl)ethanone, ENT-2,

1-(3-chloro-2D-dimethyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl)-2-[1(pyrimidin-4-yl)azetidin- 3-yl]ethanone,

1-[2-(methoxymethyl)-3,4-dimethyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6yl]-2-[1-(pyrimidin-5-yl )azetidin-3-yl]ethanone,

1-(2,4-dimethyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2(ethylamino)pyrimidin-4-yl ]azetidin-3-yl}ethanone,

1-(2,4-Dimethyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[6-(propan2-ylamino)pyrimidin- 4-yl]azetidin-3-yl}ethanone,

1-(2,4-dimethyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl)-2-[1-(2methylimidazo[1,2-b]pyridazine -6-yl)azetidin-3-yl]ethanone,

1-(3-chloro-2,4-dimethyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl)-2-[1(1 D4-thiadiazol-2 -yl)azetidin-3-yl]ethanone,

1-[2-(difluoromethyl)-4-methyl-57-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2{1-[2-(difluoromethyl)pyridin-4-yl] azetidin-3-yl}ethanone,

2-{1-[2-(difluoromethyl)pyridin-4-yl]azetidin-3-yl}-1-(2,3,4-trimethyl-5,7dihydro-6H-pyrrolo[3,4-b]pyridine -6-yl)ethanone,

1-[3-chloro-2-(methoxymethyl)-4-methyl-57-dihydro-6H-pyrrolo[3,4-b]pyridin6-yl]-2-{1-[2-(difluoromethyl)pyridin-4 -yl]azetidin-3-yl}ethanone,

1-[3-chloro-2-(methoxymethyl)-4-methyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin6-yl]-2-[1-(pyridin-3 -yl)azetidin-3-yl]ethanone,

- 16 044379

1-[3-chloro-2-(methoxymethyl)-4-methyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin6-yl]-2-[1-(6-fluoropyridin- 3-yl)azetidin-3-yl]ethanone,

2-{1-[2-(difluoromethyl)pyridin-4-yl]azetidin-3-yl}-1-[2-(methoxymethyl)-4methyl-5,7-dihydro-6/7-pyrrolo[3,4 -b]pyridin-6-yl]ethanone,

1-(3-chloro-2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2[trans-2-(pyrimidin-5-yl )cyclopropyl]ethanone, from ENT-2 in note 23, Table 6,

1-[3-chloro-2-(methoxymethyl)-4-methyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin6-yl]-2-{1-[2-(difluoromethoxy )pyridin-4-yl]azetidin-3-yl}ethanone,

1-[2-(difluoromethyl)-3,4-dimethyl-5,7-dihyde rho-6/7-pyrrolo[3,4-b]pyridin-6yl]-2-{1-[2-(difluoromethyl) pyridin-4-yl]azetidin-3-yl}ethanone, (-)-1-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl )-2-[trans-2(pyridin-3-yl)cyclopropyl]ethanone, ENT-1, (+)-1-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3, 4-b]pyridin-6-yl)-2-[trans-2(pyridin-3-yl)cyclopropyl]ethanone, ENT-2,

2-(2,3-dihydro-1/7-inden-2-yl)-1-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4b]pyridin-6-yl )ethanone,

4-{3-[2-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2oxoethyl]azetidin-1-yl}pyridin- 2-carbonitrile,

1-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2-[1-(2methoxypyridin-4-yl)azetidin-3- yl]ethanone,

2-cyclopropyl-1-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6yl)ethanone, formate salt,

1-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2-[1-(pyridin-4yl)azetidin-3-yl] ethanone,

1-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2-[1(pyrimidin-5-yl)azetidin-3-yl ]ethanone,

-(1,3,4-thiadiazol-2-yl)azetidin-3-yl 2,4-dimethyl-5,7-dihydro-6Hpyrrolo[3,4-b]pyridin-6-carboxylate,

-(1,2,4-thiadiazol-5-yl)azetidin-3-yl 2-(difluoromethyl)-3,4-dimethyl-5,7dihydro-6/7-pyrrolo[3,4-b]pyridine-6 -carboxylate,

-(1,2,4-thiadiazol-5-yl)azetidin-3-yl 2,3,4-trimethyl-5,7-dihydro-6/7pyrrolo[3,4-b]pyridin-6-carboxylate,

- 17 044379

-(1,3,4-thiadiazol-2-yl)azetidin-3-yl 2,3,4-trimethyl-5,7-dihydro-6/-(pyrrolo[3,4-b]pyridin-6-carboxylate ,

1-(pyridin-3-yl)azetidin-3-yl 3-chloro-2-(methoxymethyl)-4-methyl-5,7dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate,

-(1,2,4-thiadiazol-5-yl)azetidin-3-yl 3-chloro-2,4-dimethyl-5,7-dihydro-6/-/pyrrolo[3,4-b]pyridin-6 -carboxylate;

1-(2,4-dimethyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[4-(3methyloche!an-3- yl)phenyl]azetidin-3-yl}ethanone;

3-{3-[2-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2oxoethyl]azetidin-1-yl}-4 -methoxybenzonitrile;

4-{3-[2-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-d]pyridin-6-yl)-2oxoethyl]azetidin-1-yl}-M ,M-dimethylbenzamide;

1-(2,4-dimethyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[4(hydroxymethyl)phenyl]azetidine-3 -yl}ethanone;

2-[1-(4-cyclopropylphenyl)azetidin-3-yl]-1-(2,4-dimethyl-5,7-dihydro-6/-/pyrrolo[3,4-b]pyridin-6-yl) ethanone;

2-(1 -{4-[cyclopropyl(hydroxy)methyl]phenyl}azetidin-3-yl)-1-(2,4-dimethyl5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6 -yl)ethanone;

(5-{3-[2-(2,4-dimethyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl)-2oxoethyl]azetidin-1-yl} -2-methoxyphenyl)acetonitrile;

4-{3-[2-(2,4-dimethyl-5,7-dihydro-6/7-pyrrolo[3,4-b]pyridin-6-yl)-2oxoethyl]azetidin-1-yl}-L /-methylbenzamide;

1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-£>]pyridin-6-yl)-2-[trans-2(quinazolin-7-yl)cyclopropyl]ethanone;

1-(2,4-dimethyl-5,7-dihydro-6[-[-pyrrolo[3,4-b]pyridin-6-yl)-2-[trans-2phenylcyclopropyl]ethanone;

-(2,4-dimethyl-5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl)-2-(1 phenylazetidin-3-yl)ethanone; and an N-oxide thereof, or a pharmaceutically acceptable salt or a pharmaceutically acceptable N-oxide salt thereof.

In certain other embodiments, the present invention is directed to the use of compounds, or an N-oxide, or a pharmaceutically acceptable salt of any one compound of the present invention in the treatment of an M4-mediated (or M4-related) disease or disorder.

In certain other embodiments, the present invention is directed to a method of treating an M4-mediated (or M4-related) disease or disorder in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound, or an N-oxide, or a pharmaceutically acceptable salt of any one compounds according to the present invention.

In certain embodiments, the compounds of the present invention are M4 receptor agonists, wherein the compound has binding affinity and induces an effect on the M4 receptor in the absence of the presence of a native ligand (eg, acetylcholine).

In certain other embodiments, the compounds of the present invention are positive allosteric modulators (PAMs) of the M4 receptor, where the compound has binding affinity and induces an effect on the receptor in the presence of a suboptimal concentration of native ligand (eg, acetylcholine).

In another embodiment, the compounds of the present invention induce M4 agonist and M4 PAM activity.

In certain other embodiments, the present invention is directed to the uses mentioned above, wherein the M4-mediated (or M4-related) disease or disorder is a disease or disorder that is selected from the group consisting of Alzheimer's disease, schizophrenia, pain, addiction, disorder sleep, cognitive impairment (eg

- 18 044379 mild cognitive impairment, age-related mild cognitive impairment, and amnestic mild cognitive impairment), Parkinson's disease, Huntington's disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with Dutch type amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis , inclusion body myositis, other peripheral amyloidoses, diabetes, autism and atherosclerosis.

In certain embodiments, the M4-mediated (or M4-related) disease or disorder is a disease or disorder that is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, pain, addiction, and sleep disorder.

The present invention also provides compositions (eg, pharmaceutical compositions) containing a new compound according to the present invention. Accordingly, in one embodiment, the invention provides a pharmaceutical composition containing (in a therapeutically effective amount) a new compound according to the present invention and optionally containing a pharmaceutically acceptable carrier. In one further embodiment, the invention provides a pharmaceutical composition containing (in a therapeutically effective amount) a compound of the invention, optionally containing a pharmaceutically acceptable carrier and optionally at least one additional drug or pharmaceutical agent (such as an antipsychotic agent or an antischizophrenic agent, described below) . In one embodiment, the additional drug or pharmaceutical agent is an antischizophrenic agent, as described below.

Pharmacology.

The acetylcholine muscarinic receptor M4 (also known as muscarinic 4 or CHRM4) is a human protein that is encoded for the CHRM4 gene. M4 receptors are predominantly expressed in the brain. The key areas of the brain where M4 receptor expression occurs are the striatum, cortex, and hippocampus, with the highest expression observed in the striatum (approximately 46%), where M4 is the major muscarinic subtype. M4 is expressed sporadically in the periphery (eg, testis, skin, and colon).

M4 receptors bind to G _{q /i} proteins and function as autoreceptor inhibitors in the striatum and midbrain (Zhang et al., 2002; Tzavara et al., 2004), and as postsynaptic modulatory receptors in the striatum and neocortex brain and hippocampus (Levy et al., 1991; Zhang et al., 1997). M4 receptors are also found presynaptically at glutamatergic synapses from the cerebral cortex to the striatum (Pancani, T., et al., Allosteric activation of M4 improve behavioral and physiological alterations in early symptomatic YAC128 mice, Proceedings of the National Academy of the Sciences of the United States of America, 2015 Nov. 10;112(45):14078-83), and on hippocampal glutamate neurons, where presynaptic M4 modulates glutamate release. The highest expression of M4 receptors is found in the striatum, M4 receptors also have a regulatory effect on dopaminergic neurotransmission and are coexpressed with D1 dopamine receptors in a subset of stiatal median spiny neurons that contain GABA as the main neurotransmitter (Bernard et al., 1992; Di Chiara et al. ., 1994; Ince et al., 1997).

It has been hypothesized that administration of a selective M4 agonist would provide antipsychotic activity for the treatment of schizophrenia (Felder et al., Elucidating the Role of Muscarinic Receptors in Psychosis, Life Sci. 68:2605-2613, 2001). This assumption was also supported by studies that demonstrated that M4 receptors modulate the dynamics of dopaminergic and cholinergic neurotransmission and that a state of dopamine hyperfunction results in loss of M4 function (Tzavara et al., M4 Muscarinic Receptors Regulate the Dynamics of Cholinergic and Dopaminergic Neurotransmission: Relevance to the pathophysiology and treatment of related CNS pathologies FASEB J. 18:1410-1412, 2004).

More recently, work done on the discovery of highly selective positive allosteric modulators of M4 has helped support the hypothesis that selective activation of M4 receptors may provide a new approach for treating some symptoms associated with schizophrenia, and this work also raises the possibility that selective M4 modulators may also provide treatment for other disorders in which dopaminergic function is altered in the basal ganglia (eg, Parkinson's disease and dystonia) (Brady, et al., Centrally Active Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor Reverse Amphetamine-Induced Hyperlocomotor Activity in Rats, The Journal of Pharmacology and Experimental Therapeutics, Vol. 327, No. 3). Additional work with M1- and M4-selective modulators also suggests that selective activation of M4 receptors may provide viable therapeutic agents for the safe and effective treatment of disease

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Alzheimer's and schizophrenia.

The compounds of the present invention may also be useful for the treatment/attenuation of neuropsychiatric symptoms (i.e., behavioral symptoms) associated with Alzheimer's disease and schizophrenia (Foster, Daniel J. et. al., Activation of M1 and M4 muscarinic receptors as potential treatment for Alzheimer's disease and schizophrenia, Neuropsychiatric Disease and Treatment, Volume 2014:10, pp. 183-191). These behavioral symptoms include, but are not limited to, agitation, restlessness, irritability, combativeness, disorientation, illusion, delusion, apathy, depression, disinhibition, aberrant motor and obsessive-compulsive behavior, and sleep disturbances (Dillon, Carol, et. al ., Behavioral symptoms related to cognitive impairment, Neuropsychiatric Disease and Treatment 2013:9 1443-1455). It is believed that while treating/alleviating the above-mentioned behavioral symptoms, the compounds of the present invention will also improve cognition.

In view of the above, the compounds of the present invention may be useful for the treatment of schizophrenia and Alzheimer's disease. The compounds of the present invention may also be useful in the treatment of Parkinson's disease, Huntington's disease, addiction, depression and epilepsy.

It is believed that the selective M4 activators of the present invention may also have a wide range of other therapeutic applications for the treatment of conditions or diseases of the central nervous system, including neurological, neurodegenerative and/or psychiatric disorders. Neurological, neurodegenerative and/or psychiatric disorders include, but are not limited to, (1) mood [affective] disorders; (2) neurotic, stress-related and somatoform disorders, including anxiety disorders; (3) disorders involving symptomatic cognitive impairment in mammals, including humans; (4) disorders including attention deficits, executive function deficits (working memory deficits), impulse control dysfunction, extrapyramidal symptoms, disorders based on dysfunction of the basal ganglia, hippocampus and prefrontal cortex; (5) behavioral and emotional disorders, usually beginning in childhood and adolescence; (6) psychological development disorders; (7) systemic atrophies, primarily affecting the central nervous system; (8) extrapyramidal and movement disorders; (9) behavioral syndromes associated with physiological disorders and physical factors; (10) adult personality and behavior disorders; (11) schizophrenia and other psychotic disorders; (12) mental and behavioral disorders associated with psychoactive substance use; (13) sexual dysfunction, including excessive sexual desire; (14) mental retardation; (15) factitious disorders, such as acute hallucinatory mania; (16) episodic and paroxysmal disorders, epilepsy; (17) narcolepsy; (18) dementia and (19) amyotrophic lateral sclerosis.

Examples of mood disorders that may be treated in accordance with the present invention include, but are not limited to, bipolar I disorder, hypomania (manic and mixed), bipolar II disorder; depressive disorders such as single depressive episode or recurrent major depressive disorder, chronic depression, psychotic depression, minor depressive disorder, postpartum onset depressive disorder, depressive disorders with psychotic symptoms; persistent mood disorders [affective disorders], such as cyclothymia, dysthymia, euthymia; premenstrual syndrome (PMS) and premenstrual dysphoric disorder.

Examples of neurotic, stress-related and somatoform disorders that can be treated in accordance with the present invention include, but are not limited to, anxiety disorders, social anxiety disorders, general anxiety disorders, panic disorder with or without agoraphobia, specific phobia, social phobia, chronic anxiety disorders; obsessive-compulsive disorder; adaptation and severe stress response disorders such as post-traumatic stress disorder (PTSD), acute stress disorder; other neurotic disorders such as depersonalization-derealization syndrome.

The phrase cognitive deficit, as used herein, is a disorder involving a symptom of cognitive deficit that refers to subnormal functioning or suboptimal functioning in one or more cognitive domains, such as memory, intelligence, learning and reasoning ability, or attention and executive function ( working memory), in a given individual comparison with other individuals within the same general age population.

Examples of disorders involving the symptom of cognitive impairment that may be treated in accordance with the present invention include, but are not limited to, cognitive impairment primarily, but not exclusively, associated with memory loss, psychosis (schizophrenia), Parkinson's disease, Alzheimer's disease, multifactorial dementia, senile dementia,

- 20 044379 dementia with Lewy bodies, stroke, frontotemporal dementia, progressive supranuclear palsy, dementia associated with Huntington's disease, HIV disease (HIV-associated dementia), brain injury and drug abuse; mild cognitive impairment

ADHD, Asperger's syndrome, and age-related memory impairment; cognitive decline or postoperative delirium or in combination with intensive care.

Examples of disorders typically first diagnosed in early childhood, childhood, and adolescence that may be treated in accordance with the present invention include, but are not limited to, hyperkinetic disorders, including activity and attention disorders, attention-deficit/hyperactivity disorder (ADHD) ), hyperkinetic behavior disorder; attention deficit disorder (ADD); conduct disorder, including but not limited to depressive conduct disorder; tic disorders, including transient tic disorders, chronic motor or vocal tic disorders, combined vocal and multifactorial motor tic disorders (Gilles de la Tourette syndrome), substance-induced tic disorders; autistic disorders; Batten disease, excessive masturbation, nail biting, nose picking and thumb sucking.

Examples of developmental disorders that can be treated in accordance with the present invention include, but are not limited to, pervasive developmental disorders, including, but not limited to, Asperger's syndrome, Rett syndrome, autistic disorders, childhood autism and hyperactive disorder associated with intellectual development. retardation and stereotypical movements, specific developmental disorders of motor function, impaired development of school skills.

Examples of systemic atrophies primarily affecting the central nervous system that may be treated in accordance with the present invention include, but are not limited to, multiple sclerosis, systemic atrophies primarily affecting the basal ganglia, including Huntington's disease, and amyotrophic lateral sclerosis.

Examples of extrapyramidal and movement disorders with dysfunction and/or degeneration of the basal ganglia that can be treated in accordance with the present invention include, but are not limited to, Huntington's disease; Parkinson's disease; secondary parkinsonism such as postencephalitic parkinsonism; parkinsonism present in other disorders; Neman-Pick disease, Lewy body disease; degenerative diseases of the basal ganglia; other extrapyramidal and movement disorders including tremor, essential and drug-induced tremor, myoclonus, chorea and drug-induced chorea, drug-induced and organic tics, drug-induced acute dystonia, drug-induced tardive dyskinesia, muscle spasms and disorders associated with muscle spasticity or weakness, including tremors; mental retardation (including spasticity, Down syndrome and fragile X syndrome) caused by L-dopa dyskinesia; restless legs syndrome and stiff muscle syndrome.

Other examples of movement disorders with dysfunction and/or degeneration of the basal ganglia that may be treated in accordance with the present invention include, but are not limited to, dystonia, including, but not limited to, focal dystonia, multiple focal or segmental dystonia, torsion dystonia , hemispherical, generalized and tardive dystonia (induced by psychopharmacological drugs). Focal dystonia includes cervical dystonia (torticollis), blepharospasm (eyelid spasm), appendicular dystonia (limb spasms, like writer's cramp), or mandibular dystonia and spasmodic dysphonia (vocal cord spasm); antipsychotic-induced movement disorders including, but not limited to, neuroleptic malignant syndrome (NMS), antipsychotic-induced parkinsonism, early-onset antipsychotic-induced or acute dyskinesia, antipsychotic-induced acute dystonia, antipsychotic-induced acute akathisia, antipsychotic-induced tardive dyskinesia, antipsychotic-induced tremor .

Examples of behavioral syndromes associated with physiological disturbances and physical factors in accordance with the present invention include, but are not limited to, non-organic sleep disorders, including, but not limited to, non-organic hypersomnia, non-organic sleep and wakefulness disorder (circadian rhythm sleep disorder) , insomnia, parasomnia and sleep deprivation; mental and behavioral disorders associated with the postpartum period, including postnatal and postpartum depression; eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, binge eating disorder, hyperphagia, obesity, compulsive eating disorders and pagophagia.

Examples of personality and behavior disorders in adulthood that may be treated in accordance with the present invention include, but are not limited to, personality disorders including, but not limited to, emotionally unstable, borderline, obsessive-compulsive, anancastic, dependent and passive-aggressive personality disorder; habit and impulse disorders (impulse control disorders), including intermittent temper disorder, gambling disorder, pathological arson (pyromania), pathological theft (kleptomania), trichotillomania; Munchausen syndrome.

Examples of schizophrenia and other psychotic disorders that can be treated in accordance with the present invention include, but are not limited to, continuous or episodic schizophrenia of various types (eg, paranoid, hebephrenic, catatonic, undifferentiated, residual and schizophrenia-like disorders); schizotypal disorders (such as borderline, latent, prepsychotic, prodromal, pseudoneurotic, pseudopsychopathic schizophrenia and schizotypal personality disorder); persistent delusional disorders; acute, transient and persistent mental disorders; induced delusional disorders; schizoaffective disorders of various types (for example, manic-depressive or mixed type); postpartum psychosis and other and non-specific non-organic psychoses, such as social withdrawal in schizophrenia.

Examples of mental and behavioral disorders caused by the use of psychoactive substances that can be treated in accordance with the present invention include, but are not limited to, mental and behavioral disorders caused by the use of alcohol, opiates, cannabinoids, sedatives or hypnotics, cocaine; mental and behavioral disorders associated with the use of other stimulants, including caffeine, mental and behavioral disorders associated with drug dependence and abuse (eg, drug dependence, alcoholism, amphetamine and methamphetamine dependence, opioid dependence, cocaine dependence, nicotine dependence, drug withdrawal syndrome drugs and relapse prevention), use of hallucinogens, tobacco (nicotine), volatile solvents, and mental and behavioral disorders due to repeated drug use and use of other psychoactive substances, including the following symptom subtypes: harmful use, dependence syndrome, withdrawal and condition withdrawal with delirium.

Examples of dementia that can be treated in accordance with the present invention include, but are not limited to, vascular dementia, dementia due to Creutzfeldt-Jakob disease, HIV, traumatic brain injury, Parkinson's disease, Huntington's disease, Pick's disease, dementia of the Alzheimer's type.

In certain embodiments, the present invention is directed to the use of compounds of the present invention for the treatment of schizophrenia by administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof.

In certain other embodiments, the invention is further directed to the use of compounds of the present invention for the treatment of cognitive impairment associated with schizophrenia by administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof.

Schizophrenia or psychosis for which the above compounds, their Noxide and pharmaceutically acceptable salts according to the invention may be useful includes one or more of the following conditions: schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizophrenic affective disorder, delusional disorder, short-term psychotic disorder, general psychotic disorder, psychotic disorder due to a general health condition and caused by psychoactive substances or drugs (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine), psychosopsychotic disorder, psychosis associated with mood disorders, short-term reactive psychosis, schizoaffective psychosis, schizophrenia spectrum disorders such as schizoid or schizotypal personality disorders, or illnesses associated with psychosis (such as major depression, manic-depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both positive, and negative symptoms of schizophrenia and other psychoses; cognitive impairment, including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV infection, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other general medical conditions or abuse substances); delirium, amnestic disorders, or age-related cognitive decline.

In addition to the central nervous system disorders mentioned above, the compounds of the present invention may be used to treat other M4-mediated (or M4-related) disorders such as, but not limited to, addiction (e.g., substance dependence such as dependence on opioids, cocaine, or alcohol), pain (eg, acute pain, inflammatory pain, and neuropathic pain), and sleep disorder (eg, those associated with the regulation of REM sleep, such as those associated with the onset of REM sleep) . Additional M4-mediated (or M4-related) disorders or conditions that may be treated with compounds of the invention include dry mouth, cognitive impairment (eg, mild cognitive impairment), dyskinesias, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, Trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia (eg, degenerative dementia), hereditary cerebral hemorrhage with Dutch type amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders , amyotrophic lateral sclerosis, progressive supranuclear palsy, head injury, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism and atherosclerosis. See, for example, US 8664234. Potential sleep disorders for which the above compounds, their N-oxide and pharmaceutically acceptable salts of the present invention may be useful include improving sleep quality; improving sleep quality; increased sleep maintenance; an increase in value that is calculated from the time the subject is asleep divided by the time the subject is trying to fall asleep; reducing sleep latency or onset (the time it takes to fall asleep); reducing difficulty falling asleep; increasing sleep duration; reducing the number of awakenings during sleep; reduction of night awakenings; decreased time spent awake after the initial onset of sleep; increasing the total amount of sleep; reducing sleep fragmentation; changes in the timing, frequency, or duration of REM sleep bouts; changes in the timing, frequency, or duration of slow wave (i.e., stage 3 or 4) sleep episodes; increase in the amount and percentage of stage 2 sleep; promoting slow wave sleep; increased delta EEG activity during sleep; increased wakefulness during the day; reduction of daytime sleepiness; treating or reducing excessive daytime sleepiness; insomnia; hypersomnolence; narcolepsy; interrupted sleep; sleep apnea; wakefulness; nocturnal myoclonus; interruption of REM sleep; circadian jet lag disorder caused by jet lag; sleep disturbance caused by shift work; dissomnia; night terror; insomnia associated with depression, emotional and mood disorders, as well as sleepwalking and enuresis, as well as sleep disorders that accompany aging; evening confusion in Alzheimer's disease; conditions related to circadian rhythms, as well as mental and physical disorders associated with travel across time zones and rotating shift work schedules; conditions associated with medications that cause decreased REM sleep as a side effect; syndromes that involve non-restorative sleep and muscle pain or sleep apnea, which are associated with sleep-disturbed breathing; and conditions that arise as a result of deteriorating sleep quality.

Pain disorders for which the compounds, its N-oxide and pharmaceutically acceptable salts of the above invention can be used include neuropathic pain (such as postherpetic neuralgia, nerve damage, dynia, e.g. vulvodynia, phantom limb pain, root disorders, painful diabetic neuropathy , painful traumatic mononeuropathy, painful polyneuropathy); central pain syndromes (potentially caused by almost any lesion at any level of the nervous system); postoperative pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), pain with repetitive motion, toothache, cancer pain, myofascial pain (muscle damage, fibromyalgia); perioperative pain (general surgery, gynecology), chronic pain, dysmenorrhea, as well as pain associated with angina pectoris and inflammatory pain of various origins (for example, osteoarthritis, rheumatoid arthritis, rheumatic diseases, tenosynovitis and gout), headache, migraine and cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia or other pain caused by central sensitization.

The compounds, their N-oxides and pharmaceutically acceptable salts of the present invention can be used to reduce tolerance and/or dependence on opioid pain treatment and to treat withdrawal symptoms, for example, alcohol, opioids and cocaine.

Drugs.

The compounds of the invention can be administered orally. Oral administration may involve ingestion, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, whereby the compound enters the bloodstream directly from the oral cavity.

In another embodiment, the compounds of the invention can also be administered directly into the bloodstream, into a muscle or into an internal organ.

Acceptable routes of parenteral administration include intravenous, intra-arterial, intra-abdominal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Acceptable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques.

In another embodiment, the compounds of the invention may also be formulated such that administration topically to the skin or mucosa (ie, dermal or transdermal) results in systemic absorption of the compound. In another embodiment, the compounds of the invention may also be formulated such that intranasal or inhalation administration results in systemic absorption of the compound. In another embodiment, the compounds of the invention may be formulated such that rectal or vaginal administration results in systemic absorption of the compound.

The dosage regimen for compounds and/or compositions containing compounds is based on many factors, including the type, age, weight, sex and medical condition of the patient; severity of condition; route of administration; and the activity of the specific compounds that are used. Thus, the dosage regimen can vary within wide limits. Dosage levels on the order of about 0.01 mg to about 100 mg per kilogram of body weight per day are acceptable in the treatment of the above conditions. In another embodiment, the total daily dose of a compound of the invention (administered in a single dose or divided doses) is typically from about 0.01 to about 100 mg/kg. In another embodiment, the total daily dose of a compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg of compound of the invention per kg body weight). In one embodiment, the dosage is from 0.01 to 10 mg/kg/day. In another embodiment, the dosage is from 0.1 to 1.0 mg/kg/day. Dosed unit compositions may contain such amounts or subunits thereof as constitute a daily dose. In many cases, administration of the compound will be repeated several times a day (usually no more than 4 times). Typically, several doses per day may be used to increase the total daily dose if necessary.

For oral administration, the compositions may be presented in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25 ,0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 mg of the active ingredient for symptomatic dosage adjustment to the patient. The drug typically contains from about 0.01 mg to about 500 mg of active ingredient, or alternatively from about 1 mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

Acceptable subjects in accordance with the present invention include mammalian subjects. Mammals in accordance with the present invention include, but are not limited to, dog, cat, cow, goat, horse, sheep, pig, rodents, lagomorphs, primates and the like and include mammals in utero. In one embodiment, people are acceptable subjects. Human subjects can be of any gender and at any stage of development.

In another embodiment, the invention includes the use of one or more compounds of the invention for the preparation of a medicament for the treatment of conditions described herein.

For the treatment of the conditions mentioned above, the compound according to the invention can be administered as a compound per se. Alternatively, pharmaceutically acceptable salts are acceptable for medical applications due to their greater solubility in water compared to the parent compound.

In another embodiment, the present invention includes pharmaceutical compositions. Such pharmaceutical compositions contain a compound of the invention presented with a pharmaceutically acceptable carrier. The carrier may be solid, liquid, or both, and may be formulated with the compound in a unit dosage composition, such as a tablet, which may contain from 0.05 to 95% by weight of the active compounds. The compound of the invention may be combined with suitable polymers as useful carriers in a medicament. In addition, other pharmacologically active substances may be present.

The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such route of administration and at a dose effective for the intended treatment. The active compounds and compositions, for example, may be administered orally, rectally, parenterally, or topically (eg, intranasally or ophthalmically).

Oral administration of a solid dosage form may, for example, be presented in discrete units such as hard or soft capsules, dragees, sachets, lozenges or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, oral administration may be in the form of a powder or granules. In another embodiment, the oral dosage form is sublingual, such as, for example, lozenges. In such solid dosage forms, the compounds of the present invention are typically combined with one or more excipients. Such capsules or tablets may contain a controlled release composition. In the case of capsules, tablets and dragees, dosage forms may also contain buffering agents or may be formulated with an enteric coating.

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In another embodiment, oral administration may be in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art (eg, water). Such compositions may also contain auxiliary substances such as wetting, emulsifying, suspending, flavoring (eg, sweetening) and/or flavoring agents.

In another embodiment, the present invention includes a parenteral dosage form. Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections and infusions. Injectable preparations (eg, sterile aqueous or oleaginous injectable suspensions) may be formulated as known in the art using suitable dispersing, wetting and/or suspending agents and include depot preparations.

In another embodiment, the present invention includes a dosage form for topical administration. Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments and creams. Topical formulations may include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present invention are administered using a transdermal device, administration will be via a patch or reservoir, or porous membrane type, or various solid matrices. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, implant capsules, implants, sponges, fibers, bandages and microemulsions. In addition, liposomes can be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Included may be penetration enhancing agents; see, for example, Finnin and Morgan J. Pharm. Sci., 88(10), 955958 (1999).

Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of the present invention is dissolved or suspended in a suitable vehicle. A typical formulation suitable for ocular or auricular administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-regulated, sterile saline. Other formulations acceptable for ocular and ear administration include biodegradable ointments (eg, absorbable gel sponges, collagen) and non-biodegradable (eg, silicone) implants, implant capsules, lenses, and particle or vesicle systems. , such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer such as (hydroxypropyl)methylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer such as gellan gum may be included along with a preservative such as benzalkonium chloride. Such drugs can also be administered using iontophoresis.

For intranasal or inhalation administration, the active compounds of the invention are typically administered in the form of a solution or suspension from a nebulizer pump container that is compressed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer using an appropriate propellant. Compositions suitable for intranasal administration are typically administered as a dry powder (or alone, as a mixture, for example a dry mixture with lactose, or as mixed particulate components, for example mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, nebulizer (preferably an atomizer using electrohydrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1 ,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain bioadhesive agents such as chitosan or cyclodextrin.

In another embodiment, the present invention includes a rectal dosage form. Such rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives can be used if necessary.

In addition, other carrier materials and methods of administration known in the pharmaceutical field may be used. The pharmaceutical compositions of the invention can be prepared using any of the methods well known in the pharmaceutical art, such as methods for efficient formulation and administration. The above considerations regarding effective drugs and routes of administration are well known in the art and are described in standard textbooks. Drug formulation is discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences,

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Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel

Decker, New York, NY, 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients ( ^3rd Ed.), American Pharmaceutical Association, Washington, 1999.

The compounds of the present invention can be used alone or in combination with other therapeutic agents in the treatment of various diseases or disease states. The compound(s) of the present invention and the other therapeutic agent(s) may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. An exemplary therapeutic agent may be, for example, a metabotropic glutamate receptor agonist.

Administering two or more compounds in combination means that the two compounds are administered at a sufficiently close interval of time such that the presence of one alters the biological effects of the other. Two or more compounds may be administered simultaneously, competitively, or sequentially. In addition, simultaneous administration can be accomplished by mixing the compound prior to administration or by administering the compounds at the same time point but at different anatomical sites or using different routes of administration.

The phrases competitive administration, co-administration, simultaneous administration and co-administered mean that the compound is administered in combination.

The present invention includes the use of a combination of an M4 activator compound of the present invention and one or more additional pharmaceutically active agent(s). If a combination of active agents is administered, they may be administered sequentially or simultaneously in separate dosage forms or combined in a single dosage form. Accordingly, the present invention also includes pharmaceutical compositions containing a specified amount of: (a) a first agent containing a compound of the present invention or a pharmaceutically acceptable salt of the compound; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, excipient or diluent.

Various pharmaceutical active agents may be selected for use in combination with the compounds of the present invention depending on the disease, disorder or condition being treated. Pharmaceutically active agents that can be used in combination with the compositions of the present invention include, but are not limited to:

(i) acetylcholinesterase inhibitors such as donepezil hydrochloride (ARICEPT, MEMAS), physostigmine salicylate (ANTILIRIUM), physostigmine sulfate (ESERINE), metrifonate, neostigmine, gunstigmine, pyridostigmine (MESTINON), ambenonium (MYTELASE), demarcarium, Debio 9902 (also known as ZT 1; Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361, galantamine hydrobromide (RAZADYNE, REMINYL, NIVALIN), tacrine (COGNEX), tolserine, velnacrine maleate, memoquine, huperzine A (HUP-A; Neuro- Hitech), phenserine, edrophonium (ENLON, TENSILON) and INM-176;

(ii) amyloid-β (or fragment thereof), such as Ae1_ ₁₅ conjugated to the pan HLA DR binding epitope (PADRE), ACC-001 (Elan/Wyeth), ACI-01 ACI-24, AN-1792, Affitope AD -01, CAD106, and V-950;

(iii) amyloid-β antibodies (or fragment thereof), such as ponezumab, solanezumab, bapineizumab (also known as AAV-001), AAV-002 (Wyeth/Elan), ACI-01-Ab7, BAN-2401, intravenous Ig (GAMMAGARD), LY2062430 (humanized m266; Lilly), R1450 (Roche), ACU-5A5, huC091, and those described in international patent publication No. WO 04/032868, WO 05/025616, WO 06/036291, WO 06/069081, WO 06/118959, in US Patent Publication No. US 2003/0073655, US 2004/0192898, US 2005/0048049, US 2005/0019328, in European Patent Publication No. EP0994728 and 1257584, and in Patent US No. 5750349;

(iv) amyloid-lowering or inhibiting agents (including those that reduce the production, accumulation and fibrillization of amyloid), such as dimebon, davunetide, eprodisate, leprolide, SK-PC-B70M, celecoxib, lovastatin, Anapsos, oxiracetam, pramiracetam, varenicline, nicergoline, colostrinine, bicnorcimserine (also known as BNC), NIC5-15 (Humanetics), E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2 (Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and its Tarenflurbil R-enantiomer (FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), ibuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofen lysinate, meclofenamic acid, meclofenamate sodium (MECLOMEN), indomethacin (INDOCIN), diclofenac sodium (VOLTAREN), diclofenac potassium, sulindac (CLINORIL), sulindac sulfide, diflunisal (DOLOBID), naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031 (Archer Pharmaceuticals), CAD-106 (Cytos), LY450139 (Lilly), insulin degrading enzyme ( also known as insulin), Ginkgo biloba extract EGb761 (ROKAN, TEBONIN), tramiprosate (CEREBRIL, ALZHEMED), eprosidate (FIBRILLEX, KIACTA), compound W (3,5-bis(4-nitrophenoxy)benzoic acid), NGX-96992 , neprilysin (also known as neutral endopeptidase (NEP)), scylla-inositol (also known as scyllitol), atorvastatin (LIPITOR), simvastatin (ZOCOR), KLVFF-(EEX) 3, SKF-74652, ibutamorene mesylate, BACE inhibitors, such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609 and TTP-854; gamma secretase modulators such as ELND-007 and RAGE inhibitors (re-

- 26 044379 advanced glycation end product receptor), such as TTP488 (Transtech) and TTP4000 (Transtech), and those disclosed in US patent No. 7285293, including PTI-777;

(v) alpha adrenergic agonists and agents such as guanfacine (INTUNIV, TENEX), clonidine (CATAPRES), metaraminol (ARAMINE), methyldopa (ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine (also known as neosynephrine) , methoxamine, cirazoline, guanfacine (INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, and armodafinil (NUVIGIL);

(vi) beta-adrenergic blocking agents (beta blockers) such as carteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE), oxprenolol (lARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL), sotalol (VETARACE, SOTALEX, SOTACOR), timolol (BLOCADREN, TIMOPTIC), acebutolol (SECTRAL, PRENT), nadolol (CORGARD), metoprolol tartrate (LOPRESSOR), metoprolol succinate (TOPROL-XL), atenolol (TENORMIN), butoxamine, and SR 59230A (Sanofi );

(vii) anticholinergics such as amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), chyoscyamine, atropine (ATROPEN), scopolamine (TRANSDERM-SCOP) , scopolamine methyl bromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL, OKCMTROL), pentienate bromide, propantheline (PRO-BANTHINE), cyclizine, imipramine hydrochloride (TOFRANIL) , imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramine (SURMONTIL) and glycopyrrolate (ROBINUL);

(viii) anticonvulsants, such as carbamazepine (TEGRETOL, CARBATROL), oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), fosphenytoin (CEREBYX, PRODILANTIN), sodium divalproate (DEPAKOTE), gabapentin (NEURONTIN), pregabalin (LYRICA), torpyrimate ( TORAMAC), valproic acid (DEPAKENE), sodium valproate (DEPACON), 1-benzyl-5-bromouracil, progabide, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022, retigabine, talampanel, and primidone (MYSOLINE);

(ix) antipsychotics such as lurasidone (LATUDA, also known as SM-13496; Dainippon Sumitomo), aripiprazole (ABILIFY), chlorpromazine (THORAZINE), haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate (DEPIXOL, FLUANXOL), reserpine (SERPLAN), pimozide (ORAP), fluphenazine decanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO), asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MOBAN), perphenazine, thioridazine, thiothixine, trifluoroperazine (STELAZINE), ramelteon, clozapine (CLOZARIL), norclozapine (ACP-104), risperidone (RISPERDAL), paliperidone (INVEGA), melperone, olanzapine (ZYPREXA), quetiapine (SEROQUEL), talnetant, amisulpride, ziprasidone (GEODON), blonanserin (LONASEN) and ACP-103 (Acadia Pharmaceuticals);

(x) calcium channel blockers such as lomerizin, ziconotide, nilvadipine (ESCOR, NIVADIL), diperdipine, amlodipine (NORVASC, ISTIN, AMLODIN), felodipine (PLENDIL), nicardipine (CARDENE), nifedipine (ADALAT, PROCARDIA), MEM 1003 and its parent compound - nimodipine (NIMOTOP), nisoldipine (SULAR), nitrendipine, lacidipine (LACIPIL, MOTENS), lercanidipine (ZANIDIP), lifarizin, diltiazem (CARDIZEM), verapamil (CALAN, VERELAN), AR-R 18565 (AstraZeneca) and enecadin;

(xi) catechol O-methyltransferase (COMT) inhibitors such as nitecapone, tolcapone (TASMAR), entacapone (COMTAN) and tropolone;

(xii) central nervous system stimulants such as atomoxetine, reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine, pemoline, phencamphamine (GLUCOENERGAN, REACTIVAN), phenethyline (CAPTAGON), pipradole (MERETRAN), deanol (also known as dimethylaminoethanol), methylphenidate (Daytrana), methylphenidate hydrochloride (Ritalin), Dexmethythenidate (Focalin), amphetamine (independently or in combination with other stimulants of the central nervous system, such as Addrall (amphetamamin aspartate, amphetamine Sulfate, dextSthamphetamine Sulfate) sulfate (dexedrine, dextrostat) , methamphetamine (DESOXYN), lisdecamphetamine (VYVANSE) and benzphetamine (DIDREX);

(xiii) corticosteroids such as prednisone (STERAPRED, DELTASONE), prednisolone (PRELONE), prednisolone acetate (OMNIPRED, PRED MILD, PRED FORTE), prednisolone sodium phosphate (ORAPRED ODT), methylprednisolone (MEDROL), methylprednisolone acetate (DEPO-MEDROL) and methylprednisolone sodium succinate (A-METHAPRED, SOLU-MEDROL);

(xiv) dopamine receptor agonists such as apomorphine (APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydrexidine, dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN), terguride spergolide (PERMAX), piribedil (TRIVASTAL, TRaStAL) , pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-82958 (GlaxoSmithKline), cariprazine, pardoprunox, and sarizotan;

(xv) dopamine receptor antagonists such as chlorpromazine, fluphenazine, halogenperidol, loxapine, risperidone, thioridazine, thiothixene, trifluoroperazine, tetrabenazine (NITOMAN, XENAZINE),

- 27 044379

7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN), domperidone (MOTILIUM) L741742, L-745870, raclopride, SB-277011A, SCH-23390, ecopipam, SKF-83566, and metoclopramide (REGLAN);

(xvi) dopamine reuptake inhibitors such as bupropion, safinamide, nomifensine maleate (MERITAL), vanoxerine (also known as GBR-12909) and its decanoate ester DBL583, and aminoptine;

(xvii) gamma-aminobutyric acid (GABA) receptor agonists such as baclofen (LIORESAL, KEMSTRO), cyclofen, pentobarbital (NEMBUTAL), progabide (GABRENE) and clomethiazole;

(xviii) histamine 3 (H3) antagonists such as ciproxifan, tiprolisant, S-38093, irdabicant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP-404, SAR-110894, trans- N-ethyl3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxamide (PF-3654746 and those disclosed in US Patent Publication No. US 2005-0043354, US 2005-0267095, US 2005-0256135, US 20080096955, US 2007-1079175, and US 2008-0176925, International Patent Publication No. WO 2006/136924, WO 2007/063385, WO 2007/069053, WO 2007/0884 50, WO 2007/099423, WO 2007/ 105053, WO 2007/138431 and WO 2007/088462; and US patent No. 7115600);

(xix) immunomodulators such as glatiramer acetate (also known as copolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic protein peptide), dimethyl fumarate, fingolimod (also known as FTY720), roquinimex (LINOMIDE), laquinimod (also known as ABR-215062 and SAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab (RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX) and natalizumab (TYSABRI);

(xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX), mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN), mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR, CYTOXAN ), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, etanercept (ENBREL) and 4-(benzyloxy)-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H, 1Ή-2,2-bipyrol (also known as PNU-156804);

(xxi) interferons, including interferon beta-1a (AVONEX, REBIF) and interferon beta-1b (BETASERON, BETAFERON);

(xxii) levodopa (or its methyl or ethyl ester), alone or in combination with a DOPA dopadecarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR), α-methyldopa, monofluoromethyldopa, difluoromethyldopa, brocresin, or -hydroxybenzylhydrazine);

(xxiii) N-methyl-O-aspartate (NMDA) receptor antagonists such as memantine (NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate (CAMPRAL), besonprodil, ketamine (KETALAR), delucemine, dexanabinol, dexefaroxane, dextrometorfan, dextrofan, traxproopoli, ch283097, gimantan, Idantadol, Ipenoksazon, L-701252 (Merck), Lancicemin, Levorfanol (Dromoran), Ly-233536 and Ly-235959 (both Lily), methadone, non-grazin, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzanan, perzinan Fotel, Fenciclidine , tianeptine (STABLON), dizocilpine (also known as MK-801), EAB-318 (Wyeth), ibogaine, voacangine, tiletamine, riluzole (RILUTEK), aptiganel (CERESTAT), gavestinel and remacimide;

(xxiv) monoamine oxidase inhibitors (MAOIs), such as selegiline (EMSAM), selegiline hydrochloride (L-deprenyl, ELDEPRYL, ZELAPAR), dimethylselegiline, brofaromine, phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide (AURORIX, MANERIX), befloxatone , safinamide, isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT), iproniazid (MARSILID, IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iprocloside, toloxatone (HUMORYL, PERENUM), biphemelan, deoxypeganine, harmine ( also known as telepatin or banasterine), harmaline, linezolid (ZYVOX, ZYVOXID) and pargyline (EUDATIN, SUPIRDYL);

(xxv) muscarinic receptor agonists; (particularly subtype M1), such as cevimeline, levetiracetam, vetanecol chloride (DUVOID, URECHOLINE), itamelin, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck), L-689660 (Merck), furtretonium iodide (FURAMON , FURANOL), furtretonium benzenesulfonate, furtretonium p-toluenesulfonate, McN-A-343, oxotremorine, sabcomelin, AC90222 (Acadia Pharmaceuticals) and carbachol (CARBASTAT, MIOSTAT, CARBOPTIC);

(xxvi) neuroprotective drugs such as bosutinib, condoliase, airmoclomol, lamotrigine, perampanel, aniracetam, minaprim, riluzole, N-hydroxy-1,2,4,9-tetrahydro-3H-carbazole-3imine, desmoteplase, anatibant, astaxanthin , neuropeptide NAP (e.g. AL-108 and AL-208, both Allon Therapeutics), neurostrol, perampenel, ispronicline, bis(4-β-O-glucopyranosyloxybenzyl)-2-β-Oglucopyranosyl-2-isobutyl tartrate (also known as dactylorquine B or DHB), formobactin, xaliprobene (XAPRILA), lactacystin, dimeboline hydrochloride (DIMEBON), disufentone (CEROVIVE), arundic acid (ONO-2506, PROGLIA, CEREACT), citicoline (also known as cytidine 5'diphosphocholine), edaravone ( RADICUT), AEOL-10113 and AEOL-10150 (both Aeolus Pharmaceuticals), AGY94806 (also known as SA-450 and Msc-1), granulocyte colony stimulating factor (also known as AX-200), BAY-38-7271 (also known as KN-387271; Bayer AG), ancrod (VIPRINEX,

- 28 044379

ARWIN), DP-b99 (D-Pharm Ltd), HF-0220 (17-β-hydroxyepiandrosterone; Newron Pharmaceuticals), HF0420 (also known as oligotropin), pyridoxal 5'-phosphate (also known as MC-1), microplasmin , S-18986, piclozotan, NP031112, tacrolimus, L-seryl-E-methionyl-E-alanyl-E-lysyl-Eglutamyl-glycyl-L-valine, AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes of Health), stilbazulenil nitrone, SUN-N8075 (Daiichi Suntory Biomedical Research) and zonampanel;

(xxvii) nicotinic receptor agonists such as epibatidine, bupropion, CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328 (AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche/ Memory Pharmaceuticals), R4996 (also known as MEM63908; Roche/Memory Pharmaceuticals), TC-4959 and TC-5619 (both Targacept), and RJR-2403;

(xxviii) norepinephrine reuptake inhibitors (norepinephrine), such as atomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN), nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine (ASENDIN, DEMOLOX, MOXIDIl), reboxetine (EDRONAX, VESTRA ), viloxazine (VIVALAN), maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (WELLBUTRIN) and radaxafine;

(xxix) phosphodiesterase (PDE) inhibitors, including but not limited to, (a) PDE1 inhibitors (e.g., Vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and those disclosed in US Pat. No. 6,235,742), (b) PDE2 inhibitors (e.g. , erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, and those described in US Pat. No. 6,174,884), (c) PDE3 inhibitors (e.g., anagrelide, cilostazol, milrinone, olprinon, parogrelil and pimobendan), (d) PDE4 inhibitors (eg, apremilast, ibudilast, roflumilast, rolipram, Ro 20-1724, ibudilast (KETAS), piclamilast (also known as RP73401), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast, olemilast (also known as GRC 3886), tetomilast (also known as ORC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR), arophylline (also known as LAS-31025), doxophylline, RPR-122818, or mesembrine), and (f) PDE5 inhibitors (eg, sildenafil (VIAGRA, REVATIO), tadalafil (CIALIS), vardenafil (LEVITRA, VIVANZa), udenafil, avanafil, dipyridamole (PERSANTINE), E-4010, E-4021, E8010, zaprinast, iodenafil , mirodenafil, DA-8159, and those disclosed in international patent applications WO 2002/020521, WO 2005/049616, WO 2006/120552, WO 2006/126081, WO 2006/126082, WO 2006/126083 and WO 2 007/122466 ), (f) PDE7 inhibitors; (g) PDE8 inhibitors; (h) PDE9 inhibitors (for example, BAY 73-6691 (Bayer AG) and those disclosed in US Patent Publications No. US 2003/0195205, US 2004/0220186, US 2006/0111372, US 2006/0106035 and USSN 12/118,062 (filed May 9, 2008)), (i) PDE10 inhibitors such as 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline- 3(4H)-one and SCH-1518291 and (j) PDE11 inhibitors;

(xxx) quinolines such as quinine (including its hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate salts), chlorquine, sontoquine, hydroxychlorquine (PLAQUENIL), mefloquine (LARIAM) and amodiaquine (CAMOQUIN, FLAVOQUINE);

(xxxi) β-secretase inhibitors such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ12304146, BMS-782450, GSK-188909, NB-533, LY-2886721, E-2609, HPP- 854, (+)-phenserine tartrate (POSIPHEN), LSN-2434074 (also known as LY-2434074), KMI-574, SCH-745966, Ac-rER (N ² acetyl-O-arginyl-E-arginine), loxistatin (also known as E64d) and CA074Me;

(xxxii) γ-secretase inhibitors and modulators. such as BMS-708163 (Avagacest), WO 20060430064 (Merck), DSP8658 (Dainippon), ITI-009, L-685458 (Merck), ELAN-G, ELAN-Z, 4-chloro-N-[(2S)- 3-ethyl-1hydroxypentan-2-yl]benzenesulfonamide;

(xxxiii) serotonin (5-hydroxytryptamine) 1A receptor antagonists (5-HT _1A ), such as spiperone, leopindolol, BMY 7378, NAD-299, S-(-)-UH-301, NAN 190, lecosotan;

(xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT _2c ) receptor agonists such as vabikaserin and zicronapine;

(xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT ₄ ) receptor agonists such as PRX-03140 (Epix);

(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT6) receptor antagonists such as A-964324, AVI-101, AVN-211, mianserin (TOLVON, BOLVIDON, NORVAL), methiothepin (also known as methepine), ritanserin , ALX-1161, ALX-1175, MS-245, LY-483518 (also known as SGS518; Lilly), MS-245, Ro 04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885, SB-214111, SB258510, SB-271046, SB-357134, SB-699929, SB-271046, SB-742457 (GLAXOSMITHKLINE), LU AE58054 (LUNDBECK A/S). PRX-07034 (Epix);

(xxxvii) serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine (PONDIMIN) , norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL, SErOkCAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine, desvenlafaxine (PRISTIQ), brasofensine, vilazodone, cariprazine, neuralstem and tesofensine;

- 29 044379 (xxxviii) trophic factors such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neoblastin , meteorin, and glial-derived neurotrophic factor (GDNF), and agents that stimulate the production of trophic factors such as propentofilin, idebenone, PYM50028 (COGANE; Phytopharm) and AIT-082 (NeOTROFIN);

(xxxix) glycine transporter-1 inhibitors such as paliflutin, ORG-25935, JNJ-17305600, and ORG-26041;

(xl) AMPA-type glutamate receptor modulators such as perampanel, mibampator, selurampanel, GSK-729327 and N-{(3S,4S)-4-[4-(5-cyanothiophen-2-yl)phenoxy]tetrahydrofuran-3 -yl}propan-2sulfonamide and the like.

(xli) Janus kinase (JAK) inhibitors such as, but not limited to, tofacitinib, ruloxolitinib, baricitinib, CYT387, GLPG0634, lestaurtinib, pacritinib and TG101348.

(xlii) interleukin-1 receptor associated kinase 4 (IRAK4) inhibitors such as, but not limited to, PF-06650833.

The present invention further includes kits suitable for use in the implementation of the methods of treatment described above. In one embodiment, the kit contains a first dosage form containing one or more compounds of the present invention and a dosage container in quantities sufficient to perform the methods of the present invention.

In another embodiment, the kit of the present invention contains one or more compounds of the invention.

An example of such a set is the so-called blister packaging. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules and the like). Blister packs typically consist of a sheet of relatively rigid material covered with a clear plastic foil. During the packaging process, indentations are formed in the plastic film. The recesses are the size and shape of the tablets or capsules to be packaged. The tablets or capsules are then placed into the recesses and a sheet of relatively rigid material is pressed against the plastic foil on a surface of the foil that is opposite to the direction in which the recesses are formed. As a result, the tablets or capsules are sealed in recesses between the plastic film and the sheet. In some embodiments, the strength of the sheet is such that tablets or capsules can be removed from the blister pack by manually applying pressure to the indentations, thereby creating a hole in the sheet at the indentation. The tablet or capsule can then be removed through the designated opening.

It may be desirable to provide a memory aid in the kit, for example in the form of numbers next to the tablets or capsules, the numbers corresponding to the days of the regimen on which said tablets or capsules are to be taken orally. Another example of such a memory aid is a calendar printed on a card, for example as follows: First Week, Monday, Tuesday, etc. Second week, Monday, Tuesday, etc. Other options for memory aids will be readily apparent. The daily dose may be one tablet or capsule or several tablets or capsules to be taken on a given day. In addition, a daily dose of a compound of formula I may consist of a single tablet or capsule, while a daily dose of a second compound may consist of several tablets or capsules and vice versa. The memory aid should reflect this.

In another specific embodiment of the invention, a dispenser is provided for dispensing daily doses one at a time in the order of their intended use. For example, the dispenser is equipped with a memory aid to further facilitate adherence. An example of such a memory aid is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of such a memory aid is a battery-powered microprocessor memory device coupled to a liquid crystal readout or a reminder tone that, for example, reads the date on which the last daily dose was taken and/or reminds when the next dose is due. accepted.

As defined above, the compounds of the present invention can be used in combination with one or more additional antischizophrenic drugs that are described herein. When combination therapy is used, one or more additional antischizophrenic drugs may be administered sequentially or simultaneously with the compound of the invention. In one embodiment, the additional antischizophrenic agent is administered to the mammal (eg, human) prior to administration of the compound of the invention. In another embodiment, the additional antischizophrenic agent is administered to the mammal after administration of a compound of the invention. In another embodiment, the additional antischizophrenic agent is administered to a mammal (e.g., a human) concurrently with administration of a compound of the invention (or its N-oxide

- 30 044379 or a pharmaceutically acceptable salt of the above).

The invention also provides a pharmaceutical composition for the treatment of schizophrenia in a mammal, including a human, which contains a certain amount of a compound according to the present invention (including its N-oxide or salt of the compound or N-oxide) as defined above (including hydrates, solvates and polymorphs of the said compound or pharmaceutically acceptable salts thereof), in combination with one or more (for example, one to three) antischizophrenic drugs, such as ziprasidone, risperidone, olanzapine, quetiapine, aripiprazole, asenapine, blonanserin or iloperidone, the amount of the active agent and the combination when taken as a whole, are therapeutically effective for the treatment of schizophrenia.

The invention also provides a pharmaceutical composition for the treatment of an M4-mediated (or M4-related) disease or disorder in a mammal, including a human, which contains a specified amount of a compound of the present invention (including its Noxide or salt of the compound or N-oxide), as defined above ( including hydrates, solvates and polymorphs of the specified compound, N-oxide or pharmaceutically acceptable salt of the above), in combination with one or more (for example, one to three) other agents for treating an M4-mediated (or M4-related) disease or disorder, wherein the amount active agent and combination, when taken as a whole, are therapeutically effective for treating an M4-mediated (or M4-related) disease or disorder.

It should be understood that the compounds of the present invention depicted above (Formula I, Formula Ia and Formula Ib) are not limited to the particular stereoisomer shown (eg, enantiomer or atropisomer), but also include all stereoisomers and mixtures thereof.

General schemes.

The compounds of the present invention, or their pharmaceutically acceptable salts, or tautomers and radioisotope compounds, can be prepared using various methods similar to those known in the art from the prior art. The reaction schemes described below, together with synthetic methods known in the art of organic chemistry, or modifications and transformations of those that are similar to those of one skilled in the art, illustrate methods for preparing the compounds. Others, including modifications thereof, will be obvious to one skilled in the art from the prior art. Unless otherwise noted, substituents in the diagrams are defined as above. Isolation and purification of products is carried out according to standard procedures that are known to a qualified chemist.

The starting materials used herein are commercially available or they may be prepared by conventional methods known in the art (such as those disclosed in standard reference books such as COMPENDIUM OF ORGANIC SINTHETIC METHODS, Vol. I-XII (published Wiley-Interscience] Advantageous methods include, but are not limited to, those described below.

The reactions to prepare the compounds of the invention can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the starting materials (reagents), intermediates, or products at the temperatures at which the reactions are carried out, for example, temperatures that may range from the freezing point of the solvent to the boiling point of the solvent. This reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by one skilled in the art.

During any of the following synthetic sequences, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecules of interest. This can be achieved using conventional protecting groups, such as those described in T.W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are incorporated herein by reference.

The reactions can be controlled according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (eg, 1H or ^13C ), infrared spectroscopy, spectrophotometry (eg, electron spectroscopy), mass spectrometry, or using chromatographic techniques such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

One skilled in the art will appreciate that in some cases the compounds in Schemes 19 will form as a mixture of diastereoisomers and/or enantiomers; they can be separated at various stages of the synthesis scheme using conventional methods or a combination of such

- 31 044379 methods, such as, but not limited to, crystallization, normal phase chromatography, reverse phase chromatography and chiral chromatography, resulting in the individual enantiomers of the invention.

One skilled in the art will understand that the various symbols, superscripts and subscripts used in the diagram, methods and examples are used for convenience of presentation and/or to reflect the order in which they are included in the diagram and are not intended to must correspond to the symbols, superscripts and subscripts in the presented claims. The diagram is illustrative of methods suitable for the synthesis of compounds according to the present invention. They do not limit the scope of the invention in any way.

The compounds of the invention and their intermediates can be prepared according to the following reaction schemes and the accompanying discussion. Unless otherwise indicated, R ¹ , R ² , L, A, E and the structural formula of I in the reaction schemes and discussion are as defined above. In general, the compounds of this invention can be prepared by methods that include methods similar to those known in the art in the chemical field, in particular in light of the description included herein. Certain methods for preparing the compounds of this invention and their intermediates are provided as additional features of the invention and are illustrated by the following reaction schemes. Other methods are described in the experimental section. The diagrams and examples presented herein (including the accompanying description) are for illustrative purposes only and are not intended to limit the scope of the present invention.

Scheme 1

Scheme 1 concerns one synthetic sequence for the preparation of compounds of formula I, as depicted above. With respect to Scheme 1, amines of formula 1-1, carboxylic acids of formula 1-2 and esters of formula 1-3, in which R ¹ , R ² , a, b, L, A, and E are as described above, are either commercially available or can be prepared by the methods described herein in the appropriate diagrams.

A compound of formula I can be prepared by reacting an amine of formula 1-1 with a carboxylic acid of formula 1-2 under amide condensation conditions well known in the art, typically introducing a suitable activating reagent such as O-(7-azabenzotriazole-1- yl)-N,N,N',N'tetramethyluronium hexafluorophosphate (HATU) or 1,1'-carbonyldiimidazole, with or without a suitable base, for example N,N-diisopropylethylamine, and in a suitable solvent such as N,Ndimethylformamide ( DMF) and tetrahydrofuran (THF). Alternatively, a compound of formula I can be prepared by direct condensation of an amine of formula 1-1 and an ester of formula 1-3, under reaction conditions such as heating with 1,3,4,6,7,8-hexahydro-2H-pyrimido[ 1,2-a]pyrimidine in a suitable solvent such as DMF, or by treatment with trimethylaluminum in a suitable solvent such as 1,2-dichloroethane at reaction temperatures ranging from 50 to 100°C. During any of the reaction steps to form a given amide, the R ¹ , R ² , a and b substituents of the amine of Formula 1-1, and the L, A and E substituents of the carboxylic acids of Formula 1-2 and esters of Formula 1-3 must be represented by the same moiety as desired in the final product, Formula I, or a protected variant thereof.

- 32 044379

Scheme 2

Scheme 2 concerns the preparation of intermediates of formula 2-5 that can be used in the amide formation reaction described in Scheme 1. Referring to Scheme 2, compounds of formula 2-1 in which R ¹ and a are as described above, and X represents Cl, Br, or I, are either commercially available or can be prepared according to methods well known in the art. An ester of Formula 2-2 can be prepared by carbonylation of a compound of Formula 2-1 in methanol under carbon monoxide pressure (eg, 50 psi), in the presence of a suitable transition metal catalyst such as [1,1'-bis( diphenylphosphino)ferrocene]dichloropalladium(P) [Pd(dppf)Cl ₂ ], and a suitable base such as triethylamine. During this step, R ¹ and a of Formula 2-1 should be represented by the same moiety as desired in the final product, Formula I of Schedule I, or a protected variant thereof.

The nitrile group of a compound of Formula 2-2 can be converted to the corresponding primary amine under conditions such as Renney nickel-catalyzed hydrogenation, which can react with the ester moiety in situ to give the lactams of Formula 2-3. The compound of formula 2-4 can then be prepared in a 2-step process involving reduction of the lactam carbonyl group using a suitable reducing reagent such as a borane-dimethyl sulfide complex in a suitable solvent such as THF and subsequent Boc-protection using di-tert -butyl dicarbonate in the presence of an acceptable base such as sodium hydroxide. The intermediate of Formula 2-5 can then be prepared by deprotection of the Boc using excess hydrogen chloride in a suitable solvent such as methanol.

Scheme 3

Scheme 3 concerns the preparation of intermediates of formula 3-6 which can be used in the amide formation reaction described in scheme 1, where R ¹ and a are as described above. For example, during this step, R ¹ and a of Formula 3-1 should be represented by the same moiety, as desired in the final product, Formula I of Schedule I, or a protected variant thereof. R ¹ at the benzyl position of Formula 3-5, and Formula 3-6 represents substituents that can be readily prepared from the alcohol at the benzyl position using methods well known in the art, such as, but not limited to, alkoxymethyl groups, aldehyde , carboxylic acid, esters, and fluorinated alkyl groups such as fluoromethyl or difluoromethyl groups. Referring to Scheme 3, the compound of Formula 3-1 can be converted to the corresponding N-oxide of Formula 3-2 using a suitable oxidizing reagent such as 3-chloroperoxybenzoic acid (m-CPBA) in a suitable solvent such as dichloromethane. The compound of formula 3-3 can be prepared by treating the N-oxide of formula 3-2 with acetic anhydride at reaction temperatures ranging from 50°C to 100°C; the compound of formula 3-3 can then be converted to the corresponding alcohol of formula 3-4 under ester hydrolysis conditions well known in the art, such as exposure to aqueous sodium hydroxide. The primary alcohol moiety of the compound of Formula 3-4 can then be used as a synthetic manipulator to introduce the R ¹ substituent at the benzyl position by methods well known in the art to produce the compound of Formula 3-5. Finally, the intermediate of Formula 3-6 can then be prepared by deprotection of the Boc group using excess hydrogen chloride in a suitable solvent such as methanol.

Scheme 4

Scheme 4 concerns the preparation of intermediates of Formula 4-6 that can be used in the amide formation reaction described in Scheme 1. Referring to Scheme 4, the compound of Formula 2-2 can be converted to the lactone of Formula 4-1 by reduction of the methyl ester moiety into the appropriate alcohol using a suitable reducing reagent such as sodium borohydride (NaBH ₄ ), followed by formation of the lactone in the presence of concentrated sulfuric acid. During this step, R ¹ and a of Formulas 2-2 should be represented by the same moiety as desired in the final product, Formula I of Scheme I, or a protected variant thereof.

Lactol of formula 4-2 can then be prepared by nucleophilic addition of a Grignard reagent of formula 4-7, in which R ² is as described above, in a suitable solvent such as THF. During this step, R ² of Formula 4-7 must be represented by the same moiety as desired in the final product, Formula I of Formula I, or a protected variant thereof.

The dichlorine intermediate of Formula 4-3 can be prepared in two steps from the lactol of Formula 4-2, involving reduction to the corresponding diol using a suitable reducing reagent such as lithium aluminum hydride (LiAlH ₄ ), and subsequent chlorination using a suitable chlorination reagent such as as thionyl chloride, in a suitable solvent such as dichloromethane. The compound of formula 4-4 can be prepared by condensing the dichloro intermediate of formula 4-3 with a suitable source of protected amine (NH2-PG ¹ ), in which PG ¹ is a benzyl-based protecting group such as 2,4-dimethoxyphenylmethylamine. The compound of formula 4-5 can be prepared by removing PG ¹ using conditions well known in the art and subsequent introduction of Boc protection using di-tert-butyl dicarbonate. Finally, the intermediate of Formula 4-6 can be prepared by deprotection of the Boc group in the presence of excess hydrogen chloride in a suitable solvent such as dichloromethane.

- 34 044379

Scheme 5

5-1 5-2 5-3

5-4 5-6

1-1

Scheme 5 concerns the preparation of the compound of formula 5-8. Regarding Scheme 5, the compound of formula 51 is either commercially available or can be prepared according to methods well known in the art, where PG ² represents a suitable protecting group such as Boc. The compound of formula 5-1 can be converted to the compound of formula 5-2 by Wittig olefination using a suitable reagent such as (carboethoxymethylene)triphenylphosphorane. The compound of Formula 5-3 can then be prepared by hydrogenation in the presence of a suitable catalyst, such as 10% palladium on carbon, in a suitable solvent such as t-butyl methyl ether. By removing the PG ² using methods well known in the art, the azetidine intermediate of Formula 5-4 can be obtained. Suitable terminal substituents (E, as described above) can be introduced by condensation under suitable conditions well known in the art with the reagent of formula 5-5, where E is as described above, and X is Cl, Br, or I , obtaining compounds of formula 5-6. During this step, E of Formula 5-5 must be represented by the same moiety as desired in the final product, Formula I of Schedule I, or a protected variant thereof. For example, when E is heteroaryl and X is ortho- or para- with respect to the heteroaryl nitrogen atom, the condensation reaction can be achieved by the SNAr reaction, well known in the art, in the presence of a suitable base such as triethylamine, and a suitable salts, such as cesium bromide, in a suitable solvent such as dimethyl sulfoxide (DMSO). In another example in which E is aryl or heteroaryl and X is Cl, Br, or I not activated by the heteroaryl nitrogen, the condensation reaction can be achieved in the presence of a suitable catalyst such as tri(dibenzylideneacetone)dipalladium(0 ) [Pd ₂ (dba) ₃ ], a suitable ligand such as 1,1'binaphthalene-2,2'-diylbis(diphenylphosphane) (BINAP) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos ®), and a suitable base such as cesium carbonate, in a suitable solvent such as toluene and 1,4-dioxane. The compound of formula 5-6 can then be converted to the corresponding carboxylic acid of formula 5-7 by ester hydrolysis using a suitable base such as sodium hydroxide or lithium hydroxide. The compound of Formula 5-8 can then be prepared from a carboxylic acid of Formula 5-7 and an amine of Formula 1-1 by amide formation as described in Scheme 1. During this step, R1- ^R2 , a and b of Formula 1-1 should be represented by the same fragment, as desired in the final product, Formula I of Scheme 1, or a protected variant thereof.

- 35 044379

Scheme 6

Scheme 6 concerns an alternative preparation of the compound of formula 5-8. Referring to Scheme 6, a compound of Formula 5-3 in which PG ² is as described above can be converted to the corresponding carboxylic acid of Formula 6-1, which can be condensed with an amine of Formula 1-1 using the conditions described in Scheme 1, yielding the compound of formula 6-2. During this step, RR, a and b of Formulas 1-1 (see Scheme 1 above) should be represented by the same moiety as desired in the final product, Formula I of Scheme I, or a protected variant thereof.

The PG ² protecting group can be removed using methods well known in the art, yielding a compound of Formula 6-3, which can be converted to a compound of Formula 5-8 under the condensation conditions described in Scheme 5. During this step E of Formula 5 -5 (see Scheme 5 above) must be represented by the same moiety as desired in the final product, Formula I of Scheme I, or a protected variant thereof.

Scheme 7

PG'°' _z1 E-X 5-5

PG'°

7-2

7-3

7-1

Scheme 7 concerns the preparation of a compound of formula 7-5 in which R ¹ , R ² , a, b, and E are as described above. The compounds in this diagram are depicted as single enantiomers for illustrative purposes only, and they may be a racemate, or an enantiomer, or a mixture thereof. Referring to Scheme 7, a compound of formula 7-1 wherein PG is a suitable silyl-based protecting group such as a tert-butyl(dimethyl)silyl (TBDMS) group, and Z ¹ is a boronic ester of B(OR) ₂ . where each R independently represents H or C _1-6 alkyl, or where two or groups, together with the B atom to which they are attached, form an optionally substituted 5-10 membered heterocycloalkyl, is either commercially available or can be prepared according to methods well known in the art. The compound of Formula 7-1 can be converted to the compound of Formula 7-2 by a cyclopropanation reaction well known in the art. A typical procedure involves treating the alkene with a zincate derivative derived from diiodomethane and diethylzinc in the presence of a suitable acid such as trichloroacetic acid in a suitable solvent such as dichloromethane. The compound of formula 7-3 can be prepared by the Suzuki condensation of the compound of formula 7-2 and the reagent of formula 5-5 (see Scheme 5 above), in which E

- 36 044379 is aryl or heteroaryl, and X is Cl, Br, or I, in the presence of a suitable catalyst such as palladium(II) acetate and a suitable ligand such as di(1-adamantyl)-nbutylphosphine (cataCXium® A), in the presence of a suitable base, such as cesium carbonate, and in a suitable solvent, such as 2-methylbutan-2-ol. During this step E, formulas 5-5 should be represented by the same moiety as desired in the final product, formula I of schedule I, or a protected variant thereof.

When oxidized with a suitable reagent such as sodium periodate in the presence of a suitable catalyst such as ruthenium(III) chloride, the compound of formula 7-3 can be converted to the corresponding carboxylic acid of formula 7-4, which in turn can be condensed with the amine of formula 1 -1, producing a compound of Formula 7-5 using the amide formation conditions described in Scheme I. During this step, R^R ² , a and b of Formula 1-1 (see Scheme 1 above) must be the same moiety as desired in the final product, Formula I of Scheme 1, or a protected variant thereof.

Alternatively, the compound of Formula 7-2 can be converted to the corresponding carboxylic acid 7-6 using the conditions described above, which can then be condensed with the amine of Formula 1-1 to yield the compound of Formula 7-7 via amide formation. During this step, R ¹ · R ² , a and b of Formula 1-1 (see Scheme 1 above) should be represented by the same moiety as desired in the final product, Formula I of Scheme I, or a protected variant thereof .

A compound of Formula 7-5 can then be prepared by condensing a compound of Formula 7-7 with a reagent of Formula 5-5 using the conditions described above.

Scheme 8

8-1 8-2 ⁸ ' ³

1-1

Scheme 8 concerns the preparation of a compound of formula 8-4 in which R ¹ , R ² , a, b, and E are as described above. Regarding Scheme 8, a compound of Formula 8-2 can be prepared by condensing tert-butyl azetidin-3-ylcarbamate (8-1) with a reagent of Formula 5-5 (see Scheme 5), where E is aryl or heteroaryl and X is is Cl, Br, or I. For example, when E is heteroaryl and X is ortho or para to the heteroaryl nitrogen atom, the condensation reaction can be achieved by the S _N Ar reaction, well known in the art, in the presence of a suitable base such as triethylamine and a suitable salt such as cesium bromide in a suitable solvent such as dimethyl sulfoxide (DMSO). In another example, in which E is aryl or heteroaryl, and X is Cl, Br, or I not activated with heteroaryl nitrogen, the condensation reaction can be achieved in the presence of a suitable catalyst such as tri(dibenzylideneacetone)dipalladium(0)[Pd ₂ (dba) ₃ ], a suitable ligand such as 1,1'binaphthalene-2,2'-diylbis(diphenylphosphane) (BINAP) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and a suitable base such as cesium carbonate in a suitable solvent such as toluene and 1,4-dioxane. During this step E, formulas 5-5 should be represented by the same moiety as desired in the final product, formula I of schedule I, or a protected variant thereof.

The Boc protecting group can be removed using a suitable acid such as trifluoroacetic acid in a suitable solvent such as dichloromethane to produce a compound of Formula 8-3, which can be converted to a compound of Formula 8-4 to form an amide with an amine of Formula 1-1 using the conditions described in Scheme 1. During this step, R^R ² , a and b of Formula 1-1 (see Scheme 1 above) should be represented by the same fragment, as desired in the final product, Formula I scheme I, or its protected version.

- 37 044379

Scheme 9

9-2 9.3 9.4

Scheme 9 concerns the preparation of a compound of formula 9-4 in which R ¹ , R ² , a, b, and E are as described above. Regarding Scheme 9, the compound of Formula 9-2 can be prepared by condensing azetidin-3-ol, as the hydrochloride salt (9-1), with the reagent of Formula 5-5 (see Scheme 5 above), where E is aryl or heteroaryl , and X is Cl, Br, or I. For example, when E is heteroaryl and X is ortho- or para- with respect to the heteroaryl nitrogen atom, the condensation reaction can be achieved by the SNAr reaction, well known in the art region, in the presence of a suitable base, such as triethylamine, and a suitable salt, such as cesium bromide, in a suitable solvent, such as dimethyl sulfoxide (DMSO). In another example, when E is aryl or heteroaryl and X is Cl, Br, or I not activated with heteroaryl nitrogen, the condensation reaction can be achieved in the presence of a suitable catalyst such as tri(dibenzylideneacetone)dipalladium(0)[Pd ₂ (dba) ₃ ], a suitable ligand such as 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane) (BINAP) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and a suitable base such as cesium carbonate, in a suitable solvent such as toluene and 1,4-dioxane. During this step E, formulas 5-5 should be represented by the same moiety as desired in the final product, formula I of schedule I, or a protected variant thereof.

The compound of Formula 9-3 can be prepared from the amine of Formula 1-1 using bis(trichloromethyl)carbonate in the presence of a suitable base such as pyridine in a suitable solvent such as dichloromethane. During this step, R ¹ , R ² , a and b of Formula 1-1 (see Scheme 1 above) should be represented by the same moiety as desired in the final product, Formula I of Scheme I, or a protected variant thereof .

The compound of Formula 9-4 can then be prepared by forming a carbamate from an alcohol of Formula 9-2 and a compound of Formula 9-3 in the presence of a suitable base such as sodium hydride in a suitable solvent such as THF.

Additional starting materials and intermediates useful for preparing the compounds of the present invention can be obtained from chemical manufacturers such as Sigma-Aldrich or can be prepared in accordance with methods described in the chemical field.

Those skilled in the art will recognize that in all of the diagrams described herein, if there are functional (reactive) groups present on part of the structure of the compound, such as a group of substituents, for example R ¹ , R ² , L, A, and E and etc., further modification may be made, if appropriate and/or desired, using methods well known to those skilled in the art. For example, the -CN group can be hydrolyzed to form an amide group; a carboxylic acid can be converted to an amide; the carboxylic acid can be converted to an ester, which in turn can be reduced to an alcohol, which in turn can be further modified. In another example, the OH group can be converted to a better leaving group, such as a methanesulfonate, which in turn is suitable for nucleophilic substitution, such as with a cyanide ion (CN-). In another example, -S- may be oxidized to -S(=O)- and/or -S(=O) ₂ -. In yet another example, an unsaturated bond such as C=C or C=C can be reduced to a saturated bond by hydrogenation. In some embodiments, a primary amine or secondary amine moiety (present on a substituent group such as R ¹ , R ² , L, A, E, etc.) can be converted to an amide, sulfonamide, urea, or thiourea moiety by reacting it with an appropriate reagent such as an acid chloride, sulfonyl chloride, isocyanate or thioisocyanate compound. One skilled in the art will recognize such modifications. Thus, a compound of formula I having a substituent that contains a functional group can be converted into another compound of formula I having a different substituent group.

Likewise, those skilled in the art may also

- 38 044379 recognize that in all schemes described in this document, if there are functional (reactive) groups present in the group of substituents, such as R ¹ , R ² , L, A and E, etc., these functional groups may be protected/deprotected during the synthesis scheme described herein if necessary and/or desired. For example, the OH group may be protected with a benzyl, methyl or acetyl group, which can be deprotected and converted back to an OH group at a later stage in the synthesis process. In another example, the NH ₂ group may be protected with a benzyloxycarbonyl (Cbz) or Boc group; conversion back to the NH ₂ group can be carried out at a later stage in the synthesis process by deprotection.

As used herein, the term reacting (or reacting or reacted) refers to the combination of specified chemical reagents so that a chemical transformation occurs to form a compound different from any originally introduced into the system. Reactions can occur in the presence or absence of a solvent.

The compounds of formula I may exist as stereoisomers, such as atropoisomers, racemates, enantiomers or diastereomers. Conventional methods for preparing/isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high performance liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated using chromatography and/or fractional crystallization, and one or both diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of formula I (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, with mixed solvent systems such as, but not limited to, water plus acetonitrile, either or both of which may contain additives such as trifluoroacetic acid, formic acid, concentrated ammonium hydroxide, or by supercritical liquid chromatography performed using a combination of carbon dioxide and an organic solvent such as methanol or acetonitrile, optionally containing an additive such as diethylamine or ammonium hydroxide, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% 2-propanol, typically 2 to 20%, and 0 to 5% alkylamine, typically 0.1% diethylamine. The concentration of the eluate results in a rich mixture. Stereoisomeric conglomerates can be separated by conventional methods known to those skilled in the art. See, for example, Stereochemistry of Organic Compounds E.L. Eliel and S.H. Wilen (Wiley, New York, 1994), the disclosures of which are incorporated herein by reference in their entirety. Suitable stereoselective methods are well known to those skilled in the art.

The invention will be described in more detail with the help of specific examples. The following examples are offered for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize many non-critical parameters that can be changed or modified to obtain substantially the same results. Additional compounds within the scope of this invention can be prepared using the methods illustrated in these examples, either alone or in combination with techniques well known in the art. In the following examples and preparations, DMSO means dimethyl sulfoxide, N refers to concentration means normal, M means molar, ml means milliliter, mmol means millimole, µmol means micromoles, eq. means equivalent, °C means degrees Celsius, MHz means megahertz, HPLC means high performance liquid chromatography.

Experimental procedures

The following illustrates the synthesis of various compounds according to the present invention. Additional compounds within the scope of this invention can be prepared using the methods illustrated in these examples, either alone or in combination with techniques generally known in the art.

Experiments are typically carried out under an inert atmosphere (nitrogen or argon), particularly when oxygen- or moisture-sensitive reagents or intermediates are used. Commercial solvents and reagents were generally used without further purification. Anhydrous solvents were used where appropriate, typically AcroSeal® products from Acros Organics, Aldrich® Sure/Seal™ from Sigma-Aldrich, or DriSolv® products from EMD Chemicals. In other cases, commercial solvents were passed through columns packed with 4A molecular sieves in order to achieve the following QC standards for water content: a) <100 ppm. for dichloromethane, toluene, N,N-dimethylformamide and tetrahydrofuran; b) <180 m.h. for methanol, ethanol, 1,4-dioxane and

- 39 044379 diisopropylamine. For very sensitive reactions, solvents are further treated with sodium metal, calcium hydride or molecular sieves and distilled immediately before use. Products were typically vacuum dried before subsequent reactions or biological testing. Mass spectrometry data are reported using either liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI), or gas chromatography-mass spectrometry (GCMS). Chemical shifts for nuclear magnetic resonance (NMR) data are presented in parts per million (ppm, δ) with reference to residual peaks from the deuterated solvents that are used. In some examples, chiral resolutions were performed to separate enantiomers of specific compounds of the invention (in some examples, the separated enantiomers are designated ENT-1 and ENT-2, according to their elution order). In some examples, the optical rotation for the enantiomer was measured using a polarimeter. According to the observed light polarization plane rotation data (or its specific light polarization plane rotation data), the enantiomer with a clockwise rotation of the light polarization plane was designated as the (+)-enantiomer, and the enantiomer with a counterclockwise rotation of the light polarization plane was designated as ( -) enantiomer. Racemic compounds are indicated by the presence of a (±) next to the structure; in these cases, the reported stereochemistry represents the relative (rather than absolute) configuration of the compound's substituents.

Reactions proceeding through detectable intermediates were typically monitored by LCMS and allowed to proceed to complete conversion before adding subsequent reagents. For syntheses referred to procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. Typically, reactions were monitored by thin layer chromatography or mass spectrometry and processed if necessary. The degree of purification may vary depending on the experiment: in general, solvents and solvent ratios used for eluents/gradients were chosen to provide suitable Rf or retention times. All starting materials in these Preparations and Examples are either commercially available or can be prepared by methods known in the art or as described herein. The following are abbreviations that may appear in the experimental procedures described in this document.

9-BBN - 9-borabicyclo[3.3.1]nonane;

BF ₃ -Et ₂ O - boron trifluoride diethyletherate;

BINAP - 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane);

Boc - tert-butoxycarbonyl;

w - wide;

n-BuLi - n-butyllithium;

t-BuONa - sodium tert-butoxide;

tert-butyl XPhos - di-tert-butyl[2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane;

Bz - benzoyl;

cataCXium® A - di(1-adamantyl)-n-butylphosphine;

CDCl ₃ - deuterochloroform;

CD3OD - deuteromethanol;

CF3COOH - trifluoroacetic acid;

d - doublet;

dd - doublet of doublets;

ddd - doublet of doublet of doublets;

DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene;

DCM - dichloromethane;

DEPT - undistorted gain of polarization transmission;

DMB - (2,4-dimethoxyphenyl)methyl;

dppf - 1,1'-bis(diphenylphosphino)ferrocene;

EDC or EDCI - 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride;

EtOAc - ethyl acetate;

EtOH - ethanol;

g - gram;

GCMS - gas chromatography-mass spectrometry;

h - hour;

H ₂ O - water;

HATU - O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

HCl - hydrochloric acid;

HPLC - high performance liquid chromatography;

Hz - hertz;

- 40 044379

K2CO ₃ - potassium carbonate; KF - potassium fluoride; l - liter;

LCMS - liquid chromatography mass spectrometry; m - multiplet;

M - molar;

m-CPBA - 3-chloroperoxybenzoic acid;

MeOH - methanol; mg - milligram; MHz - megahertz; min - minute; ml - milliliter; µl - microliter; mmol - mollymol; µmol - micromole;

Mo(CO) ₆ - molybdenum hexacarbonyl; mole - mole;

MPa - megapascal;

N - normal;

N2 - nitrogen;

NaH - sodium hydride;

NaHCO ₃ - sodium bicarbonate;

NaOAc - sodium acetate;

NaOf-Bu - sodium tert-butoxide; NaOCl - sodium hypochlorite; NaOH - sodium hydroxide; NaOMe - sodium methoxide;

Na ₂ SO ₄ - sodium sulfate;

NEt ₃ - triethylamine;

NH ₄ Cl - ammonium chloride;

NH2OH-HC1 - hydroxylamine hydrochloride;

NMR - nuclear magnetic resonance; NOE - nuclear Overhauser effect; Pd(Amphos) ₂ Cl ₂ - bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(P); Pd ₂ (dba) ₃ - tri(dibenzylideneacetone)dipalladium(0);

Pd(dppf)Cl ₂ - [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(11);

Pd(dtbpf)Cl ₂ - [1,1 '-bis(di-tert-butyl-phosphino)ferrocene]dichloropalladium(P); Pd(PCy ₃ ) ₂ Cl ₂ - dichlorobis(tricyclohexylphosphine)palladium(11);

PPh ₃ - triphenylphosphine;

psi inch - pounds per square inch; sq. - quartet;

k.t. - room temperature; c - singlet;

T3P - 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan-2,4,6-trioxide;

TBAF - tetrabutylammonium fluoride;

TEA - triethylamine;

TEA-3HF - triethylamine trihydrofluoride;

TFA - trifluoroacetic acid;

THF - tetrahydrofuran;

TLC - thin layer chromatography; m - triplet;

Xantphos - 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

Receiving P1.

2,4-Dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P1)

- 41 044379

Step 1. Synthesis of methyl 3-cyano-4,6-dimethylpyridine-2-carboxylate (C1).

Triethylamine (547 g, 5.41 mol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) [Pd(dppf)Cl ₂ ; 66 g, 90 mmol] was added to a solution of 2-chloro-4,6-dimethylpyridine-3-carbonitrile (300 g, 1.80 mol) in methanol (3.5 L). Carbon monoxide gas was bubbled through the reaction mixture, which was then pressurized to 50 psi. inch of carbon monoxide and heated at 70°C for 28 hours. After this, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. Silica gel chromatography (gradient: 25 to 50% ethyl acetate in petroleum ether) provided the product as a light brown solid. Yield: 300 g, 1.6 mol, 89%. 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 4.06 (s, 3H), 2.68 (s, 3H), 2.61 (s, 3H).

Step 2. Synthesis of 2,4-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (C2).

Renney nickel (150 g, 1.75 mol) was added to a solution of C1 (300 g, 1.6 mol) in methanol (9 L) and the reaction mixture was stirred at 10° C. for 72 hours under 15 psi pressure. inch of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated in vacuo; the residue was purified using silica gel chromatography (eluents: 1:1 petroleum ether/ethyl acetate followed by 20:1 dichloromethane/methanol) to give the product as an off-white solid. Yield: 190 g, 1.17 mol, 73%. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.86 (w s, 1H), 7.14 (s, 1H), 4.38 (s, 2H), 2.66 (s, 3H), 2, 36 (s, 3H).

Step 3. Synthesis of tert-butyl 2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (C3).

Borandimethyl sulfide complex (10 M solution in dimethyl sulfide; 92.5 ml, 925 mol) was added dropwise to a solution at 0°C of C2 (30.0 g, 185 mmol) in tetrahydrofuran (500 ml). The reaction mixture was stirred at reflux (75°C) for 18 hours, after which it was cooled to 0°C and quenched by slowly adding methanol (200 ml), followed by the addition of aqueous hydrochloric acid (6 M, 500 ml ). The resulting mixture was allowed to stir at reflux (70° C.) for 3 hours and then cooled to room temperature. The pH of the solution was adjusted to 9-10 by adding 2M aqueous sodium hydroxide solution. Di-tert-butyl dicarbonate (80.7 g, 370 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was extracted with ethyl acetate (3x300 ml). The combined organic layers were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure; Silica gel chromatography (gradient: 11 to 50% ethyl acetate in petroleum ether) gave the product as an off-white solid that contained tetrahydrofuran derivative contamination. From 1H NMR analysis it was assumed that the product existed as a mixture of rotamers. Yield: 36.0 g, 145 mmol, 78%. 1H NMR (400 MHz, CDCl ₃ ), product peaks only: δ 6.84 (s, 1H), 4.65 (w s, 1H), 4.59 (s, 2H), 4.55 (w s, 1H), 2.48 (s, 3H), 2.21 (s, 3H), [1.50 (s) and 1.49 (s), total 9H].

Step 4. Synthesis of 2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P1).

A solution of hydrogen chloride in ethyl acetate (4.0 M, 141 ml, 564 mmol) was added dropwise to a solution at 0°C of C3 (35.0 g, 141 mmol) in methanol (300 ml) and the reaction mixture was stirred at room temperature for 16 hours. Then combined with two similar reactions (these reactions were carried out using a total of 11.6 g, 46.7 mmol, C3) and concentrated in vacuo. The residue was treated with ethyl acetate (200 ml), stirred for 10 minutes and filtered. The filter cake gave the product as a yellow solid. Combined yield: 27.9 g, 126 mmol, 67%. LCMS m/z 149.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 5.01 (s, 2H), 4.88 (s, 2H), 2.80 (s, 3H), 2.61 (s , 3H).

Receiving P2.

2,3,4-Trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P2)

- 42 044379

P2

Step 1. Synthesis of 4-amino-3-methylpent-3-en-2-one (C4).

A mixture of 3-methylpentane-2,4-dione (60.0 g, 526 mmol), silica gel (2 g) and aqueous ammonium hydroxide (25-28%, 180 ml) was stirred at room temperature (20°C) in for 2 hours. The reaction mixture became a solid mass, which was triturated with petroleum ether (100 ml). The resulting solid was treated with methanol (200 ml) and the mixture was heated until most of the substances had dissolved. After the hot mixture was filtered, the filtrate was concentrated in vacuo to give the product as a light yellow solid. Yield: 43.9 g, 388 mmol, 74%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.15 (s, 3H), 1.96 (s, 3H), 1.83 (s, 3H).

Step 2. Synthesis of 4,5,6-trimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (C5).

A solution of propandinitrile (25.6 g, 388 mmol) in tetrahydrofuran (100 ml) was added dropwise to a solution at 0°C of C4 (43.9 g, 388 mmol) in tetrahydrofuran (300 ml). The reaction mixture was stirred at room temperature (20°C) for 16 hours, after which the solid was collected by filtration. The filter cake was washed with ethyl acetate (300 ml) to give the product as a white solid. Yield: 48.0 g, 296 mmol, 76%. Ή NMR (400 MHz, DMSO-66) δ 11.19-10.76 (w s, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 1.93 (s, 3H ).

Step 3. Synthesis of 2-chloro-4,5,6-trimethylpyridine-3-carbonitrile (C6).

A mixture of C5 (28.0 g, 173 mmol) in phosphorus oxychloride (100 ml) was heated at 110°C for 16 hours and then cooled to room temperature (20°C). Most of the solvent was removed by concentration in vacuo and the residue was added dropwise to water (1.5 L) at room temperature (20°C). The pH of the mixture was adjusted to approximately 7 by adding solid sodium carbonate and the resulting precipitate was collected by filtration to give the product as a light yellow solid. Yield: 29 g, 160 mmol, 92%. Ή NMR (400 MHz, CDCl ₃ ) δ 2.57 (s, 3H), 2.52 (s, 3H), 2.25 (s, 3H).

Step 4. Synthesis of methyl 3-cyano-4,5,6-trimethylpyridine-2-carboxylate (C7).

The conversion of C6 to C7 was carried out using the method described for the synthesis of C1 from 2-chloro-4,6-dimethylpyridin-3-carbonitrile in the preparation of P1. The product was obtained as a light yellow solid. Yield: 13.0 g, 63.6 mmol, 77%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.05 (s, 3H), 2.67 (s, 3H), 2.59 (s, 3H), 2.35 (s, 3H).

Step 5. Synthesis of 2,3,4-trimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (C8).

Renney nickel (67 g, 0.78 mol) was added to a solution of C7 (40.0 g, 196 mmol) in methanol (2.5 L) and the reaction mixture was stirred at 20°C for 3 days under 40 psi pressure . inch of hydrogen. Then, it was filtered and the filtrate was concentrated in vacuo. The residue was washed with ethyl acetate (200 ml) to give the product as a light yellow solid. Yield: 33 g, 190 mmol, 97%. 1H NMR (400 MHz, CD3OD) δ 4.38 (s, 2H), 2.59 (s, 3H), 2.34 (s, 6H).

Step 6. Synthesis of tert-butyl 2,3,4-trimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (C9).

Borandimethyl sulfide complex (10 M solution in dimethyl sulfide; 93.6 ml, 936 mmol) was added dropwise to a suspension at 0°C of C8 (33 g, 190 mmol) in tetrahydrofuran (500 ml). The reaction mixture was stirred at 80°C for 16 hours, after which it was cooled to 0°C and quenched by slowly adding methanol (120 ml), followed by the addition of aqueous hydrochloric acid (6 M, 250 ml). The resulting mixture was allowed to stir at 90°C for 3 hours and then cooled to room temperature. The pH of the solution was adjusted to 9-10 by adding 8M aqueous sodium hydroxide solution. Di-tert-butyl dicarbonate (61.3 g, 281 mmol) was then added and the reaction mixture was stirred at room temperature (20° C.) for 2 hours. Most of the solvent was removed under reduced pressure; the residue was diluted with water (200 ml) and extracted with ethyl acetate (3x 200 ml). The combined organic layers were washed with saturated aqueous sodium chloride (500

- 43 044379 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluent: 3:1 petroleum ether/ethyl acetate) gave the product as a white solid which contained a minor amount of tetrahydrofuran derivative contamination. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 36 g, 137 mmol, 72%. 1H NMR (400 MHz, CDCl ₃ ), product peaks only: δ 4.66 (s, 1H), 4.63 (s, 1H), 4.60 (s, 1H), 4.58 (s, 1H) , [2.51 (s) and 2.51 (s), total 3H], 2.20 (s, 3H), 2.19 (s, 3H), [1.53 (s) and 1.51 ( s), total 9H].

Step 7. Synthesis of 2,3,4-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P2).

A solution of hydrogen chloride in methanol (20 ml) was added dropwise to a solution at 0°C of C9 (15.0 g, 57.2 mmol) in methanol (100 ml) and the reaction mixture was stirred at room temperature (20°C) for 2 h. Removal of the solvent in vacuo gave a solid, which was treated with ethyl acetate (50 ml) and stirred at room temperature (20°C) for 30 minutes. The solid was collected by filtration and washed with ethyl acetate to give the product as a light yellow solid. Yield: 10.4 g, 44.2 mmol, 77%. LCMS m/z 163.1 [M+H]+. ^1H NMR (400 MHz, DMSO-66) δ 10.6510.52 (ws, 2H), 4.65 (ws, 2H), 4.62 (ws, 2H), 2.63 (s, 3H), 2.36 (s, 3H), 2.26 (s, 3H).

Receiving P3.

2-(Difluoromethyl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P3)

Ac ₂ O

S14 RZ

Step 1. Synthesis of tert-butyl 2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (C3).

Borandimethyl sulfide complex (10 M solution in dimethyl sulfide; 92.5 ml, 925 mmol) was added dropwise to a suspension at 0°C of C2 (30.0 g, 185 mmol) in tetrahydrofuran (600 ml). The reaction mixture was heated at reflux for 24 hours, then cooled to 0°C and quenched by slowly adding methanol (250 ml), followed by the addition of aqueous hydrochloric acid (6M, 500 ml). The resulting mixture was allowed to stir at reflux (80° C.) for 16 hours and then cooled to room temperature. The pH of the solution was adjusted to 9-10 by adding 2M sodium hydroxide solution. Di-tert-butyl dicarbonate (60.6 g, 278 mmol) was then added and the reaction mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure; the residue was diluted with water (500 ml) and extracted with ethyl acetate (3x300 ml). The combined organic layers were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 9 to 25% ethyl acetate in petroleum ether) provided product (58 g) as a white solid that contained tetrahydrofuran derivative contamination; this substance was used directly in the next stage. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. LCMS m/z 249.1 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ), product peaks only: δ 6.86 (s, 1H), 4.69 (w s, 1H), 4.63 (s, 2H), 4.58 (w s, 1H), 2.51 (s, 3H), 2.24 (s, 3H), [1.53 (s) and 1.52 (s), total 9H].

Stage 2. Synthesis of tert-butyl 2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]niridine-6-carboxylate 1oxide (C10).

To a solution of C3 (from the previous step; 58 g, <185 mmol) in dichloromethane (500 ml) was added portionwise 3-chloroperoxybenzoic acid (m-CPBA; 85%, 48.4 g, 238 mmol) at 0°C and the reaction mixture Allowed to stir and warm to room temperature for 16 hours, after which the reaction was quenched by adding saturated aqueous sodium thiosulfate (300 ml). The resulting mixture was extracted with dichloromethane (3x200 ml) and the combined organic layers were washed successively with saturated aqueous sodium bicarbonate (300 ml) and saturated aqueous sodium chloride (300 ml), dried over sodium sulfate, filtered and concentrated

- 44 044379 in a vacuum. Silica gel chromatography (eluent: 2:1 petroleum ether/ethyl acetate, followed by

20:1 dichloromethane/methanol) gave the product as a yellow solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 29.0 g, 110 mmol, 59% over stage. ^1H NMR (400 MHz, CDCl·,) δ 7.01 (s, 1H), 4.87-4.80 (m, 2H), 4.70-4.61 (m, 2H), 2.51 (s, 3H), 2.23 (s,

3H), [1.53 (s) and 1.52 (s), total 9H].

Step 3. Synthesis of tert-butyl 2-[(acetyloxy)methyl]-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (C11).

A solution of C10 (29.0 g, 110 mmol) in acetic anhydride (170 ml) was heated at 90°C for 4 hours, after which the reaction mixture was concentrated in vacuo and treated with saturated aqueous sodium bicarbonate until no additional gas release. The resulting mixture was extracted with ethyl acetate (3x200 ml) and the combined organic layers were washed successively with saturated aqueous sodium chloride (200 ml) and water (200 ml), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product (30 g) as a black oil; this substance was used directly in the next stage. The main component in LCMS: m/z 306.9 [M+H]+.

Step 4. Synthesis of tert-butyl 2-(hydroxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6carboxylate (C12).

C11 (from the previous step; 30 g) was added to an aqueous solution of sodium hydroxide (2 M, 250 ml) and the reaction mixture was heated for 2 hours at 80°C. The reaction mixture was then cooled, extracted with dichloromethane (3x100 ml) and the combined organic layers were washed with saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (eluent: 25:1 dichloromethane/methanol) gave the product (12.0 g) as a brown solid, which was used directly in the next step. The main component in LCMS: m/z 264.9 [M+H] ⁺ .

Step 5. Synthesis of tert-butyl 2-formyl-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (C13).

To a solution of C12 (from the previous step; 12.0 g) in 1,4-dioxane (200 ml) was added manganese (IV) oxide (27.6 g, 317 mmol) and the reaction mixture was heated at 80°C for 2 h The reaction mixture was filtered and the filtered cake was washed with dichloromethane (3x100 ml); the combined filtrates were concentrated in vacuo and purified using silica gel chromatography (eluent: 6:1 petroleum ether/ethyl acetate) to give the product as a yellow solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 4.36 g, 16.6 mmol, 15% in 3 stages. 1H NMR (400 MHz, CDCl·,) δ [10.04 (s) and 10.03 (s), total 1H], 7.71 (s, 1H), 4.83-4.68 (m, 4H ), 2.38 (s, 3H), [1.55 (s) and 1.54 (s), total 9H].

Step 6. Synthesis of tert-butyl 2-(difluoromethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6carboxylate (C14).

A solution of [bis(2-methoxyethyl)amino]sulfur trifluoride (7.35 g, 33.2 mmol) in dichloromethane (20 ml) was added dropwise over 5 min to the -20°C solution of C13 (4.36 g, 16.6 mmol) in dichloromethane (80 ml) and the reaction mixture was allowed to stir and warm from -20°C to room temperature (10°C to 15°C) over 4 hours. Then a saturated aqueous solution of sodium bicarbonate (50 ml) and the resulting mixture was extracted with dichloromethane (3x100 ml). The combined organic layers were washed with saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluent: 7:1 petroleum ether/ethyl acetate, followed by 6:1 petroleum ether/ethyl acetate) provided the product as a yellow solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 2.1 g, 7.4 mmol, 45%. 1H NMR (400 MHz, CDCl ₃ ) δ 7.35 (s, 1H), [6.61 (t, J _HF =55.6 Hz) and 6.60 (t, J _hf =55.5 Hz), total 1H], 4.75 (w s, 1H), 4.70 (s, 2H), 4.66 (w s, 1H), 2.36 (s, 3H), [1.54 (s) and 1.53 (s), total 9H].

Step 7. Synthesis of 2-(difluoromethyl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P3).

A solution of hydrogen chloride in methanol (4 M, 7 ml) was added dropwise to a solution at 0°C of C14 (2.1 g, 7.4 mmol) in dichloromethane (35 ml). The reaction mixture was stirred at room temperature for 2 hours, after which it was concentrated in vacuo to give the product as a brown solid. Yield: 1.62 g, 6.30 mmol, 85%. LCMS m/z 185.1 [M+H] ⁺ . 1H NMR (400 MHz, CD3OD) δ 7.54 (s, 1H), 6.71 (t, J _hf =55.1 Hz, 1H), 4.76 (s, 2H), 4.64 (s, 2H), 2.45 (s, 3H).

Receiving P4.

tert-Butyl 2-(difluoromethyl)-3,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (PA)

- 45 044379

Step 1. Synthesis of 2,6-dibromo-4,5-dimethylpyridine-3-carbonitrile (C15).

A mixture of 2-hydroxy-4,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile (28 g, 170 mmol) and phosphorus oxybromide (97.8 g, 341 mmol) was heated at 190°C for 1 hour. The reaction mixture was cooled to room temperature and quenched by adding ice water and the pH was then adjusted to approximately 7 by adding aqueous sodium bicarbonate. The resulting suspension was extracted with dichloromethane (4x100 ml) and the combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. Silica gel chromatography (eluent: 20:1 petroleum ether/ethyl acetate) gave the product as a white solid. Yield: 25 g, 86 mmol, 51%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.60 (s, 3H), 2.41 (s, 3H).

Step 2. Synthesis of dimethyl 3-cyano-4,5-dimethylpyridine-2,6-dicarboxylate (C16). The conversion of C15 to C16 was carried out using the method described for the synthesis of C1 from 2-chloro-4,6-dimethylpyridine-3carbonitrile in the preparation of P1. The product was obtained as an almost white solid. Yield: 22 g, 89 mmol, 78%. 1H NMR (400 MHz, CDCl ₃ ) δ 4.06 (s, 3H), 4.01 (s, 3H), 2.68 (s, 3H), 2.53 (s, 3H).

Step 3. Synthesis of methyl 3,4-dimethyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxylate (C17).

Renney nickel (15.2 g, 177 mmol) was added to a solution of C16 (22.0 g, 88.6 mmol) in methanol (1.8 L) and the reaction mixture was stirred at 20°C for 72 hours under 15 lb pressure per sq. inch of hydrogen. The catalyst was removed by filtration and the filter cake was washed with dichloromethane (3x150 ml). The combined filtrates were concentrated in vacuo and the residue triturated with t-butyl methyl ether (500 ml) to give the product as an off-white solid. Yield: 18.0 g, 81.7 mmol, 92%. 1H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.28 (w s, 1H), 4.46 (s, 2H), 3.98 (s, 3H), 2.51 (s, 3H) , 2.37 (s, 3H).

Step 4. Synthesis of 6-tert-butyl 2-methyl 3,4-dimethyl-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine 2,6-dicarboxylate (C18).

To a mixture of C17 (18.0 g, 81.7 mmol) and di-tert-butyl dicarbonate (18.8 g, 86.1 mmol) in dichloromethane (800 ml) was added 4-(dimethylamino)pyridine (1.5 g, 12.3 mmol) per serving. The reaction mixture was stirred at 20°C to 25°C for 3 hours, after which the solvent was removed under reduced pressure and the residue was purified using silica gel chromatography (eluent: 2:1 petroleum ether/ethyl acetate) to give the product as a white solid. . Yield: 23 g, 72 mmol, 88%. 1H NMR (400 MHz, CDCl ₃ ) δ 4.72 (s, 2H), 3.97 (s, 3H), 2.49 (s, 3H), 2.38 (s, 3H), 1.61 ( s, 9H).

Step 5. Synthesis of tert-butyl 2-(hydroxymethyl)-3,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (C19).

Diisobutylaluminum hydride (1M solution in toluene; 47 mL, 47 mmol) was added dropwise over 5 min to a -10°C solution of C18 (7.50 g, 23.4 mmol) in tetrahydrofuran (250 mL) and the reaction mixture was stirred at -10 to -5°C for 50 minutes. Diisobutylaluminum hydride (1M solution in toluene; 47 mL, 47 mmol) was again added dropwise and stirring was continued at -5°C for 3.5 hours. The reaction was quenched by adding sodium sulfate decahydrate (10.0 g, 31.0 mmol ) and the resulting mixture was stirred at room temperature for 30 minutes, after which it was filtered. The filter cake was washed with a mixture of dichloromethane and methanol (15:1, 4 L) and the combined filtrates were concentrated in vacuo to give a light red solid (4 g). This substance was dissolved in acetic acid (100 ml) and treated with 5 portions of sodium cyanoborohydride (3.0 g, 47.7 mmol) at room temperature. After the reaction mixture was stirred at 20°C to 25°C for 18 hours, poured into saturated aqueous sodium carbonate solution (200 ml), stirred for 20 minutes and extracted with ethyl acetate (3x150 ml). Combined organic layers

- 46 044379 was added to a saturated aqueous sodium chloride solution (3x100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography (gradient: 17% to 50% ethyl acetate in petroleum ether) gave the product as a white solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 3.30 g, 11.8 mmol, 50%. LCMS m/z 278.9 [M+H]+. 1H NMR (400 MHz, CD ₃ OD) δ 4.71 (s, 2H), 4.67 (w s, 1H), 4.64 (w s, 1H), 4.63-4.59 (m, 2H), 2.30 (s, 3H), [2.27 (s) and 2.26 (s), total 3H], [1.54 (s) and 1.53 (s), total 9H].

Step 6. Synthesis of tert-butyl 2-formyl-3,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6carboxylate (C20).

This reaction was carried out in two identical series. To a solution of C19 (500 mg, 1.80 mmol) in 1,4dioxane (20 ml) was added manganese(IV) oxide (1.56 g, 17.9 mmol) and the reaction mixture was stirred at 70°C for 2 hours. Solids were removed by filtration and the filter cake was washed with ethyl acetate (100 ml). The filtrates from the two reactions were combined and concentrated in vacuo to give the product as a light yellow solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 650 mg, 2.35 mmol, 65%. 1H NMR (400 MHz, CDCl ₃ ) δ [10.18 (s) and 10.17 (s), total 1H], 4.80-4.67 (m, 4H), 2.62 (s, 3H) , 2.28 (s, 3H), [1.55 (s) and 1.54 (s), total 9H].

Step 8. Synthesis of tert-butyl 2-(difluoromethyl)-3,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine6-carboxylate (P4).

A solution of [bis(2-methoxyethyl)amino]sulfur trifluoride (841 mg, 3.80 mmol) in dichloromethane (3 ml) was added dropwise to a solution at -20°C of C20 (420 mg, 1.52 mmol) in dichloromethane ( 15 ml). The reaction mixture was allowed to warm to room temperature and stir for 72 hours, after which water (10 ml) was added and the pH was adjusted to 7-8 by adding aqueous sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane (2x15 ml); the combined organic layers were washed with saturated aqueous sodium chloride (20 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluent: 5:1 petroleum ether/ethyl acetate) gave the product as a light yellow solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 380 mg, 1.27 mmol, 84%. 1H NMR (400 MHz, CDCl ₃ ) δ [6.71 (t, Jhf=54.8 Hz) and 6.69 (t, Jhf=54.7 Hz), total 1H], 4.73-4.68 (w s, 2H), 4.684.63 (w s, 2H), 2.42 (w s, 3H), 2.25 (s, 3H), [1.54 (s) and 1.53 (s) , total 9H].

Receiving P5.

tert-Butyl 2-(methoxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (P5)

P5 C12 C23

Step 1. Synthesis of dimethyl 3-cyano-4-methylpyridine-2,6-dicarboxylate (C21).

[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(P) (97.7 g, 134 mmol) was added to a solution of 2,6-dichloro-4-methylpyridin-3-carbonitrile (500 g, 2.67 mol) and triethylamine (810 g, 8.0 mol) in methanol (5.0 L). The reaction mixture was stirred at 100°C under carbon monoxide (4 MPa) for 14 hours, then cooled to 25°C and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the residue was triturated with a mixture of tert-butyl methyl ether, dichloromethane and methanol (10:1:1, 3 L). The resulting material was partitioned between water (2.5 L) and dichloromethane (2.5 L). The organic layer was washed with saturated aqueous sodium chloride, dried, filtered and concentrated under reduced pressure to give the product as a brown solid. Yield: 273 g, 1.17 mol, 44%. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.28 (w sq, J=0.7 Hz, 1H), 4.09 (s, 3H), 4.05 (s, 3H), 2.76 ( d, J=0.6 Hz, 3H).

Step 2. Synthesis of methyl 4-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-carboxylate (C22).

Renney nickel (270 g, 3.15 mol) was added to a solution of C21 (290 g, 1.24 mmol) in methanol (3 L). The reaction mixture was heated to 50°C and stirred under hydrogen (3 MPa) for 48 hours, after which it was cooled to 25°C and dissolved in a mixture of dichloromethane and methanol (1:1, 6 l) at 70°C. The resulting solution was filtered and the filtrate was concentrated in vacuo. Grinding the residue with methanol (500 ml) gave the product as a red-white solid. Yield: 230 g, 1.12 mol, 90%. 1H

- 47 044379

NMR (400 MHz, CDCI3) δ 8.15 (s, 1H), 7.25-7.19 (w s, 1H), 4.51 (s, 2H), 4.02 (s, 3H), 2 .50 (s, 3H).

Step 3. Synthesis of 6-tert-butyl 2-methyl 4-methyl-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-2,6dicarboxylate (C23).

Di-tert-Butyl dicarbonate (254 g, 1.16 mol) and 4-(dimethylamino)pyridine (11.6 g, 95.0 mmol) were added to a solution of C22 (233 g, 1.13 mol) in dichloromethane (2 L ). The reaction mixture was stirred at 25°C for 16 hours, after which additional di-tert-butyl dicarbonate (125 g, 573 mmol) was added and stirring was continued at 25°C for 2 hours. The reaction mixture was then washed with 10% aqueous citric acid and extracted with dichloromethane (2x1 L). The combined organic layers were washed with saturated aqueous sodium chloride, dried, filtered and concentrated in vacuo. The residue was triturated with t-butyl methyl ether (2 L) to give the product as a grey-white solid. Yield: 300 g, 0.98 mol, 87%. 1H NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 4.76 (s, 2H), 4.01 (s, 3H), 2.51 (s, 3H), 1.61 ( s, 9H).

Step 4. Synthesis of tert-butyl 2-(hydroxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6carboxylate (C12).

This reaction was carried out in two identical series. To a -10°C solution of C23 (30.00 g, 97.94 mmol) in tetrahydrofuran (1.0 L) was added diisobutylaluminum hydride (1 M solution in toluene; 114 mL, 114 mmol) dropwise over approximately 5 minutes. The reaction mixture was stirred at -10 to -5°C for 50 minutes, after which another portion of diisobutylaluminum hydride (1 M solution in toluene, 285 ml, 285 mmol) was added dropwise. Stirring was continued at -10 to -5°C for 2.5 hours. The reaction was then quenched by adding sodium sulfate decahydrate until no more bubbles were observed. After the mixture was stirred at 25°C for 30 minutes, magnesium sulfate was added and the resulting mixture was filtered through a pad of diatomaceous earth. The filter layer was washed with a mixture of dichloromethane and methanol (10:1, 25x300 ml) and the combined organic filtrates were dried over sodium sulfate, filtered and concentrated in vacuo to give a red oil (21.0 g). This substance was dissolved in acetic acid (200 ml) and treated with sodium 5 portions of cyanoborohydride (12.9 g, 205 mmol) at 25°C. (Caution: gas evolution.) The reaction mixture was stirred at 20°C to 35°C for 18 hours and then poured into saturated aqueous sodium bicarbonate solution (1.2 L). After the resulting mixture was stirred for 20 minutes, extracted with ethyl acetate (3x500 ml) and the combined organic layers were washed with saturated aqueous sodium chloride (3x300 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The two reaction series were combined at this point and purified using silica gel chromatography (gradient: 33 to 66% ethyl acetate in petroleum ether) to give the product as a yellow gum. Yield: 20.8 g, 78.7 mmol, 40%. LCMS m/z 264.9 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 6.97 (w s, 1H), [4.74 (s) and 4.73 (s), total 2H], [4.72 (w s) and 4 .62 (w s), total 2H], 4.67 (s, 2H), 2.30 (s, 3H), [1.54 (s) and 1.53 (s), total 9H].

Step 5. Synthesis of tert-butyl 2-(methoxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6carboxylate (P5).

To a solution at 5°C of C12 (21.0 g, 79.4 mmol) in tetrahydrofuran (500 ml) was added sodium hydride (60% in mineral oil; 6.16 g, 154 mmol) in portions over 20 min. The resulting suspension was stirred at 20°C for 1 hour, after which iodomethane (24.0 ml, 385 mmol) was added dropwise. The reaction mixture was stirred at 20°C for 2 hours, cooled to 0°C and quenched by dropwise addition of saturated aqueous ammonium chloride solution (100 ml). The resulting mixture was extracted with ethyl acetate (3x500 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (gradient: 0% to 30% ethyl acetate in petroleum ether) provided the product as an off-white solid. From 1H NMR analysis it was assumed that the product existed as a mixture of rotamers. Yield: 21 g, 75 mmol, 94%. LCMS m/z 278.9 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 7.11 (s, 1H), 4.72-4.57 (m, 4H), [4.53 (s) and 4.52 (s), total 2H], 3.46 (s, 3H), 2.27 (s, 3H), [1.52 (s) and 1.50 (s), total 9H].

Receiving P6.

3-Chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P6)

- 48 044379

Step 1. Synthesis of methyl 5-chloro-3-cyano-4,6-dimethylpyridine-2-carboxylate (C24). Triethylamine (20.4 mL, 146 mmol), palladium(II) acetate (837 mg, 3.73 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (dppf; 4.14 g, 7.47 mmol) were added to a solution of 2,5-dichloro-4,6-dimethylpyridine-3-carbonitrile (15.0 g, 74.6 mmol) in methanol (600 ml). Carbon monoxide was bubbled through the reaction mixture and heated at 70°C for 24 hours under 50 psi pressure. inch of carbon monoxide. Thereafter, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Silica gel chromatography (eluent: 5:1 petroleum ether/ethyl acetate) gave the product as a white solid. Yield: 15.3 g, 68.1 mmol, 91%. 1H NMR (400 MHz, CDCl ₃ ) δ 4.06 (s, 3H), 2.78 (s, 3H), 2.71 (s, 3H).

Step 2. Synthesis of 3-chloro-2,4-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (C25).

Conversion of C24 to product was carried out using the method described for the synthesis of C17 from C16 in Preparation P4. The product was isolated as a yellow solid. Yield: 12.5 g, 63.6 mmol, 93%. LCMS m/z 197.0 (chlorine isotope pattern observed) [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.51-7.42 (w s, 1H), 4.41 (s, 2H), 2.77 (s, 3H), 2.42 (s, 3H ).

Step 3. Synthesis of tert-butyl 3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (C26).

To a solution at 0°C of C25 (12.5 g, 63.6 mmol) in tetrahydrofuran (500 ml) was added borane-dimethyl sulfide complex (10 M in dimethyl sulfide; 50.9 ml, 509 mmol) dropwise. The reaction mixture was stirred at reflux for 16 hours and then cooled to 0°C. The reaction was quenched by the slow addition of methanol (200 ml), followed by the addition of an aqueous solution of hydrochloric acid (6 M; 400 ml); the resulting mixture was stirred at reflux (80°C) for 3 hours, cooled to room temperature and treated with 2M aqueous sodium hydroxide until the pH of the solution was approximately 910. At this point di-tert was added -butyl dicarbonate (20.8 g, 95.3 mmol) and the mixture was stirred at room temperature for 16 hours. After removing the organic solvents under reduced pressure, the residue was diluted with saturated aqueous ammonium chloride (1 L) and extracted with ethyl acetate (3x1 L) . The combined organic layers were washed with saturated aqueous sodium chloride (2x1 L), dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (eluent: 20:1 petroleum ether/ethyl acetate) gave the product as a white solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 8.02 g, 28.4 mmol, 45%. LCMS m/z 282.9 (chlorine isotope pattern observed) [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 4.69-4.57 (m, 4H), [2.62 (s) and 2.61 (s), total 3H], 2.30 (s, 3H) , [1.53 (s) and 1.51 (s), total 9H].

Step 4. Synthesis of 3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P6).

To a solution of C26 (2.30 g, 8.13 mmol) in dichloromethane (30 ml) was added a solution of hydrogen chloride in 1,4dioxane (4 M, 6.0 ml, 24 mmol) at room temperature (~13°C). The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo to give the product as a pink solid. Yield: 1.70 g, 6.65 mmol, 82%. LCMS m/z 182.9 (chlorine isotope pattern observed) [M+H] ⁺ . 1H NMR (400 MHz, CD3OD) δ 4.81 (s, 2H), 4.77 (s, 2H), 2.74 (s, 3H), 2.52 (s, 3H).

Receiving P7.

2,4,5-Trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P7)

Stage 1. Synthesis of 2,4-dimethylfuro-[3,4-b]pyridin-5(7H)-one (C27).

Sodium borohydride (59.7 g, 1.58 mol) was added in portions to the solution at 0°C C1 (100 g, 526 mmol)

- 49 044379 in a mixture of tetrahydrofuran (900 ml) and methanol (2.5 l). The reaction mixture was stirred at 25°C for 36 hours, after which water (500 ml) was added and organic solvents were removed in vacuo. The aqueous residue was diluted with saturated aqueous ammonium chloride (500 ml) and extracted with ethyl acetate (3x150 ml). The combined organic layers were washed with saturated aqueous sodium chloride (150 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil (79.5 g). A portion of this substance (50.0 g, <331 mmol) was dissolved in ethanol (500 ml), cooled to 0°C and treated dropwise with concentrated sulfuric acid (98%, 400 ml). The reaction mixture was then heated at 90°C for 16 hours, after which it was cooled to room temperature and added dropwise to ice water (3.0 L) with stirring. The resulting mixture was then adjusted to pH 7-8 by adding solid sodium bicarbonate, most of the ethanol was removed in vacuo and the resulting mixture was extracted with ethyl acetate (3x1 L). The combined organic layers were washed with saturated aqueous sodium chloride (1.5 L), dried over sodium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography (eluent: 2:1 petroleum ether/ethyl acetate) gave the product as a light yellow solid. Yield: 42.0 g, 257 mmol, 78%. 1H NMR (400 MHz, CDCl ₃ ) δ 7.10 (s, 1H), 5.22 (s, 2H), 2.66 (s, 3H), 2.65 (s, 3H).

Step 2. Synthesis of 2,4,5-trimethyl-5,7-dihydrofuro-[3,4-b]pyridin-5-ol (C28).

Methylmagnesium bromide (3.0 M solution in diethyl ether; 51.1 ml, 153 mmol) was added dropwise to a solution at 0°C of C27 (5.00 g, 30.6 mmol) in tetrahydrofuran (150 ml). The reaction mixture was stirred at room temperature for 3 hours, then quenched with saturated aqueous ammonium chloride (150 ml) and extracted with ethyl acetate (3x150 ml). The combined organic layers were washed with saturated aqueous sodium chloride (150 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give the product as a light yellow solid. Yield: 4.3 g, 24 mmol, 78%. ^1H NMR (400 MHz, CDCI3) δ 6.89 (s, 1H), 5.05-4.85 (m, 2H), 2.52 (s, 3H), 2.43 (s, 3H), 1.80 (s, 3H).

Step 3. Synthesis of 1-[2-(hydroxymethyl)-4,6-dimethylpyridin-3-yl]ethanol (C29).

Lithium aluminum hydride (1.33 g, 35.0 mmol) was added portionwise to a solution of C28 (2.10 g, 11.7 mmol) in tetrahydrofuran (100 ml) at 0°C. The reaction mixture was stirred at room temperature (20°C) for 16 hours, after which it was treated with water (10 ml) and stirred at room temperature for 10 minutes. Aqueous sodium hydroxide solution (15%, 10 ml) was added dropwise and stirring was continued for 20 minutes, during which time additional water (30 ml) was added dropwise. The resulting mixture was stirred for 30 minutes and filtered; the filtered cake was washed with ethyl acetate (100 ml). The combined filtrates were concentrated in vacuo to remove tetrahydrofuran and the residue was diluted with water (100 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product as a brown oil. Yield: 1.70 g, 9.38 mmol, 80%. 1H NMR (400 MHz, CDCl·,) δ 6.87 (s, 1H), 5.21 (q, J=6.8 Hz, 1H), 4.80 (AB quartet, Jab=15.1 Hz, Avab=5.6 Hz, 2H), 2.47 (s, 3H), 2.41 (s, 3H), 1.50 (d, J=6.8Hz, 3H).

Step 4. Synthesis of 3-(1-chloroethyl)-2-(chloromethyl)-4,6-dimethylpyridine (C30). Thionyl chloride (33.5 g, 282 mmol) was added dropwise to a solution at 0°C of C29 (1.70 g, 9.38 mmol) in dichloromethane (100 ml) and the reaction mixture was stirred at room temperature for 4 hours. Concentration in vacuo gave the product as a dark brown solid. Yield: 2.00 g, 7.86 mmol, 98%. 1H NMR (400 MHz, CDC13) δ 7.46 (s, 1H), 5.63-5.52 (m, 2H), 5.28-5.16 (m, 1H), 2.95 (s, 3H), 2.84 (w s, 3H), 1.99 (d, J=7.0 Hz, 3H).

Step 5. Synthesis of 6-(2,4-dimethoxybenzyl)-2,4,5-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (C31).

N,N-Diisopropylethylamine (3.56 g, 27.5 mmol) was added dropwise to a solution of C30 (2.00 g, 9.17 mmol) in a mixture of dichloromethane (20 mL) and acetonitrile (100 mL). The resulting mixture was then stirred at room temperature (25°C) for 10 min, and a solution of 1-(2,4-dimethoxyphenyl)methanamine (1.69 g, 10.1 mmol) in dichloromethane (5 ml) was added dropwise ) and the reaction mixture was stirred at 75°C for 3 hours. Then cooled to room temperature, diluted with water (100 ml) and concentrated in vacuo to remove most of the acetonitrile. The resulting mixture was extracted with ethyl acetate (3x100 ml) and the combined organic layers were washed with saturated aqueous sodium chloride (1 L), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified using silica gel chromatography (eluents: 5:1, then 2:1, then 1:1 petroleum ether/ethyl acetate) to give the product as a brown oil. Yield: 900 mg, 2.88 mmol, 31%. LCMS m/z 312.9 [M+H]+. 1H NMR (400 MHz, CDC13) δ 7.29 (d, J=9.0 Hz, 1H), 6.75 (s, 1H), 6.50-6.45 (m, 2H), 4.24 -4.17 (m, 1H), 4.14 (w d, J=14.6 Hz, 1H), 3.99 (d, J=13.6 Hz, 1H), 3.87-3.75 (m, 2H), 3.82 (s, 3H), 3.82 (s, 3H), 2.46 (s, 3H), 2.26 (s, 3H), 1.43 (d, J= 6.3 Hz, 3H).

Step 6. Synthesis of tert-butyl 2,4,5-trimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

- 50 044379 (C32).

A mixture of C31 (385 mg, 1.23 mmol), trifluoroacetic acid (5 ml) and triethylsilane (1.0 ml, 6.3 mmol) was stirred at 70°C for 6 hours. After cooling to room temperature, the reaction mixture was diluted tetrahydrofuran (10 ml) and water (2 ml) and then carefully treated with aqueous sodium hydroxide solution (15%, 5 ml) until the pH became 9-10. Di-tert-butyl dicarbonate (323 mg, 1.48 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. After adding water (10 ml), the mixture was extracted with ethyl acetate (3x20 ml) and the combined organic layers were washed with saturated aqueous sodium chloride (20 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluents: 10:1, then 8:1, then 6:1 petroleum ether/ethyl acetate) gave the product as a yellow oil. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 170 mg, 0.648 mmol, 53%. LCMS m/z 263.0 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 6.85 (s, 1H), [5.21-5.14 (m) and 5.09-5.02 (m), total 1H], 4.75 -4.54 (m, 2H), 2.51 (s, 3H), 2.28 (s, 3H), [1.54 (s) and 1.51 (s), total 9H], [1, 48 (d, J=6.0 Hz) and 1.45 (d, J=6.0 Hz), total 3H].

Step 7. Synthesis of 2,4,5-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P7).

A solution of hydrogen chloride in ethyl acetate (4.0 M, 0.81 ml, 3.2 mmol) was added dropwise to a solution at 0°C of C32 (170 mg, 0.648 mmol) in dichloromethane (0.5 ml) and the reaction mixture was stirred at room temperature for 1 hour. After removing the solvents in vacuo, the solid residue was triturated with tert-butyl methyl ether (3x20 ml) to obtain the product as an off-white solid. Yield: 130 mg, 0.553 mmol, 85%.

LCMS m/z 163.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSOD) δ 10.77-10.55 (w s, 1H), 10.05-9.86 (w s, 1H), 7.29 (s, 1H), 5.19- 5.08 (m, 1H), 4.67 (w d, J=15 Hz, 1H), 4.45 (w d, J=15 Hz, 1H), 2.52 (s, 3H), 2, 37 (s, 3H), 1.55 (d, J=6.5 Hz, 3H).

Receiving P8.

2-Methoxy-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P8)

Step 1. Synthesis of 2-chloro-6-methoxy-4-methylpyridine-3-carbonitrile (C33) and 6-chloro-2-methoxy-4methylpyridine-3-carbonitrile (C34).

A solution of 2,6-dichloro-4-methylpyridin-3-carbonitrile (10.0 g, 53.5 mmol) in methanol (50 ml) was cooled to 0°C and treated dropwise with a solution of sodium methoxide in methanol (freshly prepared, 1 .07 M; 75 ml, 80.2 mmol) over 30 min. The reaction mixture was allowed to stir until thin layer chromatography analysis showed that the starting material had not been completely consumed, at which point water (50 ml) was added and methanol was removed under reduced pressure. The resulting mixture was extracted with ethyl acetate (3x50 ml) and the combined organic layers were washed with saturated aqueous sodium chloride (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. By 1H NMR, the product consisted of an approximately equimolar mixture of C33 and C34. This substance was used directly in the next stage. Yield: 9.3 g, 51 mmol, 95%. 1H NMR (400 MHz, CDCl ₃ ) δ 6.90 (s, 1H), 6.60 (s, 1H), 4.06 (s, 3H), 3.99 (s, 3H), 2.50 ( s, 6H).

Step 2. Synthesis of methyl 3-cyano-6-methoxy-4-methylpyridine-2-carboxylate (C35) and methyl 5-cyano6-methoxy-4-methylpyridine-2-carboxylate (C36).

Triethylamine (20.9 ml, 150 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (3.73 g, 5.10 mmol) were added to the mixture of C33 and C34 (from the previous step , approximately 1:1 mixture; 9.3 g, 51 mmol) in methanol (200 ml). Carbon monoxide gas was bubbled through the reaction mixture, which was then pressurized to 50 psi. inch of carbon monoxide and heated at 70°C for 19 hours. After this, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. Silica gel chromatography (eluent: 10:1 petroleum ether/ethyl acetate) gave the product as a white solid; According to 1H NMR analysis, the substance consisted of an approximately 3:1 mixture of C35 and C36. This substance was used directly in the next stage. Yield: 6.9 g, 33 mmol, 65%. 1H NMR (400 MHz, CDCl ₃ ) δ Peaks attributed to C35: 6.85 (s, 1H), 4.05 (s, 3H), 4.04 (s, 3H),

2.56 (s, 3H); The peaks are attributed to C36: 7.65 (s, 1H), 4.14 (s, 3H), 3.99 (s, 3H), 2.59 (s, 3H).

Step 3. Synthesis of 2-methoxy-4-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (C37).

Renney nickel (2.46 g, 28.7 mmol) was added to a solution of C35 and C36 (from previous step, approximately 3:1 mixture; 6.9 g, 33 mmol) in methanol (200 mL). Hydrogen was bubbled through the reaction mixture, which was then subjected to 40 psi hydrogen pressure. inch and stirred at 40°C for 48 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. Silica gel chromatography (gradient: 0 to 17% methanol in ethyl acetate) gave the product as an off-white solid. Yield: 3.2 g, 18 mmol, 34% in 3 stages. LCMS m/z 178.9 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.69-7.59 (w s, 1H), 6.74 (s, 1H), 4.33 (w s, 2H), 4.05 (s, 3H), 2.34 (s, 3H).

Step 4. Synthesis of tert-butyl 2-methoxy-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (C38).

Conversion of C37 to product was carried out using the method described for the synthesis of C3 from C2 in Preparation P1. The product was obtained as a white solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 2.2 g, 8.3 mmol, 46%. LCMS m/z 264.8 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 6.45 (s, 1H), 4.65-4.50 (m, 4H), [3.91 (s) and 3.90 (s), total 3H] , 2.22 (s, 3H), [1.53 (s) and 1.52 (s), total 9H].

Step 5. Synthesis of 2-methoxy-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (P8).

A solution of hydrogen chloride in methanol (4 M, 2 ml) was added dropwise to a solution at 0°C of C38 (100 mg, 0.378 mmol) in dichloromethane (10 ml) and the reaction mixture was stirred at room temperature for 1 hour. Concentration in vacuo gave product as an almost white solid. Yield: 74 mg, 0.31 mmol, 82%. 1H NMR (400 MHz, CD3OD) δ 6.63 (s, 1H), 4.59 (s, 2H), 4.48 (s, 2H), 3.90 (s, 3H), 2.30 (s , 3H).

Example 1.

1-(2,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[1-(pyridin-3-yl)azetidin-3yl]ethanone ( 1)

Step 1. Synthesis of tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (C39).

tert-Butyl 3-oxoazetidine-1-carboxylate (100 g, 584 mmol) was dissolved in dichloromethane (750 ml), cooled in an ice bath and stirred vigorously, while (carboethoxymethylene)triphenylphosphorane (220 g, 631 mmol) was added portionwise over 15 minutes. The reaction mixture was then heated to 40°C for 4 hours, after which most of the dichloromethane was removed in vacuo. The resulting thick suspension was diluted with a mixture of hexanes and tert-butyl methyl ether (2:1, 1 L) and stirred at room temperature for 1.5 hours. Triphenylphosphine oxide was removed by filtration; the filter cake was washed with a 2:1 mixture of hexanes and tert-butyl methyl ether and the combined filtrates were concentrated in vacuo. Silica gel chromatography (eluent: 2:1 hexanes/tert-butyl methyl ether) gave the product as a clear, light yellow oil. Yield: 141.8 g, quantitative.

Step 2. Synthesis of tert-butyl 3-(2-ethoxy-2-oxoethyl)azetidine-1-carboxylate (C40).

A solution of C39 (141 g, 584 mmol) in tert-butyl methyl ether (500 ml) was placed in a vessel

- 52 044379

Parr and treated with 10% palladium on carbon (~50% water by weight; 2.5 g). The reaction vessel was evacuated and filled with nitrogen. This pumping cycle was repeated several times and the vessel was then subjected to 40 psi hydrogen pressure. inch and shaken for 30 minutes, after which the vessel was purged with additional nitrogen/subjected to vacuum cycles. The reaction mixture was filtered through a pad of diatomaceous earth and cellulose powder, which was then washed with t-butyl methyl ether. The combined filtrates were concentrated in vacuo to give the product as a clear, colorless oil. Yield: 140.1 g, 576 mmol, 99%. 1H NMR (400 MHz, DMSO-d ₆ ) δ 4.04 (kv, J=7.0 Hz, 2H), 3.99-3.85 (m, 2H), 3.58-3.45 (m , 2H), 2.84-2.71 (m, 1H), 2.62 (d, J=7.4 Hz, 2H), 1.36 (s, 9H), 1.17 (t, J= 7.0 Hz, 3H).

Step 3. Synthesis of ethyl azetidin-3-ylacetate, trifluoroacetate salt (C41).

Trifluoroacetic acid (60 ml) was added dropwise to a solution of C40 (15.0 g, 61.6 mmol) in dichloromethane (200 ml) and the reaction mixture was stirred at room temperature for 2 hours. Removal of solvents in vacuo gave the product as light - yellow oil. Yield: 15.85 g, 61.62 mmol, quantitative. 1H NMR (400 MHz, CDCl ₃ ) δ 8.23-7.99 (w s, 1H), 7.99-7.77 (w s, 1H), 4.41-4.27 (m, 2H) , 4.16 (kv, J=7.2 Hz, 2H), 4.11-3.99 (m, 2H), 3.40-3.25 (m, 1H), 2.74 (d, J =7.2 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H).

Step 4. Synthesis of ethyl [1-(pyridin-3-yl)azetidin-3-yl]acetate (C42).

Mixture of C41 (10.0 g, 38.9 mmol), 3-bromopyridine (16.6 g, 105 mmol), 1,1'-binaphthalene-2,2'diylbis(diphenylphosphane) (BINAP; 8.7 g, 14 mmol), tri(dibenzylideneacetone)dipalladium(0) (Pd ₂ (dba) ₃ ; 6.4 g, 7.0 mmol) and cesium carbonate (91.0 g, 279 mmol) in toluene (300 ml) were heated at 90°C for 16 hours. Most of the toluene was removed by concentration in vacuo and the residue was diluted with water (3x200 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with saturated aqueous sodium chloride (2x100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography (gradient: 17% to 20% ethyl acetate in petroleum ether) provided the product as a brown oil. Yield: 4.0 g, 18 mmol, 46%.

LCMS m/z 220.9 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.01 (dd, J=4.6, 1.3 Hz, 1H), 7.85 (d, J=2.9 Hz, 1H), 7.10 (dd, J=8.2, 4.7 Hz, 1H), 6.71 (ddd, J=8.3, 2.8, 1.4 Hz, 1H), 4.16 (kv, J=7 ,2 Hz, 2H), 4.11 (dd, J=7.9, 7.5 Hz, 2H), 3.61 (dd, J=7.2, 5.6 Hz, 2H), 3.20 -3.08 (m, 1H), 2.72 (d, J=7.8 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).

Step 5. Synthesis of [1-(pyridin-3-yl)azetidin-3-yl]acetic acid (C43).

Lithium hydroxide (652 mg, 27.2 mmol) was added to a solution of C42 (3.00 g, 13.6 mmol) in a mixture of methanol (20 ml) and water (5 ml). The reaction mixture was stirred at room temperature for 2 hours, after which it was cooled to 0° C. and concentrated hydrochloric acid was added until the pH of the reaction mixture reached 7. Concentration in vacuo gave the product. Yield: 3.3 g, assumed to be quantitative. 1H NMR (400 MHz, DMSO0) δ 7.91-7.82 (m, 1H), 7.75 (s, 1H), 7.17-7.07 (m, 1H), 6.80-6, 71 (m, 1H), 3.97 (dd, J=7.7 Hz, 2H), 3.48 (dd, J=6.6 Hz, 2H), 3.02-2.89 (m, 1H ), 2.5 (2H, assumed; shaded by solvent peak).

Step 6. Synthesis of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[1-(pyridin-3yl)azetidin-3- yl]ethanone (1).

N,N-Diisopropylethylamine (7.0 g, 54 mmol) was added to the solution at 0° C. P1 (2.50 g, 13.5 mmol), C43 (2.60 g, 13.5 mmol) and O-( 7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 7.72 g, 20.3 mmol) in N,N-dimethylformamide (50 ml). The reaction mixture was stirred and allowed to warm from 0°C to room temperature over 1.5 hours, after which it was poured into water (50 ml) and the resulting mixture was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed successively with water (2x30 ml) and saturated aqueous sodium chloride (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 2 to 5% methanol in dichloromethane) followed by reverse phase HPLC [column: YMC-Actus Triart C18, 5 µm; mobile phase: 30% acetonitrile (in water containing 0.05% ammonium hydroxide)], giving the product as a white solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 3.80 g, 11.8 mmol, 87%. LCMS m/z 323.0 [M+H] ⁺ . 1H NMR (400 MHz, CD3OD) δ 7.85 (wd, J=5 Hz, 1H), 7.75 (d, J=2.8 Hz, 1H), 7.21 (dd, J=8, 3, 4.8 Hz, 1H), 7.06 (s, 1H), 6.93-6.88 (m, 1H), 4.9-4.82 (m, 2H, assumed; partially obscured by water peak ), 4.73-4.67 (m, 2H), 4.15 (dd, J=7.5, 7.5 Hz, 2H), 3.68 (w dd, J=7.6 Hz, 2H ), 3.28-3.16 (m, 1H), [2.93 (d, J=7.5 Hz) and 2.92 (d, J=7.5 Hz), total 2H], 2, 49 (s, 3H), 2.31 (s, 3H).

Example 2.

2-{1-[2-(Difluoromethyl)pyridin-4-yl]azetidin-3-yl}-1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4b]pyridin-6 -yl)ethanone (2)

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Step 1. Synthesis of 4-chloro-2-(difluoromethyl)pyridine (C44).

A solution of (diethylamino)sulfur trifluoride (854 mg, 5.30 mmol) in dichloromethane (5 ml) was added dropwise to the solution at - 30°C (dry ice-acetonitrile bath) 4-chloropyridine-2-carbaldehyde (500 mg, 3 .5 mmol) in dichloromethane (15 ml). The reaction mixture was stirred at -30°C for 4 hours and then allowed to warm to room temperature and stir for 16 hours. The reaction was quenched by adding ice and then made alkaline to pH 8-10 by adding saturated aqueous sodium bicarbonate.

The resulting mixture was extracted with dichloromethane (3x50 ml) and the combined organic layers were washed with saturated aqueous sodium chloride (2x50 ml), dried over sodium sulfate, filtered and concentrated in vacuo at low temperature to give the product as a brown liquid. It was used in the next step without further purification. {Note: [bis(2-Methoxyethyl)amino]sulfur trifluoride is also a suitable fluorinating agent for this transformation.} Yield: 500 mg, 3.1 mmol, 89%, 1H NMR (400 MHz, CDCl ₃ ) δ 8, 57 (d, J=5.3 Hz, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.45-7.42 (m, 1H), 6.63 (t, J _H F=55.2 Hz, 1H).

Step 2. Synthesis of ethyl {1-[2-(difluoromethyl)pyridin-4-yl]azetidin-3-yl}acetate (C45).

A mixture of C44 (500 mg, 3.1 mmol), C41 (1.18 g, 4.59 mmol), cesium bromide (464 mg, 3.05 mmol) and triethylamine (1.67 ml, 12.0 mmol) in dimethyl sulfoxide (10 ml) was stirred at 100°C for 18 hours, after which the reaction mixture was poured into water (30 ml) and extracted with dichloromethane (3x100 ml). The combined organic layers were washed with water (3x100 ml) and saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluent: 3:1 petroleum ether/ethyl acetate) provided the product as a yellow oil. Yield: 443 mg, 1.64 mmol, 53%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J=5.6 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 6.51 (t, Jhf =55.8 Hz, 1H), 6.28 (dd, J=5.6, 2.3 Hz, 1H), 4.19 (dd, J=8.2, 8.0 Hz, 2H), 4 .17 (kv, J=7.2 Hz, 2H), 3.70 (dd, J=8.1, 5.5 Hz, 2H), 3.23-3.12 (m, 1H), 2, 72 (d, J=7.8 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H).

Step 3. Synthesis of 2-{1-[2-(difluoromethyl)pyridin-4-yl]azetidin-3-yl}-1-(2,4-dimethyl-5,7-dihydro6H-pyrrolo[3,4-b ]pyridin-6-yl)ethanone (2).

A mixture of P1 (90 mg, 0.49 mmol), C45 (105 mg, 0.388 mmol) and 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (TBD; 203 mg, 1.46 mmol) in N,N-dimethylformamide (8 ml) was stirred at 85°C for 16 hours. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (3x10 ml). The combined organic layers were washed with water (3x10 ml) and saturated aqueous sodium chloride (10 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Reverse phase HPLC (Column: Waters XBridge C18 OBD, 5 µm; Mobile Phase A: water containing 0.05% ammonium hydroxide; Mobile Phase B: acetonitrile; Gradient: 24% to 39% B) provided the product as white solid matter. From 1H NMR analysis it was assumed that the product existed as a mixture of rotamers. Yield: 16.4 mg, 44 µmol, 11%. LCMS m/z 373.0 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J=5.5 Hz, 1H), 6.94-6.90 (m, 1H), 6.57-6.55 (m, 1H ), 6.51 (t, J _HF =55.8 Hz, 1H), 6.32-6.28 (m, 1H), 4.81-4.72 (m, 4H), [4.28 ( dd, J=8.3, 8.0 Hz) and 4.27 (dd, J=8.0, 8.0 Hz), total 2H], 3.78-3.71 (m, 2H), 3.373 .25 (m, 1H), 2.85-2.79 (m, 2H), [2.54 (s) and 2.53 (s), total 3H], [2.28 (s) and 2, 27 (c), total 3H].

Example 3.

1-(2,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[1-(pyrimidin-4-yl)azetidin-3yl]ethanone ( 3)

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Step 1. Synthesis of [1-(tert-butoxycarbonyl)azetidin-3-yl]acetic acid (C46).

Lithium hydroxide (862 mg, 36.0 mmol) was added to a solution of C40 (7.30 g, 30.0 mmol) in a mixture of tetrahydrofuran (40 ml) and water (10 ml) and the reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was adjusted to pH 4 by adding 1M aqueous hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3x100 ml). The combined organic layers were washed successively with water (100 ml) and saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give the product as a white solid. Yield: 6.0 g, 28 mmol, 93%. 1H NMR (400 MHz, CD3OD) δ 4.06 (dd, J=8.5, 8.3 Hz, 2H), 3.61 (dd, J=8.6 Hz, 2H), 2.94-2 .82 (m, 1H), 2.62 (d, J=7.8 Hz, 2H), 1.43 (s, 9H).

Step 2. Synthesis of tert-butyl 3-[2-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2oxoethyl]azetidine-1-carboxylate ( C47).

N,N-Diisopropylethylamine (2.8 g, 21.7 mmol) was added dropwise to the suspension at 0°C P1 (1.0 g, 4.5 mmol), C46 (1.17 g, 5.44 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.47 g, 6.50 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred at 27°C for 15 hours, after which it was poured into water (100 ml) and the resulting mixture was extracted with ethyl acetate (3x60 ml). The combined organic layers were washed with water (2x60 ml) and saturated aqueous sodium chloride (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 17 to 100% ethyl acetate in petroleum ether) gave the product as a brown oil. This substance was taken directly to the next stage. Yield: 1.6 g, quantitative. 1H NMR (400 MHz, CDCl ₃ ) δ 6.91 (s, 1H), 4.81-4.67 (m, 4H), 4.23-4.11 (m, 2H), 3.70-3 .61 (m, 2H), 3.09-2.97 (m, 1H), 2.77-2.66 (m, 2H), 2.53 (s, 3H), 2.26 (s, 3H ), 1.44 (s, 9H).

Step 3. Synthesis of 2-(azetidin-3-yl)-1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6yl)ethanone, trifluoroacetate salt (C48) .

To a solution of C47 (1.6 g, 4.5 mmol) in dichloromethane (50 ml), trifluoroacetic acid (15 ml) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. Removal of solvents under reduced pressure provided the product as brown butter. Yield: 1.2 g, 3.3 mmol, 73%.

Step 4. Synthesis of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[1-(pyrimidin-4yl)azetidin-3- yl]ethanone (3).

A mixture of C48 (1.0 g, 2.8 mmol), 4-chloropyrimidine (421 mg, 3.68 mmol), cesium bromide (372 mg, 2.45 mmol) and triethylamine (991 mg, 9.79 mmol) in dimethyl sulfoxide (15 ml) was stirred at 100°C for 15 hours. After this, the reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (3x15 ml), the combined organic layers were washed with water (15 ml) and saturated aqueous sodium chloride solution (15 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 2 to 5% methanol in dichloromethane) followed by reverse phase HPLC (column: Waters XBridge C18 OBD, 5 µm; mobile phase A: water containing 0.05% ammonium hydroxide; mobile phase B: acetonitrile ;gradient: 26 to 56% B) gave the product as a light yellow solid.

From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 450 mg, 1.39 mmol, 50%. LCMS m/z 323.9 [M+H]+. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 8.39 (s, 1H), 8.07 (d, J=6.0 Hz, 1H), 7.06 (s, 1H), 6.39 (w d, J=6.5 Hz, 1H), [4.88 (s), 4.70 (s) and 4.68 (s), total 3H], 4.34 (dd, J=9, 0, 8.5 Hz, 2H), 3.92-3.85 (m, 2H), 3.30-3.18 (m, 1H), [2.94 (d, J=7.5 Hz) and 2.93 (d, J=7.5 Hz), 2H total], 2.49 (s, 3H), [2.31 (s) and 2.31 (s), 3H total].

Example 4.

2-{1-[2-(Difluoromethoxy)pyridin-4-yl]azetidin-3-yl} -1 -(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4b]pyridin-6 -yl)ethanone (4)

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Step 1. Synthesis of 4-bromo-2-(difluoromethoxy)pyridine (C49).

Sodium chloro(difluoro)acetate (5.26 g, 34.5 mmol) and potassium carbonate (3.57 g, 25.8 mmol) were added to a solution of 4-bromopyridin-2(1H)-one (3.00 g, 17.2 mmol) in N,N-dimethylformamide (30 ml) and the reaction mixture was stirred at 95°C for 2 hours. Water (100 ml) was added and the resulting mixture was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed successively with water (200 ml) and saturated aqueous sodium chloride (150 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluent: 15:1 petroleum ether/ethyl acetate) gave the product as a light yellow oil. Yield: 1.5 g, 6.7 mmol, 39%. ¹ H NMR (400 MHz, CDCl3) δ 8.04 (d, J=5.5 Hz, 1H), 7.44 (t, J _H f=72.6 Hz, 1H), 7.27 (dd, J=5.4, 1.6 Hz, 1H), 7.12 (wd, J=1.5 Hz, 1H).

Step 2. Synthesis of ethyl {1-[2-(difluoromethoxy)pyridin-4-yl]azetidin-3-yl}acetate (C50).

Mixture of C41 (120 mg, 0.467 mmol), C49 (105 mg, 0.469 mmol), tri(dibenzylideneacetone)dipalladium(0) (12.8 mg, 14.0 μmol), 4,5-bis(diphenylphosphino)-9, 9-dimethylxanthene (Xantphos; 17.8 mg, 30.8 µmol) and cesium carbonate (608 mg, 1.87 mmol) in 1,4-dioxane (5 ml) were stirred at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified using silica gel chromatography (eluent: 20:1 petroleum ether/ethyl acetate) to give the product as a yellow oil. Yield: 50 mg, 0.17 mmol, 36%. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=5.9 Hz, 1H), 7.42 (t, Jhf=73.7 Hz, 1H), 6.08 (dd, J=5 ,8, 2.1 Hz, 1H), 5.75 (d, J=2.0 Hz, 1H), 4.20-4.11 (m, 4H), 3.66 (dd, J=8, 0, 5.5 Hz, 2H), 3.20-3.09 (m, 1H), 2.71 (d, J=7.9 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H).

Step 3. Synthesis of 2-{1-[2-(difluoromethoxy)pyridin-4-yl]azetidin-3-yl}-1-(2,4-dimethyl-5,7dihydro-6H-pyrrolo[3,4-b ]pyridin-6-yl)ethanone (4).

A mixture of C50 (50 mg, 0.17 mmol), P1 (32.3 mg, 0.146 mmol) and 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine ( 97.2 mg, 0.698 mmol) in N,N-dimethylformamide (3 ml) was heated at 80°C for 16 hours. The reaction mixture was directly purified using reverse phase HPLC (column: Waters XBridge C18 OBD, 5 μm; mobile phase A: water containing 0.05% ammonium hydroxide; mobile phase B: acetonitrile; gradient: 25 to 55% B) yielding the product as a white solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 14.4 mg, 37.1 µmol, 25%. LCMS m/z 389.0 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, J=5.8 Hz, 1H), [7.43 (t, Jhf=73.8 Hz) and 7.42 (t, Jhf=73 .8 Hz), total 1H], [6.92 (s) and 6.91 (s), total 1H], 6.11-6.07 (m, 1H), 5.78-5.75 (m , 1H), 4.80-4.71 (m, 4H), 4.25-4.18 (m, 2H), 3.73-3.65 (m, 2H), 3.35-3.24 (m, 1H), 2.84-2.77 (m, 2H), [2.54 (s) and 2.53 (s), total 3H], [2.27 (s) and 2.27 ( c), total 3H].

Example 5.

2-[1-(1,2,4-Thiadiazol-5-yl)azetidin-3-yl]-1-(2,3,4-trimethyl-5,7-dihydro-6H-pyrrolo[3,4b] pyridin-6-yl)ethdnon (5)

Step 1. Synthesis of ethyl[1-(1,2,4-thiadiazol-5-yl)azetidin-3-yl]acetate (C51).

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[5-Bromo-1,2,4-thiadiazole was reacted with C41 using the method described for the synthesis of C45 from C44 and C41 in Example 2. The product was obtained as a yellow oil. Yield: 1.10 g, 4.84 mmol,

76%. 1H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 4.37-4.31 (m, 2H), 4.15 (q, J=7.2 Hz, 2H), 3, 89 (dd, J=9.1, 5.6

Hz, 2H), 3.32-3.21 (m, 1H), 2.74 (d, J=7.9 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H).

Step 2. Synthesis of 2-[1'-(1,2,4-thiadiazol-5-yl)azetidin-3-yl]-1-(2,3,4-trimethyl-5,7-dihydro-6Hpyrrolo[3 ,4-b]pyridin-6-yl)ethanone (5).

This reaction was carried out in two identical series. A mixture of P2 (100 mg, 0.425 mmol), C51 (114 mg, 0.502 mmol) and 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (280 mg, 2 .01 mmol) in N,N-dimethylformamide (3 ml) was heated at 80°C for 16 hours. The two reaction mixtures were combined and purified directly using reverse phase HPLC (column: Waters XBridge C18 OBD, 5 μm; mobile phase A: water containing 0.05% ammonium hydroxide; mobile phase B: acetonitrile; gradient: 16 to 46% B) giving the product as a white solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 99.9 mg, 0.291 mmol, 34%. LCMS m/z 343.9 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 4.78-4.71 (m, 4H), 4.464.39 (m, 2H), 3.97-3.89 ( m, 2H), 3.47-3.35 (m, 1H), [2.85 (d, J=7.8 Hz) and 2.82 (d, J=7.8 Hz), total 2H] , [2.54 (s) and 2.53 (s), total 3H], 2.22 (w s, 6H).

Example 6.

1-[2-(Difluoromethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-{1-[2(trifluoromethyl)pyridin-4- yl] azetidin-3-yl} ethanone (6)

Step 1. Synthesis of ethyl {1-[2-(tristoromethyl)pyridin-4-yl]azetidin-3-yl}acetate (C52).

4-Chloro-2-(trifluoromethyl)pyridine was reacted with C41 using the method described for the synthesis of C45 from C44 and C41 in Example 2. The product was isolated as a light yellow oil. Yield: 5.10 g, 17.7 mmol, 91%. LCMS m/z 289.1 [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J=5.6 Hz, 1H), 6.57 (d, J=2.3 Hz, 1H), 6.32 (dd, J= 5.6, 2.3 Hz, 1H), 4.23-4.17 (m, 2H), 4.17 (kv, J=7.2 Hz, 2H), 3.72 (dd, J=8 ,3, 5.5 Hz, 2H), 3.25-3.13 (m, 1H), 2.73 (d, J=7.9 Hz, 2H), 1.28 (t, J=7, 2 Hz, 3H).

Step 2. Synthesis of {1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}acetic acid (C53). Lithium hydroxide (498 mg, 20.8 mmol) was added to a solution of C52 (2.0 g, 6.9 mmol) in a mixture of water (4 ml) and tetrahydrofuran (20 ml) and the reaction mixture was stirred at room temperature for 2 hours , and then cooled to 0°C. The pH was then adjusted to 7 by adding 3M aqueous hydrochloric acid and the mixture was concentrated in vacuo to give the product as a white solid. Yield: 1.7 g, 6.5 mmol, 94%. 1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=5.8 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.48 (dd, J=5 ,8, 2.3 Hz, 1H), 4.20 (dd, J=8.4, 8.3 Hz, 2H), 3.74 (dd, J=8.5, 5.5 Hz, 2H) , 3.21-3.09 (m, 1H), 2.64 (d, J=7.9 Hz, 2H).

Step 3. Synthesis of 1-[2-(difluoromethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-{1[2-(trifluoromethyl) pyridin-4-yl] azetidin-3-yl} ethanone (6).

A mixture of C53 (177 mg, 0.680 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (388 mg, 1.02 mmol) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 30 min, after which R3 (150 mg, 0.583 mmol) was added. N,N-Diisopropylethylamine (0.60 mL, 3.4 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 h, after which it was immediately purified using reverse phase HPLC (column: Waters XBridge C18 OBD, 5 µm; mobile phase A: water containing 0.05% ammonium hydroxide; mobile phase B: acetonitrile; gradient: 27 to 57% B) giving the product as a white solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 157 mg, 0.368 mmol, 63%. LCMS m/z 427.1 [M+H] ⁺ . 1H NMR (400 MHz, CD3OD) δ 8.14 (d, J=5.8 Hz, 1H), 7.47 (s, 1H), 6.72-6.68 (m, 1H), 6.69 (t, Jhf=55.2 Hz, 1H), 6.53-6.48 (m, 1H), 4.99-4.90 (m, 2H), 4.82-4.74 (m, 2H ), 4.31-4.24 (m, 2H), 3.85-3.78 (m, 2H), 3.33-3.21 (m, 1H, assumed; partially obscured by solvent peak), [2 .96 (d, J=7.6 Hz) and 2.95 (d, J=7.8 Hz), total 2H], 2.42 (s, 3H).

Example 7.

1-[2-(Methoxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-{1-[2-(trifluoromethyl-57 044379 )pyridin-4-yl]azetidin-3-yl}ethanone (7)

Step 1. Synthesis of 2-(methoxymethyl)-4-methyl-6,7-gihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (C54).

A solution of P5 (780 mg, 2.80 mmol) in dichloromethane (5.6 mL) was cooled in an ice bath and treated for 10 min with a solution of hydrogen chloride in 1,4-dioxane (4 M, 3.5 mL, 14 mmol). The ice bath was then removed and the reaction mixture was stirred at room temperature overnight before being concentrated in vacuo. The resulting material was used without further purification. Yield: 600 mg, 2.4 mmol, 86%.

Step 2. Synthesis of 1-[2-(methoxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-{1[2-(trifluoromethyl) pyridin-4-yl] azetidin-3 -yl} ethanone (7).

A mixture of C53 (584 mg, 2.24 mmol) and 1,1'-carbonyldiimidazole (423 mg, 2.61 mmol) in tetrahydrofuran (9 ml) was stirred at room temperature for 1.5 hours. This mixture was added to the flask containing C54 (600 mg, 2.4 mmol) and the reaction mixture was stirred at room temperature for 64 hours. Then diluted with ethyl acetate and washed three times with water, once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo; the resulting foam was treated with hot 2-propanol and stirred at room temperature overnight. The resulting solid was collected by filtration and dissolved in a 1:1 mixture of dichloromethane and methanol. After a spoonful of activated carbon (Darco) was added, the mixture was heated at reflux for 20 minutes and then filtered through diatomaceous earth. The filter layer was washed with dichloromethane and the combined filtrates were concentrated under reduced pressure. The residue was suspended in hot 2-propanol for 2 hours and stirred at room temperature overnight. The resulting solid was isolated by filtration to obtain the product. From ¹ H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 450 mg, 1.07 mmol, 48%. LCMS m/z 421.3 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J=5.7 Hz, 1H), 7.18 (s, 1H), 6.60-6.57 (m, 1H), 6, 33 (dd, J=5.7, 2.2 Hz, 1H), 4.83-4.74 (m, 4H), [4.56 (s) and 4.55 (s), total 2H], [4.29 (dd, J=8.4, 8.0 Hz) and 4.28 (dd, J=8.2, 8.2 Hz), total 2H], 3.803.72 (m, 2H), [3.50 (s) and 3.49 (s), total 3H], 3.40-3.27 (m, 1H), [2.84 (d, J=8.0 Hz) and 2.81 (d, J=7.6 Hz), total 2H], [2.33 (s) and 2.32 (s), total 3H].

Example 8.

2-{1-[2-(Difluoromethoxy)pyridin-4-yl]azetidin-3-yl} -1 -[2-(methoxymethyl)-4-methyl-5,7-dihydro6H-pyrrolo[3,4-b ]pyridin-6-yl]ethanone (8)

Step 1. Synthesis of 2-(methoxymethyl)-4-methyl-6,7-gihygro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (C54).

A solution of hydrogen chloride in methanol (4 M, 4.5 ml, 18 mmol) was added to a solution at 0° C. P5 (1.00 g, 3.59 mmol) in dichloromethane (15 ml). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was triturated with tert-butyl methyl ether (3x50 ml) to give the product as a brown solid. Yield: 700 mg, 2.79 mmol, 78%. ^1H NMR (400 MHz, CD3OD) δ 7.82 (w s, 1H), 5.00 (s, 2H), 4.90-4.88 (w s, 2H), 4.87-4.85 (m, 2H), 3.58

- 58 044379 (s, 3H), 2.63 (w s, 3H).

Step 2. Synthesis of 2-{1-[2-(difluoromethoxy)pyridin-4-yl]azetidin-3-yl}-1-[2-(methoxymethyl)-4methyl-5,7-dihydro-6H-pyrrolo[3 ,4-b]pyridin-6-yl]ethanone (8).

A mixture of C54 (120 mg, 0.478 mmol), C50 (160 mg, 0.559 mmol) and 1,3,4,6,7,8-hexahydro-2Hpyrimido[1,2-a]pyrimidine (311 mg, 2.23 mmol) in N,N-dimethylformamide (4 ml) was heated at 80°C for 16 hours. The reaction mixture was directly purified using reverse phase HPLC (column: Waters XBridge C18 OBD, 5 μm; mobile phase A: water containing 0.05% ammonium hydroxide; mobile phase B: acetonitrile; gradient: 25% to 55% B), followed by supercritical liquid chromatography [Column: Chiral Technologies Chiralpak AS, 5 μm; mobile phase: 3:1 carbon dioxide/(methanol containing 0.1% ammonium hydroxide)], giving the product as a white solid. From ¹ H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 31.5 mg, 75.3 µmol, 16%. LCMS m/z 419.1 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, J=5.8 Hz, 1H), [7.42 (t, J _H F=73.7 Hz) and 7.42 (t, J _H F=73.8 Hz), total 1H], 7.17 (s, 1H), 6.11-6.06 (m, 1H), 5.785.74 (m, 1H), 4.83-4, 73 (m, 4H), [4.56 (s) and 4.54 (s), total 2H], [4.22 (dd, J=8.0, 8.0 Hz) and 4.21 (dd , J=8.2, 8.0 Hz), total 2H], 3.73-3.65 (m, 2H), [3.49 (s) and 3.49 (s), total 3H], 3 ,34-3.22 (m, 1H), [2.82 (d, J=7.8 Hz) and 2.79 (d, J=7.8 Hz), total 2H], [2.32 ( s) and 2.31 (s), total 3H].

Example 9.

1-[2-(Hydroxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-[1-(pyridin-3yl)azetidin-3- yl]ethanone (9)

Step 1. Synthesis of (4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)methanol, dihydrochloride salt (C55).

A solution of hydrogen chloride in methanol (4 M; 2 ml, 8 mmol) was added dropwise to a solution at 0°C of C12 (200 mg, 0.757 mmol) in dichloromethane (4 ml). The reaction mixture was then stirred at room temperature for 1 hour and concentrated in vacuo to give the product as a dark red solid. Yield: 123 mg, 0.519 mmol, 69%.

Step 2. Synthesis of 1-[2-(hydroxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-[1(pyridin-3-yl) )azetidin-3-yl] ethanone (9).

N,N-Diisopropylethylamine (0.62 ml, 3.56 mmol) was added to the solution at 0° C. C55 (123 mg, 0.519 mmol), C43 (144 mg, 0.749 mmol) and O-(7-azabenzotriazole-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (427 mg, 1.12 mmol) in N,N-dimethylformamide (3 ml) and the reaction mixture was stirred at 0°C to room temperature for 1 hour Then directly purified using reverse phase HPLC (column: YMC-Actus Triart C18, 5 µm; mobile phase A: water containing 0.05% ammonium hydroxide; mobile phase B: acetonitrile; gradient: 18 to 48% B ), followed by supercritical liquid chromatography [column: Chiral Technologies Chiralpak AS, 5 μm; mobile phase A: 7:3 carbon dioxide/(methanol containing 0.1% ammonium hydroxide]. The product was isolated as an almost white solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 33. 4 mg, 98.6 µmol, 19% LCMS m/z 339.0 [M+H] ⁺ 1H NMR (400 MHz, CD ₃ OD), characteristic peaks: δ 7.86 (d, J=4, 5 Hz, 1H), 7.75 (w s, 1H), 7.30 (s, 1H), 7.21 (dd, J=8.3, 4.5 Hz, 1H), 6.94-6 .88 (m, 1H), 4.92 (s, 1H), [4.74 (s) and 4.71 (s), total 2H], 4.66 (s, 2H), 4.16 (w dd, J=8.8 Hz, 2H), 3.68 (dd, J=7.3, 5.8 Hz, 2H), 3.27-3.18 (m, 1H), 2.93 (dd , J=7.3, 7.0 Hz, 2H), 2.37 (s, 3H).

Example 10.

2-{1-[2-(Difluoromethoxy)pyridin-4-yl]azetidin-3-yl}-1-[2-(difluoromethyl)-3,4-dimethyl-5,7dihydro-6H-pyrrolo[3,4 -b]pyridin-6-yl]ethanone (10)

- 59 044379

Step 1. Synthesis of {1-[2-(difluoromethoxy)pyridin-4-yl]azetidin-3-yl}acetic acid (C56). Lithium hydroxide (50.2 mg, 2.10 mmol) was added to a solution of C50 (300 mg, 1.05 mmol) in tetrahydrofuran (4 ml) and water (1 ml). The reaction mixture was stirred at room temperature for 2 hours, after which it was cooled to 0°C and the pH was adjusted to <7 by adding concentrated hydrochloric acid. The resulting mixture was diluted with tetrahydrofuran (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product as a white solid. Yield: 271 mg, 1.05 mmol, 100%. LCMS m/z 258.1 [M+H]+. 1H NMR (400 MHz,

DMSOA) δ 7.75 (d, J=5.5 Hz, 1H), 7.61 (t, Jhf=73.8 Hz, 1H), 6.18 (wd, J=5.5 Hz, 1H ), 5.81 (w s, 1H), 4.00 (dd, J=8.0, 7.5 Hz, 2H), 3.58-3.50 (m, 2H), 3.02-2 .87 (m, 1H), 2.29 (d, J=8.0 Hz, 2H).

Step 2. Synthesis of 2-(difluoromethyl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, dihydrochloride salt (C57).

A solution of hydrogen chloride in methanol (4M, 2 ml, 8 mmol) was added to a solution of P4 (300 mg, 1.01 mmol) in methanol (10 ml) and the reaction mixture was stirred at room temperature for 3 hours. Removal of solvents in vacuo provided the product as a brown oil, which was used without further purification. Yield: 275 mg. 1.01 mmol, 100%.

Step 3. Synthesis of 2-{1-[2-(difluoromethoxy)pyridin-4-yl]azetidin-3-yl}-1-[2-(difluoromethyl)-3,4dimethyl-5,7-dihydro-6H-pyrrolo [3,4-b]pyridin-6-yl]ethanone (10).

To a mixture of C57 (90 mg, 0.33 mmol), C56 (103 mg, 0.399 mmol) and O-(7-azabenzotriazol-1-yl)N,N,N',N'-tetramethyluronium hexafluorophosphate (151 mg, 0.397 mmol) in N,N-dimethylformamide (5 ml), N,N-diisopropylethylamine (172 mg, 1.33 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Then directly purified using reverse phase HPLC (column: Waters XBridge C18 OBD, 5 µm; mobile phase A: water containing 0.05% ammonium hydroxide; mobile phase B: acetonitrile; gradient: 33 to 63% B). The product was isolated as a white solid; From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 84.2 mg, 0.192 mmol, 58%. LCMS m/z 439.0 [M+H]+. ¹ H NMR (400 MHz, CD3OD) δ [7.75 (d, J=5.9 Hz) and 7.75 (d, J=5.9 Hz), total 1H], [7.36 (t, Jhf=73.8 Hz) and 7.36 (t, Jhf=73.8 Hz), total 1H], [6.84 (t, JHF=54.4 Hz) and 6.83 (t, Jhf=54 .5 Hz), total 1H], [6.22 (dd, J=5.9, 2 Hz) and 6.21 (dd, J=5.9, 2 Hz), total 1H], 5.84- 5.82 (m, 1H), 4.98-4.95 (w s, 1H), 4.89-4.86 (m, 1H, assumed; most obscured by water peak), 4.80-4, 77 (w s, 1H), 4.73-4.71 (w s, 1H), 4.23-4.16 (m, 2H), 3.73 (dd, J=8.1, 5.5 Hz, 2H), 3.27-3.18 (m, 1H), [2.94 (d, J=7.8 Hz) and 2.92 (d, J=7.8 Hz), total 2H] , 2.42 (w s, 3H), 2.33 (s, 3H).

Example 11.

1-(2,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2-(trifluoromethyl)pyridin-4yl]azetidin-3 -yl}ethanone (11)

ABOUT

P1 C53 11

A mixture of C53 (462 mg, 1.78 mmol) and 1,1'-carbonyldiimidazole (332 mg, 2.05 mmol) in tetrahydrofuran (6.0 ml) was stirred at room temperature for 1.5 h, after which it was added additional 1,1'-carbonyldiimidazole (10 mg, 62 µmol) and stirring was continued for 30 min. P1 (360 mg, 1.63 mmol) was added to the reaction mixture and stirring was continued overnight. The reaction mixture was then diluted with ethyl acetate and washed three times with water, once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. Or

- 60 044379 the ganic layer was dried over sodium sulfate, filtered and concentrated in vacuo; the resulting foam was diluted with hot 2-propanol (6 ml) and stirred at room temperature overnight. The solution was then stirred with activated carbon (Darco) for 3 minutes and filtered through diatomaceous earth using methanol. The filtrate was then concentrated in vacuo, diluted with hot 2-propanol (8 ml) and allowed to stir at room temperature overnight. Filtration using diethyl ether provided the product as a white solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 353 mg, 0.904 mmol, 55%. LCMS m/z 391.3 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J=5.7 Hz, 1H), [6.93 (s) and 6.91 (s), total 1H], 6.61- 6.57 (m, 1H), 6.34 (dd, J=5.7, 2.2 Hz, 1H), 4.81-4.71 (m, 4H), [4.29 (dd, J =8.2, 8.2 Hz) and 4.28 (dd, J=8.2, 8.2 Hz), total 2H], 3.80-3.72 (m, 2H), 3.39- 3.27 (m, 1H), 2.862.78 (m, 2H), [2.54 (s) and 2.53 (s), total 3H], [2.28 (s) and 2.27 (s ), total 3H].

Example 12.

1-(3-Chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2-(difluoromethyl)pyridin-4 -yl] azetidin-3 -yl} ethanone (12)

Step 1. Synthesis of {1-[2-(difluoromethyl)pyridin-4-yl]azetidin-3-yl}acetic acid (C58). Conversion of C45 to product was carried out using the method described for the synthesis of C56 from C50 in Example 10. The product was obtained as a white solid. Yield: 890 mg, 3.67 mmol, 50%. NMR data were obtained from running the C45 reaction under similar conditions. 1H NMR (400 MHz, CD3OD) δ 8.10 (d, J=6.0 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 6.57 (t, JHF=55 ,2 Hz, 1H), 6.45 (dd, J=5.9, 2.4 Hz, 1H), 4.22 (dd, J=8.5, 8.3 Hz, 2H), 3.76 (dd, J=8.7, 5.6 Hz, 2H), 3.21-3.09 (m, 1H), 2.72 (d, J=7.8 Hz, 2H).

Step 2. Synthesis of 1-(3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2-(difluoromethyl )pyridin-4-yl]azetidin-3-yl}ethanone (12).

A mixture of C58 (558 mg, 2.30 mmol) and 1,1'-carbonyldiimidazole (373 mg, 2.30 mmol) in acetonitrile (4 ml) was stirred at room temperature for 75 min and then added to P6 (575 mg , 2.25 mmol). After adding acetonitrile (2 ml), the reaction mixture was stirred at room temperature for 1.25 hours, after which it was diluted with dichloromethane (30 ml) and saturated aqueous sodium carbonate (20 ml) and stirring was continued for 2 minutes. The organic layer was washed successively with saturated aqueous sodium carbonate (2x15 ml) and saturated aqueous sodium chloride (15 ml), then treated with activated carbon (Darco G-60; 35 mg) and stirred at room temperature overnight. Sodium sulfate and diatomaceous earth were added and the resulting mixture was stirred for 2 minutes and filtered through a pad of diatomaceous earth using dichloromethane. The filtrate was concentrated in vacuo, treated with 2-propanol (12 ml) and heated at reflux for 15 min. While cooling to room temperature, the mixture was stirred for 30 minutes before being filtered and the collected solid washed with 2-propanol (2x12 ml) and diethyl ether (12 ml) to give the product as an off-white solid. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 651 mg, 1.60 mmol, 71%. LCMS m/z 407.2 (chlorine isotope pattern observed) [M+H] ⁺ . 1H NMR (400 MHz, CDC^) δ 8.22 (d, J=5.7 Hz, 1H), 6.55 (d, J=2.0 Hz, 1H), 6.51 (t, Jhf= 55.8 Hz, 1H), 6.29 (dd, J=5.7, 2.2 Hz, 1H), 4.79-4.73 (m, 4H), [4.27 (dd, J= 8.1, 8.1 Hz) and 4.26 (dd, J=8.1, 8.1 Hz), total 2H], 3.77-3.70 (m, 2H), 3.37-3 .24 (m, 1H), 2.84-2.77 (m, 2H), [2.64 (s) and 2.63 (s), total 3H], [2.34 (s) and 2, 33 (c), total 3H].

Example 13.

1-(3-Chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[1-(pyridin-3-yl)azetidin3- yl]ethanone (13)

- 61 044379

To a suspension at room temperature (14°C) of P6 (44.8 mg, 0.175 mmol) in 1,2-dichloroethane (0.5 ml) was added a solution of trimethylaluminum (2.0 M in toluene; 0.25 ml, 0.5 mmol) in one serving. After this, the reaction mixture was stirred at room temperature (14°C) for 20 min, a solution of C42 (30 mg, 0.14 mmol) in 1,2-dichloroethane (0.5 ml) was added in one portion and the reaction mixture was stirred at 75 °C for 4 hours, then cooled and allowed to stand at room temperature for 16 hours. A saturated aqueous solution of ammonium chloride (1 ml) was added, followed by the addition of water (5 ml) and dichloromethane (15 ml) and the aqueous layer was extracted successively with dichloromethane (2x15 ml) and a mixture of dichloromethane and methanol (10:1, 10 ml). The combined organic layers were washed with saturated aqueous sodium chloride (10 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Purification using reverse phase HPLC (column: Agela Durashell, 5 µm; mobile phase A: 0.05% ammonium hydroxide in water; mobile phase B: acetonitrile; gradient: 29 to 49% B) provided the product as a white solid substances. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 33 mg, 92 µmol, 66%. LCMS m/z 357.1 (chlorine isotope pattern observed) [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 8.01 (wd, J=4.5 Hz, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.11 (dd, J =8.3, 4.8 Hz, 1H), 6.76-6.70 (m, 1H), 4.82-4.73 (m, 4H), [4.20 (dd, J=7, 5, 7.5 Hz) and 4.19 (dd, J=7.5, 7.5 Hz), total 2H], 3.70-3.63 (m, 2H), 3.34-3.22 (m, 1H), [2.84 (d, J=7.5 Hz) and 2.81 (d, J=7.5 Hz), total 2H], [2.65 (s) and 2.64 (s), total 3H], [2.34 (s) and 2.34 (s), total 3H].

Examples 14 and 15.

2-[1-(Pyridin-3-yl)azetidin-3-yl]-1-(2,4,5-trimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6yl) ethanone, ENT-1 (14) and 2-[1-(pyridin-3-yl)azetidin-3-yl]-1-(2,4,5-trimethyl-5,7-dihydro-6H-pyrrolo[3 ,4-b]pyridin-6-yl)ethanone, ENT-2 (15)

ENT-2

To a suspension of C43 (98.1 mg, 0.510 mmol) in N,N-dimethylformamide (3 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (194 mg , 0.510 mmol) at room temperature and the reaction mixture was stirred for 1 hour, after which N,N-diisopropylethylamine (176 mg, 1.36 mmol) was added, followed by the addition of P7 (80.0 mg, 0.340 mmol). Stirring was continued for 16 hours, during which time the reaction mixture was concentrated in vacuo and directly purified using reverse phase HPLC (column: YMC-Actus Triart C18, 5 μm; mobile phase A: water containing 0.05% ammonium hydroxide ; mobile phase B: acetonitrile; gradient: 28 to 58% B), yielding the racemic product as a brown solid. Yield: 30.0 mg, 89.1 µmol, 26%. A portion of this substance (25 mg) was separated into its enantiomer components using supercritical liquid chromatography (column: Chiral Technologies Chiralpak AS, 5 μm; mobile phase A: carbon dioxide; mobile phase B: methanol containing 0.05% diethylamine; gradient: from 5% to 40% B). The first elution enantiomer was designated as 14 and the second elution enantiomer as 15; both were obtained as brown solids. From analysis of the 1H NMR spectra, both compounds exist as a mixture of rotamers.

- Yield: 9.0 mg, 36% for separation. LCMS m/z 337.1 [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 8.057.95 (m, 1H), 7.92-7.81 (m, 1H), 7.15-7.06 (m, 1H), [6.89 ( s) and 6.88 (s), total 1H], 6.76-6.70 (m, 1H), [5.45-5.36 (m) and 5.24-5.16 (m), only 1H], [4.73 (w AB quartet, Jab=14.8 Hz, Δυλβ=30 Hz), 4.93 (d, J=17.1 Hz) and 4.62 (d, J=17, 6 Hz), total 2H], 4.23-4.13 (m, 2H), 3.73-3.60 (m, 2H), 3.33-3.20 (m, 1H), [2, 97-2.80 (m) and 2.78 (d, J=8.0 Hz), total 2H], [2.53 (s) and 2.52 (s), total 3H], 2.30 ( s, 3H), 1.53-1.46 (m, 3H).

- Yield: 7.5 mg, 30% for separation. LCMS m/z 337.1 [M+H] ⁺ . 1H NMR (400 MHz, CDCi ₃ ) δ 8.047.96 (m, 1H), 7.87 (w s, 1H), 7.11 (w dd, J=8.2, 4.6 Hz, 1H), [6.89 (w s) and 6.88 (w s), total 1H], 6.76-6.70 (m, 1H), [5.40 (w sq, J=6 Hz) and 5, 20 (w square, J=6 Hz), total 1H], [4.73 (w AB quartet, J _AB =14.6 Hz, Δν _ΛΒ =30 Hz), 4.93 (d, J=17 Hz) and 4.62 (d, J=17 Hz), total 2H], 4.23-4.14 (m, 2H), 3.72-3.60 (m, 2H), 3.33-3.20 (m, 1H), [2.962.80 (m) and 2.78 (d, J=7.8 Hz), total 2H], [2.53 (s) and 2.52 (s), total 3H] , 2.30 (s, 3H), [1.51 (d, J=6.5 Hz) and 1.49 (d, J=6.5 Hz), total 3H].

Example 16.

1-(2,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[(1S,2R)-2-(6-methylpyridin-3- yl) cyclopropyl]ethanone (16)

- 62 044379

CH2I2, Et2Zn;

Step 1. Synthesis of tert-butyl(dimethyl){2-[trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)cyclopropyl]ethoxy}silane (C59).

Diiodomethane (2.1 kg, 7.8 mol) was added dropwise to a -40°C solution of diethylzinc (1 M, 3.85 L, 3.85 mol) in dichloromethane (8 L).

The mixture was then stirred for 2 hours, a solution of trichloroacetic acid (0.628 kg, 3.84 mol) in dichloromethane (1 L) was added dropwise and the reaction mixture was warmed to -10°C and allowed to stir for an additional 2 hours. The solution was tert -butyl(dimethyl){[(3E)-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)but-3-en-1-yl]oxy}silane (400 g , 1.28 mol) in dichloromethane (1 L) was added slowly and the reaction mixture was stirred at room temperature overnight before being quenched by adding cold aqueous citric acid (10%, 10 L). The organic layer was washed with saturated aqueous sodium chloride and concentrated in vacuo; Purification of the residue using silica gel chromatography (gradient: 0 to 7% ethyl acetate in petroleum ether) provided the product as a light yellow oil. Yield: 260 g, 797 mmol, 62%. 1H NMR (400 MHz, CDCl ₃ ) δ 3.71-3.64 (m, 2H), 1.51-1.44 (m, 2H), 1.22 (s, 12H), 1.04-0 .95 (m, 1H), 0.90 (s, 9H), 0.710.65 (m, 1H), 0.46-0.39 (m, 1H), 0.06 (s, 6H), -0 .35 to -0.42 (m, 1H).

Step 2. Synthesis of 5-[(1R,2S)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)cyclonropyl]-2-methylpyridine (C60) and 5-[(1S,2R) -2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)cyclopropyl]-2-methylpyridine (C61).

Palladium(P) acetate (251 mg, 1.12 mmol) and di(1-adamantyl)-n-butylphosphine (cataCXium® A; 667 mg, 1.86 mmol) were dissolved in degassed 2-methylbutan-2-ol (150 ml) and the reaction vessel was evacuated and filled with nitrogen. This pumping cycle was repeated twice and the mixture was stirred at room temperature for one hour, after which degassed water (10 ml) was added, followed by the addition of cesium carbonate (18.2 g, 55.9 mmol) and 5-bromo-2-methylpyridine (3.20 g, 18.6 mmol). A solution of C59 (6.70 g, 20.5 mmol) in 2-methylbutan-2-ol (40 ml) was added via syringe and nitrogen pump/fill cycles were repeated. The reaction mixture was then heated at 75°C for 16 hours, cooled to room temperature and filtered through diatomaceous earth. The filter layer was washed with methanol until no additional color eluted and the combined filtrates were concentrated in vacuo. The residue was diluted with ethyl acetate (250 ml) and the organic layer was washed with water (150 ml). The aqueous layer was extracted with ethyl acetate (2x250 ml) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography (gradient: 0 to 50% ethyl acetate in heptane) provided the racemic product as a light tan oil. Yield of racemic product: 3.00 g, 10.3 mmol, 55%. Component enantiomers were separated using supercritical liquid chromatography [Column: Phenomenex Lux Cellulose-1, 5 μm; mobile phase: 95:5 carbon dioxide/(acetonitrile containing 0.2% ammonium hydroxide)]. The first enantiomer of elution was designated as C60 and the second enantiomer of elution as C61; both were obtained as oils. These absolute stereochemistries were determined using crystal structure determination by X-ray diffraction analysis,

- 63 044379 which was carried out on 18, which was obtained from C61 through C63.

C60 - Yield: 1.20 g, 40% for separation. LCMS m/z 292.4 [M+H]+. 1H NMR (500 MHz, CDCl ₃ ) δ 8.28 (d, J=2.2 Hz, 1H), 7.19 (dd, J=8.0, 2.3 Hz, 1H), 7.03 ( d, J=8.1 Hz, 1H), 3.73 (t, J=6.5 Hz, 2H), 2.52 (s, 3H), 1.68-1.56 (m, 3H), 1.14-1.07 (m, 1H), 0.90-0.81 (m, 2H), 0.89 (s, 9H), 0.04 (s, 3H), 0.04 (s, 3H).

C61 - Yield: 1.30 g, 43% for separation. LCMS m/z 292.4 [M+H] ⁺ . ^1H NMR (500 MHz, CDCl ₃ ) δ 8.28 (d, J=2.0 Hz, 1H), 7.21 (dd, J=8.0, 2.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 3.73 (t, J=6.5 Hz, 2H), 2.53 (s, 3H), 1.68-1.56 (m, 3H) , 1.15-1.07 (m, 1H), 0.92-0.82 (m, 2H), 0.89 (s, 9H), 0.04 (s, 3H), 0.04 (s , 3H).

Step 3. Synthesis of [(1S,2R)-2-(6-methylpyridin-3-yl)cyclopropyl]acetic acid (C62). Ruthenium(III) chloride (11 mg, 53 µmol) was added to a solution of C60 (500 mg, 1.72 mmol) in acetonitrile (10 ml) at room temperature. A solution of sodium periodate (1.10 g, 5.14 mmol) in water (7.5 ml) was then added to the stirred reaction mixture and stirring was continued for 4 hours. After adding aqueous hydrochloride acid (1 M, 5 ml), the mixture was concentrated in vacuo and the residue was dissolved in acetonitrile (50 ml) and filtered through a pad of diatomaceous earth. The filter bed was washed with additional acetonitrile (60 ml) and the combined filtrates were concentrated under reduced pressure to give the product as a gum. Yield: 310 mg, 1.62 mmol, 94%. 1H NMR (500 MHz, CD3OD), characteristic peaks: δ 8.53 (d, J=2.0 Hz, 1H), 8.22 (dd, J=8.4, 2.1 Hz, 1H), 7 .79 (d, J=8.6 Hz, 1H), 2.73 (s, 3H), 2.61 (dd, half of the ABX pattern, J=16.9, 5.9 Hz, 1H), 2 .36 (dd, half of the ABX pattern, J=16.9, 8.1 Hz, 1H).

Step 4. Synthesis of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[(1S,2R)-2-(6methylpyridin- 3-yl)cyclopropyl]ethanone (16).

Compound C62 (130 mg, 0.680 mmol) and P1 (115 mg, 0.520 mmol) were dissolved in N,Ndimethylformamide (6 mL) and treated with N,N-diisopropylethylamine (0.43 mL, 2.47 mmol). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (284 mg, 0.747 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. After adding semisaturated aqueous sodium solution chloride (10 ml), the mixture was extracted with ethyl acetate (3x150 ml). The combined organic layers were washed three times with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification using reverse phase HPLC (column: Waters XBridge C18, 5 µm; mobile phase A: water containing 0.03% ammonium hydroxide; mobile phase B: acetonitrile containing 0.03% ammonium hydroxide; gradient: 20 to 40% B) gave the product in the form of glass. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 15.0 mg, 46.6 µmol, 9%. LCMS m/z 322.4 [M+H] ⁺ . ^1H NMR (500 MHz, CD3OD) δ 8.26 (w s, 1H), 7.44 (dd, J=8.1, 2.4 Hz, 1H), 7.18 (d, J=8, 1 Hz, 1H), 7.05 (s, 1H), [4.87 (s), 4.82 (s), 4.71 (s) and 4.70 (s), total 4H], 2, 69-2.56 (m, 2H), [2.49 (s) and 2.49 (s), total 3H], 2.47 (s, 3H), [2.31 (s) and 2.30 (s), total 3H], 1.89-1.83 (m, 1H), 1.50-1.42 (m, 1H), 1.08-0.98 (m, 2H).

Example 17.

1-(2,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[(1R,2S)-2-(6-methylpyridin-3yl) cyclopropyl]ethanone (17)

Step 1. Synthesis of [(1R,2S)-2-(6-methylpyridin-3-yl)cyclopropyl]acetic acid (C63).

Conversion of C61 to product was carried out using the method described for the synthesis of C62 from C60 in Example 16. In this case, purification was carried out using silica gel chromatography (gradient: 0 to 10% methanol in dichloromethane), obtaining the product as an oil. Yield: 210 mg, 1.10 mmol, 64%. LCMS m/z 192.2 [M+H] ⁺ . ^1H NMR (400 MHz, CD3OD) δ 8.40 (w s, 1H), 7.92 (dd, J=8.2, 2 Hz, 1H), 7.56 (d, J=8.6 Hz , 1H), 2.62 (s, 3H), 2.51 (dd, half of the ABX pattern, J=16.8, 6.2 Hz, 1H), 2.33 (dd, half of the ABX pattern, J =16.8, 7.8 Hz, 1H), 1.96-1.89 (m, 1H), 1.46-1.36 (m, 1H), 1.16-1.09 (m, 1H ), 1.070.99 (m, 1H).

Step 2. Synthesis of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[(1R,2S)-2-(6methylpyridin- 3-yl)cyclopropyl]ethanone (17).

The reaction of C63 with P1 was carried out using the method described for the synthesis of 16 from C62 in example 16. Purification was carried out using reverse phase HPLC (column: Waters XBridge C18, 5 μm; mobile phase A: water containing 0.03% ammonium hydroxide ; mobile phase B: acetonitrile, co

- 64 044379 containing 0.03% ammonium hydroxide; gradient: 2 from 0 to 30% B), resulting in a light tan glass product. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 35 mg, 0.11 mmol, 16%. LCMS m/z 322.4 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.26 (w s, 1H), 7.44 (dd, J=8.1, 2.4 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.05 (s, 1H), [4.87 (s, assumed; obscured by water peak), 4.82 (s), 4.71 (s), and 4.70 (s), total 4H], 2.70-2.56 (m, 2H), [2.49 (s) and 2.49 (s), total 3H], 2.47 (s, 3H), [2.31 (s ) and 2.30 (s), total 3H], 1.89-1.84 (m, 1H), 1.50-1.42 (m, 1H), 1.08-0.98 (m, 2H ).

Example 18.

1-[2-(Difluoromethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-[(1R,2S)-2-(6- methylpyridin-3-yl)cyclopropyl]ethanone (18)

1,1'-Carbonyldiimidazole (17.8 mg, 0.110 mmol) and C63 (15.0 mg, 78.4 μmol) were mixed with acetonitrile (0.8 ml) and stirred at room temperature for 2 hours, then added P3 (33.0 mg, 0.128 mmol) and the reaction mixture was stirred for an additional 2 hours. Then diluted with ethyl acetate and washed three times with aqueous sodium bicarbonate; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (gradient: 0 to 7% methanol in dichloromethane) gave the product as a solid. From ¹ H NMR analysis it was assumed that the product existed as a mixture of rotamers. Determination of the crystal structure was carried out by X-ray diffraction analysis (see below), where the crystal was obtained by recrystallization from ethanol. Yield: 12 mg, 34 mmol, 43%. LCMS m/z 358.3 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 8.34 (w s, 1H), 7.39 (s, 1H), 7.34-7.29 (m, 1H), 7.07-7.02 (m , 1H), [6.61 (t, Jhf = 55.4 Hz) and 6.60 (t, J _hf = 55.6 Hz), total 1H], 4.89-4.79 (m, 4H) , 2.68-2.46 (m, 2H), 2.51 (s, 3H), [2.38 (s) and 2.37 (s), total 3H], 1.84-1.76 ( m, 1H), 1.55-1.44 (m, 1H), 1.11-1.03 (m, 1H), 1.00-0.93 (m, 1H).

X-ray diffraction analysis of a single crystal of compound 18.

X-ray diffraction analysis of a single crystal.

Data collection was carried out on a Bruker-AXS X8 Kappa diffractometer at 100°K using CuK _a radiation (λ=1.54178 A) from an IμS microsource. Data collection consisted of omega and fi scans.

Data reconstruction was carried out using the SAINT ¹ program and semi-empirical absorption correction based on equivalents was performed using the SADABS ² program.

Structure was determined by direct methods using SHELX ³ software and refined by F ² for all data using SHELXL ⁴ using established refinement methods ⁵ . All non-hydrogen atoms were determined anisotropically. All hydrogen atoms were placed in geometrically calculated positions and allowed to jump onto their atoms with carriers and refined using the rider model while limiting their U _lso to 1.2 times the U _{eq of} the atoms to which they are attached (1.5 times for methyl groups). No restrictions were used to refine structure 18.

The compound crystallizes in the orthorhombic chiral space group P212121 with one target molecule per asymmetric unit.

The molecule is chiral and the absolute structure was determined by both the methods of Parsons ⁶ and Hooft ⁷ .

The corresponding crystal, data collection and clarification of information are given in table. 1. Atomic coordinates, bond lengths, bond angles and displacement parameters are given in Table. 2-5.

Software and links

1. Broker (2011). SAINT, Bruker-AXS Inc., Madison, Wisconsin, USA.

2. Sheldrick, G. M., (2009). SADABS, University of Gottingen, Germany.

3. Sheldrick, G. M., Acta Cryst. 2015, A71, 3-8.

4. Sheldrick, G. M., Acta Cryst. 2015, C71, 3-8.

5. MOIIer, P., Crystallography Reviews 2009, 15, 57-83.

6. Parsons, S. & Flack, H. D., Acta Cryst. 2004, A60, s61.

7. Hooft, R. W. W., Straver, L. H., Spek, A. L., J. Appl. Christ. 2008, 41, 96-103.

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Table 1. Crystal data and structure refinement for 18

Empirical formula

Mass according to the formula Temperature

Wavelength Syngony

Space group Unit cell parameters

Volume

Z

Density (calculated) Absorption coefficient

F(000)

Crystal size

Theta band for data acquisition

Index Ranges

Collected reflections Independent reflections Occupancy k theta = 67.679° Absorption correction Refinement method

Data / restrictions / parameters Consistency criterion for F ² Final R indices [/>2о(/)] R indices (all data) Largest differential. peak and pit

C ₂₀ H ₂₁ F ₂ N ₃ O

357.40

100(2) K

1.54178 A

Rhombic r^^ a = 9.6591 (2) A a = 90°

b = 10.2245(2) A /3 = 90° c = 17.3206(4) A γ =90°

1710.57(6) A ³

1.388 Mg/ ^m3

0.849 mm' ¹

752

0.340x0.300x0.200 mm ³

5.023 to 68.184°

-11<=/7<=11, -10<=/s<=12, -20<=/<=20 18544

3126 [R _int = 0.0314]

100.0%

Semi-empirical of equivalents Full-matrix least squares on F ² 3126/0/237

1,030

R1 =0.0281, wR2 = 0.0755

R1 = 0.0285, wR2 = 0.0759

0.255 and -0.135 e.A' ³

Table 2. Atomic coordinates (x10 ⁴ ) and equivalent isotropic substitution parameters (A ² x10 ³ ) for 18. u(eq) is defined as one third of the trace of the orthogonalized tensor U ^1J

X U z u(eq.) F(1) 1635(1) -1567(1) 5371(1) 34(1) F(2) 3530(1) -2097(1) 5968(1) 36(1) 0(1) 5050(1) 5192(1) 3195(1) 25(1) N(1) 310(2) 11243(2) 3712(1) 29(1) N(2) 4222(2) 3741(2) 4050(1) 21(1) N(3) 3072(2) 1086(2) 5251(1) 22(1) C(1) 4252(2) 4940(2) 3725(1) 20(1) C(2) 3268(2) 5957(2) 4053(1) 21(1) C(3) 3060(2) 7090(2) 3506(1) 21(1) C(4) 2024(2) 6948(2) 2865(1) 26(1) C(5) 1702(2) 7827(2) 3550(1) 21(1) C(6) 1597(2) 9267(2) 3436(1) 20(1) C(7) 556(2) 9966(2) 3802(1) 25(1) C(8) 2465(2) 9972(2) 2948(1) 23(1) C(9) 2238(2) 11295(2) 2852(1) 25(1) C(10) 1148(2) 11904(2) 3234(1) 26(1) C(11) 851(3) 13338(2) 3123(1) 35(1) C(12) 3329(2) 3320(2) 4689(1) 22(1) C(13) 3700(2) 1900(2) 4763(1) 20(1) C(14) 4753(2) 1564(2) 4258(1) 21(1) C(15) 5176(2) 2712(2) 3779(1) 22(1) C(16) 5242(2) 282(2) 4244(1) 22(1) C(17) 4607(2) -579(2) 4758(1) 22(1) C(18) 3542(2) -146(2) 5233(1) 22(1) C(19) 2750(2) -1052(2) 5756(1) 24(1) C(20) 6349(2) -136(2) 3686(1) 27(1)

-66044379

Table 3. Bond length [A] and angles [°] for 18

F(1)-C(19) 1.373(2) F(2)-C(19) 1.358(2) 0(1)-0(1) 1.227(2) N(1)-C(7) 1.337(3) N(1)-C(10) 1,340(3) N(2)-C(1) 1,350(2) N(2)-C(12) 1.468(2) N(2)-C(15) 1.475(2) N(3)-C(13) 1.332(3) N(3)-C(18) 1.339(3) 0(1)-0(2) 1.518(3) C(2)-C(3) 1,509(3) C(2)-H(2A) 0.9900 C(2)-H(2B) 0.9900 0(3)-0(4) 1,503(3) 0(3)-0(5) 1,514(3) C(3)-H(3) 1.0000 C(4)-C(5) 1.520(3) C(4)-H(4A) 0.9900 C(4)-H(4B) 0.9900 0(5)-0(6) 1,488(3) C(5)-H(5) 1.0000 0(6)-0(7) 1,386(3) 0(6)-0(8) 1,392(3) C(7)-H(7) 0.9500 0(8)-0(9) 1,381(3) C(8)-H(8) 0.9500 C(9)-C(10) 1,391(3) C(9)-H(9) 0.9500 C(10)-C(11) 1,507(3) C(11)-H(11A) 0.9800 C(11)-H(11B) 0.9800 C(11)-H(11C) 0.9800

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C(12)-C(13) 1,501(3) C(12)-H(12A) 0.9900 C(12)-H(12B) 0.9900 C(13)-C(14) 1.385(3) C(14)-C(16) 1.393(3) C(14)-C(15) 1.495(3) C(15)-H(15A) 0.9900 C(15)-H(15B) 0.9900 C(16)-C(17) 1.395(3) C(16)-C(20) 1,504(3) C(17)-C(18) 1,389(3) C(17)-H(17) 0.9500 C(18)-C(19) 1.505(3) C(19)-H(19) 1.0000 C(20)-H(20A) 0.9800 C(20)-H(20B) 0.9800 C(20)-H(20C) 0.9800 C(7)-N(1)-C(10) 117.20(18) C(1)-N(2)-C(12) 126.41(16) C(1)-N(2)-C(15) 120.09(16) C(12)-N(2)-C(15) 113.48(15) C(13)-N(3)-C(18) 114.76(17) O(1)-C(1)-N(2) 121.10(17) O(1)-C(1)-C(2) 121.95(18) N(2)-C(1)-C(2) 116.94(16) C(3)-C(2)-C(1) 112.03(15) C(3)-C(2)-H(2A) 109.2 C(1)-C(2)-H(2A) 109.2 C(3)-C(2)-H(2B) 109.2 C(1)-C(2)-H(2B) 109.2 H(2A)-C(2)-H(2B) 107.9 C(4)-C(3)-C(2) 118.62(16) C(4)-C(3)-C(5) 60.52(13) C(2)-C(3)-C(5) 117.83(16) C(4)-C(3)-H(3) 116.1 C(2)-C(3)-H(3) 116.1

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C(5)-C(3)-H(3) 116.1 C(3)-C(4)-C(5) 60.12(13) C(3)-C(4)-H(4A) 117.8 C(5)-C(4)-H(4A) 117.8 C(3)-C(4)-H(4B) 117.8 C(5)-C(4)-H(4B) 117.8 H(4A)-C(4)-H(4B) 114.9 C(6)-C(5)-C(3) 123.05(17) C(6)-C(5)-C(4) 119.72(17) C(3)-C(5)-C(4) 59.36(13) C(6)-C(5)-H(5) 114.5 C(3)-C(5)-H(5) 114.5 C(4)-C(5)-H(5) 114.5 C(7)-C(6)-C(8) 116.56(17) 0(7)-0(6)-0(5) 119.94(18) 0(8)-0(6)-0(5) 123.45(18) N(1)-0(7)-0(6) 125.40(19) N(1)-C(7)-H(7) 117.3 C(6)-C(7)-H(7) 117.3 0(9)-0(8)-0(6) 119.08(19) C(9)-C(8)-H(8) 120.5 C(6)-C(8)-H(8) 120.5 0(8)-0(9)-0(10) 120.03(19) C(8)-C(9)-H(9) 120.0 C(10)-C(9)-H(9) 120.0 N(1)-C(10)-C(9) 121.73(19) N(1)-C(10)-C(11) 117.0(2) C(9)-C(10)-C(11) 121.3(2) C(10)-C(11)-H(11A) 109.5 C(10)-C(11)-H(11B) 109.5

H(11A)-C(11)-H(11B) 109.5

C(10)-C(11)-H(11C) 109.5

H(11A)-C(11)-H(11C) 109.5

H(11B)-C(11)-H(11C) 109.5

N(2)-C(12)-C(13) 101.99(15)

N(2)-C(12)-H(12A) 111.4

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С(13)-С(12)-Н(12А) 111.4 N(2)-C(12)-H(12B) 111.4 С(13)-С(12)-Н(12В) 111.4 Н(12А)-С(12)-Н(12В) 109.2 N(3)-C(13)-C(14) 125.46(18) N(3)-C(13)-C(12) 123.37(17) С(14)-С(13)-С(12) 111.17(17) С(13)-С(14)-С(16) 119.56(18) С(13)-С(14)-С(15) 110.91(16) С(16)-С(14)-С(15) 129.52(18) N(2)-C(15)-C(14) 102.26(15) N(2)-C(15)-H(15A) 111.3 С(14)-С(15)-Н(15А) 111.3 N(2)-C(15)-H(15B) 111.3 С(14)-С(15)-Н(15В) 111.3 N(15A)-C(15)-N(15V) 109.2 С(14)-С(16)-С(17) 115.69(18) С(14)-С(16)-С(20) 121.33(18) С(17)-С(16)-С(20) 122.94(18) С(18)-С(17)-С(16) 120.16(17) С(18)-С(17)-Н(17) 119.9 С(16)-С(17)-Н(17) 119.9 N(3)-C(18)-C(17) 124.36(17) N(3)-C(18)-C(19) 113.12(17) С(17)-С(18)-С(19) 122.46(17) F(2)-C(19)-F(1) 105.38(16) F(2)-C(19)-C(18) 111.40(16) F(1)-C(19)-C(18) 109.98(16) F(2)-C(19)-H(19) 110.0 F(1)-C(19)-H(19) 110.0 C(18)-C(19)-H(19) 110.0 C(16)-C(20)-H(20A) 109.5 C(16)-C(20)-H(20B) 109.5 H(20A)-C(20)-H(20B) 109.5 C(16)-C(20)-H(20C) 109.5 H(20A)-C(20)-H(20C) 109.5 H(20B)-C(20)-H(20C) 109.5

Symmetry transformation used to generate equivalent atoms.

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Table 4. Anisotropic displacement parameters (A ² x10 ³ ) for 18. The exponent of the anisotropic displacement coefficient takes the form: -2n ² [h ² ax ² U ¹¹ +...+2hkaxbxU ¹² ]

U11 U22 U33 U23 U13 U12 F(1) 30(1) 37(1) 35(1) 3(1) -3(1) -12(1) F(2) 29(1) 28(1) 51(D 17(1) 6(1) 5(D 0(1) 23(1) 25(1) 27(1) 3(1) 4(1) 4(1) N(1) 34(1) 24(1) 29(1) 0(1) 0(1) 7(1) N(2) 19(1) 19(1) 24(1) 0(1) 2(1) 3(1) N(3) 22(1) 21(1) 22(1) 0(1) -1(1) 2(1) 0(1) 16(1) 22(1) 22(1) -2(1) -3(1) -1(1) 0(2) 21(1) 18(1) 24(1) 1(1) 2(1) 1(1) 0(3) 21(1) 19(1) 23(1) -1(1) 1(1) 1(1) 0(4) 31(1) 20(1) 28(1) -1(1) -5(1) 2(1) 0(5) 21(1) 20(1) 23(1) 1(1) 1(1) 0(1) 0(6) 19(1) 19(1) 21(1) -1(1) -3(1) 0(1) 0(7) 27(1) 23(1) 26(1) 4(1) 3(1) 2(1) 0(8) 22(1) 24(1) 23(1) -1(1) -1(1) 0(1) 0(9) 28(1) 24(1) 24(1) 4(1) -5(1) -6(1) C(10) 31(1) 20(1) 26(1) 0(D -11(1) 0(D C(11) 41(1) 21(1) 43(1) 3(1) -14(1) 0(1) C(12) 24(1) 20(1) 23(1) 0(1) 2(1) 3(1) C(13) 21(1) 20(1) 20(1) -1(1) -4(1) 1(1) C(14) 20(1) 22(1) 20(1) -1(1) -4(1) 1(1) C(15) 20(1) 21(1) 25(1) 0(1) 0(1) 3(1) C(16) 22(1) 22(1) 22(1) -1(1) -5(1) 2(1) C(17) 23(1) 19(1) 23(1) 0(1) -6(1) 2(1) C(18) 22(1) 21(1) 22(1) 0(1) -6(1) 1(1) C(19) 23(1) 22(1) 28(1) 2(1) -2(1) 0(1) C(20) 28(1) 24(1) 29(1) 2(1) 2(1) 7(1)

Table 5. Hydrogen coordinates (x10 ⁴ ) and isotropic substitution parameters (A ² x10 ³ ) for 18

X U z U(3kb.) H(2A) 2363 5542 4160 25 H(2B) 3642 6289 4547 25 H(3) 3900 7624 3387 25 H(4A) 1515 6110 2824 31 H(4B) 2237 7373 2365 31 H(5) 1018 7456 3923 25 H(7) -thirty 9498 4145 thirty H(8) 3203 9549 2685 28 H(9) 2827 11790 2524 thirty H(11A) 228 13454 2682 53 H(11B) 1719 13806 3026 53 H(11C) 412 13689 3589 53 H(12A) 2337 3434 4561 27 H(12B) 3540 3806 5169 27 H(15A) 6153 2955 3876 26 H(15B) 5048 2535 3222 26 H(17) 4903 -1464 4784 26 H(19) 2430 -568 6225 29 H(20A) 6603 -1048 3787 41 H(20B) 7165 423 3750 41 H(20C) 6000 -56 3156 41

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Example 19.

2,4-Dimethyl-N-[1-(pyridin-3-yl)azetidin-3-yl]-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6carboxamide (19)

NEt ₃

Step 1. Synthesis of tert-butyl[1-(pyridin-3-yl)azetidin-3-yl]carbamate (C64).

Mixture of tert-butylazetidin-3-ylcarbamate (6.0 g, 35 mmol), 3-bromopyridine (3.8 g, 24 mmol), cesium carbonate (25.0 g, 76.7 mmol), 1,1'- binaphthalene-2,2'-diylbis(diphenylphosphane (BINAP; 900 mg, 1.45 mmol) and tri(dibenzylideneacetone)dipalladium (450 mg, 0491 mmol) in toluene (150 ml) were stirred at 90 °C for 4 h. The reaction mixture was then cooled to room temperature, filtered and the filter cake washed with ethyl acetate (100 ml).The combined filtrates were washed successively with water (200 ml) and saturated aqueous sodium chloride (200 ml) and concentrated under reduced pressure. Silica gel chromatography (gradient : 17 to 50% ethyl acetate in petroleum ether) provided the product as a light yellow solid Yield: 4.98 g, 20.0 mmol, 83% 1H NMR (400 MHz, CDCL) δ 8.04 (d , J=4.5 Hz, 1H), 7.87 (d, J=3.0 Hz, 1H), 7.11 (dd, J=8.3, 4.8 Hz, 1H), 6.77 -6.71 (m, 1H), 5.12-4.95 (w s, 1H), 4.74-4.59 (w s, 1H), 4.26 (dd, J=7.5, 7.5 Hz, 2H), 3.67 (dd, J=7.5, 5.5 Hz, 2H), 1.46 (s, 9H).

Step 2. Synthesis of 1-(pyridin-3-yl)azetidin-3-amine, ditrifluoroacetate salt (C65).

Trifluoroacetic acid (30 ml) was added to a solution of C64 (9.9 g, 40 mmol) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature at 25°C for 4 hours, then concentrated in vacuo and triturated with tert-butyl methyl ether to give the product as a light yellow solid. Yield: 13.9 g, 36.8 mmol, 92%. LCMS m/z 150.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.11 (d, J=5.3 Hz, 1H), 8.02 (d, J=2.8 Hz, 1H), 7.75 (dd, J=8 ,7, 5.5 Hz, 1H), 7.587.52 (m, 1H), 4.44 (dd, J=8.5, 7.8 Hz, 2H), 4.35-4.27 (m, 1H), 4.13 (dd, J=9.5, 4.0 Hz, 2H).

Step 3. Synthesis of 2,4-dimethyl-N-[1-(pyridin-3-yl)azetidin-3-yl]-5,7-dihydro-6H-pyrrolo[3,4b]pyridin-6-carboxamide (19 ).

Potassium carbonate (91.6 mg, 0.663 mmol) was added to a mixture of C65 (100 mg, 0.265 mmol) in tetrahydrofuran (2 ml) and the resulting mixture was stirred at room temperature for 20 minutes. The solid was filtered and washed with tetrahydrofuran (2 ml) and the combined filtrates were added dropwise to a suspension of P1 (49.0 mg, 0.222 mmol), triethylamine (80.5 mg, 0.796 mmol) and 1,1'-carbonyldiimidazole (86.0 mg, 0.530 mmol) in tetrahydrofuran (4 ml). The reaction mixture was stirred at room temperature for 16 hours, after which it was poured into water (15 ml) and extracted with ethyl acetate (3x15 ml). The combined organic layers were washed successively with water (10 ml) and saturated aqueous sodium chloride (10 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Purification using reverse phase HPLC (column: YMCActus Triart C18, 5 µm; mobile phase A: water containing 0.05% ammonium hydroxide; mobile phase B: acetonitrile; gradient: 25 to 40% B) provided product as white solid. Yield: 34.9 mg, 0.108 mmol, 49%. LCMS m/z 323.9 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-dg) δ 7.92 (dd, J=4.5, 1.2 Hz, 1H), 7.85 (d, J=2.8 Hz, 1H), 7.17 (dd, J=8.3, 4.8 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.98 (s, 1H), 6.86 (ddd, J= 8.2, 2.9, 1.2 Hz, 1H), 4.74-4.63 (m, 1H), 4.55 (w s, 2H), 4.52 (w s, 2H), 4 ,19 (dd, J=7.5, 7.5 Hz, 2H), 3.76 (dd, J=7.3, 6.5 Hz, 2H), 2.41 (s, 3H), 2, 21 (s, 3H).

Example 20.

1-(Pyridin-3-yl)azetidin-3-yl 2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-carboxylate (20)

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Step 1. Synthesis of 1-(pyridin-3-yl)azetidin-3-ol (C66).

Mixture of azetidin-3-ol, hydrochloride salt (347 mg, 3.17 mmol), 3-bromopyridine (500 mg, 3.16 mmol), tri(dibenzylideneacetone)dipalladium(0) (86.9 mg, 94.9 µmol), 4,5-bis(diphenylphosphino)-9,9dimethylxanthene (Xantphos; 110 mg, 0.190 mmol) and cesium carbonate (3.09 g, 9.48 mmol) in 1,4-dioxane (20 ml) were stirred at from 95 to 100°C for 18 hours. The reaction mixture was then cooled to room temperature, water (50 ml) was added and the resulting mixture was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with saturated aqueous sodium chloride (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluent: 30:1 dichloromethane/methanol) provided the product as a yellow solid. Yield: 249 mg, 1.66 mmol, 52%. 1H NMR (400 MHz, CDCl ₃ ) δ 8.01 (dd, J=4.6, 1.3 Hz, 1H), 7.86 (d, J=2.9 Hz, 1H), 7.11 ( dd, J=8.2, 4.6 Hz, 1H), 6.75 (ddd, J=8.3, 2.8, 1.3 Hz, 1H), 4.82 (tt, J=6, 4, 4.6 Hz, 1H), 4.26-4.20 (m, 2H), 3.74 (w dd, J=8.7, 4.6 Hz, 2H).

Step 2. Synthesis of 2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carbonyl chloride (C67).

To a solution of P1 (125 mg, 0.565 mmol) and pyridine (214 mg, 2.71 mmol) in dichloromethane (10 ml) was added bis(trichloromethyl) carbonate (71 mg, 0.24 mmol) and the reaction mixture was stirred at room temperature ( ~7°С) for 20 min. The reaction mixture was concentrated in vacuo to give the crude product (440 mg) as a brown solid, which was used directly in the next step.

Step 3. Synthesis of 1-(pyridin-3-yl)azetidin-3-yl 2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4b]pyridin-6-carboxylate (20).

Sodium hydride (60% suspension in mineral oil; 80 mg, 2 mmol) was added to a solution of C66 (100 mg, 0.666 mmol) in tetrahydrofuran (10 ml) at 0°C and the reaction mixture was stirred at room temperature (~7°C ) for 1 hour. Crude C67 (from the previous step; <0.565 mmol) was added at 0°C and stirring was continued at room temperature for 2 days. The reaction mixture was then treated with water (20 ml) and extracted with ethyl acetate (3x20 ml); the combined organic layers were washed with saturated aqueous sodium chloride (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Purification using reverse phase HPLC (column: Agela Durashell C18, 5 µm; mobile phase A: 0.05% ammonium hydroxide in water; mobile phase B: acetonitrile; gradient: 26 to 46% B) gave the product as white solid matter. From 1H NMR analysis it was assumed that this substance exists as a mixture of rotamers. Yield: 112 mg, 0.345 mmol, 61% in 2 stages. LCMS m/z 324.8 [M+H]+. 1H NMR (400 MHz, CDQ3) δ 8.05 (d, J=4.5 Hz, 1H), 7.91 (d, J=3.0 Hz, 1H), 7.13 (dd, J=8 ,3, 4.8 Hz, 1H), 6.88 (s, 1H), 6.80-6.74 (m, 1H), 5.49-5.39 (m, 1H), 4.77- 4.64 (m, 4H), 4.34 (dd, J=8.0, 7.0 Hz, 2H), 3.99-3.91 (m, 2H), [2.52 (s) and 2.51 (s), total 3H], [2.25 (s) and 2.24 (s), total 3H].

Using the methodology described above for Examples 1-20, Examples 21-78 were synthesized. See table. 6 for the specific methods used, as well as the characteristic data for these examples.

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Table 6. Preparation method, structure and physicochemical data for examples 21-78

Example number Method of synthesis; non-commercial source materials Structure Ή NMR (400 MHz, CDCI ₃ ) δ; Mass spectrum, observed ion m/z [M+H] ⁺ or HPLC retention time; Mass spectrum m/z [M+H] ⁺ (unless otherwise indicated) ¹ 21 Example 1; P8, C43 / O z ά ¹ H NMR (400 MHz, CD ₃ OD) δ 7.86 (d, J=5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.21 (dd, J= 8.5 Hz, 1H), 6.94-6.88 (m, 1H), 6.56 (w s, 1H), 4.69-4.51 (m, 4H), 4.16 (dd, 4=7.5, 7.5 Hz, 2H), [3.88 (s) and 3.88 (s), total ZN], 3.68 (w dd, 4=6.5, 6.5 Hz , 2H), 3.3-3.15 (m, 1H), 2.95-2.88 (m, 2H), 2.28 (s, ZN); 339.1 22 Example G; S38, C43 s/ 2 UG G ά ^1H NMR (400 MHz, CD3OD) δ 7.85 (d, 4=4.5 Hz, 1H), 7.77-7.71 (w s, 1H), 7.20 (dd, 4=8, 0, 4.5 Hz, 1H), 6.89 (wd, 4=8.0 Hz, 1H), [4.81 (s) and 4.76 (s), total 2H], [4.65 (s) and 4.59 (s), total 2H], 4.14 (dd, 4=7.5, 7.5 Hz, 2H), [3.97 (s) and 3.96 (s), total ZN], 3.67 (dd, 4=7.0, 6.0 Hz, 2H), 3.27-3.15 (m, 1H), 2.95-2.85 (m, 2H), 2.31 (s, ZN); 373.0 (chlorine isotope pattern observed)

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23 Example 1; P2, C43 7.99 (wd, J=4.5 Hz, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.10 (dd, J=8.3, 4.5 Hz, 1 Η), 6.72 (dd, J=8.3, 2.8, 1.2 Hz, 1H), 4.78-4.71 (m, 4H), [4.19 (dd, J= 7.5, 7.5 Hz) and 4.18 (dd, J=7.8, 7.5 Hz), total 2H], 3.69-3.63 (m, 2H), 3.34-3 .21 (m, 1H), [2.83 (d, J=7.8 Hz) and 2.80 (d, J=7.5 Hz), total 2H], [2.53 (s) and 2 .52 (s), total ZN], [2.22 (s) and 2.21 (s), total 6N]; 337.2 24 Example ^{3 3} o no L Χ/ ^Ν 4 z ^N= \ Ή NMR (600 MHz, DMSO-s/ ₆ ), characteristic peaks: δ 8.12 (wd, J=6 Hz, 1H), 7.22-7.19 (m, 1H), [6.37 ( d, J=6 Hz) and 6.37 (d, J=6 Hz), total 1H], [4.84 (s) and 4.78 (s), total 2H], [4.61 (s) and 4.56 (s), total 2H], 4.53-4.50 (w s, 2H), 4.18 (dd, J=8.5, 8.5 Hz, 2H), 3.75- 3.71 (m, 2H), [2.86 (d, J=7.5 Hz) and 2.85 (d, J=7.5 Hz), total 2H], [2.28 (s) and 2.27 (s), total ZN]; 340.2 25 Example 2; RZ, S50 z γϊ z ¹ H NMR (400 MHz, CD ₃ OD) δ 7.75 (d, J=5.5 Hz, 1H), 7.46 (s, 1H), 7.35 (t, Jhf=73.8 Hz, 1H), 6.69 (t, J _H f=55.5 Hz, 1H), 6.20 (d, J=5.0 Hz, 1H), 5.82 (s, 1H), [4.96 (s), 4.91 (s), 4.79 (s), and 4.75 (s), total 4H], 4.19 (dd, J=8.0, 7.5 Hz, 2H), 3.73 (dd, J=7.0, 6.5 Hz, 2H), 3.28-3.17 (m, 1H), 2.97-2.89 (m, 2H), 2.41 ( s, ZN); 425.1

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26 Example 1 ² '⁴; C41 0 JL Σ ^N Y a /= ^N ΎΥν^ ⁷ /) ⁴⁷ Ν 8.64 (s, 1Η), 7.96 (s, 2Η), 4.774.66 (μ, 4Η), 4.30-4.21 (m, 2Η), [4.02 (s) and 4, 00 (s), total ZN], 3.77-3.67 (m, 2Η), 3.41-3.27 (m, 1 Η), 2.88-2.77 (m, 2Η), [ 2.33 (s) and 2.32 (s), total ZN]; 373.9 (chlorine isotope pattern observed) 27 Example 1; S54, S43 \ Ο ζ ^ζ ό 8.01 (w d, 4=4.5 Hz, 1H), 7.87 (d, 4=2.8 Hz, 1H), 7.18 (w s, 1H), 7.11 (dd, 4 =8.3, 4.5 Hz, 1H), 6.73 (ddd, 4=8.3, 3.0, 1.2 Hz, 1H), 4.84-4.75 (m, 4H), [4.56 (s) and 4.55 (s), total 2H], [4.20 (dd, 4=7.8, 7.3 Hz) and 4.19 (dd, 4=7.5, 7.5 Hz), total 2H], 3.70-3.64 (m, 2H), [3.50 (s) and 3.49 (s), total ZN], 3.34-3.22 ( m, 1H), [2.85 (d, 4=7.8 Hz) and 2.82 (d, 4=7.8 Hz), total 2H], [2.33 (s) and 2.32 ( c), total ZN]; 353.0 28 Example 1 ⁵ ; S38, S43 ¥ ί ά ^1H NMR (400 MHz, CD ₃ OD) δ 7.85 (wd, 4=4.3 Hz, 1H), 7.75 (d, 4=2.3 Hz, 1H), 7.21 (dd , 4=8.3, 4.8 Hz, 1H), 6.93-6.87 (m, 1H), [4.80 (s) and 4.75 (s), total 2H], [4, 63 (s) and 4.60 (s), total 2H], 4.15 (dd, 4=7.8, 7.5 Hz, 2H), [3.91 (s) and 3.91 (s) , total ZN], 3.68 (dd, 4=7.3, 5.8 Hz, 2H), 3.27-3.15 (m, 1H), 2.94-2.87 (m, 2H) , 2.21 (s, ZN), 2.13 (s, ZN); 353.0

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29 Example G ⁵ A A A ^1H NMR (400 MHz, CD ₃ OD) δ 8.46 (s, 1H), 8.00 (s, 2H), [4.82 (s) and 4.76 (s), total 2H], [ 4.65 (s) and 4.60 (s), total 2H], 4.23 (dd, 4=7.5, 7.5 Hz, 2H), [3.91 (s) and 3.91 ( s), total ZN], 3.77 (dd, 4=7.0, 6.0 Hz, 2H), 3.3-3.21 (m, 1H, assumed; partially obscured by solvent peak), 2.97 -2.89 (m, 2H), 2.22 (s, ZN), 2.13 (s, ZN); 354.2 thirty Example 1 ⁶ ; P1, C41 р J 1 ^N \ γΝ ^V \ _y ^N \ ^{N 1H} NMR (400 MHz, CD ₃ OD) δ 8.52-8.49 (m, 1H), 8.38-8.36 (m, 1H), 7.07 (w s, 1H), 6, 56-6.52 (m, 1H), 4.9-4.83 (m, 2H, inferred; partially obscured by water peak), [4.71 (s) and 4.70 (s), total 2H], 4.32 (wdd, 4=8.8 Hz, 2H), 3.89-3.83 (m, 2H), 3.35-3.24 (m, 1H, assumed; partially obscured by solvent peak), 2.98-2.93 (m, 2H), 2.50 (s, ZN), 2.32 (s, ZN); 323.9 31 Example G; C54 \ ABOUT ^z: A ζ^,ζ ^1H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.01 (w s, 2H), 7.26 (s, 1H), 4.95-4.85 (m, 2H, assumed; partially obscured by water peak), [4.75 (s) and 4.72 (s), total 2H], 4.51 (s, 2H), 4.24 (w dd, 4=8, 8 Hz, 2H), 3.77 (w dd, 4=7.6 Hz, 2H), 3.44 (s, ZH), 3.3-3.23 (m, 1H, assumed; partially obscured by solvent peak) , 2.99-2.92 (m, 2H), 2.36 (s, ZN); 353.9

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32 Example G ⁷ ; C38 X JL/= ^N '—\N-< /) I ^v FF 8.63 (s, 1H), 7.94 (s, 2H), [7.45 (t, J _H f=72.3 Hz) and 7.39 (t, Jhf=72.4 Hz), total 1H], 4.804.68 (m, 4H), [4.25 (dd, 4=7.8, 7.5 Hz) and 4.24 (dd, 4=7.8, 7.5 Hz), total 2H], 3.71 (dd, 4=6.8, 5.8 Hz, 2H), 3.39-3.26 (m, 1H), [2.84 (d, 4=7.8 Hz) and 2.81 (d, 4=7.8 Hz), total 2N], [2.37 (s) and 2.36 (s), total ZN]; 409.9 (chlorine isotope pattern observed) 33 Example 1 ⁸ ; S54, S53 Aa ⁰ CF ₃ HO XX/ ^N 4 /X Ή 8.29 (d, 4=5.7 Hz, 1H), [7.04 (s) and 7.03 (s), total 1H], 6.61-6.58 (m, 1H), 6, 34 (dd, 4=5.7, 2.3 Hz, 1H), 4.85-4.73 (m, 6H), [4.30 (dd, 4=8.2, 8.2 Hz) and 4.29 (dd, 4=8.2, 8.2 Hz), total 2H], 3.80-3.73 (m, 2H), 3.43-3.23 (m, 2H), [2 .85 (d, 4=7.6 Hz) and 2.83 (d, 4=7.8 Hz), total 2H], [2.33 (s) and 2.32 (s), total ZN]; 407.3 34 Example G; RZ LgO ⁰ nC ^x ) F ^V N ¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.01 (d, 4=1.5 Hz, 2H), 7.47 (s, 1H), 6.69 ( t, 4 _HF =55 Hz, 1H), [4.98 (s), 4.92 (s), 4.80 (s), and 4.76 (s), total 4H], 4.284.21 (m , 2H), 3.80-3.74 (m, 2H), 3.3-3.24 (m, 1H, assumed; partially obscured by solvent peak), [2.96 (d, 4=7.8 Hz ) and 2.95 (d, 4=7.3 Hz), total 2H], 2.42 (s, ZN); 359.9 35 Example 1 ⁹ ; P2, C41 ^ ^N=x 8.59 (s, 1H), 8.17 (d, 4=6.0 Hz, 1H), 6.18 (shd, 4=6 Hz, 1H), 4.794.72 (m, 4H), 4, 40-4.32 (m, 2H), 3.88-3.81 (m, 2H), 3.36-3.25 (m, 1H), [2.83 (d, 4=8.0 Hz ) and 2.80 (d, 4=7.8 Hz), total 2H], [2.54 (s) and 2.53 (s), total ZN], [2.23 (s) and 2.22 (s), total 6H]; 337.9

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36 P2, C66 ¹⁰ About Ao zv ^{z 1} H NMR (500 MHz, CDCI ₃ ) δ 8.088.04 (Μ, 1H), 7.94-7.91 (m, 1H), 7.14 (dd, J=8.2, 4.7 Hz, 1H), 6.806.76 (μ, 1H), 5.49-5.40 (m, 1H), 4.73-4.68 (μ, 4H), 4.38-4.33 (m, 2H) , 3.98-3.93 (μ, 2H), [2.53 (s) and 2.52 (s), total 3H], [2.22 (s), 2.21 (s), and 2 .20 (s), total 6H], 339.0 37 Example 13 ¹¹¹² ; P2 νΛ. o \=/ I X l l - N trans, ENT-1 2.52 minutes ¹³ ; 322.6 38 Example 13 ¹¹¹² ; P2 W trans, ENT-2 3.58 minutes ¹³ ; 322.3 39 Example 13 ¹⁴ ; P6 ^C| xol° x ⁿ⁼ \ 8.58 (s, 1H), 8.17 (d, J=6.0 Hz, 1H), 6.18 (wd, J=6.0 Hz, 1H), 4.81-4.73 ( m, 4H), [4.36 (dd, J=9.0, 8.0 Hz) and 4.35 (dd, J=8.5, 8.5 Hz), total 2H], 3.88- 3.79 (m, 2H), 3.35-3.23 (m, 1H), 2.85-2.77 (m, 2H), [2.65 (s) and 2.64 (s), total ZN], 2.34 (w s, ZN); 358.1 (chlorine isotope pattern observed) 40 Example G ¹¹⁵ ; C9 \ o z ^y <j^° z ^z fXl z^z 8.64 (s, 1H), 7.96 (s, 2H), 4.834.73 (m, 4H), [4.62 (s) and 4.61 (s), total 2H], [4.26 (dd, J=7.5, 7.5 Hz) and 4.25 (dd, J=8.0, 7.5 Hz), total 2H], 3.78-3.70 (m, 2H), 3.46 (s, ZN), 3.40-3.29 (m, 1H), [2.85 (d, J=8.0 Hz) and 2.82 (d, J=8.0 Hz) , total 2Н], 2.31 (s, ZN), [2.25 (s) and 2.24 (s), total ZN]; 367.9

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41 Example G ⁶ ; S41, P1 0 H1\A j Г να nY 1.96 minutes ¹⁷ ; 367 42 Example G ⁸ ; S41, P1 Z tA ^Z^ Z 1.98 minutes ¹⁷ ; 381 43 Example G ⁹ ; S41, P1 /A P I n4 Ν-Ν Ύ ^ν 4/ ^Ν Λ ₌ Ζ 1.88 minutes ¹⁷ ; 377 44 Example 2 ²⁰ ; S41, P6 ci^A^-x o IA ^N X^ _M d-n AD/ U ^1H NMR (400 MHz, CD ₃ OD) δ [8.64 (s) and 8.63 (s), total 1H], [4.92 (s), 4.85 (s, assumed; obscured by water peak ), 4.74 (s), and 4.68 (s), total 4H], [4.36 (dd, J=8, 8 Hz) and 4.36 (dd, J=8, 8 Hz), total 2H], 3.96-3.90 (m, 2H), 3.37-3.3 (m, 1H, assumed; strongly obscured by solvent peak), [2.96 (d, J=7.5 Hz ) and 2.95 (d, J=7.5 Hz), total 2H], 2.61 (s, ZN), [2.38 (s) and 2.38 (s), total ZN]; 363.8 (chlorine isotope pattern observed)

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45 Example 2; RZ, S45 1 F. AgL P >— F f Λ AA x A Α ^ν γΝγ_Ν F ¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (d, J=6.0 Hz, 1H), 7.47 (s, 1H), 6.69 (t, J _H f=55.2 Hz, 1H), 6.62-6.59 (μ, 1H), 6.54 (t, Jhf=55.5 Hz, 1H), 6.47-6.42 (m, 1H), [4, 97 (c), 4.92 (c), 4.80 (c), and 4.77 (c), total 4H], [4.26 (dd, J=8.5, 8.3 Hz) and 4.26 (dd, J=8.3, 8.3 Hz), total 2H], 3.83-3.77 (m, 2H), 3.3-3.22 (m, 1H, assumed; partially shaded by the solvent peak), [2.96 (d, J=7 Hz) and 2.95 (d, J=8 Hz), total 2H], 2.42 (s, ZH); 409.0 46 Example 2; P2, C45 1 R p )-f Λ A ^N 4 x A ¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (d, 4=5.8 Hz, 1H), 6.61-6.58 (m, 1H), 6.53 (t, J _H f =55.5 Hz, 1H), 6.44 (w d, J=6 Hz, 1H), [4.81 (s), 4.72 (s), 4.67 (s), and 4.59 (s), total 4H], [4.25 (dd, J=8.3, 8.3 Hz) and 4.25 (dd, 4=8.3, 8.3 Hz), total 2H], 3 .82-3.76 (m, 2H), 3.30-3.21 (m, 1H), 2.97-2.91 (m, 2H), 2.51 (s, ZN), 2.28 (s, ZN), 2.26 (s, ZN); 387.1

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47 Example 1 ²¹ ; S26, S45 I F. 0 )-F 0 D JU ^N 4 Z ^{4 1} Η NMR (400 MHz, CD ₃ OD) δ 8.10 (d, 4=6.0 Hz, 1 Η), 6.62-6.58 (w s, 1H), 6.53 (t, 4 _HF =55.5 Hz, 1H), 6.44 (wd, 4=5.5 Hz, 1H), [4.95 (s), 4.87 (s, assumed; obscured by water peak), 4, 78 (s), and 4.72 (s), total 4H], 4.68 (s, 2H), 4.25 (w dd, 4=8.5, 8.0 Hz, 2H), 3.79 (w dd, 4=7.0, 6.5 Hz, 2H), 3.45 (s, ZN), 3.30-3.20 (m, 1H), [2.95 (d, J=7 Hz) and 2.93 (d, 4=7.5 Hz), total 2H], 2.40 (s, ZN); 437.1 (chlorine isotope pattern observed) 48 Example 1 ²¹ ; C43 9 ζ °Ύ^ ζ θ d \ 8.01 (dd, 4=4.8, 1.2 Hz, 1H), 7.87 (d, 4=2.8 Hz, 1H), 7.11 (dd, 4=8.3, 4, 8 Hz, 1H), 6.73 (ddd, 4=8.3, 3.0, 1.5 Hz, 1H), 4.86-4.77 (m, 4H), 4.71 (s, 2H ), [4.19 (dd, 4=7.8, 7.5 Hz) and 4.19 (dd, 4=7.5, 7.5 Hz), total 2H], 3.69-3.63 (m, 2H), 3.53 (s, ZN), 3.33-3.21 (m, 1H), [2.84 (d, 4=7.8 Hz) and 2.81 (d, 4 =7.5 Hz), total 2N], [2.37 (s) and 2.36 (s), total ZN]; 386.9 (chlorine isotope pattern observed) 49 Example 1 ^21.22 ; C41 o o Λ Χ/ ^Ν 4 /=\ ^V % _Z N^^F 7.37-7.32 (m, 1H), 6.89-6.82 (m, 1H), 6.76 (dd, half of the ABX pattern, 4 = 8.5, 3.0 Hz, 1H) , 4.85-4.76 (m, 4H), 4.71 (s, 2H), [4.15 (dd, 4=7.5, 7.5 Hz) and 4.14 (dd, 4= 7.5, 7.5 Hz), total 2H], 3.66-3.59 (m, 2H), 3.53 (s, ZN), 3.31-3.19 (m, 1H), [ 2.83 (d, 4=7.8 Hz) and 2.80 (d, 4=7.5 Hz), total 2H], [2.36 (s) and 2.35 (s), total ZN] ; 404.9 (chlorine isotope pattern observed)

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50 Example 2; S54, S45 I to Αν 0/F o A HuA a la 8.22 (d, J=5.5 Hz, 1H), 7.18 (s, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.51 (t, J _H f =55.8 Hz, 1H), 6.29 (dd, J=5.6, 2.1 Hz, 1H), 4.83-4.74 (m, 4H), [4.56 (s) and 4.54 (s), total 2H], [4.27 (dd, J=8.3, 8.0 Hz) and 4.27 (dd, J=8.3, 8.0 Hz), total 2H ], 3.78-3.71 (m, 2H), [3.49 (s) and 3.49 (s), total ZN], 3.37-3.26 (m, 1H), [2, 83 (d, J=7.8 Hz) and 2.81 (d, J=7.8 Hz), total 2H], [2.33 (s) and 2.32 (s), total ZN], 403 ,1 51 Example 7 ²³ ; S59, P6 1 . ^N =\CivXv. 0 V/ Hd>chg trans, ENT-2 in note 23 9.03 (s, 1H), 8.56 (s, 2H), 4.78 (s, 2H), 4.75 (s, 2H), 2.68-2.58 (m, 1H), [ 2.64 (s) and 2.63 (s), total ZN], 2.54-2.43 (m, 1H), [2.33 (s) and 2.32 (s), total ZN], 1.83-1.76 (m, 1H), 1.65-1.53 (m, 1H), 1.19-1.11 (m, 1H), 1.10-1.02 (m, 1H ); 343.3 (chlorine isotope pattern observed) 52 Example G ¹ ; C56 \ R o 7.81 (d, J=5.8 Hz, 1H), [7.43 (t, Jhf=73.5 Hz) and 7.43 (t, J _H f=73.8 Hz), total 1H] , 6.11-6.07 (m, 1H), 5.78-5.75 (m, 1H), 4.85-4.76 (m, 4H), 4.72 (s, 2H), [ 4.23 (dd, J=8.3, 8.3 Hz) and 4.22 (dd, J=8.3, 8.0 Hz), total 2H], 3.73-3.66 (m, 2H), 3.54 (s, ZN), 3.33-3.23 (m, 1H), [2.82 (d, J=8 Hz) and 2.79 (d, J=8.0 Hz ), total 2N], [2.37 (s) and 2.36 (s), total ZN]; 453.0 (chlorine isotope pattern observed)

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53 Example 1; S57, S58 I ^F \ O /—F f D γΧ ^V \y ^N \ J F ^{— 1} H NMR (400 MHz, CD ₃ OD) δ 8.10 (d, 0=6.0 Hz, 1H), [6.84 (t, 0 _HF =54.2 Hz) and 6.83 (t, 0 _HF =54.5 Hz), total 1H], 6.62-6.58 (w s, 1H), 6.53 (t, 0 _HF =54.5 Hz, 1H), 6.44 (w d , 0=5.5 Hz, 1H), [4.96 (s), 4.87 (s, assumed; obscured by water peak), 4.79 (s), and 4.72 (s), total 4H] , [4.26 (dd, 0=8.5, 8.0 Hz) and 4.25 (dd, 0=8.5, 8.0 Hz), total 2H], 3.79 (dd, 0= 8.0, 6.0 Hz, 2H), 3.31-3.20 (m, 1H), 2.98-2.91 (m, 2H), 2.42 (s, ZN), 2.33 (s, ZN); 423.0 54 Example 16 ²⁴ ; S59, P1 I ^N= \ D.O DD ' ^N (-) trans, ENT-1 ^1H NMR (400 MHz, CD ₃ OD) δ 8.43-8.39 (w s, 1H), 8.30 (w d, 0=5.0 Hz, 1H), 7.56 (DDD, 0 =8.0, 2.0, 2.0 Hz, 1H), 7.32 (dd, 0=8.0, 5.0 Hz, 1H), 7.06 (s, 1H), [4.88 (s), 4.85 (s, assumed; obscured by water peak), 4.73 (s), and 4.71 (s), total 4H], 2.732.57 (m, 2H), [2.50 ( s) and 2.49 (s), total ZN], 2.31 (s, ZN), 1.95-1.88 (m, 1H), 1.56-1.46 (m, 1H), 1.141 .02 (m, 2H); 308.0 55 Example 16 ²⁴ ; S59, P1 I ^N= \ ,D o DD dl^g ^N ₍₊₎ trans, ENT-2 ^1H NMR (400 MHz, CD ₃ OD) δ 8.43-8.39 (w s, 1H), 8.30 (w d, 0=4.5 Hz, 1H), 7.56 (ddd, 0 =8.0, 2, 2 Hz, 1H), 7.32 (dd, 0=8.0, 4.5 Hz, 1H), 7.06 (s, 1H), [4.88 (s), 4.84 (s), 4.73 (s) and 4.71 (s), total 4H], 2.73-2.57 (m, 2H), [2.50 (s) and 2.49 ( s), total ZN], 2.31 (s, ZN), 1.95-1.88 (m, 1H), 1.56-1.46 (m, 1H), 1.14-1.02 ( m, 2H); 308.1

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56 Example 1; P1 7.25-7.18 (m, 2H), 7.18-7.12 (m, 2H), [6.91 (s) and 6.89 (s), total 1H], 4.84-4 .68 (m, 4H), 3.30-3.19 (m, 2H), 3.13-3.02 (m, 1H), 2.752.66 (m, 2H), 2.57 (w d, J=7.0 Hz, 2H), [2.54 (s) and 2.52 (s), total ZN], [2.27 (s) and 2.23 (s), total ZN]; 306.9 57 Example 4 ²⁵ ; S41, P1 ^1H NMR (400 MHz, DMSO-s/ ₆ ) δ 8.16 (d, J=5.8 Hz, 1H), [7.00 (s) and 7.00 (s), total 1H], 6 .97 (d, J=2.5 Hz, 1H), 6.55 (dd, 4=5.8, 2.5 Hz, 1H), [4.81 (s) and 4.76 (s), total 2H], [4.58 (s) and 4.54 (s), total 2H], 4.15 (dd, 4=8.3, 8.3 Hz, 2H), 3.69 (dd, 4 =8.4, 5.6 Hz, 2H), 3.163.06 (m, 1H), 2.85 (d, 4=7.5 Hz, 2H), 2.42 (s, ZN), [2, 23 (s) and 2.22 (s), total ZN]; 347.9 58 Example 2 ²⁶ ; P1, C41 ^1H NMR (400 MHz, DMSO-s/ ₆ ) δ 7.74 (d, 4=5.5 Hz, 1H), [7.00 (s) and 6.99 (s), total 1H], 6 .06 (dd, 4=6.0, 2.0 Hz, 1H), 5.62 (d, 4=1.5 Hz, 1H), [4.81 (s) and 4.76 (s), total 2H], [4.58 (s) and 4.53 (s), total 2H], 4.04 (dd, 4=8.0, 8.0 Hz, 2H), 3.74 (s, ZN ), 3.60-3.54 (m, 2H), 3.12-3.01 (m, 1H), 2.82 (d, 4=7.5 Hz, 2H), 2.42 (s, ZN), [2.23 (s) and 2.21 (s), total ZN]; 353.0 59 Example 1; P1 •nsoon 8.14 (s, 1H), [6.95 (s) and 6.92 (s), total 1H], [4.82 (s), 4.76 (s), and 4.73 (s) , total 4H], 2.54 (w s, ZN), [2.37 (d, 4=6.5 Hz) and 2.36 (d, 4=6.5 Hz), total 2H], [2 .29 (s) and 2.27 (s), total ZN], 1.23-1.10 (m, 1H), 0.66-0.57 (m, 2H), 0.27-0.19 (m, 2H); 230.8

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60 Example G ⁷ ; P1, C41 ό ¹ H NMR (400 MHz, CD ₃ OD) δ 8.06-8.02 (Μ, 2H), 7.07 (s, 1H), 6.39-6.35 (μ, 2H), [4, 89 (s, assumed; obscured by water peak), 4.84 (s), 4.72 (s), and 4.70 (s), total 4H], 4.21 (dd, J=8.0, 7 .5 Hz, 2H), 3.78-3.71 (m, 2H), 3.28-3.18 (m, 1H), [2.94 (d, J=7.8 Hz) and 2, 93 (d, J=7.8 Hz), total 2H], 2.50 (s, ZN), 2.32 (s, ZN); 322.9 61 Example G; P1, C41 Αν Р II I ΝΑ / h rN ^ААА ^x > \=Ν ^1H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.00 (s, 2H), 7.07 (s, 1H), [4.89 (s), 4.85 (s), 4.71 (s), and 4.70 (s), total 4H], 4.24 (dd, J=7.8, 7.8 Hz, 2H), 3.80-3.73 (m, 2H), 3.33-3.23 (m, 1H, assumed; partially obscured by solvent peak), [2.95 (d, J=7.5 Hz) and 2.94 (d, J=7 ,8 Hz), total 2H], 2.50 (s, ZN), 2.32 (s, ZN); 324.0 62 Example 36 ²⁸ ; P1 Αν° ί A/N ν Λν ^1H NMR (400 MHz, CD ₃ OD) δ 8.69 (s, 1H), 7.04 (s, 1H), 5.485.40 (m, 1H), [4.76 (s), 4.71 (s), 4.66 (s), and 4.63 (s), total 4H], 4.55-4.48 (m, 2H), 4.23 (w dd, J=9.4, 4 ,1 Hz, 2H), 2.48 (s, ZN), [2.29 (s) and 2.28 (s), total ZN]; 331.8 63 Example 36 ²⁹ ; C57 F ΑίΑΑ ¹ ^ / ⁴ Λ VX °<NL A F ^b 7.98 (s, 1H), [6.71 (t, J _H f=54.7 Hz) and 6.70 (t, J _H f=54.5 Hz), total 1H], 5.56- 5.47 (m, 1H), 4.81-4.74 (m, 4H), 4.59-4.51 (m, 2H), 4.26 (dd, J=10.0, 4.0 Hz, 2H), 2.43 (w s, ZN), 2.27 (s, ZN); 381.9

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64 Example 36 ²⁹ ; P2 ,о 1 JL \ a ^N > о 7.97 (s, 1Η), 5.55-5.45 (m, 1Η), 4.75-4.67 (μ, 4Η), 4.58-4.50 (μ, 2Η), 4, 26 (w dd, 4=10, 4 Hz, 2H), [2.53 (s) and 2.53 (s), total ZN], 2.22 (s, ZN), 2.21 (w s, ZN); 345.9 65 Example 36 ²⁸ ; P2 R D DM /h N' _N 0~\N—and _s > ^1H NMR (400 MHz, CD ₃ OD) δ 8.69 (s, 1H), 5.48-5.41 (m, 1H), [4.80 (s), 4.72 (s), 4 .70 (s), and 4.64 (s), total 4H], 4.56-4.49 (m, 2H), 4.24 (dd, 4=9.5, 4.0 Hz, 2H) , 2.50 (s, ZN), [2.27 (s) and 2.26 (s), total 6H]; 345.9 66 Example 36 ²¹ ; S66 o I JLM /=n 8.07 (wd, 4=4.5 Hz, 1H), 7.947.90 (m, 1H), 7.15 (dd, 4=8.5, 5.0 Hz, 1H), 6.81- 6.76 (m, 1H), 5.505.39 (m, 1H), 4.81-4.73 (m, 4H), 4.71 (s, 2H), 4.35 (dd, 4=7, 5, 7.5 Hz, 2H), 3.99-3.92 (m, 2H), [3.53 (s) and 3.53 (s) total ZN], [2.36 (s) and 2 ,34 (s), total ZN]; 388.8 (chlorine isotope pattern observed) 67 Example 36 ²⁹ ; P6 О 1 JLjH Д' Λ °Λ/ ^Ν ^ 1 Ο 7.98 (w s, 1H), 5.55-5.46 (m, 1H), 4.76-4.70 (m, 4H), 4.58-4.51 (m, 2H), 4 ,29-4.23 (m, 2H), [2.64 (s) and 2.63 (s), total ZN], 2.33 (s, ZN); 365.9 (chlorine isotope pattern observed) 68 Example 4 ³⁰ ; C48 οα 0 ζ ι 1.51 minutes ³¹ , 392.1 69 Example 4 ³⁰ ; C48 1 / ο ο l )=\ CN 1.82 minutes ³¹ , 377.1

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70 Example 4 ³⁰ ; C48 yHw /° Ji JT nY . /=\o '-\/ ^N N #—\ N— / 1.55 minutes ³¹ , 393.1 71 Example 4 ³⁰ ; C48 /kv р ί /=\ '-''ή''^ ^{7 4} —\ ν—4 #—\ he 1.12 minutes ³¹ , 352.2 72 Example 4 ³⁰ ; C48 R ί XtN /\ /=\ . 1.68 minutes ³¹ , 362.2 73 Example 4 ³⁰ ; C48 ί* ζ ζ 1.40 minutes ³¹ , 392.2 74 Example 4 ³⁰ ; C48 ζ^ Υ ο .ο ζ 1.40 minutes ³¹ , 392.2 75 Example 4 ³⁰ ; C48 ΑγΛ Ρ ji X ^Ν \ /2 / ⁼ \ ρ ΗΝ— 1.43 minutes ³¹ , 378.1 76 Example 16 ³² ; P1, C59 /=Ν ι υΧΖ ji XD ⁿ X wf ''ν ΎΙ (racemic) 2.20 minutes ³³ , 359.3 77 Example 16 ³⁴ ; P1, C59 γΉκ? ^Ύ] (racemic) 2.70 minutes ³³ , 307.3 78 Example 4 ³⁰ ; C48 ζ -^ζ Ή NMR (400 MHz, CD ₃ OD) δ ppm 2.31 (s, 3 Η) 2.49 (s, 3 Η) 2.89 (t, J=7.03 Hz, 2 Η) 3.12 ( m, 1 Η) 3.55 - 3.60 (m, 2 Η) 4.06 (τ, J=7.53 Hz, 2 Η) 4.70 (d, J=4.52 Hz, 2 Η) 4.81-4.88 (m, 2 Η) 6.48 (d, J=8.53 Hz, 2 Η) 6.70 (τ, J=7.28 Hz, 1 Η) 7.06 (s , 1 Η) 7.16 (t, J=7.78 Hz, 2 Η)

1. Analysis of ¹ H NMR spectra showed that these examples can exist as a mixture of rotamers in solution.

2. Reaction of C38 with N-chlorosuccinimide followed by removal of the tert-butoxycarbonyl group with hydrogen chloride gave the desired 3-chloro-2-methoxy-4-methyl-6,7-dihydro-5H-pyrrolo[3,4b]pyridine.

3. Example 3 (800 nmol) was incubated with liver microsomes (from female rabbits; 2.0 mg/ml), magnesium chloride (3.3 mM) and NADPH (1.3 mM), in 0.1 M potassium phosphate buffer (pH 7.4; total volume of incubation solution, 40 ml). The reaction mixture was shaken at 37°C in a water bath for

- 88 044379 min, after which acetonitrile (40 ml) was added and the mixture was centrifuged at 1700 g for 5 min. The supernatant was vacuum centrifuged to a volume of approximately 15 ml, to which formic acid (0.5 ml), acetonitrile (0.5 ml) and water (enough to reach a total volume of 50 ml) were added. This mixture was centrifuged at 40,000 g for 30 minutes. The supernatant was purified using reverse phase chromatography (column: Agilent Polaris C18, 5 µm; mobile phase A: 0.1% aqueous formic acid; mobile phase B: acetonitrile; gradient: 2% B from 0 to 5 min; from 2% B to 20% B at 65 min; 20% B to 95% B at 75 min), giving Example 24. Yield: 17 μg, 11 nmol, 1%.

4. [1-(Pyrimidin-5-yl)azetidin-3-yl]acetic acid was synthesized from C41 using the general method described for the conversion of C41 to C43 in Example 1.

5. The interaction of C38 with N-chlorosuccinimide was provided by tert-butyl 3-chloro-2-methoxy-4-methyl5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, which was reacted with trimethylboroxine in the presence of palladium(P) acetate, tricyclohexylphosphine and cesium carbonate, yielding tert-butyl 2-methoxy-3,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate. Removal of the protecting group with hydrogen chloride gave the desired 2-methoxy-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4b]pyridine.

6. The interaction of C41 with 3,5-dichloropyridazine was carried out using cesium bromide and triethylamine, obtaining ethyl [1-(6-chloropyridazin-4-yl)azetidin-3-yl]acetate. Reductive removal of chlorine by hydrogenation over palladium on carbon, followed by hydrolysis of the ester with lithium hydroxide, gave [1-(pyridazin-4-yl)azetidin-3-yl]acetic acid.

7. The interaction of C38 with N-chlorosuccinimide was provided by tert-butyl 3-chloro-2-methoxy-4-methyl5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, which was subjected to methyl ether elimination hydrogen chloride, followed by reintroduction of the tert-butoxycarbonyl protecting group to give tert-butyl 3-chloro-4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridinium- 6-carboxylate. Interaction with sodium chloro(difluoro)acetate and potassium carbonate provided tert-butyl 3-chloro-2-(difluoromethoxy)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate ; Removal of the protecting group with hydrogen chloride gave the desired 3-chloro-2-(difluoromethoxy)-4-methyl-6,7dihydro-5H-pyrrolo[3,4-b]pyridine.

8. At the final stage of the synthesis, the methyl ether was cleaved by exposure to boron trichloride to give Example 33.

9. The interaction of C41 with 4-chloropyrimidine was carried out using cesium bromide and triethylamine, obtaining ethyl [1-(pyrimidin-4-yl)azetidin-3-yl]acetate; hydrolysis of the lithium ester with hydroxide gave [1-(pyrimidin-4-yl)azetidin-3-yl]acetic acid.

10. Reaction of P2 and C66 with bis(pentafluorophenyl)carbonate and triethylamine provided Example 36.

11. Cyclopropanation of ethyl (2E)-3-(pyridin-3-yl)prop-2-enoate was carried out by reaction with trimethylsulfoxonium iodide and sodium hydride, obtaining ethyl trans-2-(pyridin-3-yl)cyclopropanecarboxylate. This substance was reduced with lithium aluminum hydride and the resulting primary alcohol was converted to chloride by treatment with thionyl chloride; subsequent substitution using potassium cyanide provided [trans-2-(pyridin-3-yl)cyclopropyl]acetonitrile, which was hydrolyzed to acid by treatment with hydrochloric acid. Exposure to sulfuric acid and methanol then gave the desired methyl [trans-2-(pyridin-3-yl)cyclopropyl] acetate.

12. The racemic mixture of Examples 37 and 38 was separated into its enantiomer components using supercritical liquid chromatography (column: Chiral Technologies Chiralcel OJ-H, 5 μm; mobile phase: 9:1 carbon dioxide/methanol). Example 37 was the first enantiomer of the elution and Example 38 was the second enantiomer of the elution.

13. Conditions for analytical HPLC. Column: Chiral Technologies Chiralcel OJ-H, 4.6x100 mm, 5 µm; mobile phase: 85:15 carbon dioxide/methanol; flow rate: 1.5 ml/min.

14. Ethyl[1-(pyrimidin-4-yl)azetidin-3-yl]acetate was used; see note 9.

15. Conversion of C9 to tert-butyl 2-(hydroxymethyl)-3,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4b]pyridine-6-carboxylate was carried out using the method described for the synthesis of C12 from C3 in receiving P3. Reaction with iodomethane and sodium hydride then provided the methyl ether and subsequent deprotection with hydrogen chloride gave the desired 2-(methoxymethyl)-3,4-dimethyl-6,7dihydro-5H-pyrrolo[3,4-b]pyridine.

16. Reaction of C41 with 4-chloro-N-ethylpyrimidin-2-amine and cesium carbonate, followed by hydrolysis of the lithium ester with hydroxide, gave {1-[2-(ethylamino)pyrimidin-4-yl]azetidin-3yl}acetic acid .

17. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1x 50 mm, 5 µm; mobile phase A: 0.0375% trifluoroacetic acid in water; mobile phase B: 0.01875% trifluoroacetic acid in acetonitrile; gradient: from 1% to 5% B over 0.6 min; from 5 to 100% B for 3.4 minutes; flow rate: 0.8 ml/min.

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18. The Buchwald reaction using RuPhos between C41 and 6-chloro-N-(propan-2-yl)pyrimidin-4-amine followed by hydrolysis of the lithium ester with hydroxide provided {1-[6(propan-2-ylamino)pyrimidine -4-yl]azetidin-3-yl}acetic acid.

19. The interaction of C41 with 6-chloro-2-methylimidazo[1,2-b]pyridazine, cesium carbonate and potassium fluoride, followed by hydrolysis of the lithium ester with hydroxide provided [1-(2-methylimidazo[1,2-b]pyridazine- 6-yl)azetidin-3-yl]acetic acid.

20. The reaction of C41 with 2-bromo-1,3,4-thiadiazole was carried out using the method described for the synthesis of C42 from C41 in example 1, obtaining ethyl [1-(1,3,4-thiadiazol-2-yl)azetidine -3-yl]acetate.

21. The desired 3-chloro-2-(methoxymethyl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine was synthesized as follows: C26 was converted to tert-butyl 3-chloro-2- (hydroxymethyl)-4-methyl-5,7dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate using the method described for the synthesis of C12 from C3 in the preparation of P3. Methyl ether formation using iodomethane and sodium hydride is then followed by deprotection with hydrogen chloride.

22. The reaction of C41 with 5-bromo-2-fluoropyridine was carried out using the method described for the synthesis of C50 from C41 and C49 in example 4; hydrolysis of the lithium ester with hydroxide then gave the desired [1-(6-fluoropyridin-3-yl)azetidin-3-yl]acetic acid.

23. 5-Bromopyrimidine was reacted with C59 using the method described for the synthesis of C60 and C61 in Example 16. The component enantiomers of the product were separated using supercritical liquid chromatography [column: Phenomenex Lux Cellulose-2, 5 μm; mobile phase: 9:1 carbon dioxide/(acetonitrile containing 0.2% ammonium hydroxide)]. The second enantiomer of the elution (ENT-2) was oxidized to the corresponding carboxylic acid using the procedure described in Example 16 to convert C60 to C62, yielding the single enantiomer of [trans-2-(pyrimidin-5yl)cyclopropyl]acetic acid from ENT-2.

24. In this case, 3-bromopyridine was used and the intermediate [trans-2-(pyridin3-yl)cyclopropyl]acetic acid was used as a racemate. The racemic mixture of the final product was separated into its enantiomer components using supercritical liquid chromatography [column: Chiral Technologies Chiralpak AD, 10 μm; mobile phase: 55:45 carbon dioxide/(methanol containing 0.1% ammonium hydroxide)]. The first enantiomer to elute that exhibited negative (−) rotation was designated as example 54 (ENT-1); the second eluting enantiomer, which exhibited positive (+) rotation, was designated example 55 (ENT-2).

25. The intermediate ethyl [1-(2-cyanopyridin-4-yl)azetidin-3-yl]acetate was synthesized by reacting C41 with 4-chloropyridine-2-carbonitrile in the presence of an amine base.

26. The reaction of C41 with 4-iodo-2-methoxypyridine was carried out using the method described for the synthesis of C42 from C41 in example 1, obtaining ethyl [1-(2-methoxypyridin-4-yl)azetidin-3-yl]acetate.

27. The reaction of C41 with 4-iodopyridine was carried out using the method described for the synthesis of C50 from C49 in example 4; hydrolysis of the lithium ester with hydroxide then yielded [1-(pyridin-4yl)azetidin-3-yl]acetic acid.

28. The desired 1-(1,3,4-thiadiazol-2-yl)azetidin-3-ol was synthesized from azetidin-3-ol and 2-bromo1,3,4-thiadiazole in the presence of tri(dibenzylideneacetone)dipalladium(0) , 1,1'-binaphthalin-2-yl(di-tert-butyl)phosphane (TrixiePhos) and cesium carbonate.

29. The reaction of azetidin-3-ol and 5-bromo-1,2,4-thiadiazole in the presence of potassium carbonate provided 1-(1,2,4-thiadiazol-5-yl)azetidin-3-ol.

30. The C48-mediated template was synthesized as shown in Example 3. Examples 68-75 and Example 78 were synthesized by reacting the C48 intermediate with the appropriate aryl bromides using the condensation conditions described in Example 4, Step 2 [Pd2(dba)3, Xantphos, Cs ₂ CO ₃ , 1,4-dioxane].

31. Conditions for analytical HPLC. Column: Waters Atlantis dC18, 4.6 x 50 mm, 5 µm; mobile phase A: 0.05% trifluoroacetic acid in water; mobile phase B: 0.05% trifluoroacetic acid in acetonitrile; gradient: from 5 to 95% B for 4 min; then held 95% for up to 5 min; flow rate: 2 ml/min.

32. The desired compound was prepared following the same procedure as in Example 16, the condensation of intermediate C59 being carried out with 7-bromoquinazoline.

33. Conditions for analytical HPLC. Column: Waters Atlantis dC18, 4.6 x 50 mm, 5 µm; mobile phase A: 0.05% trifluoroacetic acid in water; mobile phase B: 0.05% trifluoroacetic acid in acetonitrile; gradient: held at 5% B for up to 1 min, then from 5 to 95% B for 4 min, then held at 95% B for up to 5 min; flow rate: 2 ml/min.

34. The desired compound was prepared following the same procedure as in Example 16, the condensation of intermediate C59 being carried out with bromobenzene.

The PAM M4 binding affinity for the compounds of the present invention was determined using the following biological assay(s).

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Biological analyses.

M4 Pam cAMP assay.

The cAMP M4 assay was developed to determine the productivity and effectiveness of muscarinic positive allosteric modulators (PAMs). Human M4 receptors were stably expressed in human embryonic kidney cells (HEK293) expressed using Promega GloSensor™ cAMP technology.

Cells: HEK293 GloSensor cells expressing hM4 cells were cultured in growth medium containing DMEM with 10% FBS, 1% penicillin/streptomycin, 500 μg/ml G418, 200 μg/ml hygromycin B and 1% Glutamax. When cells had grown to 80-90% confluence, cells were harvested and seeded at a density of 25,000 cells per 40 μl in 384-well white-walled plates (Becton Dickinson 356661). The plates were incubated at 37°C and 5% CO ₂ for use after 24 hours.

Compound Preparation for Agonist Screening: Test compounds were initially prepared as 100% DMSO stock solutions, then transferred and serially diluted into 384-well compound plates (Matrix #4325). Each compound was tested at 10 concentrations in duplicate per experiment. Compound plates are coated with 0.2 μl/well of agonist at 400 times the final assay concentration.

Positive and negative controls for the agonist response of one compound were 10 μM acetylcholine (Sigma #A2661) and DMSO, respectively. Acetylcholine EC ₂₀ was also used to determine PAM activities.

cAMP assay: Promega GloSensor™ reagent (Promega #E1291) was previously aliquoted. For each experiment, the GloSensor™ stock solution was thawed and equilibration medium was prepared with 88% CO ₂ independent medium (Invitrogen #18045088), 10% fetal bovine serum, and 2% GloSensor™ cAMP reagent stock solution. The initial solution was mixed. The culture media in the cell plates were discarded, then replaced with 40 μl/well of prewarmed equilibration medium, then incubated in the dark at room temperature for 2 hours. During incubation, stimulating medium containing agonist and EC ₂₀ acetylcholine was prepared. CO ₂ -independent medium containing 50 nM (nano instead of milli) isoproterenol, which is an EC ₈₀ of b-adrenergic receptor activity (Sigma #16504, 400 times the final concentration) and EC 20 acetylcholine in 1.25% DMSO, was added to all columns Tablet connections, with the exception of column 12 in order to ensure control of EC0. Control EC0 wells received stimulation medium that did not contain EC20 acetylcholine. Compounds are now 5 times the final assay concentration. The plate was mixed using a plate mixer. At the end of the 2 hour GloSensor™ incubation, add 10 µl of CO ₂ -independent medium containing the agonist, EC20 acetylcholine and isoproterenol to the cell plate. The cell plate was then incubated for 10 min at room temperature and then read using an EnVision plate reader (Perkin Elmer).

Data Analysis: Data were exported from an EnVision tablet reader. The percentage effect for each well was determined using the average values for the positive and negative controls in each plate for each reading, e.g.

100x(compound - negative control)/(positive control - negative control).

Dose-response curves were fitted to the percent compound effect data using a four-parameter logistic fit model. The data were presented as EC ₅₀ and E _max , with E _max representing the maximum asymptotic behavior of the dose response curve.

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Table 7. Biological activity of examples 1-78

Example number M4 GloSensor EC ₅₀ Average asymptotic maximum (%) ^a M4 GloSensor EC ₅₀ (nM) ^a IUPAC name 1 89.5 ^b 24.9 ^b 1 -(2,4-d imethyl-5,7-d ihydro-6/7pyrrolo[3,4-b]pyridin-6-yl)-2-[1- (pyridin-Z-yl)azetidine-Zyl]ethanone 2 94.4 19.8 2-{1-[2-(d iforomethyl)pyrid in-4yl]azetidin-3-yl}-1 -(2,4-d imethyl5,7-dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl)ethanone 3 95.1 ^b 36, ^Зь 1 -(2,4-d imethyl-5,7-dihyde po-QHpyrrolo[3,4-b]pyridin-6-yl)-2-[1(pyrimidin-4-yl)azetidin-3yl]ethanone 4 100 24.2 2-{1-[2-(difluoromethoxy)pyridin4-yl]azetidin-3-yl}-1-(2,4- d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6yl)ethanone 5 98.2 8.88 2-[1-(1,2,4-thiadiazol-5yl)azetide in-3-yl]-1 -(2,3,4trimethyl-5,7-dihydro-6/7pyrrolo[3,4-b] pyridin-6yl)ethanone 6 92.4 9.75 1 -[2-(d fluoromethyl)-4-methyl-5,7dihydro-6/7-pyrrolo[3,4b]pyridin-6-yl]-2-{1 -[2(trifluoromethyl)pyridin-4yl] azetidin-3-yl}ethanone

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7 99.8 ^b 17.4 ^b 1-[2-(methoxymethyl)-4-methyl-5,7dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl]-2-{1-[2(trifluoromethyl)pyridin-4yl]azetidin-3-yl}ethanone 8 99.1 22.7 2-{1 -[2-(d fluoromethoxy)pyrid in4-yl]azetide in-3-yl}-1 -[2(methoxymethyl)-4-methyl-5,7- Dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl]ethanone 9 86.5 ^b 17.2 ^b 1-[2-(hydroxymethyl)-4-methyl-5,7dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl]-2-[1-(pyridin-3- yl)azetidin-3-yl]ethanone 10 99.5 ^e 28.9 ^e 2-{1 -[2-(d fluoromethoxy)pyrid in4-yl]azetide in-3-yl}-1 -[2(difluoromethyl)-3,4-d imethyl-5,7dihydro-6/7-πippolo[ 3.4- b]pyridin-6-yl]ethanone eleven 104 ^b 12.3 ^b 1 -(2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2-{1- [2-(trifluoromethyl)pyridine-4- yl]azetidin-3-yl}ethanone 12 119 ^b 7.10 ^b 1 -(3-chloro-2,4-d imethyl-5,7dihydro-6/7-pyrrolo[3,4b]pyridin-6-yl)-2-{1 -[2(difluoromethyl)pyridin-4yl ]azetidin-3-yl}ethanone 13 101 ^b 2.04 ^b 1 -(3-chloro-2,4-d imethyl-5,7dihydro-6/7-pyrrolo[3,4b]pyridin-6-yl)-2-[1-(pyridin-3yl)azetidin-3- yl]ethanone 14 62.5 9080 2-[1-(pyridin-3-yl)azetidin-3yl]-1 -(2,4,5-trimethyl-5,7dihydro-6/-/-pyrrolo[3,4b]pyridin-6-yl)ethanone ENT-1 15 106 28.0 2-[1-(pyridin-3-yl)azetidin-3yl]-1 -(2,4,5-trimethyl-5,7dihydro-6/7-pyrrolo[3,4b]pyridin-6-yl)ethanone, ENT-2

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16 ND ^d >10000 ^e 1 -(2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2[(15,2/?)-2-(6-methylpyridine -3yl)cyclopropyl]ethanone 17 107 ^e 71.9 ^e 1 -(2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2[(1 /?,25)-2-(6-methylpyridine -3yl)cyclopropyl]ethanone 18 89.0 ^e 37.7 ^e 1 -[2-(d fluoromethyl)-4-methyl-5,7dihydro-6/7-pyrrolo[3,4b]pyridin-6-yl]-2-[(1/?,25)-2-(6methylpyridine -3yl)cyclopropyl]ethanone 19 87.5 178 2,4-d imethyl-/\/-[1 -(pyridin-3yl)azetidin-3-yl]-5,7-dihyde ro6/7-pyrrolo[3,4-b]pyridin-6carboxamide 20 58.0 51.1 1 -(pyridine in-3-yl)azetide in-3-yl 2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridine-6carboxylate 21 86.6 ^b 23.9 ^b 1 -(2-methoxy-4-methyl-5,7dihydro-6H-pyrrolo[3,4b]pyridin-6-yl)-2-[1 -(pyridin-3yl)azetidin-3-yl]ethanone 22 109 ^b 4.82 ^b 1 -(3-chloro-2-methoxy-4-methyl-5,7dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl)-2-[1 -(pyridin-3yl)azetidin-3-yl]ethanone 23 92.2 ^b 6.23 ^b 2-[1 -(pyridin-3-yl)azetidin-3yl]-1 -(2,3,4-trimethyl-5,7dihydro-6H-pyrrolo[3,4b]pyridin-6-yl)ethanone 24 93.8 31.0 1-[2-(hydroxymethyl)-4-methyl-5,7dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl]-2-[1-(pyrimidin- 4-yl)azetidin-3-yl]ethanone

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25 78.7 ^e 25.7 ^e 2-{1 -[2-(d fluoromethoxy)pyride in- 4-yl]azetidin-3-yl}-1-[2- (difluoromethyl)-4-methyl-5,7- Dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl]ethanone 26 117 13.9 1 -(3-chloro-2-methoxy-4-methyl-5,7dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl)-2-[1-(pyrimidin5-yl)azetidin-3-yl]ethanone 27 94.4 16.8 1-[2-(methoxymethyl)-4-methyl-5,7dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl]-2-[1-(pyridin-3yl)azetidin-3-yl]ethanone 28 116 21.6 1 -(2-methoxy-3,4-d imethyl-5,7dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl)-2-[1-(pyridin-3yl)azetidin-3-yl]ethanone 29 99.8 26.1 1 -(2-methoxy-3,4-d imethyl-5,7dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl)-2-[1-(pyrimidin5-yl)azetidin-3-yl]ethanone thirty 103 30.3 1 -(2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2-[1- (pyridazin-4-yl)azetidin-3yl]ethanone 31 89.3 17.8 1-[2-(methoxymethyl)-4-methyl-5,7dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl]-2-[1-(pyrimidin5-yl)azetidin-3-yl]ethanone 32 109 11.0 1 -[3-chloro-2-(d fluoromethoxy)-4methyl-5,7-dihyde rho-6/7- pyrrolo[3,4-b]pyridin-6-yl]-2-[1(pyrimidin-5-yl)azetidin-3yl]ethanone 33 100 ^e 14.0 ^e 1-[2-(hydroxymethyl)-4-methyl-5,7dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl]-2-{1-[2(trifluoromethyl)pyridin-4yl]azetidin-3-yl}ethanone

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34 86.0 ^e 18.0 ^e 1 -[2-(d iforomethyl)-4-methyl-5,7dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl]-2-[1-(pyrimidin5-yl)azetidin-3-yl]ethanone 35 87.9 2.56 2-[1-(pyrimidin-4-yl)azetidin-3yl]-1 -(2,3,4-trimethyl-5,7- Dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl)ethanone 36 93.0 10.4 1 -(pyridine in-3-yl)azetide in-3-yl 2,3,4-trimethyl-5,7-dihyde rho-6/-/pyrrolo[3,4-b]pyridine-6carboxylate 37 85.8 1790 2-[trans-2-(n-3yl)cyclopropyl]-1-(2,3,4trimethyl-5,7-dihydro-6/7pyrrolo[3,4-b]pyridin-6yl)ethanone ENT-1 38 111 15.9 2-[trans-2-(n-3yl)cyclopropyl]-1-(2,3,4trimethyl-5,7-dihydro-6/7pyrrolo[3,4-b]pyridin-6yl)ethanone ENT-2 39 96.4 ^b <1.39 ^b 1 -(3-chloro-2,4-d imethyl-5,7dihydro-6/7-πippolo[3,4b]pyridin-6-yl)-2-[1-(pyrimidin4-yl)azetidin-3- yl]ethanone 40 97.9 ^e 23.6 ^e 1-[2-(methoxymethyl)-3,4-dimethyl- 5,7-dihydro-6/7-pyrrolo[3,4b]pyridin-6-yl]-2-[1-(pyrimidin- 5-yl)azetidin-3-yl]ethanone 41 95.6 ^b 7.35 ^b 1 -(2,4-d imethyl-5,7-dihyde rho-6Hpyrrolo[3,4-b]pyridin-6-yl)-2-{1- [2-(ethylamino)pyrimidine-4- yl]azetidin-3-yl}ethanone 42 93.9 ^b 5.05 ^b 1 -(2,4-d imethyl-5,7-dihyd rho-6Hpyrrolo[3,4-b]pyridin-6-yl)-2-{1[6-(propan-2-ylamino)pyrimidin4-yl] azetidin-3-yl}ethanone

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43 88.6 ^e 25.2 ^e 1 -(2,4-dimethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2-[1(2-methylimidazo[1,2- b]pyridazin-6-yl)azetidin-3yl]ethanone 44 112 16.8 1-(3-chloro-2,4-dimethyl-5,7dihydro-6/7-pyrrolo[3,4b]pyridin-6-yl)-2-[1-(1,3,4thiadiazol-2-yl) azetidin-3yl]ethanone 45 93.5 ^e 15.6 ^e 1 -[2-(d fluoromethyl)-4-methyl-5,7dihydro-6/7-pyrrolo[3,4b]pyrid in-6-yl]-2-{1 -[2- (difluoromethyl)pyridin-4yl]azetidin-3-yl}ethanone 46 106 9.53 2-{1 -[2-(d iforomethyl)pyrid in-4yl]azetidin-3-yl}-1 -(2,3,4trimethyl-5,7-dihydro-6/7pyrrolo[3,4-b] pyridin-6yl)ethanone 47 110 2.19 1 -[3-chloro-2-(methoxymethyl)-4- methyl 5,7-dihyde rho-6/7- pyrrolo[3,4-b]pyridin-6-yl]-2-{1[2-(difluoromethyl)pyridin-4yl]azetidin-3-yl}ethanone 48 105 2.99 1 -[3-chloro-2-(methoxymethyl)-4methyl-5,7-dihyde rho-6/7- pyrrolo[3,4-b]pyridin-6-yl]-2-[1(pyridin-3-yl)azetidine-Zyl]ethanone 49 101 ^e 11.2 ^e 1 -[3-chloro-2-(methoxymethyl)-4methyl-5,7-dihyde rho-6/7- pyrrolo[3,4-b]pyridin-6-yl]-2-[1(b-fluoropyridin-3-yl)azetidine-Zyl]ethanone 50 99.2 ^e 14.3 ^e 2-{1-[2-(d iforomethyl)pyride in-4yl]azetidin-3-yl}-1-[2- (methoxymethyl)-4-methyl-5,7- Dihydro-6/7-pyrrolo[3,4- b]pyridin-6-yl]ethanone

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51 102 ^e 4.75 ^e 1 -(3-chloro-2,4-d imethyl-5,7dihydro-6/7-pyrrolo[3,4b] p irid and n-6-yl)-2-[trans-2(pyrimidine-5 - yl)cyclopropyl]ethanone, from ENT-2 in note 23, Table 6 52 111 ^e 4.68 ^e 1 -[3-chloro-2-(methoxymethyl)-4- methyl 5,7-dihyde rho-6/7- pyrrolo[3,4-b]pyridin-6-yl]-2-{1[2-(difluoromethoxy)pyridin-4yl]azetidin-3-yl}ethanone 53 104 ^e 38.6 ^e 1 -[2-(d iforomethyl)-3,4-d imethyl5,7-dihydro-6/7-pyrrolo[3,4y]pyrid in-6-yl]-2-{1 -[2- (difluoromethyl)pyridin-4yl]azetidin-3-yl}ethanone 54 80.0 ^e 8650 ^e (-)-1 -(2,4-dimethyl-5,7-dihyde po6/7-pyrrolo[3,4-b]pyridin-6-yl)2-[trans-2-(p and read and n- 3- yl)cyclopropyl]ethanone, ENT-1 55 99.5 40.5 (+)-1 -(2,4-d imethyl-5,7-dihyde po6/7-pyrrolo[3,4-b]pyridin-6-yl)2-[trans-2-(p and rid and n -3- yl)cyclopropyl]ethanone, ENT-2 56 71.8 ^e 209 ^e 2-(2,3-dihyde rho-1/7-inden-2-yl)-1(2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6yl )ethanone 57 96.1 94.2 4-{3-[2-(2,4-d imethyl-5,7-dihyde po6/7-pyrrolo[3,4-b]pyridin-6-yl)2-oxoethyl]azetidin-1yl}pyridin-2 -carbonitrile 58 98.8 88.8 1 -(2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2-[1- (2-methoxypyridine-4- yl)azetidin-3-yl]ethanone 59 93.5 816 2-cyclopropyl-1 -(2,4-d imethyl5,7-dihydro-6/7-pyrrolo[3,4b]pyridin-6-yl)ethanone, formate salt

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60 96.0 102 1 -(2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2-[1- (pyridin-4-yl)azetidin-3yl]ethanone 61 90.8 ^b 60.5 ^b 1 -(2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2-[1- (pyrimidin-5-yl)azetidin-3yl]ethanone 62 47.0 95.7 1 -(1,3,4-thiad iazol-2-yl)azetide in3-yl 2,4-dimethyl-5,7-dihydro-6/7pyrrolo[3,4-b]pyridine-6carboxylate 63 51.8 ^e 42.4 ^e 1 -(1,2,4-thiad iazol-5-yl)azetide in3-yl 2-(difluoromethyl)-3,4- d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridine-6carboxylate 64 88.5 ^e 40.2 ^e 1 -(1,2,4-thiad iazol-5-yl)azetide in3-yl 2,3,4-trimethyl-5,7-dihydro6/7-pyrrolo[3,4-b]pyridine-6carboxylate 65 88.2 ^e 62.6 ^e 1 -(1,3,4-thiad iazol-2-yl)azetide in3-yl 2,3,4-trimethyl-5,7-dihydro6/7-pyrrolo[3,4-b]pyridine-6carboxylate 66 163 ^e 52.3 ^e 1-(pyridin-3-yl)azetidin-3-yl 3chloro-2-(methoxymethyl)-4-methyl5,7-dihydro-6/7-pyrrolo[3,4b]pyridine-6-carboxylate 67 98.6 ^e 18.5 ^e 1 -(1,2,4-thiad iazol-5-yl)azetide in- 3-yl 3-chloro-2,4-dimethyl-5,7- Dihydro-6/7-pyrrolo[3,4- b]pyridine-6-carboxylate 68 99.4 485 1 -(2,4-d imethyl-5,7-dihyde rho-6Hpyrrolo[3,4-b]pyridin-6-yl)-2-{1- [4-(3-methylochelan-3- yl)phenyl]azetidin-3-yl}ethanone

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69 41.5 1356 3-{3-[2-(2,4-dimethyl-5,7-dihyde rho6/7-pyrrolo[3,4-b]pyridin-6-yl)2-oxoethyl]azetide in-1 -yl}- 4methoxybenzonitrile 70 95.0 184 4-{3-[2-(2,4-dimethyl-5,7-dihyde rho6/7-pyrrolo[3,4-b]pyridin-6-yl)2-oxoethyl]azetidin-1-yl}-M ,Mdimethylbenzamide 71 90.5 195 1 -(2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2-{1- [4- (hydroxymethyl)phenyl]azetidine- 3-yl}ethanone 72 90.6 537 2-[1-(4- cyclopropylphenyl)azetidin-3yl]-1 -(2,4-d imethyl-5,7-dihyde po6/7-pyrrolo[3,4-b]pyridin-6yl)ethanone 73 95.3 90.5 2-(1-{4- [cyclopropyl(hydroxy)methyl]phenyl}azetide in-3-yl)-1 -(2,4d imethyl-5,7-dihydro-6/7pyrrolo[3,4-b]pyridin-6yl)ethanone 74 84.4 460 (5-{3-[2-(2,4-d imethyl-5,7-dihyde po6/7-pyrrolo[3,4-b]pyridin-6-yl)2-oxoethyl]azetide in-1 -yl }-2methoxyphenyl)acetonitrile 75 89.2 105 4-{3-[2-(2,4-d imethyl-5,7-dihyde rho6/7-pyrrolo[3,4-b]pyridin-6-yl)2-oxoethyl]azetide in-1 -yl} -/\/methylbenzamide 76 45 1397 1 -(2,4-d imethyl-5,7-dihyd rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2[trans-2-(quinazolin-7yl)cyclopropyl]ethanone 77 176 ^e 2884 ^e 1 -(2,4-d imethyl-5,7-dihyde rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2[trans-2- phenylcyclopropyl]ethanone 78 97.3 88.1 1 -(2,4-d imethyl-5,7-dihyd rho-6/7pyrrolo[3,4-b]pyridin-6-yl)-2-(1phenylazetidin-3-yl)ethanone

A. The value is the geometric mean of 2-4 determinations unless otherwise noted.

b. The value represents the geometric mean of >5 determinations.

With. The value represents one definition.

d. Not determined.

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Claims (18)

CLAIM 1. Compound of formula (I) (I) or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein each R ¹ is independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, (C ₁ -C ₆ )alkoxy, wherein (C ₁ -C ₆ )alkyl is optionally substituted with 1-2 halogens or hydroxy, (C ₁ -C ₆ )alkylthio and (C ₁ -C ₆ )alkoxy are optionally substituted 1-2 halogens; a is an integer selected from 0, 1, 2 and 3; each R ² when present is (C ₁ -C ₆ )alkyl; b is an integer selected from 0 and 1; L is selected from -(CH ₂ ) _m -, -O-, or -NH-, where m is an integer selected from 1 and 2; A is absent or selected from the group consisting of (C ₃ -C ₆ )cycloalkyl and (4-6 membered) heterocycloalkyl, wherein heterocycloalkyl contains 1 nitrogen atom, with the proviso that when L is -NH-, A is (C ₃ -C ₆ )cycloalkyl or (4-6-membered) heterocycloalkyl; E is selected from (C ₃ -C ₁₀ )cycloalkyl, (C ₆ -C ₁₀ )aryl and (5-10 membered) heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein said cycloalkyl, aryl and heteroaryl is substituted with 0 to 3 substituents, which are independently selected from the group consisting of halogen, cyano, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, (C ₁ -C ₆ )alkoxy, ( C ₃ -C ₆ )cycloalkyl, methyloxetanyl, -N(R ³ )(R ⁴ ) and -C(=O)N(R ³ )(R ⁴ ), wherein (C1-C ₆ )alkyl, (C ₁ -C ₆ )alkylthio, (C ₁ -C ₆ )alkoxy and (C ₃ -C ₆ )cycloalkyl are optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, cyano and (C ₃ -C ₆ )cycloalkyl with the proviso that when L is -NH-, E is (5-10 membered) heteroaryl; And R ³ and R ⁴ are in each case independently selected from hydrogen or (C ₁ -C ₆ )alkyl. 2. A compound according to claim 1, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or Noxide, wherein L represents -(CH ₂ ) _m - and m represents an integer selected from 1 and 2. 3. A compound according to any one of claims 1, 2, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein A is (C ₃ -C ₆ )cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 4. A compound according to claim 3, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or Noxide, wherein A is cyclopropyl. 5. A compound according to any one of claims 1, 2, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein A is a (4-6 membered) heterocycloalkyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl. 6. A compound according to claim 5, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or Noxide, wherein A is (4-6 membered) heterocycloalkyl and heterocycloalkyl is azetidinyl. 7. A compound according to any one of claims 1 to 6, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein E is a (5-10 membered) heteroaryl, which is selected from the group consisting of from triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl, furanopyridinyl, imidazopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, thienopyridinyl, quinolinyl, isoquinolinyl, wherein said heteroaryl is optionally substituted from one to three substituents that are independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ )alkyl and optionally substituted (C ₁ -C ₆ )alkoxy. 8. A compound according to claim 7, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or Noxide, wherein the heteroaryl is a (5-6 membered) nitrogen-containing heteroaryl, which is selected from the group consisting of triazolyl, imidazolyl, pyrazolyl, pyridinyl , pyrazinyl, pyrimidinyl and pyridazinyl, wherein said nitrogen-containing heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, -N(R ³ )(R ⁴ ), optionally substituted (C ₁ -C ₆ )alkyl and optionally substituted (C ₁ -C ₆ )alkoxy. 9. Compound of formula Ia - 101 044379 or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein each R ¹ is independently selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy, wherein (C ₁ -C ₆ )alkyl is optionally substituted with 1-2 halogens or hydroxy and (C ₁ -C ₆ )alkoxy is optionally substituted with 1-2 halogens; a is an integer selected from 1, 2 and 3; R ² when present is (C ₁ -C ₆ )alkyl; b is an integer selected from 0 and 1; E is a (5-6 membered) heteroaryl containing 1-3 heteroatoms, N, O or S, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and -N(R ³ )(R ⁴ ), wherein (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, cyano and (C ₃ -C ₆ )cycloalkyl, and R ³ and R ⁴ are in each case independently selected from hydrogen and (C ₁ -C ₆ )alkyl. 10. A compound according to claim 9, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or Noxide, wherein E is a (5-6 membered) nitrogen-containing heteroaryl, which is selected from the group consisting of pyrazolyl, thiazolyl, thiadiazolyl, pyridinyl , pyrimidinyl and pyrazinyl. 11. Compound of formula Ib or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein each R ¹ is independently selected from the group consisting of halogen, (O ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy, wherein ( C ₁ -C ₆ )alkyl is optionally substituted with 1-2 halogens or hydroxy and (C ₁ -C ₆ )alkoxy is optionally substituted with 1-2 halogens; a is an integer selected from 1, 2 and 3; R ² when present is (C ₁ -C ₆ )alkyl; b is an integer selected from 0 and 1; E is a (5-6 membered) heteroaryl containing 1-3 heteroatoms, N, O or S, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, hydroxy, ( C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and -N(R ³ )(R ⁴ ), wherein (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy are optionally substituted with 1- 3 substituents selected from the group consisting of halogen, hydroxy, cyano and (C ₃ -C ₆ )cycloalkyl, and R ³ and R ⁴ are in each case independently selected from hydrogen and (C ₁ -C ₆ )alkyl. 12. A compound according to claim 11, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or N-oxide, wherein E is a (5-6 membered) nitrogen-containing heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl and pyrazinyl. 13. A compound selected from the group consisting of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4b]pyRidin-6-yl)-2-[ 1 -(pyridin-3- yl)azetidin-3-yl]ethanone, 1-[2-(methoxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-{1-[2-(trifluoromethyl)pyridin-4 -yl] azetidin-3 -yl} ethanone, 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2-(trifluoromethyl)pyridin-4yl]azetidin-3 -yl} ethanon, 1-(3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2-(difluoromethyl)pyridin-4 -yl] azetidin-3 -yl} ethanone, 1-[3-chloro-2-(methoxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-{1-[2-(difluoromethyl )pyridin-4-yl]azetidin-3-yl}ethanone, 1-(3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[trans-2-(pyrimidin-5yl)cyclopropyl] ethanon and 1-[2-(hydroxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-{1-[2-(trifluoromethyl)pyridin-4 -yl]azetidin-3-yl}ethanone, or its N-oxide, or a pharmaceutically acceptable salt thereof, - 102 044379 or pharmaceutically acceptable N-oxide salt. 14. A pharmaceutical composition for the treatment of an M4-mediated disease or disorder, comprising a therapeutically effective amount of a compound or N-oxide or pharmaceutically acceptable salt according to any one of claims 1 to 13, and a pharmaceutically acceptable carrier. 15. A method of treating an M4-mediated disease or disorder in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound, or Noxide, or pharmaceutically acceptable salt according to any one of claims 1 to 13. 16. The method of claim 15, wherein the M4-mediated disease or disorder is a disease or disorder that is selected from the group consisting of Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorder, cognitive disorder, Parkinson's disease, dyskinesia, levodopa-induced in Parkinson's disease, Huntington's disease and dyskinesia. 17. The method of claim 15, wherein the M4-mediated disease or disorder is a disease or disorder that is selected from the group consisting of Alzheimer's disease, schizophrenia or psychosis, pain, addiction and sleep disorder. 18. The method of claim 16, wherein the M4-mediated disease or disorder is a cognitive disorder, wherein the cognitive disorder is a mild cognitive impairment of function. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 103 -