JP2008536927A - N-alkyl-azacycloalkyl NMDA / NR2B antagonist - Google Patents

Abstract

Compounds of formula (I) and / or pharmaceutically acceptable salts thereof, individual enantiomers and stereoisomers are ischemic brain including pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, stroke It is effective as an NMDA / NR2B antagonist useful for the treatment of symptoms such as disorders.

Description

  The present invention relates to N-alkyl-azacycloalkyl compounds. In particular, the present invention is an NMDA / NR2B antagonist useful for the treatment of neurological symptoms such as pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, ischemic brain disorders including stroke, and other symptoms. It relates to N-alkyl-azacycloalkyl compounds.

  Ions such as glutamate play an important role in the processes associated with chronic pain and neurotoxicity associated with pain by acting primarily through the N-methyl-D-aspartate (“NMDA”) receptor. Fulfill. Thus, inhibiting such effects by using ion channel antagonists, particularly NMDA antagonists, can be beneficial in the treatment and management of Parkinson's disease and pain.

  The NMDA receptor is a heteromeric construct of subunits in which two major subunit families, termed NR1 and NR2, have been cloned. Without being bound by theory, various functional NMDA receptors in the mammalian central nervous system (“CNS”) are expressed by a combination of NR1 and NR2 subunits that express glycine and glutamate recognition sites, respectively. It is generally considered that only is formed. The NR2 subunit family is classified into four distinct subunit types: NR2A, NR2B, NR2C and NR2D. T.A. Ishii, et al. , J. et al. Biol. Chem. 268: 2836-2843 (1993) and D.C. J. et al. Laurie et al. , Mol. Brain Res. , 51: 23-32 (1997), as a result of various combinations, various NMDA receptors with different physiological and pharmacological properties such as ion-gated properties, magnesium sensitivity, pharmacological profiles, and anatomical distribution. Describes how the body is generated.

  For example, NR1 is found throughout the brain, but the NR2 subunits are unevenly distributed. In particular, the NR2B distribution map is believed to reduce the probability of side effects occurring during the treatment of Parkinson's disease or pain. Accordingly, it is desirable to provide novel NMDA antagonists that target the NR2B receptor.

  The present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof.

（式中、Ｗ、Ｘ、Ａ、Ｂ、Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は本明細書に記載されている。）本発明は、さらに、本化合物及び組成物を利用して、とう痛、パーキンソン病、アルツハイマー病、てんかん、抑うつ、不安、脳卒中を含めた虚血性脳障害及び他の症状を含めた神経症状を治療し、予防する方法も提供する。

(W, X, A, B, R ¹ , R ² , R ³ and R ⁴ are described herein.) The present invention further utilizes the present compounds and compositions, Also provided are methods of treating and preventing neurological symptoms, including ischemic brain damage and other symptoms including pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, stroke.

  The compounds of the invention are represented by Formula I, and pharmaceutically acceptable salts and individual enantiomers and stereoisomers.

W is aryl or heteroaryl, wherein the aryl or heteroaryl is independently selected from the group consisting of halogen, C _3-6 cycloalkyl, cyano, C _1-4 alkoxy and C _1-6 alkyl 1-5 May be substituted with one or more substituents, the alkoxy may be substituted with one or more halogens, and the alkyl is one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl. May be replaced,
X is absent or is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl, (═O) and cyano, C _1-4 alkoxy and C _1- Selected from the group consisting of ₃ alkyls,
A is a bond, or a hydrogen, a halogen, a hydroxyl, and C _1-3 optionally C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, said alkyl May be substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, C _1-4 alkoxy and cyano,
B is hydrogen, halogen, a hydroxyl, and C _1-3 1 or more optionally C ₁ alkyl optionally substituted with a substituent selected from the group consisting of alkyl, wherein alkyl is halogen, hydroxyl, C _{1 -4} optionally substituted with one or more substituents selected from the group consisting of alkoxy and cyano, wherein the ring is formed comprising A and B, each carbon atom in A and each individual in B Carbon atoms may be bonded to bridge the ring,
R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-3 alkyl;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, hydroxyl, cyano and C _1-3 alkyl, wherein the alkyl is selected from the group consisting of halogen, hydroxyl, C _1-4 alkoxy and cyano 1 May be substituted with more than one substituent,
R ³ and R ⁴ may be joined together with the ring to which they are attached to form a bridged cycloalkyl.

  One embodiment of the present invention provides compounds of formula (I) and / or pharmaceutically acceptable salts, individual enantiomers and stereoisomers thereof.

W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is selected from the group consisting of C _1-4 alkoxy and C _1-3 alkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl and (═O) And
R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-3 alkyl;
R ³ and R ⁴ are each independently hydrogen,
A is a bond, or C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
B is C ₁ alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen, and the ring is formed containing A and B, wherein each carbon atom in A And individual carbon atoms in B may be bonded to bridge the ring.

  Another embodiment of the present invention includes compounds of formula Ia and / or pharmaceutically acceptable salts, individual enantiomers and stereoisomers thereof.

式中、
Ｗは、ハロゲン、Ｃ_３−６シクロアルキル、Ｃ_１−４アルコキシ及びＣ_１−６アルキルからなる群から独立に選択される１−５個の置換基で置換されていてもよいアリールであって、前記アルキルは水素、ハロゲン及びヒドロキシルからなる群から選択される１個以上の置換基で置換されていてもよく、
Ｘは、水素、ハロゲン、ヒドロキシル及び（＝Ｏ）からなる群から選択される１個以上の置換基で置換されていてもよいＣ_１−３アルキルであり、
Ｒ^１及びＲ^２は、水素及びＣ_１−３アルキルからなる群から各々独立に選択され、
Ａは、結合であり、又は水素及びハロゲンからなる群から選択される１個以上の置換基で置換されていてもよいＣ_１−３アルキルである。

Where
W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl and (═O);
R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-3 alkyl;
A is a bond, or C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen.

  Another embodiment of the present invention includes compounds of formula Ib and / or pharmaceutically acceptable salts, individual enantiomers and stereoisomers thereof.

式中、
Ｗは、ハロゲン、Ｃ_３−６シクロアルキル、Ｃ_１−４アルコキシ及びＣ_１−６アルキルからなる群から独立に選択される１−５個の置換基で置換されていてもよいアリールであって、前記アルキルは水素、ハロゲン及びヒドロキシルからなる群から選択される１個以上の置換基で置換されていてもよく、
Ｘは、水素、ハロゲン、ヒドロキシル及び（＝Ｏ）からなる群から選択される１個以上の置換基で置換されていてもよいＣ_１−３アルキルであり、
Ｂは、水素及びハロゲンからなる群から選択される１個以上の置換基で置換されていてもよいＣ_１アルキルである。

Where
W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl and (═O);
B is C ₁ alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen.

  Another embodiment of the present invention includes compounds of formula Ic and / or pharmaceutically acceptable salts, individual enantiomers and stereoisomers thereof.

式中、
Ｗは、ハロゲン、Ｃ_３−６シクロアルキル、Ｃ_１−４アルコキシ及びＣ_１−６アルキルからなる群から独立に選択される１−５個の置換基で置換されていてもよいアリールであって、前記アルキルは水素、ハロゲン及びヒドロキシルからなる群から選択される１個以上の置換基で置換されていてもよく、
Ｘは、水素、ハロゲン、ヒドロキシル及び（＝Ｏ）からなる群から選択される１個以上の置換基で置換されていてもよいＣ_１−３アルキルである。

Where
W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is C _1-3 alkyl which may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl and (═O).

  Another embodiment of the present invention includes compounds of formula Id and / or pharmaceutically acceptable salts, individual enantiomers and stereoisomers thereof.

式中、
Ｗは、ハロゲン、Ｃ_３−６シクロアルキル、Ｃ_１−４アルコキシ及びＣ_１−６アルキルからなる群から独立に選択される１−５個の置換基で置換されていてもよいアリールであって、前記アルキルは水素、ハロゲン及びヒドロキシルからなる群から選択される１個以上の置換基で置換されていてもよく、
Ｘは、水素及びハロゲンからなる群から選択される１個以上の置換基で置換されていてもよいＣ_１−３アルキルであり、
Ａは、結合であり、又は水素及びハロゲンからなる群から選択される１個以上の置換基で置換されていてもよいＣ_１−３アルキルであり、
Ｒ^３及びＲ^４は、水素、ヒドロキシル、シアノ及びＣ_１−３アルキルからなる群から各々独立に選択され、前記アルキルはハロゲン、ヒドロキシル、Ｃ_１−４アルコキシ及びシアノからなる群から選択される１個以上の置換基で置換されていてもよく、
Ｒ^３とＲ^４は、これらが結合している環と一緒に、結合して架橋シクロアルキルを形成し得る。

Where
W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
A is a bond, or C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, hydroxyl, cyano and C _1-3 alkyl, wherein the alkyl is selected from the group consisting of halogen, hydroxyl, C _1-4 alkoxy and cyano 1 May be substituted with more than one substituent,
R ³ and R ⁴ , together with the ring to which they are attached, can be joined to form a bridged cycloalkyl.

  Another embodiment of the present invention includes compounds of formula Ie and / or pharmaceutically acceptable salts, individual enantiomers and stereoisomers thereof.

式中、
Ｗは、ハロゲン、Ｃ_３−６シクロアルキル、Ｃ_１−４アルコキシ及びＣ_１−６アルキルからなる群から独立に選択される１−５個の置換基で置換されていてもよいアリールであって、前記アルキルは水素、ハロゲン及びヒドロキシルからなる群から選択される１個以上の置換基で置換されていてもよく、
Ｘは、水素、ハロゲン、ヒドロキシル及び（＝Ｏ）からなる群から選択される１個以上の置換基で置換されていてもよいＣ_１−３アルキルであり、
Ａは、結合であり、又は水素及びハロゲンからなる群から選択される１個以上の置換基で置換されていてもよいＣ_１−３アルキルであり、
Ｂは、水素及びハロゲンからなる群から選択される１個以上の置換基で置換されていてもよいＣ_１アルキルであり、環はＡとＢを含んで形成され、Ａ中の個々の炭素原子とＢ中の個々の炭素原子は結合して、前記環を架橋していてもよい。

Where
W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl and (═O);
A is a bond, or C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
B is C ₁ alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen, and the ring is formed containing A and B, wherein each carbon atom in A And individual carbon atoms in B may be bonded to bridge the ring.

As used herein, other terms including “alkyl” and the prefix “alk”, eg, alkane, alkanoyl, alkenyl, alkynyl, etc., refer to carbon chains that may be linear, branched, or combinations thereof. means. Examples of suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl and heptyl. Thus, C _1-6 alkyl is defined as a group having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, methyl, ethyl, n-propyl, isopropyl, Examples include n-butyl, isobutyl, tert-butyl, pentyl, hexyl and the like. Similarly, C _1-4 alkyl is defined as a group having 1, 2, 3 or 4 carbons in a linear or branched arrangement, specifically methyl, ethyl, n-propyl, Examples include isopropyl, n-butyl, isobutyl, tert-butyl and the like. Likewise, C _0, as in C ₀ alkyl is alkyl when a terminal group is a hydrogen atom substituent, is a direct bond when the alkyl is a bridging group. “Alkenyl”, “alkynyl” and other like terms include carbon chains containing at least one unsaturated C—C bond.

  As used herein, the term “alkoxy”, alone or in combination, includes alkyl ether groups. Here, the term “alkyl” is defined above and “ether” means two alkyl groups having an oxygen atom between them. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, methoxymethane (also referred to as “dimethyl ether”) and (“ethyl methyl ether” And methoxyethane).

  As used herein, the term “cycloalkyl” refers to carbocycles containing no heteroatoms and includes monocyclic, bicyclic and tricyclic saturated carbocycles and fused ring structures. Such fused ring structures may include one ring that is partially or fully unsaturated, such as a benzene ring that forms a fused ring structure such as a benzofused carbocycle. Cycloalkyl includes fused ring structures such as spiro fused ring structures. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl and fluorenyl, 1,2,3,4-tetrahydronaphthalene.

  As used herein, “aryl” shall mean stable monocyclic or bicyclic carbocycles in which at least one ring is aromatic and each ring is up to 7 members. Examples of such aryl include phenyl, naphthyl and tolyl.

  As used herein, “bridged cycloalkyl” shall mean two or more cycloalkyl groups, heterocycloalkyl groups, or combinations thereof connected by adjacent or non-adjacent atoms. Examples of such bridged cycloalkyl groups include 8-azabicyclo [3.2.1] oct-3-yl and 3-azabicyclo [3.1.0] hex-6-yl.

  As used herein, the term “heteroaryl”, unless stated otherwise, is a stable 5 to 7 membered monocyclic or stable 9 to 10 membered fused bicyclic heterocyclic structure containing an aromatic ring, Any of the rings may be saturated such as piperidinyl, partially saturated or unsaturated such as pyridinyl, consisting of carbon atoms and 1 to 4 heteroatoms selected from the group consisting of N, O and S; Nitrogen and sulfur heteroatoms may optionally be oxidized, nitrogen heteroatoms may be quaternary in some cases, meaning a structure containing a bicyclic group in which any of the above heterocycles is fused to a benzene ring It shall be. Heterocycles can be attached at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl groups include pyridine, pyrimidine, pyrazine, thiophene, oxazole, thiazole, triazole, thiadiazole, oxadiazole, pyrrole, 1,2,4-oxadiazole, 1,3,4-oxadiazole. 1,2,4-thiadiazole, 1,3,4-thiadiazole, and 1,2,4-triazole, but are not limited thereto.

The term “hetero” unless specifically stated otherwise includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring structures that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. A heteroatom replaces a ring carbon atom. Thus, for example, heterocyclo C ₅ alkyl is a five membered ring containing from 4 to no carbon atoms. Examples of heterocycloalkyl include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one and thiomorpholinyl.

  In the structures described throughout this application, a hydrogen atom on an unsubstituted nitrogen atom may be explicit or implicit.

  The same rules apply to all general structures and structures representing individual species. It goes without saying that the nitrogen atom can also be replaced by atoms and / or moieties other than hydrogen as indicated in this application.

  It should be understood by those skilled in the art that the term halo, ie, halogen, as used herein includes chloro, fluoro, bromo and iodo.

  The term “optionally substituted” is intended to include both substituted and unsubstituted. That is, for example, optionally substituted aryl may represent a pentafluorophenyl ring or a phenyl ring. In addition, a plurality of optionally substituted moieties such as, for example, alkylaryl, mean that the alkyl group and the aryl group may be substituted. When only one of the plurality of moieties may be substituted, it is specifically described such as “alkylaryl, the aryl may be substituted with halogen or hydroxyl”.

  The compounds described herein can contain one or more asymmetric centers and can thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure separated enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Formula I (including Formulas Ia, Ib, Ic, Id, and Ie) is not limited in stereochemistry at specific positions. The present invention includes all stereoisomers of Formula I, and pharmaceutically acceptable salts thereof. Also included are mixtures of stereoisomers and isolated specific stereoisomers. In the course of synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the product of such procedures can be a mixture of stereoisomers.

  These diastereomers or chromatographic isolates thereof can be synthesized individually by appropriately modifying the methods disclosed herein, as is known in the art. Its absolute configuration can be determined by x-ray crystallography of crystalline products or crystalline intermediates derivatized with reagents containing asymmetric centers of known absolute configuration as necessary. .

  If desired, racemic mixtures of the compounds can be separated and the individual enantiomers isolated. Separation can be performed by methods well known in the art. For example, a racemic mixture of compounds is coupled with an enantiomerically pure compound to form a diastereomeric mixture, which is subsequently separated into individual diastereomers by standard methods such as fractional crystallization, chromatography, etc. Can do. The coupling reaction is often the formation of a salt using an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to the pure enantiomer by cleavage of the added enantiomeric residue. Racemic mixtures of compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, well known in the art.

  Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis by methods well known in the art using optically pure starting materials or reagents of known configuration.

  As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper ((II) and (I)), iron (III), iron (II), lithium, magnesium, manganese ((III) and (II )), Potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of substituted amines such as primary amines, secondary amines, tertiary amines, cyclic amines, natural substituted amines, synthetic substituted amines, etc. Is mentioned. Other pharmaceutically acceptable non-toxic organic bases that can form salts include, for example, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethyl. Aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, Examples include ion exchange resins such as triethylamine, trimethylamine, tripropylamine, and tromethamine.

  When the compound of the present invention is a base, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Examples of such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, Examples include malic acid, mandelic acid, methanesulfonic acid, mucoic acid, nitric acid, pamonic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali salts or organic salts of acidic residues such as carboxylic acids, and the like. Not. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and acetic acid, propionic acid, succinic acid, glycolic acid, stearin. Acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamonic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid And salts prepared from organic acids such as methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid.

  The subject or patient to be treated in this method is generally a male or female mammal, such as a human, who is required to antagonize NMDA / NR2B receptor activity. The subject or patient to be treated in the present method may also be an animal such as a dog, cat, horse, pig, cow. The term “therapeutically effective amount” means the amount of a compound of interest that elicits a biological, medical response of a tissue, system, animal or human as sought by a researcher, veterinarian, physician or other clinician. As used herein, the term “treatment” refers to both treatment and prevention or prevention treatment of the above symptoms, particularly in patients susceptible to such diseases or disorders.

  As used herein, the term “composition” includes products containing specified ingredients in specified amounts, and any product obtained directly or indirectly by combining each specified ingredient in each specified amount. To do. Such terms relating to a pharmaceutical composition include products comprising an active ingredient and an inert ingredient that constitutes a carrier, and from any combination, combination or collection of any two or more ingredients, or one or more. Any product obtained directly or indirectly from the dissociation of one component or from another type of reaction or interaction of one or more components is intended to be included. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier. “Pharmaceutically acceptable” means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

  The terms “administration” of a compound and / or “administering” a compound should be understood to mean administering to the individual in need of treatment a compound of the invention or a prodrug of a compound of the invention.

  The pharmaceutical composition of the present invention comprises a compound of formula I (and / or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Also good. The compositions include compositions suitable for oral, rectal, topical and parenteral administration (including subcutaneous, intramuscular and intravenous), but the most suitable route in any given case is the individual route It depends on the host and the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical composition can conveniently be in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art.

  The present invention is further directed to a method of producing a medicament for antagonizing NMDA / NR2B receptor activity in humans and animals comprising combining a compound of the present invention and a drug carrier or diluent.

  Indeed, the compounds of formula I of the present invention or pharmaceutically acceptable salts thereof can be mixed with the drug carrier by conventional drug compounding techniques as the active ingredient in a homogeneous mixture. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral (including intravenous). Therefore, the pharmaceutical composition of the present invention can be a separate unit suitable for oral administration, such as a capsule, a cachet, and a tablet each containing a predetermined amount of an active ingredient. The composition may also be a powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid emulsion. In addition to the general dosage forms described above, the compounds of formula I and / or pharmaceutically acceptable salts thereof can also be administered by controlled release means and / or delivery devices. The composition can be prepared by any of the dispensing methods. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly mixing the active ingredient with a liquid carrier, a finely divided carrier or both. The product can then be conveniently shaped into the desired presentation.

  Accordingly, the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt thereof. A compound of formula I or a pharmaceutically acceptable salt thereof can also be included in a pharmaceutical composition in combination with one or more other therapeutically effective compounds.

  The drug carrier used can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, clay, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil and water. Examples of gas carriers include carbon dioxide and nitrogen.

  Any convenient pharmaceutical medium may be used in preparing the oral dosage form composition. For example, oral liquid preparations such as suspensions, elixirs and solutions can be formed using water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. Oral solid preparations such as powders, capsules, and tablets can be formed using carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants. . Tablets and capsules are preferred oral dosage units because of their ease of administration, whereby solid drug carriers are used. Tablets may be coated by standard aqueous or non-aqueous techniques.

  A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets are made by compressing in a suitable machine free-flowing active ingredients such as powders, granules, which may be mixed with binders, lubricants, inert diluents, surfactants or dispersants. Can be prepared. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert diluent. Each tablet preferably contains from about 0.5 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.5 mg to about 5 g of the active ingredient.

  The pharmaceutical composition of the present invention comprises a compound of formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. You may go out. The compositions include compositions suitable for oral, rectal, topical and parenteral administration (including subcutaneous, intramuscular and intravenous), but the most suitable route in any given case is the individual route It depends on the host and the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical composition can conveniently be in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art.

  The pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as aqueous solutions or suspensions of the active compounds. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersants can also be prepared in glycerin, in liquid polyethylene glycols, and mixtures thereof in oil. In addition, a preservative can be added to prevent harmful growth of microorganisms.

  Suitable pharmaceutical compositions of the present invention for injection include sterile aqueous solutions or dispersions. The composition can also be in the form of a sterile powder for the immediate preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable dosage form must be sterile and must be effectively fluid to facilitate injection. The pharmaceutical composition should be stable under the conditions of manufacture and storage and should therefore preferably be protected against the contaminating action of microorganisms such as bacteria, fungi and the like. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

  The pharmaceutical composition of the present invention can be made into a dosage form suitable for topical use such as an aerosol, a cream, an ointment, a lotion, or a spray powder. The composition can also be in a dosage form suitable for use in a transdermal device. These formulations can be prepared by conventional processing methods utilizing the compounds of Formula I of the present invention or pharmaceutically acceptable salts thereof. By way of example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 5% to about 10% by weight of the compound to produce a cream or ointment having the desired consistency. Is done.

  The pharmaceutical composition of the invention can be in a form suitable for rectal administration wherein the carrier is a solid. The mixture preferably forms unit dose suppositories. Suitable carriers include cocoa butter, other materials commonly used in the art, and the like. Suppositories can be conveniently formed by first mixing the composition with a softened or molten carrier, followed by cooling and molding in a mold.

  In addition to the carrier component described above, the drug may be one or more of a diluent, a buffer, a flavoring agent, a binder, a surfactant, a thickener, a lubricant, a preservative (including an antioxidant), etc. These additional carrier components can be included as appropriate. Other adjuvants can also be included to make the formulation isotonic with the blood of the intended recipient. Compositions comprising a compound of formula I and / or pharmaceutically acceptable salts thereof can also be prepared in the form of a powder or concentrated liquid.

  The usefulness of the compounds according to the invention as antagonists of NMDA / NR2B receptor activity can be demonstrated by methods known in the art. Inhibition of binding to the NMDA receptor and functional antagonism of calcium efflux through the NMDA channel were confirmed as follows.

Cell-based functional assay to determine IC _{50 of} NR2B antagonists NR1a / NR2B NMDA receptor inhibitory ability of selected compounds as measured by NR1a / NR2B receptor-mediated Ca ²⁺ influx is assessed by the following calcium influx assay procedure did.

L (tk−) cells transfected with the NR1a / NR2B receptor were seeded at 3 × 10 ⁴ cells / well in a 96-well format and grown in normal growth medium (Na pyruvate, glucose 4500 mg, pen / strep, glutamine, 10% Dulbecco's MEM containing FCS and 0.5 mg / mL geneticin) for 1 to 2 days. NR1a / NR2B expression in these cells was induced by adding 4-20 nM dexamethasone in the presence of 500 μM ketamine for 16-24 hours. NR2B antagonist solution was prepared in DMSO and serially diluted with DMSO to obtain 10 solutions with 3 times different concentrations. DMSO solution was added to assay buffer (20 mM HEPES, 2 mM CaCl ₂ , 0.1% BSA and 250 μM probenecid (Sigma # P-8761) and Mg ²⁺ free Hanks Balanced Salt Solution (HBSS) (Gibco # 14175-079) A 96-well drug plate was prepared by diluting 250 fold). After induction, cells are washed twice with assay buffer (Labsystem cell wash, 3-fold dilution to 100 μL), in assay buffer containing Pluronic F-127 (Molecular Probes # P-3000) and 10 μM ketamine. Of 4 μM calcium fluorescent indicator fluo-3 AM (Molecular Probes # P-1241) was added at 37 ° C. for 1 hour. The cells were then washed 8 times with assay buffer, leaving 100 μL of buffer in each well. Fluorescence intensity was measured immediately by FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices) using excitation at 488 nm and emission at 530 nm. 5 seconds after the start of recording the fluorescence intensity, 50 μL of the working substance solution (40 μM glutamic acid / glycine, final concentration 10 μM) is added, and after 1 minute, if the fluorescence signal is stable, 50 μL of the NR2B antagonist and control solution are added from the drug plate. The fluorescence intensity was recorded for an additional 30 minutes. The IC ₅₀ value was determined by fitting the end point fluorescence value to the following equation # 1 in a nonlinear least squares fit.

式中、Ｙｍｉｎは、ＡＭＤ−２ １μＭを含む対照ウェルの平均終点蛍光であり、Ｙｍａｘは、０．１％ＤＭＳＯアッセイ緩衝溶液を含むウェルの平均終点蛍光である。

Where Ymin is the mean endpoint fluorescence of control wells containing 1 μM AMD-2 and Ymax is the mean endpoint fluorescence of wells containing 0.1% DMSO assay buffer solution.

Binding Assay for K _I NR2B Antagonists Radioligand binding assays were performed at room temperature with a final assay volume of 1.0 mL in 20 mM Hepes buffer (pH 7.4) containing 150 mM NaCl in 96-well microtiter plates. NR2B antagonist solutions were prepared in DMSO and serially diluted with DMSO to obtain 20 μL of 10 solutions each having a three-fold different concentration. Non-specific binding (NSB) was assessed using AMD-1 (final concentration 10 μM) and total binding (TB) was measured by adding DMSO (final concentration 2%). Membrane expressing NR1a / NR2B receptor (final concentration 40 pM) and tritiated AMD-2 (final concentration 1 nM) were added to all wells of the microtiter plate. After 3 hours incubation at room temperature, the sample was filtered through a Packard GF / B filter (previously soaked in 0.05% PEI, polyethylenethymine Sigma P-3143) and cold 20 mM Hepes buffer per wash. Wash 10 times with 1 mL of agent. After the filter plate was vacuum dried, 40 μL of Packard Microscint-20 was added, and the bound radioactivity was measured with a Packard TopCount. The bound radioactivity (bound CPM) is non-linear least squares fitted to the following equation # 2, and the apparent dissociation constant (K _I ), maximum inhibition rate (% I _max ), minimum inhibition rate (% I _min ), and slope (hill slope) ) (NH).

式中、Ｋ_Ｄは、加熱飽和実験（ｈｏｔ ｓａｔｕｒａｔｉｏｎ ｅｘｐｅｒｉｍｅｎｔ）によって求められた、受容体の放射性リガンドに対する見掛け解離定数であり、ＳＢは、ＴＢとＮＳＢ対照ウェルの差から求められた特異的結合放射能である。

Wherein, _{K D} was determined by heating saturation experiments (hot saturation experiment), and the apparent dissociation constant for the radioligand for the receptor, SB is the specific binding radiation obtained from the difference of TB and NSB control wells Noh.

  AMD-1 and AMD-2 can be synthesized by the following reaction scheme.

  The precursor E for synthesis of radiolabeled AMD-1 can be synthesized according to the following procedure.

  Reaction 1

  According to the procedure of Reaction 1, hydrogen chloride is bubbled through a solution of cinnamic nitrile A in methanol at room temperature. Volatiles are removed under reduced pressure, and the resulting residue is triturated with ether and filtered to give intermediate imidate B. Imidart B is dissolved in methanol at ambient temperature, treated with amine D (commercially available from Acros Chemicals) at ambient temperature and stirred under argon. Volatiles are removed under reduced pressure and the residue is purified by preparative HPLC or triturated with ether to give amidine E.

  Tritiated AMD-2 can be synthesized by the following procedure.

  Reaction 2

  Tritiated AMD-2 was prepared by the following procedure shown in Reaction 2 above. That is, Precursor E (2 mg, 0.008 mmol) was dissolved in dimethylformamide (0.6 mL) and potassium carbonate (1.2 mg) for 1 hour. High specific activity tritiated methyl iodide (50 mCi, 0.0006 mmol, 1 mL toluene solution, commercially available from American Radiolabeled Chemicals, St. Louis, Missouri) was added at room temperature and stirred for 2 hours. The reaction mixture is filtered using Whatman PTFE 0.45 μm syringeless filter device to remove insoluble potassium carbonate, washed with absolute ethanol (2 mL, commercially available from Pharmco), and the mixed filtrate is rotated on a rotary evaporator. Concentrated to dryness at room temperature. This also removed unreacted tritiated methyl iodide. The residue was subjected to HPLC chromatography using a Phenomenx Luna C8 semi-prep column (Luna 5 micro C8 (2), 250 × 10.0 mm) to 0. 20 acetonitrile / water containing 0.1% trifluoroacetic acid. Purified using a 20 minute gradient system to 100% acetonitrile with 1% trifluoroacetic acid. The total activity of the product was 8 mCi. Absorbed on a column (Waters Sep-Pak® PLUS C18 column commercially available from Waters Corporation, Milford, Massachusetts) and eluted with water followed by absolute ethanol for further purification. The product was diluted with absolute ethanol (10 mL) before being subjected to final analysis.

  AMD-1 is a C.I. F. It can be synthesized according to the general procedure described in Claiborne et al. (Bioorganic & Med. Chem. Letters 13, 697-700 (2003)).

  Unlabeled AMD-2 is prepared as follows.

  Reaction 3

  According to reaction 3, hydrogen chloride is bubbled through a methanolic solution of cinnamic nitrile A at room temperature. Volatiles are removed under reduced pressure, and the resulting residue is triturated with ether and filtered to give intermediate imidate B. Imidart B is dissolved in methanol at ambient temperature, treated with amine F at ambient temperature, and stirred under argon. Volatiles are removed under reduced pressure and the residue is purified by preparative HPLC or triturated with ether to give amidine G.

_{IC 50} and _{K I} values of the compounds of the present invention is less than 50μM in each functional and binding assays. IC ₅₀ and _{K I} values is advantageously less than 5μM in each functional and binding assays. IC ₅₀ and K _I values, it is more advantageously less than 1μM in each functional and binding assays. More advantageously, the IC ₅₀ and K _I values are less than 0.1 μM in the functional assay and the binding assay, respectively.

  The compounds are NMDA NR2B receptor antagonists and are therefore useful in the treatment, prevention, management, amelioration or risk reduction of diseases and disorders mediated by NR2B receptors. Such diseases and disorders include (postherpetic neuralgia, nerve injury, “dynias”, eg, perineal pain, phantom limb pain, nerve root extraction injury, painful diabetic neuropathy, compression Mononeuropathy, ischemic neuropathy, painful traumatic mononeuropathy, neuropathic pain (such as painful polyneuropathy), can be caused by virtually any lesion at any level of the nervous system ) Central pain syndrome and postoperative pain syndrome (eg post-mastectomy syndrome, post-thoracotomy syndrome, stump pain)), bone pain and joint pain (osteoarthritis, rheumatoid arthritis, ankylosing spondylitis), Repetitive movement pain, carpal tunnel syndrome, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia), intraoperative pain (general surgery, gynecology), chronic pain, dysmenorrhea, and Pain associated with angina, and various origins (eg Osteoarthritis, rheumatoid arthritis, rheumatic diseases, tendonitis and gout), inflammatory pain, headache, migraine and cluster headache, depression, anxiety, schizophrenia, stroke, traumatic brain injury, Alzheimer's disease, brain failure Blood, spinal cord injury, cerebrovascular disease, Meniere's disease, dizziness, amyotrophic lateral sclerosis, Huntington's disease, sensorineural hearing loss, tinnitus, macular degeneration, glaucoma, epileptic seizures, or neurotoxin or glucose to the brain And / or neuropathy due to hypoxia, blindness due to neurodegeneration of the visual pathway, restless leg syndrome, multiple system atrophy, non-vascular headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia Such as primary allodynia, secondary allodynia, or other pain due to central sensitization. But it is not limited to.

  The compounds of formula I include Parkinson's disease, dyskinesia (including side effects associated with normal doses of L-dopa), delayed dyskinesia, drug-induced parkinsonism, post-encephalitic parkinsonism, progressive supranuclear paralysis, multiple system atrophy Cerebral cortex basal ganglia degeneration, Parkinson's disease-like ALS dementia complex, basal ganglia mineralization, ataxia, akinetic-rigid syndrome, slow movement, dystonia, drug-induced Parkinson's disease, It is useful for the treatment or prevention of movement disorders such as Gilles de la Tourette syndrome, Huntington's disease, tremor, chorea, muscle clonus, tick disorder, dystonia.

  As used herein, the term “movement disorder” refers to (neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute restlessness, neuroleptic-induced delayed dyskinesia, Includes ataxia and ataxia-rigid syndrome (such as drug-induced postural tremor), dyskinesia, and drug-induced parkinsonism. Examples of “immobility-rigid syndrome” include Parkinson's disease, drug-induced parkinsonism, post-encephalitic parkinsonism, progressive supranuclear paralysis, multiple system atrophy, cortical basal ganglia degeneration, parkinsonism-ALS dementia Complications and basal ganglia mineralization are included. Examples of “dyskinesia” include tremor (including resting tremor, posture tremor and intention tremor), (Sydenham chorea, Huntington's disease, benign hereditary chorea, neurocytic erythrocytosis, symptomatic Chorea (such as chorea, drug-induced chorea, unilateral balism), muscular clonus (including systemic and localized muscular clonus), tic (complex and symptomatic tic) tic and dystonia ( Systemic dystonia such as idiopathic dystonia, drug dystonia, symptomatic dystonia, paroxymal dystonia, and eye spasms, stomatognathic oral dystonia, convulsive vocal disorders, cervical torticollis, axial dystonia, Dystonia such as dystonia and hemiplegic dystonia).

  The compounds of formula I may also be used to reduce substance abuse disorders, including by reducing tolerance and / or dependence on pain opioid treatment and / or by treating withdrawal syndromes of alcohol, opioids, heroin and cocaine, for example. Can be used for treatment. As used herein, the term “substance abuse” includes substance dependence or abuse, with or without physiological dependence. Substances associated with these disorders include alcohol, amphetamine (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), Sedatives-hypnotics or benzodiazepines, other (or unknown) substances and combinations of all of the above.

  In particular, the term “substance abuse disorder” refers to alcohol withdrawal with or without sensory perception; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; Drug withdrawal or anxiolytic withdrawal; including sedative, hypnotic or anxiolytic withdrawal delirium; drug withdrawal disorders such as withdrawal symptoms due to other substances. It should be understood that the term nicotine withdrawal treatment includes treatment of symptoms associated with smoking cessation.

  Other “substance abuse disorders” include substance-induced anxiety disorders that develop during withdrawal, substance-induced mood disorders that develop during withdrawal, substance-induced sleep disorders that develop during withdrawal.

  In particular, compounds of structural formula I are useful in helping to quit smoking and are useful in the treatment of nicotine dependence and nicotine withdrawal. The compounds of formula I result in complete or partial smoking cessation for nicotine consumers such as smokers. Also, withdrawal symptoms are alleviated and weight gain generally associated with smoking cessation is suppressed or absent. In the case of smoking cessation, the compound of formula I may be a nicotinic agonist or nicotine partial agonist, or a monoamine oxidase inhibitor (MAOI), or another active ingredient that has the ability to aid smoking cessation, such as bupropion, doxepin, nortriptyline, etc. It can be used in combination with antidepressants or anxiolytics such as buspirone and clonidine.

  The compounds of the present invention may be used to treat or prevent HIV-induced neuropathy, HIV treatment-induced neuropathy, chronic pelvic pain, neuroma pain, complex local pain syndrome, chronic arthritic pain and related neuralgia, chronic low back pain Treatment or prevention, as well as treatment or prevention of traumatic nerve injury, nerve compression or strangulation, pain caused by or associated with postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, cancer and chemotherapy Useful.

  It should be understood that the compounds of the present invention can be administered at prophylactically effective dosage levels for the prevention of the above symptoms and for the prevention of other symptoms mediated by the NMDA NR2B receptor.

  The compounds of formula I can be used in combination with other drugs used in the treatment / prevention / suppression or amelioration of the diseases or conditions for which compounds of formula I are useful. Such other drugs can be administered simultaneously or sequentially with the compounds and compounds of formula I in the routes and amounts normally used therefor. When a compound of formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of formula I is preferred. Accordingly, the pharmaceutical compositions of the present invention include pharmaceutical compositions that, in addition to a compound of formula I, also include one or more other drugs or therapeutic agents. Examples of other therapeutic agents or drugs that can be used in combination with a compound of formula I and that can be administered separately or as the same pharmaceutical composition include: (1) a non-steroidal anti-inflammatory agent, (2 ) COX-2 inhibitor, (3) Bradykinin B1 receptor antagonist, (4) Sodium channel blocker and antagonist, (5) Nitric oxide synthase (NOS) inhibitor, (6) Glycine site antagonist, 7) potassium channel opener, (8) AMPA / kainate receptor antagonist, (9) calcium channel antagonist, (10) GABA-A receptor modulator (eg, GABA-A receptor agonist), 11) Matrix metalloproteinase (MMP) inhibitor, (12) Thrombolytic agent, (13) Opioids such as morphine, (14) Neutrophil inhibitory factor (NIF), (15) L (16) carbidopa, (17) levodopa / carbidopa, (18) dopamine agonists such as bromocriptine, pergolide, pramipexole, ropinirole, (19) anticholinergic, (20) amantadine, (21) carbidopa, (22) ) Catechol O-methyltransferase (“COMT”) inhibitors such as entacapone, tolcapone, (23) monoamine oxidase B (“MAO-B”) inhibitors, (24) opiate agonists or antagonists, (25) 5HT receptor Body agonists or antagonists, (26) NMDA receptor agonists or antagonists, (27) NK1 antagonists, (28) selective serotonin reuptake inhibitors (“SSRI”) and / or selective serotonin and norepinephrine reactivation Uptake inhibitors (“SSNRI”), (29 Tricyclic antidepressants, (30) norepinephrine modulators, (31) lithium, (32) valproate and (33) neurontin (gabapentin), (34) pregabalin, (35) antiplatelet drug, (36) VR1 Examples include, but are not limited to, antagonists, (37) COX-3 inhibitors, (38) antioxidants, (39) metal chelators, (40) CGRP antagonists, and (41) memantine.

  Suitable anti-parkinsonian drugs for use in combination with deramcicline include levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa, benserazide), its hydrochloride or lactic acid (Which may be a salt) and anticholinergic drugs such as biperiden and trihexyphenidyl (benzhexol) hydrochloride, and dopamine agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It should be understood that the dopaminergic agent can be in the form of a pharmaceutically acceptable salt, such as alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexole are generally used in forms other than salt.

  Delamcyclane or a pharmaceutically acceptable salt thereof includes acetophenazine, arentemol, benzhexol, bromocriptine, biperidene, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa and benserazide, levodopa and Selected from the group consisting of carbidopa, lisuride, loxapine, mesoridazine, molindrone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, and trifluxazine In combination with other compounds.

  Suitable neuroleptics used in combination with deramcyclane or a pharmaceutically acceptable salt thereof include the neuroleptic phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthene include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of butyrophenone is haloperidol. An example of diphenylbutyl piperidine is pimozide. An example of Indrone is Morindron. Other neuroleptic agents include loxapine, sulpiride, risperidone and the like. Neuroleptics when used in combination with deramcicrane are pharmaceutically acceptable salt forms such as chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, enanthate fluphenazine, decane It should be understood that it may be the acid fluphenazine, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and morindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are generally used in forms other than salts.

  Creams, ointments, jellies, solutions or suspensions containing this compound can be used for topical use. Mouthwashes and mouthwashes are within the scope of topical use in the present invention.

  A human oral dosage formulation may conveniently contain from about 0.05 mg to about 5 g of the active agent, combined with a suitable and convenient amount of carrier material, which may be from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain about 0.05 mg to about 1000 mg of the active ingredient.

  The symptoms listed herein can be treated or prevented by administering the compound at about 0.01 mg to about 140 mg / kilogram body weight / day.

  However, it should be understood that the specific dose level for an individual patient will depend on a variety of factors. Such factors include the patient's age, weight, general health, sex, diet, and the like. Other factors include administration time and route, elimination rate, drug combination, specific disease type and severity being treated. For example, inflammatory pain can be effectively treated by administering about 0.01 mg to about 75 mg / kg body weight / day or about 0.5 mg to about 3.5 g / patient / day of the compound. . Neuropathic pain can be effectively treated by administering about 0.01 mg to about 125 mg / kg body weight / day or about 0.5 mg to about 5.5 g / patient / day of the compound.

  Abbreviations used in this specification are as follows unless otherwise specified.

TEA triethylamine NaOAc sodium acetate DMF dimethylformamide DIPEA diisopropylethylamine EtOAc ethyl acetate TFA trifluoroacetic acid TFAA anhydrous trifluoroacetic acid THF tetrahydrofuran DMAP 4-dimethylaminopyridine RT room temperature H hour Min min DCM dichloromethane MeCN acetonitrile Selectfluor 1- (chloromethyl) 1- (chloromethyl) -Fluoro-1,4-diazoniabicyclo [2.2.2] octaneditetrafluoroborate MeOH Methanol EtOH Ethanol IPA 2-Propanol n-BuOH 1-Butanol EDC 1- (3-Dimethylaminopropyl) -3- Ethylcarbodiimide hydrochloride HOBt 1-hydroxy-benzotriazole NMP N- Methyl-2-pyrrolidinone DAST (diethylamino) sulfur trifluoride

  The compounds of the present invention can be readily prepared according to the following schemes and specific examples or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, variants which are known per se to the person skilled in the art but are not described in great detail can also be used. One skilled in the art can readily understand and evaluate the general procedure for producing the claimed compounds in the present invention by considering the following schemes.

  Preparation of compounds of formula I can proceed via structures such as that of intermediate II.

  Compounds of formula I can be synthesized via intermediate II as shown in Scheme 1. In general, Intermediate II is prepared in the presence of a base including sodium carbonate or diisopropylethylamine in standard alkylation conditions such as heated alcohol solvents including isopropanol or 1-butanol (RK Robins, J. Amer. Chem. Soc., 78, 784-790 (1956)) is alkylated with 4-chloro-1H-pyrazolo [3,4-d] pyrimidine 1. Intermediate II can also be alkylated with an appropriately protected derivative of compound 1. Suitable protecting groups include alkoxymethyl derivatives such as N-tetrahydropyranyl, as shown by compound 2 and its isomer 3. Use of 2 and 3 in the alkylation reaction produces intermediates III and IV, respectively. Suitable protecting groups of this type are readily removed by treating intermediate III or IV with a protonic acid such as hydrochloric acid to form compounds of formula I.

  The synthesis of certain alkoxy heterocycle-containing compounds is shown in Scheme 2. In the first step, an appropriately protected amine 4 is treated with a halide 5 under basic conditions to give an alkylated heterocycle 6. The nitrogen protecting group in 6 is removed under standard conditions such as acid hydrolysis, and intermediate 7 is converted to the final compound by the reaction sequence shown in Scheme 1. Alternatively, an appropriately protected amino heterocycle is alkylated with an epoxide (eg as shown in Example 6), an aldehyde, or a ketone under reducing conditions (eg as shown in Example 12). Alternatively, an appropriately protected amino heterocycle is alkylated with an alpha-bromoketone (eg, as shown in Example 14). In each of these examples, the intermediate can be further made final by the reaction sequence shown in Scheme 1 using standard chemical reactions including removal of the nitrogen protecting group.

  The synthesis of certain aryl difluoroethyl-containing compounds is shown in Scheme 3. In the first stage, 2-bromo-2,2-difluoroacetic acid ester 8 is arylated with 4-chloroiodobenzene 9 in the presence of copper powder to produce ester 10. An alternative synthesis of ester 10 is to acylate the aryl ring with an acid chloride such as ethyl oxalyl chloride in the presence of a Lewis acid such as aluminum chloride and then halogenate the keto ester using a reagent such as DAST. is there. Hydrolysis of ester 10 under basic conditions produces acid 11. Carboxylic acid 11 is converted to acid chloride 12. Acylation of the appropriately protected amine 13 with acid chloride 12 under standard conditions produces amide 14. Deprotection of amide 14 under standard conditions such as acid hydrolysis produces amine 15. Reduction of amine 15 under standard conditions such as treatment with borane-THF complex or LAH produces intermediate 16. Intermediate 16 is converted to the final compound by the reaction sequence shown in Scheme 1.

  The synthesis of certain fluoropiperidine-containing compounds is shown in Scheme 4. In the first step, ketone 17 is converted to silyl enol ether 18 by treatment with silyl triflate under basic conditions. Treatment of 18 with an electrophilic fluorine source such as Selectfluor® (commercially available from Air Products and Chemicals, Inc., Allentown, Pa.) Produces α-fluoroketone 19. Reduction of 19 under standard conditions produces alcohol 20. Alcohol 20 can be converted to a suitable leaving group such as mesylate 21 and reacted with azide to give azide 22. Removal of the protecting group under standard conditions produces amine 23. Coupling of amine 23 with acid chloride 24 under standard conditions can give amide 25. Reduction of amide 25 under standard conditions produces intermediate 26. Intermediate 26 is converted to the final compound by the reaction sequence shown in Scheme 1.

  Certain azabicyclo [3.1.0] hex-6-yl-containing compounds are derived from appropriately protected diamines such as tert-butylexo-3-azabicyclo [3.1.0] hex-6-ylcarbamate. Can be synthesized by the reaction sequence shown in Schemes 1 and 3. tert-Butylexo-3-azabicyclo [3.1.0] hex-6-ylcarbamate can be prepared according to literature procedures (Norris, T., Braish, TF, Butters, M., DeVries, KM, Hawkins, JM, Massett, SS, Rose, PR, Santafianos, D, Sklavunos, CJ Chem. Soc, Perkin Trans. 1615-1622).

  The synthesis of certain octahydrocyclopenta [c] pyrrol-4-yl-containing compounds is shown in Scheme 5. In the first stage, reaction of amine 27 with enone 28 under acidic conditions produces ketone 29. Ketone 29 can be reduced under standard conditions to give alcohol 30. After adjusting the protecting group under standard conditions, alcohol 31 can be converted to a leaving group such as mesylate 32. Substitution of mesylate with azide produces 33. Deprotection under standard conditions such as acid hydrolysis produces amine 34. Coupling of amine 34 with 24 under standard conditions produces amide 35. Reduction of amide 35 produces intermediate 36. Intermediate 36 is converted to the final compound by the reaction sequence shown in Scheme 1.

  The synthesis of certain azabicyclo [3.2.1] oct-3-yl-containing compounds is shown in Scheme 6. In the first stage, reaction of ketone 37 with hydroxylamine hydrochloride produces imine 38. The imine 38 can be reduced under standard conditions to give the endo 39. The exoamine related to 39 (shown in Example 45) can be utilized by changing the reducing conditions to sodium metal in an alcohol solvent such as propanol. Blocking the primary amine at endo 39 with a suitable protecting group yields 40. Deprotection of the secondary amine under appropriate conditions such as acid hydrolysis produces amine 41. Coupling of amine 41 with 42 under standard conditions produces amide 43. Deprotection of amide 43 under standard conditions produces amide 44. Reduction of amide 44 produces intermediate 45. Intermediate 45 is converted to the final compound by the reaction sequence shown in Scheme 1.

  The final product may be further modified, for example, by substituent manipulation. This operation includes, but is not limited to, reduction, oxidation, alkylation, acylation, halogenation and hydrolysis reactions generally known to those skilled in the art.

  The order in which the above reaction schemes are performed may be altered to facilitate the reaction or to avoid unwanted reaction products. The invention will be further understood by the following examples. These examples are illustrative only and should not be construed as limiting the invention in any way.

  N- {1- [2- (benzyloxy) ethyl] pyrrolidin-3-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Stage A: tert-butyl {1- [2- (benzyloxy) ethyl] pyrrolidin-3-yl} carbamate

To a solution of tert-butylpyrrolidin-3-ylcarbamate (1.5 g, 0.81 mmol) and TEA (2.3 mL 1.6 mmol) in methylene chloride (100 mL) [(2-bromoethoxy) methyl] benzene (1. 7 g, 0.81 mmol) was added at room temperature. After 1 hour, 1M NaOH (500 mL) was added and the aqueous layer was extracted with methylene chloride. The combined organic layer was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% isopropanol / methylene chloride → 30% isopropanol / methylene chloride) gave the title compound (1.4 g). MS: 321 (M + H ^< + ^> ).

  Step B: 1- [2- (Benzyloxy) ethyl] pyrrolidin-3-amine

To tert-butyl {1- [2- (benzyloxy) ethyl] pyrrolidin-3-yl} carbamate (1.2 g, 3.9 mmol) was added trifluoroacetic acid (10 mL) and the resulting solution was stirred at room temperature. . After 60 minutes, the reaction mixture was concentrated to give the trifluoroacetate salt of the title compound (1.2 g). MS: 221 (M + H ^< + ^> ).

  Step C: N- {1- [2- (benzyloxy) ethyl] pyrrolidin-3-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

To a solution of 1- [2- (benzyloxy) ethyl] pyrrolidin-3-amine (0.10 g, 0.35 mmol) in isopropanol (5 mL) was added DIPEA (2 mL) and 4-chloro-1- (tetrahydro-pyran-2- Yl) -1H-pyrazolo [3,4-d] pyrimidine (0.82 g, 0.35 mmol) was added. The solution was then heated at 85 ° C. for 4 hours, then cooled to room temperature and concentrated. The resulting residue was dissolved in methanol (3 mL) and treated with HCl saturated ethyl acetate solution (10 mL). After 1 hour, the mixture was concentrated and the resulting residue was treated with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was dehydrated using sodium sulfate, filtered and concentrated to dryness. Purification by silica gel chromatography (2% isopropanol / methylene chloride → 30% isopropanol / methylene chloride) gave the title compound (0.78 g) as a white solid. MS: 339 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 13.48 (s, 1H), 11.08-10.75 (m, 2H), 8.78 (s, 1H ), 8.25 (s, 2H), 7.32 (s, 5H), 4.78 (s, 1H), 4.48 (s, 1H), 3.98 (s, 1H), 3.78. -3.22 (m, 4H), 2.48 (s, 2H), 2.09-1.94 (m, 2H), 1.81 (m, 1H).

  Examples 2-5 below were prepared by procedures similar to those described in Example 1 above.

  N- {1- [2- (2-phenylethoxy) ethyl] pyrrolidin-3-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

MS: 353 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 8.58 (s, 1H), 7.38-7.15 (m, 5H) ), 4.86 (s, 1H), 4.00 (m, 1H), 3.90 (m, 1H), 3.78-3.15 (m, 10H), 2.38-2.10 ( m, 2H).

  N- {1- [2- (benzyloxy) ethyl] piperidin-3-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

MS: 353 (M + H ⁺ ), ¹ H NMR (400 MHz, CD ₃ OD): δ 8.45 (s, 2H), 7.38-7.20 (m, 7H), 4.65 (s, 1H) 4.50-4.40 (m, 3H), 3.80-3.25 (m, 5H), 3.00-2.80 (m, 2H), 2.15-1.25 (m, 4H).

  N- {1- [2- (benzyloxy) ethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

MS: 353 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 8.52 (s, 2H), 7.40-7.22 (m, 5H) ), 4.85 (s, 1H), 4.08 (m, 1H), 3.85 (m, 1H), 3.78-3.20 (m, 10H), 2.40-2.08 ( m, 2H).

  N- [1- (2-phenoxyethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

MS: 339 (M + H ⁺ ); ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 8.60 (s, 1H), 7.38-7.15 (m, 5H) ), 4.85 (s, 1H), 3.95 (m, 1H), 3.90 (m, 1H), 3.80-3.22 (m, 10H), 2.40-2.15 ( m, 2H).

  1-phenyl-3- [3- (1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) pyrrolidin-1-yl] propan-2-ol

  Stage A: tert-butyl [1- (2-hydroxy-3-phenylpropyl) pyrrolidin-3-yl] carbamate:

To a solution of tert-butylpyrrolidin-3-ylcarbamate (3.1 g, 16 mmol) in ethanol (100 mL) was added 2-benzyloxirane (2.2 g, 16 mmol) and the resulting reaction mixture was heated at 100 ° C. After 1 hour, the reaction mixture was concentrated to give the title compound (2.5 g). MS: 321 (M + H ^< + ^> ).

  Step B: 1- (3-Aminopyrrolidin-1-yl) -3-phenylpropan-2-ol

To tert-butyl [1- (2-hydroxy-3-phenylpropyl) pyrrolidin-3-yl] carbamate (1.5 g, 4.7 mmol) was added trifluoroacetic acid (0.75 mL), and the resulting solution was stirred at room temperature. Stir with. After 30 minutes, the reaction mixture was concentrated to give the trifluoroacetate salt (1.3 g) of the title compound. MS: 221 (M + H ^< + ^> ).

  Step C: 1-Phenyl-3- [3- (1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) pyrrolidin-1-yl] propan-2-ol

To a solution of 1- (3-aminopyrrolidin-1-yl) -3-phenylpropan-2-ol (0.22 g, 0.77 mmol) in 1-butanol (0.5 mL) was added DIPEA (0.5 mL) and 4- Chloro-1- (tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (0.18 g, 0.77 mmol) was added and the solution was microwaved at 150 ° C. for 10 minutes. Heated. The mixture was cooled and concentrated. The resulting residue was dissolved in methanol (3 mL) and treated with HCl saturated ethyl acetate solution (10 mL). After 1 hour, the solution was concentrated and the residue was treated with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was dehydrated using sodium sulfate, filtered and concentrated to dryness. Purification by silica gel chromatography (1% isopropanol / methylene chloride → 30% isopropanol / methylene chloride) gave the title compound (0.12 g) as a white solid. HRMS (M + H ⁺ ): Calculated value = 339.1928, found value = 339.918.

  N- [1- (2,2-difluoro-3-phenylpropyl) pyrrolidin-3-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Step A: tert-butyl [1- (2-oxo-3-phenylpropanoyl) pyrrolidin-3-yl] carbamate

To a solution of tert-butylpyrrolidin-3-ylcarbamate (4.4 g, 23 mmol) in methylene chloride (50 mL) was added 2-oxo-3-phenylpropanoic acid (3.8 g, 23 mmol), HOBT (3.2 g, 23 mmol). , DIPEA (3.0 g, 23 mmol) and EDC (4.5 g, 23 mmol) were added at room temperature. After 1 hour, saturated sodium bicarbonate was added and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (2% isopropanol / methylene chloride → 30% isopropanol / methylene chloride) gave the title compound (2.5 g). MS: 333 (M + H ^< + ^> ).

  Step B: tert-butyl [1- (2,2-difluoro-3-phenylpropanoyl) pyrrolidin-3-yl] carbamate

DAST (2.4 g, 15 mmol) was added to a solution of tert-butyl [1- (2-oxo-3-phenylpropanoyl) pyrrolidin-3-yl] carbamate (2.5 g, 7.5 mmol) in methylene chloride (50 mL). The resulting solution was heated to 50 ° C. After 5 hours, the reaction mixture was cooled to room temperature, poured onto ice and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (2.2 g). MS: 335 (M + H ^< + ^> ).

  Step C: 1- (2,2-difluoro-3-phenylpropyl) pyrrolidin-3-amine

To tert-butyl [1- (2,2-difluoro-3-phenylpropanoyl) pyrrolidin-3-yl] carbamate (2.2 g, 6.4 mmol) was added trifluoroacetic acid (15 mL) and the resulting solution was Stir at room temperature. After 60 minutes, the reaction mixture was concentrated to dryness. The resulting residue was treated with 1M borane THF solution (39 mL, 39 mmol) and heated to 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, quenched with 6N HCl (25 mL) and heated to 80 ° C. After 1 hour, the reaction mixture was cooled to room temperature, basified with NaOH to pH> 8 and extracted with chloroform. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (1.7 g). MS: 241 (M + H ^< + ^> ).

  Step D: N- [1- (2,2-difluoro-3-phenylpropyl) pyrrolidin-3-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

A solution of 1- (2,2-difluoro-3-phenylpropyl) pyrrolidin-3-amine (0.070 g, 0.29 mmol) in 1-butanol (0.5 mL) was added to DIPEA (0.5 mL) and 4-chloro- 1- (Tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (0.070 g, 0.29 mmol) was added and the solution was heated by microwave irradiation at 150 ° C. for 10 minutes. . The mixture was cooled and concentrated. The resulting residue was dissolved in methanol (3 mL) and treated with HCl saturated ethyl acetate solution (10 mL). After 1 hour, the solution was concentrated and the residue was treated with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was dehydrated using sodium sulfate, filtered and concentrated to dryness. Purification by silica gel chromatography (2% isopropanol / methylene chloride → 30% isopropanol / methylene chloride) gave the title compound (0.50 g) as a white solid. HRMS (M + H ⁺ ): calculated value = 359.1751, found value = 3599.1804; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.30 (s, 1H), 8.10 (s, 1H), 7.30-7.20 (m, 5H), 4.75 (m, 1H), 3.28-3.20 (m, 5H), 3.08-2.90 (m, 2H), 2. 80-2.62 (m, 4H), 2.40 (m, 1H), 1.90 (m, 1H).

  N- [1- (2,2-difluoro-3-phenylpropyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Step A: tert-Butyl [1- (2-oxo-3-phenylpropanoyl) piperidin-4-yl] carbamate

  To a solution of 2-oxo-3-phenylpropanoic acid (0.53 g, 3.2 mmol) in methylene chloride (3.0 mL) was added oxalyl chloride (0.33 mL, 3.9 mmol) and 1 drop of DMF at room temperature. After 1 hour, DIPEA (2.5 mL, 14 mmol) was added followed by tert-butylpiperidin-4-ylcarbamate (0.71 g, 3.6 mmol). After 14 hours, the reaction mixture was poured into 1M citric acid and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the title compound (0.95 g). MS: 291 (M-55).

  Step B: tert-butyl [1- (2,2-difluoro-3-phenylpropanoyl) piperidin-4-yl] carbamate

DAST (0.68 mL, 5.5 mmol) was added to a solution of tert-butyl [1- (2-oxo-3-phenylpropanoyl) piperidin-4-yl] carbamate (0.95 g, 2.7 mmol) in DCE (10 mL). Was added at room temperature. The reaction mixture was heated to 60 ° C. After 14 hours, the reaction mixture was cooled to room temperature, poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with 1M citric acid, 1M NaOH, brine, dried over sodium sulfate, filtered and concentrated to give the title compound (0.94 g) as a brown solid. MS: 369 (M + H ^< + ^> ).

  Step C: 1- (2,2-Difluoro-3-phenylpropanoyl) piperidin-4-amine

To a solution of tert-butyl [1- (2,2-difluoro-3-phenylpropanoyl) piperidin-4-yl] carbamate (0.94 g, 2.6 mmol) in methylene chloride (10 mL) was added HCl saturated ethyl acetate solution (5 0.0 mL) was added at room temperature. After 2 hours, the reaction mixture was concentrated. The resulting residue was dissolved in acetonitrile / water (1: 1), loaded onto Mega BE-SCX ion exchange resin (commercially available from Varian Inc., Walnut Creek, Calif.), Rinsed with acetonitrile, and 10% ammonia in water. Elute with ethanol solution and concentrate. The resulting oil was dissolved in methylene chloride and methanol, treated with HCl saturated ethyl acetate solution and concentrated to give the hydrochloride salt of the title compound (0.10 g). MS: 269 (M + H ^< + ^> ).

  Step D: 1- (2,2-difluoro-3-phenylpropyl) piperidin-4-amine

A solution of 1- (2,2-difluoro-3-phenylpropanoyl) piperidin-4-amine (0.10 g, 0.30 mmol) in THF (1 mL) at 0 ° C. under nitrogen with 1 M borane THF solution (3.6 mL). 3.6 mmol) was added and the reaction mixture was warmed to room temperature and then heated to 70 ° C. After 2 hours, the reaction mixture was cooled to room temperature, quenched with 6N HCl (10 mL) and heated to 70 ° C. After 1 hour, the reaction mixture was basified with 5M NaOH to pH> 8 and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in methylene chloride and methanol, treated with HCl saturated ethyl acetate solution and concentrated to give the hydrochloride salt of the title compound (0.10 g). MS: 255 (M + H ^< + ^> ).

  Step E: N- [1- (2,2-difluoro-3-phenylpropyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

A solution of 1- (2,2-difluoro-3-phenylpropyl) piperidin-4-amine (0.10 g, 0.31 mmol) in 1-butanol (2.5 mL) was added to DIPEA (2.5 mL) and 4-chloro- 1- (Tetrahydro-pyran-2-yl) -1H-pyrazolo [3,4-d] pyrimidine (0.78 g, 0.33 mmol) was added and the solution was heated to 90 ° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in methylene chloride and methanol and treated with HCl saturated ethyl acetate solution (5.0 mL) at room temperature for 2 hours. The reaction mixture was quenched with 1M NaOH and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Reversed phase chromatography (5% acetonitrile / 0.1% trifluoroacetic acid / water → 95% acetonitrile / 0.1% trifluoroacetic acid / water, XTerra® MSC8 column available from Waters Corporation, Milford, Massachusetts ) To give the product. The product was dissolved in methylene chloride and methanol, treated with HCl saturated ethyl acetate solution and concentrated to give the hydrochloride salt of the title compound (0.54 g) as a white solid. HRMS (M + H ⁺ ): calculated value = 3733.1947, actual value = 3733.164; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.60-8.52 (s, 2H), 7.41-7 .31 (m, 5H), 4.69-4.51 (s, 1H), 3.86-3.68 (m, 4H), 3.46-3.33 (m, 4H), 2.41 -2.31 (m, 2H), 2.19-2.03 (m, 2H).

  N- [1- (2-Phenylethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 1 above. HRMS (M + H ⁺ ): calculated value = 3233.1373, found value = 323.1999; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.68-5.85 (m, 2H), 7.40-7 .25 (m, 5H), 4.75-4.65 (m, 1H), 3.86-3.79 (m, 2H), 3.44-3.38 (m, 1H), 3.17 -3.10 (m2H), 2.47-2.39 (m, 2H), 2.18-2.07 (m, 2H).

  N- [1- (3-Phenylpropyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 1 above. HRMS (M + H ⁺ ): calculated value = 337.2135, actual value = 337.2164; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.23-8.19 (s, 1H), 8.15-8 .11 (s, 1H), 7.29-7.23 (m, 2H), 7.23-7.18 (m, 2H), 7.18-7.13 (m, 1H), 4.19 -4.09 (m, 1H), 3.06-2.98 (m, 2H), 2.68-2.61 (m, 2H), 2.47-2.39 (m, 2H), 2 .24-2.13 (m, 2H), 2.10-2.01 (m, 2H), 1.91-1.82 (m, 2H), 1.75-1.64 (m, 2H) .

  N-[(1S, 3R) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) cyclopentyl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Stage A: tert-butyl {1- [2- (4-methylphenyl) ethyl] piperidin-4-yl} carbamate

To a solution of tert-butylpiperidin-4-ylcarbamate (0.40 g, 2.0 mmol) in toluene (1.0 mL) was added 2- (4-methylphenyl) ethanol (0.27 g, 2.0 mmol), potassium carbonate ( 0.014 g, 0.10 mmol) and dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (0.040 g, 0.050 mmol) were added under a nitrogen atmosphere and the reaction mixture was heated to 110 ° C. . After 17 hours, the reaction mixture was filtered, rinsed with ethyl acetate, and concentrated. Purification by silica gel chromatography (1% isopropanol / methylene chloride → 40% isopropanol / methylene chloride) gave the title compound (0.25 g) as a solid. HRMS (M + H ⁺ ): Calculated value = 319.2380, found value = 319.2373.

  Step B: N-[(1S, 3R) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) cyclopentyl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 8, Steps C and E above. HRMS (M + H ⁺ ): calculated value = 337.2135, actual value = 3377.2145; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.22 (s, 1H), 8.13 (s, 1H), 7.10 (s, 4H), 4.17 (s, 1H), 3.13-3.10 (m, 2H), 2.82-2.78 (m, 2H), 2.65-2. 61 (m, 2H), 2.29 (s, 1H), 2.11-1.08 (m, 2H), 1.77-1.72 (m, 2H).

  N- {1- [1-methyl-2- (4-methylphenyl) ethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Stage A: tert-butyl {1- [1-methyl-2- (4-methylphenyl) ethyl] piperidin-4-yl} carbamate

To a pure water mixture of tert-butylpiperidin-4-ylcarbamate (0.85 g, 4.2 mmol) and 1- (4-methylphenyl) acetone (0.55 mL, 3.5 mmol) was added titanium isopropoxide (2. 1 mL, 7.1 mmol) was added at room temperature under nitrogen. After 20 hours, a solution of sodium cyanoborohydride (0.44 g, 7.1 mmol) in EtOH (10 mL) was added at room temperature. After an additional 16 hours, 1M NaOH was added to slowly quench the reaction mixture and the resulting precipitate was filtered through celite and rinsed with ethyl acetate. The filtrate was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% isopropanol / methylene chloride → 20% isopropanol / methylene chloride) gave the title compound (0.86 g) as a yellow oil. HRMS (M + H ⁺ ): Calculated value = 333.2537, found value = 333.2527.

  Stage B: N- {1- [1-methyl-2- (4-methylphenyl) ethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 8, Steps C and E above. HRMS (M + H ⁺ ): calculated value = 351.2292, found value = 351.2291; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.71-8.65 (s, 1H), 8.63-8 .56 (s, 1H), 7.24-7.11 (m, 4H), 4.78-4.65 (m, 1H), 3.82-3.52 (m, 3H), 3.48 -3.66 (m, 2H), 3.36-3.33 (m, 1H), 2.80-2.69 (m, 1H), 2.49-2.36 (s, 2H), 2 .35-2.29 (s, 3H), 2.29-2.16 (m2H), 1.33-1.21 (m, 3H).

  N- (1-benzylpiperidin-4-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 1 above. HRMS (M + H ⁺ ): calculated value = 309.1822, found value = 309.1839; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.24-8.18 (s, 1H), 8.16-8 .09 (s, 1H), 7.39-7.31 (m, 4H), 7.31-7.25 (m, 1H), 4.19-4.08 (m, 1H), 3.60 -3.55 (s, 2H), 3.02-2.94 (m, 2H), 2.28-2.17 (m, 2H), 2.08-2.00 (m, 2H), 1 .76-1.65 (m, 2H).

  1-phenyl-2- [4- (1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) piperidin-1-yl] ethanol

  Step A: tert-Butyl [1- (2-oxo-2-phenylethyl) piperidin-4-yl] carbamate

To a solution of 2-bromo-1-phenylethanone (0.63 g, 3.2 mmol) and tert-butylpiperidin-4-ylcarbamate (0.68 g, 3.4 mmol) in THF (5 mL) was added DIPEA (0.57 mL). 3.5 mmol) and the mixture was heated to 130 ° C. for 10 minutes by microwave irradiation. The reaction mixture was poured into 1M NaOH and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (50% ethyl acetate / hexane → 100% ethyl acetate / hexane) gave the title compound (0.79 g) as a yellow solid. HRMS (M + H ⁺ ): calculated value = 319.2016, found value = 319.2022.

  Step B: 2- (4-Aminopiperidin-1-yl) -1-phenylethanone

The title compound was prepared from tert-butyl [1- (2-oxo-2-phenylethyl) piperidin-4-yl] carbamate according to the procedure described in Example 8, Step C above. MS: 219 (M + H ^< + ^> ).

  Step C: 2- (4-Aminopiperidin-1-yl) -1-phenylethanol

To a solution of 2- (4-aminopiperidin-1-yl) -1-phenylethanone (0.35 g, 1.1 mmol) in MeOH (3 mL) was added sodium borohydride (0.13 g, 3.3 mmol) at room temperature. Added. After 1 hour water (3 mL) was added dropwise to quench the reaction mixture. The reaction mixture was poured into 1M NaOH and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (0.34 g) as a white solid. HRMS (M + H ⁺ ): calculated = 221.1649, found = 221.1657.

  Step D: 1-Phenyl-2- [4- (1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) piperidin-1-yl] ethanol

The title compound was prepared by a procedure similar to that described in Example 1, Step C above. HRMS (M + H ⁺ ): calculated value = 339.1928, found value = 339.1935; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.68-8.63 (m, 1H), 8.63-8 .55 (m, 1H), 7.53-7.45 (m, 2H), 7.45-7.30 (m, 3H), 5.22-5.12 (m, 1H), 4.76 -4.61 (m, 1H), 4.02-3.91 (m, 1H), 3.89-3.79 (m, 1H), 3.76-3.45 (m, 1H), 2 0.52-2.28 (m, 2H), 2.28-2.04 (m, 2H).

  1-phenyl-2- [4- (1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) piperidin-1-yl] ethanone

The title compound was prepared from 2- (4-aminopiperidin-1-yl) -1-phenylethanone (Example 14, Step B) according to the procedure described in Example 1, Step C above. HRMS (M + H ⁺ ): calculated value = 337.1772, found value = 337.1778; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.25 (s, 1H), 8.17 (s, 1H), 8.06-8.00 (m, 2H), 7.65-7.59 (m, 1H), 7.54-7.47 (m, 2H), 4.24-4.14 (m, 1H) ), 4.02 (s, 2H), 3.16-3.07 (m, 2H), 2.44-2.34 (m, 2H), 2.11-2.03 (m, 2H), 1.86-1.75 (m, 2H).

  (1R) -1- (2-Fluorophenyl) -2- [4- (1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) piperidin-1-yl] ethanol

The title compound was prepared from (2R) -2-fluorophenyloxirane according to the procedure described in Example 6 above. MS 357 (M + H ^< + ^> ).

  N- [1- (2-Fluoro-2-phenylethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Stage A: Methylfluoro (phenyl) acetate

To a solution of methylhydroxy (phenyl) acetate (2.0 g, 12 mmol) in methylene chloride (25 mL) under nitrogen was added DAST (2.5 mL, 20 mmol) at 0 ° C. and the reaction mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (2.0 g) as a yellow oil. MS: 337 (2M + H ^< + ^> ).

  Step B: Fluoro (phenyl) acetic acid

  To a solution of methylfluoro (phenyl) acetate (2.0 g, 12.0 mmol) in methanol (20 mL) and water (5 mL), crushed KOH pellets (2.0 g, 36 mmol) were added at 0 ° C. and the reaction mixture was Warmed to room temperature. After 3 hours, the reaction mixture was cooled to 0 ° C., acidified to pH <3 using 6N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (1.8 g) as a brown solid.

  Step C: N- [1- (2-Fluoro-2-phenylethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 8, Steps A, C, D and E above. HRMS (M + H ⁺ ): calculated value = 341.1885, found value = 341.1888; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.70-8.65 (s, 1H), 8.64-8 .59 (s, 1H), 7.55-7.43 (m, 5H), 6.25-6.18 (m, 0.5H), 6.13-6.06 (m, 0.5H) 4.79-4.64 (m, 1H), 4.03-3.95 (m, 1H), 3.95-3.70 (m, 2H), 3.69-3.47 (m, 1H), 3.47-3.33 (m, 2H), 2.52-2.32 (m, 2H), 2.30-2.10 (m, 2H).

  N- [1- (2,2-difluoro-2-phenylethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared according to the procedure described in Example 8, Steps A, C, D and E above, difluoro (phenyl) acetic acid (Hagele, G., Haas, A. J. of Fluorine Chemistry (1996) 76, 15-19. ). HRMS (M + H ⁺ ): calculated value = 359.1791, found value = 359.9797; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.82-8.72 (s, 1H), 8.64-8 .58 (s, 1H), 7.70-7.63 (m, 2H), 7.63-7.53 (m, 3H), 4.78-4.64 (m, 1H), 4.24 -4.08 (m, 2H), 4.01-3.87 (m, 2H), 3.63-3.47 (m, 2H), 2.49-2.37 (m, 2H), 2 .35-2.20 (m, 2H).

  N- {1- [2- (4-chlorophenyl) -2,2-difluoroethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Step A: (4-Chlorophenyl) (difluoro) acetic acid

To a solution of 1-chloro-4-iodobenzene (5.9 g, 25 mmol) in DMSO (100 mL) was added ethyl bromo (difluoro) acetate (5.0 g, 25 mmol) and copper powder (3.1 g, 49 mmol) and the mixture was Heated at 80 ° C. After 20 hours, the reaction mixture was poured into a solution of potassium hydrogen phosphate trihydrate (56 g, 250 mmol) in water (500 mL) with vigorous stirring. The suspension was filtered and the solid was rinsed with ether. The filtrate was added to brine and extracted with ether (2x). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting oil was dissolved in methanol (100 mL) and treated with 50% aqueous KOH (250 mL) at room temperature. After 2 hours, the reaction mixture was concentrated, dissolved in CHCl ₃ and extracted with 1M HCl. The aqueous layer was basified with NaOH and extracted with CHCl ₃ . The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (3.5 g) as a waxy solid.

  Step B: tert-butyl {1-[(4-chlorophenyl) (difluoro) acetyl] piperidin-4-yl} carbamate

The title compound was prepared by a procedure analogous to that described in Example 8, Step A above. MS: 389 (M + H ^< + ^> ).

  Step C: 1- [2- (4-Chlorophenyl) -2,2-difluoroethyl] piperidin-4-amine

To tert-butyl {1-[(4-chlorophenyl) (difluoro) acetyl] piperidin-4-yl} (0.42 g, 1.1 mmol) was added trifluoroacetic acid (5 mL) and the resulting solution was stirred at room temperature. did. After 60 minutes, the reaction mixture was concentrated, treated with HCl saturated ethyl acetate solution and concentrated. To the resulting residue was added THF (1 mL) and 1M borane THF solution (6.6 mL, 6.6 mmol) under nitrogen and the reaction mixture was heated to 70 ° C. After 2 hours, the reaction mixture was cooled to room temperature, quenched with 6N HCl (20 mL) and heated to 70 ° C. After 1 hour, the reaction mixture was basified with 5M NaOH to pH> 8 and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to give the title compound (0.25 g). MS: 275 (M + H ^< + ^> ).

  Stage D: N- {1- [2- (4-chlorophenyl) -2,2-difluoroethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure analogous to that described in Example 8, Step E above. HRMS (M + H ⁺ ): Calculated value = 393.1401, found value = 393.1421; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.20 (s, 1H), 8.10 (s, 1H), 7.58-7.42 (m, 4H), 4.10 (m, 1H), 3.10-2.95 (m, 2H), 2.86 (m, 2H), 2.48 (m, 2H), 1.85 (m, 2H), 1.58 (m, 2H).

  N- {1- [2,2-difluoro-2- (4-methylphenyl) ethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 19 above. HRMS (M + H ⁺ ): calculated value = 3733.1947, actual value = 3733.161; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.75-8.63 (s, 1H), 8.63-8 .57 (s, 1H), 7.56-7.48 (m, 2H), 7.41-7.34 (m, 2H), 4.76-4.62 (m, 1H), 4.17 -4.01 (m, 2H), 3.99-3.83 (m, 2H), 3.59-3.41 (m, 2H), 2.47-2.36 (m, 5H), 2 .31-2.13 (m, 2H).

  N- {1- [2,2-difluoro-2- (4-fluorophenyl) ethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared according to a procedure similar to that described in Example 19, Steps B, C and D above (Hagele, G., Haas, A. J. of Fluorine Chemistry (1996). 76, 15-19). HRMS (M + H ⁺ ): calculated value = 377.696, found value = 377.1690; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.68-8.57 (m, 2H), 7.74-7 .66 (m, 2H), 7.36-7.29 (m, 2H), 4.73-4.62 (m, 1H), 4.17-4.03 (m, 2H), 3.95 -3.82 (m, 2H), 3.54-3.41 (m, 2H), 2.47-2.37 (m, 2H), 2.26-2.12 (m, 2H).

  N- {1- [2,2-difluoro-2- (2-fluorophenyl) ethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 19 above. HRMS (M + H ⁺ ): calculated value = 377.696, found value = 377.177; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.71-8.63 (s, 1H), 8.63-8 .57 (s, 1H), 7.73-7.61 (m, 2H), 7.44-7.30 (m, 2H), 4.75-4.63 (m, 1H), 4.24 -4.09 (m, 2H), 3.96-3.82 (m, 2H), 3.59-3.43 (m, 2H), 2.46-2.36 (m, 2H), 2 .27-2.13 (m, 2H).

  N- {1- [2- (2,6-difluorophenyl) -2,2-difluoroethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Stage A: 1,3-difluoro-2-iodobenzene

  To a 1,4-dioxane solution of 2-bromo-1,3-difluorobenzene (5.7 g, 30 mmol), copper iodide (0.28 g, 1.5 mmol), sodium iodide (8.9 g, 59 mmol) and N , N′-dimethylethane-1,2-diamine (0.32 mL, 3.0 mmol) was added and the reaction mixture was heated at 110 ° C. under a nitrogen atmosphere. After 48 hours, the reaction mixture was poured into aqueous ammonium hydroxide (20 mL in 200 mL water) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (5.1 g).

  Step B: N- {1- [2- (2,6-difluorophenyl) -2,2-difluoroethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared according to the procedure described in Example 19 above. HRMS (M + H ⁺ ): calculated value = 395.1602, found value = 395.598; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.65-8.61 (s, 1H), 8.61-8 .58 (s, 1H), 7.71-7.62 (m, 1H), 7.23-7.15 (m, 2H), 4.70-4.59 (m, 1H), 4.23 -4.06 (m, 2H), 3.88-3.76 (m, 2H), 3.50-3.38 (m, 2H), 2.43-3.34 (m, 2H), 2 .21-2.07 (m, 2H).

  N- (1- {2,2-difluoro-2- [4- (trifluoromethyl) phenyl] ethyl} piperidin-4-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 19 above. HRMS (M + H ⁺ ): calculated value = 421.664, actual value = 427.645; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.73-8.65 (s, 1H), 8.64-8 .57 (s, 1H), 7.94-7.84 (m, 4H), 4.76-4.63 (m, 1H), 4.22-4.08 (m, 2H), 3.96 -3.84 (m, 2H), 3.56-3.43 (m, 2H), 2.47-2.37 (m, 2H), 2.29-2.15 (m, 2H).

  N- {1- [2- (4-Bromophenyl) -2,2-difluoroethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Step A: Difluoro (4-bromophenyl) acetic acid

  Bromobenzene (1.5 mL, 14 mmol) was added dropwise at room temperature under a nitrogen atmosphere to a suspension of aluminum chloride (2.2 g, 16 mmol) and ethylchloro (oxo) acetate (1.9 mL, 16 mmol). After 24 hours, a solution of ice water and saturated sodium bicarbonate solution was added dropwise. The aqueous layer was extracted with diethyl ether, the combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% ethyl acetate / hexane → 10% ethyl acetate / hexane) gave the keto-ester (1.4 g) as a yellow oil. DAST (2.1 mL, 17 mmol) was added to a solution of the resulting oil (1.4 g, 5.6 mmol) in DCE (15 mL) at room temperature. The reaction mixture was heated to 60 ° C. After 14 hours, the reaction mixture was cooled to room temperature, poured into ice water and extracted with diethyl ether. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the difluoroester as an oil. The resulting oil was dissolved in methanol: water (100 mL: 20 mL), cooled to 0 ° C., and KOH pellets (1.0 g, 17 mmol) were added with stirring. After 2 hours, the reaction mixture was washed with methylene chloride. The mixed aqueous layer was then basified with 5M NaOH to pH> 8 and extracted with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (1.4 g) as a waxy solid.

  Step B: N- {1- [2- (4-Bromophenyl) -2,2-difluoroethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared from difluoro (4-bromophenyl) acetic acid by a procedure similar to that described in Example 19, Steps B, C and D above. HRMS (M + H ⁺ ): calculated value = 437.0876, found value = 437.0846; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.72-8.66 (s, 1H), 8.63-8 .60 (s, 1H), 7.79-7.74 (m, 2H), 7.61-7.56 (m, 2H), 4.75-4.65 (m, 1H), 4.17 -4.07 (m, 2H), 3.95-3.87 (m, 2H), 3.55-3.43 (m, 2H), 2.47-2.38 (m, 2H), 2 .28-2.16 (m, 2H).

  N- {1- [2- (4-cyclopropylphenyl) -2,2-difluoroethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 25 above. HRMS (M + H ⁺ ): calculated value = 399.2104, found value = 399.210; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.70-8.64 (s, 1H), 8.64-8 .58 (s, 1H), 7.54-7.48 (m, 2H), 7.29-7.23 (m, 2H), 4.76-4.63 (m, 1H), 4.14 -4.01 (m, 2H), 3.97-3.85 (m, 2H), 3.56-3.41 (m, 2H), 2.47-2.37 (m, 2H), 2 .27-2.14 (m, 2H), 2.04-1.96 (m, 1H), 1.09-1.03 (m, 2H), 0.79-0.73 (m, 2H) .

  N- {1- [2,2-difluoro-2- (4-methoxyphenyl) ethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 25 above. HRMS (M + H ⁺ ): calculated value = 389.1896, found value = 3899.1905; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.22-8.18 (s, 1H), 8.14-8 .07 (s, 1H), 7.49-7.44 (m, 2H), 7.01-6.96 (m, 2H), 4.13-4.02 (m, 1H), 3.85 -3.82 (s, 3H), 3.06-2.98 (m, 2H), 2.94-2.88 (m, 2H), 2.49-2.40 (m, 2H), 1 .98-1.90 (m, 2H), 1.68-1.57 (m, 2H).

  N-[(3R, 4R) -3-fluoro-1- (2-phenylethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Step A: Benzyl 4-{[tert-butyl (dimethyl) silyl] oxy} -3,6-dihydropyridine-1 (2H) -carboxylate

To a solution of benzyl 4-oxopiperidine-1-carboxylate (170 g, 750 mmol) in DMF (400 mL) was added DIPEA (195 mL) and tert-butyl (dimethyl) silyl trifluoromethanesulfonate (220 g, 840 mmol) at room temperature. After 5 hours, the reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (240 g). MS: 348 (M + H ^< + ^> ).

  Step B: Benzyl 3-fluoro-4-oxopiperidine-1-carboxylate

Benzyl 4-{[tert-butyl (dimethyl) silyl] oxy} -3,6-dihydropyridine-1 (2H) -carboxylate (240 g, 700 mmol) in a DMF (1.0 L) solution to 1- (chloromethyl)- 4-Fluoro-1,4-diazoniabicyclo [2.2.2] octaneditetrafluoroborate (310 g, 880 mmol) was added at room temperature. After 2 hours, the reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (251 g). MS: 252 (M + H ^< + ^> ).

  Step C: cis- and trans-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate

  Sodium borohydride (5.5 g, 150 mmol) in a solution of benzyl 3-fluoro-4-oxopiperidine-1-carboxylate (24 g, 97 mmol) in methanol (250 mL) at 0 ° C. so that the reaction mixture does not exceed room temperature The addition was made in portions at a moderate rate. After 4 hours, the reaction mixture was concentrated. The resulting residue was dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. Purification by silica gel chromatography (10% ethyl acetate / hexane → 60% ethyl acetate / hexane) gave both title compounds.

Cis-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate: 18 g; colorless oil; MS: 254 (M + H ⁺ ); 1H MMR (400 MHz, CDCl ₃ ): δ 7.40-7.32 (m, 5H), 5.20 (s, 2H), 4.72-4.52 (m, 1H), 4.15-3.25 (m, 6H), 2.17 (s, 1H), 1.88. -1.67 (m, 2H);

Trans-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate: 4.5 g; colorless oil; MS: 254 (M + H ⁺ ); ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.40-7.32 (M, 5H), 5.18 (s, 2H), 4.40-3.80 (m, 4H), 3.25-3.05 (m, 2H), 2.30 (s, 1H), 2.00 (s, 1H) 1.58 (s, 1H).

  Step D: Cis-benzyl 3-fluoro-4-[(methylsulfonyl) oxy] piperidine-1-carboxylate

To a solution of cis-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (24 g, 97 mmol) in methylene chloride (150 mL) was added DIPEA (28 mL, 190 mmol) and methanesulfonyl chloride (9.0 g, 79 mmol) at −10 ° C. The reaction mixture was gradually warmed to room temperature. After 3 hours, the reaction mixture was poured into brine, extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated to give the title compound (31 g) as an oil. MS: 332 (M + H ^< + ^> ).

  Step E: trans-benzyl 4-azido-3-fluoropiperidine-1-carboxylate

To a solution of cis-benzyl 3-fluoro-4-[(methylsulfonyl) oxy] piperidine-1-carboxylate (10 g, 30 mmol) in DMF (25 mL) was added sodium azide (9.8 g, 150 mmol) and the reaction mixture Was heated to 80 ° C. After 48 hours, the reaction mixture was poured into brine, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% isopropanol / methylene chloride → 10% IPA / methylene chloride) gave the title compound (6.6 g) as an oil. MS: 279 (M + H ^< + ^> ).

  Step F: trans-4-azido-3-fluoropiperidine

To a solution of trans-benzyl 4-azido-3-fluoropiperidine-1-carboxylate (15 g, 54 mmol) in TFA (5 mL) was added thioanisole (13 g, 110 mmol) and the solution was heated at 70 ° C. for 1 hour. The mixture was cooled and concentrated. The resulting residue was dissolved in ethyl acetate (60 mL), treated with HCl saturated ethyl acetate solution (50 mL) at room temperature and concentrated. Recrystallization from ethyl acetate and hexane gave the title compound (6.5 g) as a white solid. MS: 145 (M + H ^< + ^> ).

  Step G: trans-4-azido-3-fluoro-1- (phenylacetyl) piperidine

To a solution of trans-4-azido-3-fluoropiperidine (1.2 g, 8.7 mmol) in methylene chloride (25 mL) was added DIPEA (3.8 mL, 26 mmol) and phenylacetyl chloride (1.3 g, 8.7 mmol) at room temperature. Added at. After 1 hour, the reaction mixture was poured into saturated sodium bicarbonate and extracted with chloroform. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (1.7 g). MS: 263 (M + H ^< + ^> ).

  Stage H: trans-3-fluoro-1- (2-phenylethyl) piperidin-4-amine

To a solution of trans-4-azido-3-fluoro-1- (phenylacetyl) piperidine (1.7 g, 6.5 mmol) in THF (20 mL) was added 1M borane THF solution (79 mL, 79 mmol) under nitrogen at room temperature. The reaction mixture was heated to 80 ° C. After 1 hour, the reaction mixture was cooled to room temperature, quenched with 6N HCl (50 mL) and heated to 80 ° C. After 1 hour, the reaction mixture was basified with 5M NaOH to pH> 8 and extracted with chloroform. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (1.0 g). MS: 223 (M + H ^< + ^> ).

  Step I: N- [trans-3-fluoro-1- (2-phenylethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 1, Step C above. HRMS (M + H ⁺ ): calculated value = 341.1878, found value = 341.1885; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.30 (s, 1H), 8.15 (s, 1H), 7.38-7.18 (m, 5H), 4.70-4.40 (m, 2H), 3.40 (m, 1H), 3.00 (m, 1H), 2.85-2. 58 (m, 4H), 2.30 (m, 2H), 2.25 (m, 1H), 1.60 (m, 1H).

  N- [cis-3-fluoro-1- (2-phenylethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Step A: cis-4-azido-3-fluoropiperidine

The title compound is obtained from trans-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (Example 28, Step C) by a procedure similar to that described in Example 28, Steps D, E and F above. Prepared. MS: 145 (M + H ^< + ^> ).

  Step B: N- [cis-3-fluoro-1- (2-phenylethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 28, Steps G, H and I above. HRMS (M + H ⁺ ): calculated value = 341.1876, found value = 341.1885; ¹ H NMR (400 MHz, CD ₃ OD) 8.30-8.20 (m, 2H), 7.32-7.18 (M, 5H), 5.00-4.80 (m, 1H), 4.50-4.40 (m, 1H), 3.40 (m, 1H), 3.10 (m, 1H), 2.85-2.60 (m, 4H), 2.50-2.10 (m, 3H), 1.90 (m, 1H).

  N- {trans-3-fluoro-1- [2- (4-methylphenyl) ethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 28, Steps G, H and I above. HRMS (M + H ⁺ ): Calculated value = 355.4317, Found value = 355.4216; ¹ H NMR (400 MHz, CD ₃ OD) 8.65 (s, 2H), 7.30-7.18 (m, 4H ), 4.58-4.20 (m, 2H), 4.15-3.85 (m, 1H), 3.80-3.35 (m, 7H), 3.15 (m, 2H), 2.38 (s, 3H).

  N- {cis-3-fluoro-1- [2- (4-methylphenyl) ethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 29 above. HRMS (M + H ⁺ ): Calculated value = 355.4317, Found value = 355.4128; ¹ H NMR (400 MHz, CD ₃ OD) 8.62 (s, 2H), 7.28-7.20 (m, 4H) ), 5.38-4.80 (m, 1H), 4.20-3.83 (m, 1H), 3.85-3.42 (m, 7H), 3.25 (m, 2H), 2.35 (s, 3H).

  N- [trans-3-fluoro-1- (2-fluoro-2-phenylethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Step A: 2- [trans-4-azido-3-fluoropiperidin-1-yl] -1-phenylethanol

The title compound was prepared by a procedure similar to that described in Example 6, Step A above. MS: 265 (M + H ^< + ^> ).

  Step B: trans-4-azido-3-fluoro-1- (2-fluoro-2-phenylethyl) piperidine

The title compound was prepared by a procedure analogous to that described in Example 17, Step A above. MS: 267 (M + H ^< + ^> ).

  Step C: trans-3-fluoro-1- (2-fluoro-2-phenylethyl) piperidin-4-amine

The title compound was prepared by a procedure analogous to that described in Example 28, Step H above. MS: 241 (M + H ^< + ^> ).

  Step D: N- [trans-3-fluoro-1- (2-fluoro-2-phenylethyl) piperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 1, Step C above. HRMS (M + H ⁺ ): calculated value = 359.1780, found value = 359.1791; ¹ H NMR 400 MHz, CD ₃ OD): δ 8.25-8.15 (m, 2H), 7.40-7. 35 (m, 5H), 5.80-5.60 (m, 1H), 4.80-4.35 (m, 2H), 3.45 (m, 1H), 3.10-2.95 ( m, 2H), 2.85-2.70 (m, 1H), 2.40 (m, 2H), 2.18 (m, 1H), 1.70 (m, 1H).

  N- [trans-1- (2,2-difluoro-2-phenylethyl) -3-fluoropiperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Step A: trans-4-azido-1- [difluoro (phenyl) acetyl] -3-fluoropiperidine

Difluoro (phenyl) acetic acid (Hagele, G., Haas, AJ of Fluorine Chemistry (1996) 76, 15-19) (1.7 g, 10.4 mmol) in a solution of oxalyl chloride (5 mL) in methylene chloride (25 mL). 2 mL, 2M methylene chloride solution, 10.4 mmol) and 1 drop of DMF were added at room temperature. After 1 hour, the reaction mixture was added to a suspension of trans-4-azido-3-fluoropiperidine (1.5 g, 10 mmol) and resin-DIPEA (40 mmol equivalent) in methylene chloride (50 mL) at room temperature. After 2 hours, the reaction mixture was filtered and concentrated to give the title compound (2.5 g) as a solid. MS: 299 (M + H ^< + ^> ).

  Step B: N-[(3R, 4R) -1- (2,2-difluoro-2-phenylethyl) -3-fluoropiperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidine-4 -Amine

The title compound was prepared from trans-4-azido-1- [difluoro (phenyl) acetyl] -3-fluoropiperidine according to the procedure described in Example 28, Steps H and I above. HRMS (M + H ⁺ ): calculated value = 377.676, found value = 377.696; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.20 (s, 1H), 8.10 (s, 1H), 7.55-7.45 (m, 5H), 4.51-4.31 (m, 2H), 3.17-3.10 (m, 3H), 2.80 (m, 2H), 2. 52 (m, 2H), 2.00 (m, 1H), 1.51 (m, 1H).

  N- [cis-1- (2,2-difluoro-2-phenylethyl) -3-fluoropiperidin-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared from cis-4-azido-3-fluoropiperidine (Example 29, Step A) by a procedure similar to that described in Example 33 above. HRMS (M + H ⁺ ): calculated value = 377.676, found value = 377.696; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.22 (m, 2H), 7.56 (m, 2H), 7.44 (m, 3H), 4.84-4.70 (m, 1H), 4.39-4.33 (m, 1H), 3.31-3.12 (m, 3H), 2. 87-2.57 (m, 3H), 2.07 (m, 1H), 1.70 (m, 1H).

  N- {trans-1- [2,2-difluoro-2- (4-methylphenyl) ethyl] -3-fluoropiperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure analogous to that described in Example 33 above. HRMS (M + H ⁺ ): calculated value = 391.1853, found value = 391.811; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.22 (s, 1H), 8.12 (s, 1H), 7.55-7.22 (m, 4H), 4.58-4.30 (m, 2H), 3.30-3.12 (m, 3H), 2.78 (m, 1H), 2. 52 (m, 2H), 2.42 (s, 3H), 1.98 (m, 1H), 1.62 (m, 1H).

  N- (trans-1- {2,2-difluoro-2- [4- (trifluoromethyl) phenyl] ethyl} -3-fluoropiperidin-4-yl) -1H-pyrazolo [3,4-d] pyrimidine -4-amine

The title compound was prepared by a procedure analogous to that described in Example 33 above. HRMS (M + H ⁺ ): calculated value = 445.1570, actual value = 445.1567; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.31-8.22 (m, 2H), 7.81-7 .62 (m, 4H), 4.42-4.20 (m, 1H), 3.21 (m, 2H), 2.89-2.62 (m, 4H), 2.04 (m, 2H) ) 1.73 (m, 1H).

  N- (cis-1- {2,2-difluoro-2- [4- (trifluoromethyl) phenyl] ethyl} -3-fluoropiperidin-4-yl) -1H-pyrazolo [3,4-d] pyrimidine -4-amine

The title compound was prepared by a procedure similar to that described in Example 34 above. HRMS (M + H ⁺ ): calculated value = 445.1570, actual value = 445.1539; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.70 (s, 1H), 8.62 (s, 1H), 7.82 (m, 4H), 5.18-5.12 (m, 1H), 3.88-3.78 (m, 4H), 3.52-3.19 (m, 2H), 2. 42 (m, 2H), 2.08 (m, 1H).

  N- [1- (2,2-difluoro-2-phenylethyl) azepan-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

  Step A: 1- [Difluoro (phenyl) acetyl] azepan-4-one

The title compound was prepared by a procedure analogous to that described in Example 19, Step B above. MS: 268 (M + H ^< + ^> ).

  Step B: N- [1- (2,2-difluoro-2-phenylethyl) azepan-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 28, Steps C, D, E, H and I above. HRMS (M + H ⁺ ): calculated value = 3733.1947, actual value = 3733.1955; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.67 (s, 1H), 8.57 (s, 1H), 7.66-7.55 (m, 5H), 4.72 (m, 1H), 4.19-4.10 (m, 2H), 3.89-3.65 (m, 4H), 2. 42-2.34 (m, 3H), 2.21-2.08 (m, 1H), 1.98-1.90 (m, 1H). Purified by chiral HPLC (15% isopropanol / hexane / 0.1% DEA → 20% isopropanol / hexane / 0.1% DEA; Chiralpak AD, commercially available from Chiral Technologies, Inc., Exton, Pa) and optical Pure product was obtained. This was treated with anhydrous hydrochloric acid in ethyl acetate and concentrated to give the hydrochloride salt of the title compound: (R or S) -N- [1- (2,2-difluoro-2-phenylethyl) azepane- 4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine: peak 1, HRMS (M + H ⁺ ): calculated value = 3733.1947, actual value = 3733.1935; (S or R) − N- {1- [2,2-difluoro-2- (4-methylphenyl) ethyl] azepan-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine: peak 2, HRMS ( M + H ⁺ ): calculated value = 3733.1947, actual value = 3733.1958.

  N- [1- (2,2-difluoro-2- (4-methylphenyl) ethyl) azepan-4-yl] -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure analogous to that described in Example 38 above. Purification by chiral HPLC (Chiralcel OJ, 60% isopropanol / hexane / 0.1% DEA) gave the enantiomer of the title compound: (R or S) -N- {1- [2,2-difluoro -2- (4-methylphenyl) ethyl] azepan-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine: peak 1, HRMS (M + H ⁺ ): calculated value = 387.2104, Found = 387.2075; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.22 (s, 1H), 8.10 (s, 1H), 7.43 (d, J = 6.4 Hz, 2H) ), 7.27 (d, J = 6.4 Hz, 2H), 4.38 (m, 1H), 3.20 (t, J = 11.4 Hz, 2H), 2.88-2.77 (m 4H), 2.38 (s, 3H), 1.9 -1.96 (m, 1H), 1.80-1.71 (m, 3H), 1.64-1.62 (m, 1H); (S or R) -N- {1- [2, 2-Difluoro-2- (4-methylphenyl) ethyl] azepan-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine: peak 2, HRMS (M + H ⁺ ): calculated value = 387 2104, found = 387.2104; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.22 (s, 1H), 8.10 (s, 1H), 7.43 (d, J = 6. 4 Hz, 2H), 7.27 (d, J = 6.4 Hz, 2H), 4.38 (m, 1H), 3.20 (t, J = 11.4 Hz, 2H), 2.88-2. 77 (m, 4H), 2.38 (s, 3H), 1.99-1.96 (m, 1H), 1.80-1.71 (m, H), 1.64-1.62 (m, 1H).

  N- {exo-3- [2,2-difluoro-2- (4-methylphenyl) ethyl] -3-azabicyclo [3.1.0] hex-6-yl} -1H-pyrazolo [3,4 d] Pyrimidine-4-amine

The title compound was prepared by a procedure similar to that described in Example 19 above (Literature: Norris, T., Braish, TF, Butters, M., DeVries, KM, Hawkins, J.M. , Massett, SS, Rose, PR, Santafianos, D., Sklavunos, CJ Chem. Soc, Perkin Trans. 1 (2000) 1615-1622) tert- Prepared from butyl exo-3-azabicyclo [3.1.0] hex-6-ylcarbamate. HRMS (M + H ⁺ ): calculated value = 371.1791, found value = 371.801; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.62-8.57 (s, 1H), 8.54-8 .49 (s, 1H), 7.51-7.44 (m, 2H), 7.39-7.32 (m, 2H), 4.16-3.80 (m, 3H), 3.63 -3.56 (m, 1H), 2.51-2.42 (m, 2H), 2.42-2.36 (s, 3H).

Racemic-N-[(3aS ^* , 4R ^* , 6aR ^* )-2- (2-phenylethyl) octahydrocyclopenta [c] pyrrol-4-yl] -1H-pyrazolo [3,4-d] pyrimidine- 4-amine

  Step A: Racemic-2-benzylhexahydrocyclopenta [c] pyrrol-4 (1H) -one

To a solution of N-benzyl-1-methoxy-N-[(trimethylsilyl) methyl] methenamine (11 g, 46 mmol) and cyclopent-2-en-1-one (3.8 g, 46 mmol) in methylene chloride (50 mL) was added TFA (12 mL). 68 mmol) at room temperature. After 1 hour, the reaction mixture was poured into 1M NaOH (500 mL) and extracted with ethyl acetate. The combined organic layer was dehydrated using sodium sulfate, filtered and concentrated to dryness. The resulting residue was dissolved in ethyl acetate, treated with HCl saturated ethyl acetate solution and concentrated to give the HCl salt of the title compound (11 g) as a solid. MS: 216 (M + H ^< + ^> ).

Step B: Racemic- (3aS ^* , 4S ^* , 6aR ^* )-2-benzyloctahydrocyclopenta [c] pyrrol-4-ol

A solution of racemic-2-benzylhexahydrocyclopenta [c] pyrrol-4 (1H) -one (10 g, 46 mmol) in THF (50 mL) was added to L-Selectride (8.8 g, 46 mmol, Sigma-Aldrich, Inc., St. (Commercially available from Louis, Mo.) was added at −78 ° C. and the reaction mixture was allowed to warm slowly to room temperature. After 2 hours, the reaction mixture was poured into 1M NaOH (500 mL) and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% IPA / methylene chloride → 10% isopropanol / methylene chloride) gave the title compound (5.0 g). MS: 218 (M + H ^< + ^> ).

Step C: Racemic-tert-butyl (3aS ^* , 4S ^* , 6aR ^* )-4-hydroxyhexahydrocyclopenta [c] pyrrole-2 (1H) -carboxylate

Racemic- (3aS ^* , 4S ^* , 6aR ^* )-2-benzyloctahydrocyclopenta [c] pyrrol-4-ol (1.4 g, 6.2 mmol) in ethanol (100 mL) was added to di-tert-butyl. Dicarbonate (1.5 g, 7.0 mmol) and palladium hydroxide (commercially available from Sigma-Aldrich, Inc., St. Louis, Mo.), carbon-supported 20 wt% Pd (dry basis), wet. And the reaction mixture was allowed to stand at room temperature under 50 psi of hydrogen (0.3 MPa). After 20 hours, the reaction mixture was filtered and concentrated to give the title compound (0.85 g). MS: 228 (M + H ^< + ^> ).

Step D: Racemic-tert-butyl (3aS ^* , 4R ^* , 6aR ^* )-4-azidohexahydrocyclopenta [c] pyrrole-2 (1H) -carboxylate

The title compound was prepared by a procedure similar to that described in Example 28, Steps D and E above. MS: 253 (M + H ^< + ^> ).

  Step E: Racemic-N-[(3aS, 4R, 6aR) -2- (2-phenylethyl) octahydrocyclopenta [c] pyrrol-4-yl] -1H-pyrazolo [3,4-d] pyrimidine- 4-amine

The title compound was prepared by a procedure similar to that described in Example 28, Steps G, H and I above. HRMS (M + H ⁺ ): calculated value = 349.2135, actual value = 3499.2146; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.32 (s, 1H), 8.20 (s, 1H), 7.35-7.15 (m, 5H), 4.38 (s, 1H), 2.89-2.60 (m, 10H), 2.38 (s, 1H), 2.20-2. 08 (m, 2H), 1.70 (m, 1H), 1.50 (m, 1H).

Racemic-N-[(3aS ^* , 4R ^* , 6aR ^* )-2- (2,2-difluoro-2-phenylethyl) octahydrocyclopenta [c] pyrrol-4-yl] -1H-pyrazolo [3 4-d] pyrimidin-4-amine

The title compound was prepared by a procedure analogous to that described in Example 33 above, racemic- (3aS ^* , 4R ^* , 6aR ^* )-4-azidooctahydrocyclopenta [c] pyrrole (see Example 41, Step D). ). HRMS (M + H ⁺ ): calculated value = 385.1947, found value = 3855.1923; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.28 (s, 1H), 8.15 (s, 1H), 7.60 (s, 2H), 7.38 (m, 3H), 4.32 (s, 1H), 3.10 (m, 2H), 2.80-2.42 (m, 6H), 2 0.00 (m, 2H), 1.52 (m, 1H), 1.40 (m, 1H).

Racemic-N-{(3aS ^* , 4R ^* , 6aR ^* )-2- [2,2-difluoro-2- (4-methylphenyl) ethyl] octahydrocyclopenta [c] pyrrol-4-yl} -1H -Pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure analogous to that described in Example 33 above, racemic- (3aS ^* , 4R ^* , 6aR ^* )-4-azidooctahydrocyclopenta [c] pyrrole (see Example 41, Step E). ). HRMS (M + H ⁺ ): calculated value = 399.2104, found value = 399.2095; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.82 (s, 1H), 8.60 (s, 1H), 7.58-7.40 (m, 4H), 4.70 (s, 1H), 4.28-4.10 (m, 4H), 3.29-3.08 (m, 3H), 2. 50-2.30 (m, 4H), 2.28-2.00 (m, 2H), 1.80 (m, 1H).

  Endo-N- [8- (2,2-difluoro-2-phenylethyl) -8-azabicyclo [3.2.1] oct-3-yl] -1H-pyrazolo [3,4-d] pyrimidine-4 -Amine

  Stage A: tert-Butyl 3- (hydroxyimino) -8-azabicyclo [3.2.1] octane-8-carboxylate

To a solution of tert-butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate difluoro (3.0 g, 13 mmol) in methanol (35 mL) was added hydroxylamine hydrochloride (4.6 g, 67 mmol). And sodium acetate (11 g, 133 mmol) was added at room temperature. After 72 hours, the mixture was poured into water and extracted with ether. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (3.1 g) as a white solid. MS: 241 (M + H ^< + ^> ).

  Step B: Endo-tert-butyl 3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate

The following procedure is described by Suzuki, M .; , Ouchi, Y .; Asanuma, H .; Kaneko, T .; Yokomori, S .; , Ito, C, Isobe, Y. , Muramatsu, M .; Chem. Pharm. Bull. (2001) Based on the method reported by 49 (1), 29-39. To a solution of tert-butyl 3- (hydroxyimino) -8-azabicyclo [3.2.1] octane-8-carboxylate (2.0 g, 8.3 mmol) in acetic acid (25 mL) was added platinum dioxide (0.10 g). And the solution was exposed to 50 psi of hydrogen gas (0.3 MPa) using a Parr hydrogenator (commercially available from Parr Instrument Company, Moline, Ill.). After 17 hours, the mixture was filtered and concentrated. The residue was poured into 5M NaOH and extracted with methylene chloride. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (2.0 g) as an oil. MS: 227 (M + H ^< + ^> ).

  Step C: endo-tert-butyl 3-{[(benzyloxy) carbonyl] amino} -8-azabicyclo [3.2.1] octane-8-carboxylate

To a solution of exo-tert-butyl 3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (2.0 g, 8.7 mmol) in methylene chloride (18 mL) was added DIPEA (3.0 mL, 17 mmol). ) And benzylchloroformate (1.1 mL, 13 mmol) were added at room temperature. After 2 h, the reaction mixture was diluted with ethyl acetate, washed with water, 1M citric acid, water, 1M NaOH, brine, dried over sodium sulfate, filtered and concentrated to give the title compound (3.3 g ) MS: 361 (M + H ^< + ^> ).

  Step D: Endo-benzyl 8-azabicyclo [3.2.1] oct-3-ylcarbamate

The title compound was prepared by a procedure analogous to that described in Example 1, Step B above. MS: 261 (M + H ^< + ^> ).

  Step E: Endo-benzyl {8- [difluoro (phenyl) acetyl] -8-azabicyclo [3.2.1] oct-3-yl} carbamate

The title compound was prepared by a procedure analogous to that described in Example 19, Step B above. MS: 415 (M + H ^< + ^> ).

  Step F: Endo-N- [8- (2,2-difluoro-2-phenylethyl) -8-azabicyclo [3.2.1] oct-3-yl] -1H-pyrazolo [3,4-d] Pyrimidine-4-amine

The title compound was prepared by a procedure analogous to that described in Example 28, Steps F, H and I above. HRMS (M + H ⁺ ): calculated value = 385.1947, found value = 385.933; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.88 (s, 1H), 8.66 (s, 1H), 7.69-7.67 (m, 2H), 7.61-7.57 (m, 3H), 4.60 (m, 1H), 4.31 (br s, 2H), 4.00 (m 2H), 2.75 (m, 2H), 2.59-2.45 (m, 6H).

  Exo-N- [8- (2,2-difluoro-2-phenylethyl) -8-azabicyclo [3.2.1] oct-3-yl] -1H-pyrazolo [3,4-d] pyrimidine-4 -Amine

  Step A: Exo-tert-butyl 3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate

tert-Butyl 3- (hydroxyimino) -8-azabicyclo [3.2.1] octane-8-carboxylate (1.0 g, 4.2 mmol; Example 44, Step A) 1-propanol (15 mL, 4Å) Metallic sodium (1.0 g, 42 mmol) was added in portions to the solution at a room temperature in a nitrogen atmosphere at room temperature for 10 minutes. The reaction mixture was heated to reflux for 4.5 hours and cooled to room temperature. The reaction mixture was quenched with water and extracted with methylene chloride. The combined organic layer was extracted with 2M HCl and the combined aqueous layer was basified with solid potassium hydroxide and extracted with methylene chloride. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (0.36 g) as a colorless oil. MS: 227 (M + H ^< + ^> ).

  Step B: Exo-N- [8- (2,2-difluoro-2-phenylethyl) -8-azabicyclo [3.2.1] oct-3-yl] -1H-pyrazolo [3,4-d] Pyrimidine-4-amine

The title compound was prepared by a procedure similar to that described in Example 44, Steps C, D, E and F above. HRMS (M + H ⁺ ): calculated value = 385.1947, found value = 385.1960; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.18 (s, 1H), 8.07 (s, 1H), 7.57-7.55 (m, 2H), 7.45-7.43 (m, 3H), 4.49-4.48 (m, 1H), 3.14 (brs, 2H), 3 .06 (t, J = 13.6 Hz, 2H), 1.95-1.93 (m, 2H), 1.80-1.76 (m, 4H), 1.70-1.64 (m, 2H).

  N- (1- {2- [4- (difluoromethyl) phenyl] -2,2-difluoroethyl} piperidin-4-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure similar to that described in Example 19 above. HRMS (M + H ⁺ ): calculated value = 4099.1759, found value = 4019.1725; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.74-8.65 (s, 1H), 8.65-8 .58 (s, 1H), 7.83-7.73 (m, 4H), 7.01-6.75 (m, 1H), 4.77-4.64 (m, 1H), 4.22 -4.07 (m, 2H), 3.98-3.87 (m, 2H), 3.58-3.44 (m, 2H), 2.48-2.37 (m, 2H), 2 .29-2.15 (m, 2H).

  N- {1- [2- (4-Ethylphenyl) -2,2-difluoroethyl] piperidin-4-yl} -1H-pyrazolo [3,4-d] pyrimidin-4-amine

N- {1- [2- (4-Bromophenyl) -2,2-difluoroethyl] piperidin-4-yl} -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4 -D] To a solution of pyrimidine-4-amine (Example 46, 0.21 g, 0.39 mmol) in anhydrous toluene (1.5 mL), ethyl boronic acid (0.04 g, 0.59 mmol), tribasic potassium phosphate anhydrous (0.25 g, 1.18 mmol), bis (dibenzylideneacetone) palladium (Pd (dba) ₂ ) (0.01 g, 0.02 mmol) and 1,2,3,4,5-pentaphenyl-1′- (Di-tert-butylphosphino) ferrocene (Q-phos) (0.028 g, 0.04 mmol) was added. The solution was heated in a heated oil bath at 120 ° C. for 48 hours with stirring. The mixture was cooled and dissolved in ethyl acetate (30 mL) and washed with 1M NaOH, then water, and finally brine. The combined organic layer was dehydrated using sodium sulfate, filtered and concentrated to dryness. The resulting residue was dissolved in methanol (2.5 mL) and reverse phase chromatography (5% acetonitrile / 0.1% trifluoroacetic acid / water → 95% acetonitrile / 0.1% trifluoroacetic acid / water, Waters Corporation, Purification by XTerra® MSC8 column, commercially available from Milford, Massachusetts). The desired fraction was concentrated and the resulting residue was dissolved in methanol (3 mL) and treated with HCl saturated ethyl acetate solution (10 mL) at room temperature. After 1 hour, a solid precipitated out of solution. The solution was then filtered to give the hydrochloride salt of the title compound (0.014 g) as a yellow solid. HRMS (M + H ⁺ ): calculated value = 387.2104, found value = 387.2055; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.64-8.54 (m, 2H), 7.57-7 .51 (m, 2H), 7.43-7.38 (m, 2H), 4.72-4.60 (m, 1H), 4.14-3.98 (m, 2H), 3.96 -3.82 (m, 2H), 3.54-3.39 (m, 2H), 2.77-2.69 (m, 2H), 2.46-2.36 (m, 2H), 2 .26-2.12 (m, 2H), 1.30-1.22 (m, 3H).

  N-((3S, 4S) -1- {2- [4- (difluoromethyl) phenyl] -2,2-difluoroethyl} -3-fluoropiperidin-4-yl) -1H-pyrazolo [3,4 d] pyrimidine-4-amine

The title compound was prepared by a procedure analogous to that described in Example 33 above. MS (M + H ⁺ ) = 426.2; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.77 (s, 1H), 8.62 (s, 1H), 7.74 (q, J = 8. 3Hz, 4H), 6.86 (t, J = 55.9Hz, 1H), 3.86 (m, 3H), 3.59 (brs, 1H), 3.22 (brs, 2H), 2 .40 (br s, 1H), 2.03 (s, 1H).

  N-((3S, 4S) -3-fluoro-1- {2- [4- (trifluoromethyl) phenyl] ethyl} piperidin-4-yl) -1H-pyrazolo [3,4-d] pyrimidine-4 -Amine

The title compound was prepared by a procedure analogous to that described in Example 33 above. MS (M + H ⁺ ) 409.2; ¹ H NMR (500 MHz, CD ₃ OD): δ 8.72 (s, 1H), 8.66 (s, 1H), 7.68 (d, J = 8.1 Hz) 2H), 7.56 (d, J = 7.8 Hz, 2H), 5.25 (m, 1H), 5.05 (s, 1H), 4.11 (s, 1H), 3.97 ( s, 1H), 3.56 (s, 2H), 3.39 (s, 1H), 2.54 (s, 1H), 2.38-2.18 (m, 1H), 2.04 (s) 1H).

  N- (1- {2,2-difluoro-2- [4- (trifluoromethyl) phenyl] ethyl} azepan-4-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine

The title compound was prepared by a procedure analogous to that described in Example 38 above. Purification by chiral HPLC (20% isopropanol / 80% hexane / 0.1% DEA, Chiralpak AD commercially available from Chiral Technologies, Inc., Exton, Pa) gave the enantiomer of the title compound: ( R or S) -N- (1- {2,2-difluoro-2- [4- (trifluoromethyl) phenyl] ethyl} azepan-4-yl) -1H-pyrazolo [3,4-d] pyrimidine- 4-amine: peak 1, HRMS (M + H ⁺ ): calculated value = 441.1821, found value = 441.1782; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.21 (s, 1H), 8. 09 (s, 1H), 7.78 (s, 4H), 4.33 (m, 1H), 3.27 (m, 2H), 2.85-2.76 (m, 4H) ), 1.97-1.94 (m, 2H), 1.72-1.59 (m, 4H); (S or R) -N- (1- {2,2-difluoro-2- [4 -(Trifluoromethyl) phenyl] ethyl} azepan-4-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine: peak 2, HRMS (M + H ⁺ ): calculated value = 441.1821, found Value = 441.1821; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.21 (s, 1H), 8.09 (s, 1H), 7.78 (s, 4H), 4.33 (m 1H), 3.27 (m, 2H), 2.85-2.76 (m, 4H), 1.97-1.94 (m, 2H), 1.72-1.59 (m, 4H) ).

Claims (19)

Compounds of formula (I) and / or their pharmaceutically acceptable salts, individual enantiomers and stereoisomers.

(Where
W is aryl or heteroaryl, wherein the aryl or heteroaryl is independently selected from the group consisting of halogen, C _3-6 cycloalkyl, cyano, C _1-4 alkoxy and C _1-6 alkyl 1-5 May be substituted with one or more substituents, the alkoxy may be substituted with one or more halogens, and the alkyl is one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl. May be replaced,
X is absent or is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl, (═O) and cyano, C _1-4 alkoxy and C _1- Selected from the group consisting of ₃ alkyls,
A is a bond, or a hydrogen, a halogen, a hydroxyl, and C _1-3 optionally C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of alkyl, said alkyl May be substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, C _1-4 alkoxy and cyano,
B is hydrogen, halogen, a hydroxyl, and C _1-3 1 or more optionally C ₁ alkyl optionally substituted with a substituent selected from the group consisting of alkyl, wherein alkyl is halogen, hydroxyl, C _{1 -4} optionally substituted with one or more substituents selected from the group consisting of alkoxy and cyano, wherein the ring is formed comprising A and B, each carbon atom in A and each individual in B Carbon atoms may be bonded to bridge the ring,
R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-3 alkyl;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, hydroxyl, cyano and C _1-3 alkyl, wherein the alkyl is selected from the group consisting of halogen, hydroxyl, C _1-4 alkoxy and cyano 1 May be substituted with more than one substituent,
R ³ and R ⁴ may be joined together with the ring to which they are attached to form a bridged cycloalkyl. ) W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy, and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is selected from the group consisting of C _1-4 alkoxy and C _1-3 alkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl and (═O) And
R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-3 alkyl;
R ³ and R ⁴ are each independently hydrogen,
A is a bond or C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
B is C ₁ alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen, and the ring is formed containing A and B, wherein each carbon atom in A And individual carbon atoms in B may be bonded to bridge the ring,
2. A compound of claim 1 and / or individual enantiomers, diastereomers, or pharmaceutically acceptable salts thereof. Compounds of formula (Ia) and / or their individual enantiomers, diastereomers or pharmaceutically acceptable salts.

(Where
W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl and (═O);
R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-3 alkyl;
A is a bond, or C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen. ) Compounds of formula (Ib) and / or their individual enantiomers, diastereomers or pharmaceutically acceptable salts.

(Where
W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl and (═O);
B is C ₁ alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen. ) Compounds of formula (Ic) and / or their individual enantiomers, diastereomers or pharmaceutically acceptable salts.

(Where
W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is C _1-3 alkyl which may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl and (═O). ) A compound of formula (Id) and / or its individual enantiomers, stereoisomers or pharmaceutically acceptable salts.

(Where
W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
A is a bond, or C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, hydroxyl, cyano and C _1-3 alkyl, wherein the alkyl is selected from the group consisting of halogen, hydroxyl, C _1-4 alkoxy and cyano 1 May be substituted with more than one substituent,
R ³ and R ⁴ may be joined together with the ring to which they are attached to form a bridged cycloalkyl. ) A compound of formula (Ie) and / or its individual enantiomers, stereoisomers or pharmaceutically acceptable salts.

(Where
W is aryl optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C _3-6 cycloalkyl, C _1-4 alkoxy and C _1-6 alkyl, The alkyl may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
X is C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl and (═O);
A is a bond, or C _1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
B is C ₁ alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen, and the ring is formed containing A and B, wherein each carbon atom in A And individual carbon atoms in B may be bonded to bridge the ring. )

And / or individual enantiomers, diastereomers, or pharmaceutically acceptable salts thereof.   A pharmaceutical composition comprising an inert carrier and a therapeutically effective amount of the compound of claim 1.   (I) a non-steroidal anti-inflammatory agent, (ii) a COX-2 inhibitor, (iii) a bradykinin B1 receptor antagonist, (iv) a sodium channel blocker and antagonist, (v) nitric oxide synthase (NOS) Inhibitors, (vi) glycine site antagonists, (vii) potassium channel openers, (viii) AMPA / kainic acid receptor antagonists, (ix) calcium channel antagonists, (x) GABA-A receptor modulators ( For example, GABA-A receptor agonist), (xi) matrix metalloprotease (MMP) inhibitor, (xii) thrombolytic agent, (xiii) morphine and other opioids, (xiv) neutrophil inhibitory factor (NIF), (Xv) L-dopa, (xvi) carbidopa, (xvii) levodopa / carbidopa, (xviii) bromocriptine Dopamine agonists such as pergolide, pramipexole, ropinirole, (xix) anticholinergic drugs, (xx) amantadine, (xxi) carbidopa, (xxii) entacapon, tolcapone and other catechol O-methyltransferase (“COMT”) inhibitors, xxiii) a monoamine oxidase B ("MAO-B") inhibitor, (xiv) an opiate agonist or antagonist, (xv) a 5HT receptor agonist or antagonist, (xvi) an NMDA receptor agonist or antagonist, xvii) an NK1 antagonist, (xviii) a selective serotonin reuptake inhibitor (“SSRI”) and / or a selective serotonin and norepinephrine reuptake inhibitor (“SSNRI”), (xxix) a tricyclic antidepressant, ( xxx) Norepinephrine regulator , (Xxxi) lithium, (xxxii) valproate and (xxxiii) further comprises a second therapeutic agent selected from the group consisting of neurontin (gabapentin), pharmaceutical composition according to claim 9.   10. The pharmaceutical composition according to claim 9, which is useful for the treatment of ischemic brain disorders including pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety and stroke.   The pharmaceutical composition according to claim 9, which is useful for treating Parkinson's disease.   The compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment or prevention of ischemic encephalopathy including pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, and stroke. A method for treating or preventing ischemic brain damage including pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, and stroke in the patient, comprising administering a therapeutically effective amount or a prophylactically effective amount.   Administration of a therapeutically effective amount or a prophylactically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need of treatment or prevention of chronic visceral inflammatory and neuropathic pain syndrome A method of treating or preventing chronic visceral inflammatory and neuropathic pain syndrome in said patient.   Patients in need of treatment or prevention of traumatic nerve injury, nerve compression or strangulation, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, pain caused by cancer and chemotherapy, or concomitant pain Further comprising administering a therapeutically effective amount or a prophylactically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, traumatic nerve injury, nerve compression or squeezing, zonal band in said patient A method of treating or preventing post-rash neuralgia, trigeminal neuralgia, diabetic neuropathy, pain caused by cancer and chemotherapy, or incidental pain.   Chronic low back pain in the patient, comprising administering to a patient in need of treatment or prevention of chronic low back pain a therapeutically effective amount or prophylactically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof. How to treat or prevent.   A phantom limb in said patient comprising administering to a patient in need of treatment or prevention of phantom limb pain a therapeutically effective or prophylactically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof. A method of treating or preventing pain.   A patient in need of treatment or prevention of HIV-induced neuropathy, HIV treatment-induced neuropathy, chronic pelvic pain, neuroma pain, complex local pain syndrome, chronic arthritic pain and related neuralgia. HIV-induced neuropathy, HIV therapy-induced neuropathy, chronic pelvic pain, neuroma pain in said patient comprising administering a therapeutically effective amount or a prophylactically effective amount of the described compound, or a pharmaceutically acceptable salt thereof A method of treating or preventing complex local pain syndrome, chronic arthritic pain and related neuralgia.   Administering to a patient in need of treatment or prevention of epilepsy and partial and systemic tonic seizures a therapeutically effective amount or a prophylactically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof. A method of treating or preventing epilepsy and partial and generalized tonic seizures in said patient.