RU2803741C2 - Chemical compound - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: group of inventions includes N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide, composition and combination on its basis, a method of the treatment of pruritus and atopic dermatitis, and its use.

EFFECT: N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide which has inhibitory activity against JAK 1 and is used for treatment of itching and atopic dermatitis.

8 cl, 2 tbl, 30 ex

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under the U.S. provisional application. No. 62/755679, filed November 5, 2018, the entire contents of which are incorporated herein by reference.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention describes new compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and their use in medicine. The compounds of the present invention have Janus kinase (JAK) inhibitory activity and are useful for the treatment or control of itch associated with allergic dermatitis or atopic dermatitis in animals and other disorders and diseases where immunosuppression/immunomodulation is desired. The present invention also describes methods of treating pruritus or atopic dermatitis by administering compounds of the present invention that are JAK inhibitors.

BACKGROUND OF THE ART

Itching is defined as an unpleasant sensation that leads to scabies, namely the desire to scratch. Itching, like pain, is one of the body's main defense mechanisms. The fundamental biological function of itch is to alert the animal to the presence of potentially harmful toxins or other hazards, such as disease-carrying insects, and to stimulate a reflex to get rid of these hazards. Itching can be active as a reflex to remove fleas and other parasites. Alternatively, chronic itch, such as pain, may itself become persistent and pathological. Chronic itch results in overstimulation of peripheral and central nerves, resulting in activation and proliferation of itch-mediating nerve fibers. It has been shown that sensitized nerve fibers stimulate itch more easily. Chronic itch requires more than symptomatic treatment, requiring careful diagnosis to identify the underlying cause, and multimodal therapy to treat gradually developing effects.

Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly divided into tyrosine and serine/threonine kinases. Inappropriate kinase activity due to mutation, overexpression or misregulation, dysregulation or deregulation, and over or underproduction of growth factors or cytokines are implicated in many diseases, including, but not limited to, cancer, cardiovascular disease, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cellular responses related to cell growth, differentiation, survival, apoptosis, cell mitagenesis, cell cycle regulation, and cell motility involved in the above and related diseases. Thus, protein kinases have become an important class of enzymes that are targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK-1, JAK-2, JAK-3, and Tyk-2) plays a central role in cytokine signaling (Kisseleva et al. Gene, 2002, 285, 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK, which then phosphorylates the cytokine receptor, thereby forming docking sites for signaling molecules, namely members of the signal transducers and activators of transcription (STAT) family, which ultimately lead to gene expression that stimulates biological responses such as an itch signal. Activation of the JAK-STAT pathway also results in several other biological activities that contribute to the inflammation and itch processes that contribute to acute allergies in animals, but may also exacerbate clinical signs and contribute to chronic allergies.

There is a significant need for safe and effective treatments for atopic dermatitis in animals, including mammals, birds and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats and other livestock or domestic mammals. Examples of birds include turkeys, chickens, ostriches and other livestock or poultry. The market for the treatment of atopic dermatitis in animals is currently dominated by corticosteroids, which cause pain and unwanted side effects in animals, especially companion animals such as dogs. Antihistamines are also used, but they are ineffective. A drug called cyclosporine (ATOPICA™) is currently marketed for the treatment of atopic dermatitis in dogs and cats, but is expensive and slow to show effectiveness. In addition, ATOPICA™ is poorly tolerated in the gastrointestinal tract. WO 2010/020905 discloses JAK inhibitors for the treatment of itching.

SUMMARY OF THE INVENTION

The compounds of the present invention are novel JAK inhibitors that are effective against JAKs, including JAK 1. These compounds will provide an alternative to steroid use and JAK inhibitors are already commercially available and provide control of chronic itching and inflammation that is present or ongoing. in atopic dermatitis, or slowly regresses after removal of the allergen or causative agent, such as fleas in flea allergic dermatitis.

One embodiment of the present invention is a compound of formula I or a pharmaceutical or veterinary salt thereof:

Where

X is N, CH or CR ³ ;

Y is N, CH or CR ³ ;

R ¹ means (CH ₂ ) _n SO ₂ N(R ² ) ₂ , (CH ₂ ) _m NHSO ₂ R ² , (CH ₂ ) _n CON(R ² ) ₂ or (CH ₂ ) _m NHCOR ²

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, 3 or 4;

each R ² is independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or

two R ² may combine with the nitrogen atom to which they are attached to form an unsubstituted or substituted 5- to 7-membered ring, which may include one or more additional heteroatoms selected from the group consisting of N, O or S, and which may include one or more multiple bonds;

And

each R ³ is independently C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, hydroxy, C _1-6 alkoxy, C _1-6 haloalkyloxy group, C _1-6 alkylsulfonyl, C _1-6 thioalkyl, mercapto group, halogen, nitro group, cyano group, amino group, C _1-6 alkylamino group, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl,

if X is CR ³ and Y is CR ³ , each CR ³ can combine with the atoms to which they are attached to form a fused 5- to 7-membered ring.

In one embodiment, X is CH. In one embodiment, Y is CH. In one embodiment, both X and Y are CH.

In one embodiment, one or more of X and Y are CR ³ , where each R ³ is halogen, cyano or C _1-6 alkyl.

In one embodiment, R ¹ is (CH ₂ ) _n SO ₂ NHR ² or (CH ₂ ) _m NHSO ₂ R ² .

In one embodiment, n is 0 or 1. In one embodiment, m is 0 or 1.

In one embodiment, R ² is C _1-6 alkyl, C _1-6 haloalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted aryl. In one embodiment, R ² is C _1-6 alkyl, C _1-6 haloalkyl, or unsubstituted or substituted cycloalkyl.

In one embodiment, the present invention includes compounds of formula (I), wherein R¹means (CH₂)_nSO₂NHR² _.In one embodiment, the present invention includes compounds of formula (I), where n is 0. In one embodiment, the present invention includes compounds of formula (I), where n is 1. In one embodiment, the present invention includes compounds of formula (I), wherein R² means C_1-6 alkyl In one embodiment, the present invention includes compounds of formula (I), wherein R² means unsubstituted or substituted cycloalkyl. In one embodiment, the present invention includes compounds of formula (I), wherein R² means C_1-6haloalkyl. In one embodiment, the present invention includes compounds of formula (I), wherein R² means unsubstituted or substituted aryl. In one embodiment, the present invention includes compounds of formula (I), wherein R²means aryl substituted with one or more of the following: halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 haloalkenyl, C_2-6 alkynyl, C_2-6 haloalkynyl, CN, NO₂, N.H.₂,N(C_1-6 alkyl)₂, OH or OC_1-6 alkyl

In one embodiment, the present invention includes compounds of formula (I) wherein R ¹ is (CH ₂ ) _m NHSO ₂ R ² . In one embodiment, the present invention includes compounds of formula (I), where m is 0. In one embodiment, the present invention includes compounds of formula (I), where m is 1. In one embodiment, the present invention includes compounds of formula (I), where R ² is C _1-6 alkyl. In one embodiment, the present invention includes compounds of formula (I) wherein R ² is unsubstituted or substituted cycloalkyl. In one embodiment, the present invention includes compounds of formula (I) wherein R ² is haloalkyl. In one embodiment, the present invention includes compounds of formula (I) wherein R ² is unsubstituted or substituted aryl. In one embodiment, the present invention includes compounds of formula (I) wherein R ² is aryl substituted with one or more of the following: halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, CN, NO ₂ , NH ₂ , N(C _1-6 alkyl) ₂ , OH or OC _1-6 alkyl.

One embodiment includes a compound selected from the group consisting of:

N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-ethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-propylspiro[3.3]heptane-2-sulfonamide;

N-isopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-cyclopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(2,2,2-trifluoroethyl)spiro[3.3]heptane-2-sulfonamide;

N-isobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-tert-butyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-cyclobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-cyclopentyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide;

2-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide;

4-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]-4-(trifluoromethyl)benzenesulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]methanesulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]ethanesulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-2-sulfonamide;

2-methyl-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propane-1-sulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]cyclopentanesulfonamide;

3,3,3-trifluoro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide;

N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)methanesulfonamide;

N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)ethanesulfonamide;

N-methyl-6-[methyl(9H-purin-6-yl)amino]spiro[3.3]heptane-2-sulfonamide;

(enantiomer A)-N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

(enantiomer B)-N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N,N-dimethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-methyl-N-(2-pyrrolidin-1-ylsulfonylspiro[3.3]heptan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

or a veterinary or pharmaceutically acceptable salt thereof.

In one embodiment, the present invention includes a composition containing a compound of the present invention and a pharmaceutically or veterinarily acceptable carrier.

In one embodiment, the present invention includes a combination containing a compound of the present invention and one or more other pharmaceutically or veterinary active substances.

In one embodiment, the present invention includes a method of treating pruritus or atopic dermatitis, comprising administering to a subject in need thereof an effective amount of a compound of the present invention. In one embodiment, the subject is an animal, including mammals, birds and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats and other livestock, domestic mammals or companion mammals. Examples of birds include turkeys, chickens, ostriches and other livestock or poultry. In another embodiment, the subject is a mammal. In another embodiment, the subject is an animal companion.

In one embodiment, the present invention includes a compound of the present invention for use in medicine.

In one embodiment, the present invention includes a compound of the present invention for the preparation of a medicament for the treatment of itching or atopic dermatitis.

In one embodiment, the present invention includes the use of a compound of the present invention for the treatment of itching or atopic dermatitis.

One or more objects and embodiments may be included in another embodiment even if not specifically described. Thus, all objects and embodiments can be combined in any manner or combination.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are novel JAK inhibitors that are effective against JAKs, including JAK 1. These compounds will provide an alternative to steroid use and JAK inhibitors are already commercially available and provide control of chronic itching and inflammation that is present or ongoing. in atopic dermatitis, or slowly regresses after removal of the allergen or causative agent, such as fleas in flea allergic dermatitis.

Definitions

In relation to the compounds disclosed in the present invention, the following terms have the following meanings unless otherwise indicated. The following terms are intended to clarify and not to limit certain terms. If a particular term used in the present invention is not specifically defined, such term should not be considered undefined. On the contrary, the terms are used in their generally accepted meanings.

As used herein, "alkyl" means monovalent saturated aliphatic hydrocarbyl groups containing from 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The hydrocarbon chain can be linear or branched. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Likewise, an "alkenyl" group means an alkyl group containing one or more double bonds in the chain, and an "alkynyl" group means an alkyl group containing one or more triple bonds in the chain.

As used in the present invention, "aryl" means a carbocyclic aromatic ring system, single or fused, such as phenyl, naphthyl, tetrahydronaphthyl, indan or biphenyl.

As used herein, "cycloalkyl" means an unsaturated or partially saturated hydrocarbon ring containing from 3 to 6 ring atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, as well as partially saturated variants thereof such as cyclohexenyl and cyclohexadienyl.

As used in the present invention, "halogen" means halogen. In some embodiments, the halogen is preferably Br, Cl, or F.

As used herein, "haloalkyl", "haloalkenyl" and "haloalkynyl" each respectively mean a hydrocarbyl group containing from 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, wherein at least one atom hydrogen is replaced by halogen, including, but not limited to, perhalogenated groups in which all hydrogen atoms are replaced by halogen atoms. The chain can be linear or branched. Exemplary haloalkyl groups include trifluoromethyl, trichloromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl and pentafluoroethyl. Likewise, a "haloalkenyl" group means a haloalkyl group containing one or more double bonds in the chain, and a "haloalkenyl" group means a haloalkyl group containing one or more triple bonds in the chain.

The term “heteroaryl” or “heteroaromatic” means aromatic ring groups containing from 5 to 14 ring atoms selected from the group consisting of carbon and at least one (usually 1-4, more often 1 or 2) heteroatom (e.g., oxygen, nitrogen or sulfur). These include monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other carbocyclic aromatic or heteroaromatic rings. Examples of monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl , 5-isoxazolyl), oxadiazolyl (e.g. 2-oxadiazolyl, 5-oxazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g. 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g. 2-triazolyl, 5-triazolyl), tetrazolyl (e.g. tetrazolyl) and thienyl (e.g. 2-thienyl, 3-thienyl.Examples of monocyclic 6-membered nitrogen-containing heteroaryl groups include pyrimidinyl, pyridinyl and pyridazinyl.Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquino linyl , indolyl, isoindolyl, acridinyl or benzisoxazolyl.

As used herein, "optionally substituted" means the replacement of a hydrogen atom that would otherwise be present in the substituent. When discussing ring systems, substitution with 1, 2 or 3 substituents replacing the normally contained hydrogen is optimal. However, when indicating linear and branched fragments, the number of substituents may be greater; they are usually introduced when hydrogen is contained. The substituents may be the same or different. Exemplary substituents include nitro, -NR'R ^'' , cyano, ^{-NR'COR ''} , alkyl, alkenyl, -C(O), -SO ₂ R''', -NR'SO ₂ R''', -SO ₂ NR'R', -CONR'R'', -CONHC ₆ H ₅ , hydroxy, alkoxy, alkylsulfonyl, haloalkyl, haloalkenyl, haloalkoxy, mercapto (-SH), thioalkyl, halogen, cycloalkyl, heterocyclyl, aryl or heteroaryl which are all known in the art and wherein R' and R'' are the same or different and each is hydrogen or alkyl; or if R' and R'' are both attached to a nitrogen atom, they may form a saturated or unsaturated heterocyclic ring containing from 4 to 6 ring atoms, and where R''' is alkyl or haloalkyl.

As used herein, the expression veterinary or veterinary or pharmaceutical or pharmaceutically acceptable salt means any salt of a compound disclosed herein that retains its biological characteristics and is not toxic or otherwise undesirable for veterinary or human use. Such salts can be formed from a variety of organic and inorganic counterions known in the art. Such salts include acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyrovicone, lactic, malonic , succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, bezoic, 3-(4-hydroxybenzoyl)bezoic, picric, cinnamon, almond, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2- hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalene sulfonic, 4-toluene sulfonic, camphor, camphor sulfonic, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic, glucopeptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic , lauryl sulfuric, gluconic, bezoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and similar acids.

Salts further include, by way of example only, salts of non-toxic organic or inorganic acids such as halides such as chloride and bromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate , pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzoyl) benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate , 1,2-ethane disulfonate, 2-hydroxyethane sulfonate, benzene sulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalene sulfonate, 4-toluene sulfonate, camphorate, camphor sulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1 -carboxylate, glucoheptonate, 3-phenylpropionate, trimethyl acetate, tert-butyl acetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexyl sulfamate, quinate, muconate, etc.

Examples of inorganic bases that can be used to form base addition salts include, but are not limited to, metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal amides such as lithium amide and sodium amide; metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; and ammonium bases such as ammonium hydroxide and ammonium carbonate.

Examples of organic bases that can be used to form addition salts with bases include, but are not limited to, metal alkoxides such as lithium, sodium and potassium alkoxides, including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide and potassium tert-butoxide; quaternary ammonium hydroxides such as choline hydroxide; and amines, including, but not limited to, aliphatic amines (i.e., alkylamines, alkenylamines, alkynylamines and alicyclic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars and polyamines.

In embodiments of the present invention, the base may be a quaternary ammonium hydroxide, wherein one or more alkyl groups of the quaternary ammonium ion are optionally substituted with one or more suitable substituents. Preferably, at least one alkyl group is replaced by one or more hydroxy groups. Non-limiting examples of quaternary ammonium hydroxides that can be used in accordance with the present invention include choline hydroxide, trimethylethylammonium hydroxide, tetramethylammonium hydroxide and preferably choline hydroxide. In embodiments of the present invention, the alkylamine may be substituted or unsubstituted. Non-limiting examples of unsubstituted alkylamines that can be used in accordance with the present invention include methylamine, ethylamine, diethylamine and triethylamine. The substituted alkylamine is preferably substituted with one or more hydroxy groups and preferably one to three hydroxy groups. Non-limiting examples of substituted alkylamines that can be used in accordance with the present invention include 2-(diethylamino)ethanol, N,N-dimethylethanolamine (2-dimethylaminoethanol), tromethamine, ethanolamine and diolamine.

In some cases, these substituents may contribute to optical and/or stereoisomerism. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called “isomers.” Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers" and those that are not superimposed mirror images of each other are called "enantiomers." If a compound contains an asymmetric center, for example if it is linked to four different groups, a pair of enantiomers is possible. An enantiomer can be described by the absolute configuration of its asymmetric center and designated as ( R ) or ( S ), according to the rules of Cahn and Prelog (Cahn et al. , 1966, Angew. Chem . 78: 413-447, Angew. Chem., Int. Ed. Engl . 5: 385-414 (errata: Angew. Chem., Int. Ed. Engl . 5:511); Prelog and Helmchen, 1982, Angew. Chem . 94: 614-631, Angew. Chem . Internat. Ed. Eng . 21: 567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4: 657-668) or can be described by the way the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (namely, as (+)- or (-)-isomers, respectively). A chiral compound can exist as a single enantiomer or as a mixture of both. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

In some embodiments, the compounds disclosed in the present invention may have one or more asymmetric centers; and therefore such compounds can be obtained as individual ( R )- or ( S )-enantiomers or as mixtures thereof. Unless otherwise indicated, for example by reference to the stereochemical configuration at any position in the formula, the description or name of a particular compound in the specification and claims is intended to include both the individual enantiomers and mixtures thereof, racemic or otherwise. Techniques for determining stereochemical configuration and separating stereoisomers are well known in the art.

In some embodiments, the compounds disclosed in the present invention are "stereochemically pure." A stereochemically pure compound has a degree of stereochemical purity at which it would be considered "pure" by those skilled in the art. Of course, this degree of purity may be less than 100%. In some embodiments, “stereochemically pure” means a compound that is substantially free of alternative isomers, i.e., contains at least about 85% or more of the primary isomer. In preferred embodiments, the compound contains at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99 %, about 99.5%, or about 99.9% of the main isomer.

When used in the present invention, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "subjects" mean human beings. In one embodiment, the subject is an animal companion such as a dog or cat. In another embodiment, the subject is an agriculturally important animal such as a sheep, cow, horse, goat, fish, pig, or poultry (such as a chicken, turkey, duck, or goose). In another embodiment, the subject is a primate, such as a monkey, such as a cynomolgus monkey, a chimpanzee, and a human or non-primate animal.

In addition, a pharmaceutically acceptable prodrug of the compound described by formula (I) is also included in the present invention. A pharmaceutically acceptable prodrug means a compound containing a group that can be converted to an amino group, a hydroxy group, a carboxy group, etc. by solvolysis or under physiological conditions. Examples of prodrug-forming groups include those described in Prog. Med., 5, 2157-2161 (1985) or "Pharmaceutical Research and Development" (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198. The term prodrug is used herein to describe any pharmaceutically acceptable form of a compound that, when administered to a patient, provides the active compound. Pharmaceutically acceptable prodrugs mean a compound that is metabolized, eg hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that possess a biologically labile protecting group on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to form the active compound.

The present invention includes all pharmaceutically acceptable isotopically labeled compounds provided herein in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen such as ² H and ³ H, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ Cl, fluorine such as ¹⁸ F, iodine such as ¹²³ I and ¹²⁵ I, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus such as ³² P, and senes such as ³⁵ S Some isotopically labeled compounds of the present invention, such as those containing a radioactive isotope, can be used to study the distribution of a drug or substrate in tissue. The radioactive isotopes tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C, are particularly suitable for this purpose due to their ease of inclusion and simple detection techniques. Substitution with heavier isotopes such as deuterium, i.e. ^2H , may provide some therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or the ability to use lower doses, and may therefore be preferable in some cases. Substitution with positron-emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N can be useful in positron emission topography (PET) studies to study substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by conventional procedures known to those skilled in the art, or by methods similar to those described in the accompanying Examples and Syntheses using a suitable isotopically labeled reagent in place of the previously used unlabeled reagent.

Compositions and methods of administration

The compounds of formula (I) used in the methods disclosed in the present invention can be administered in some embodiments using veterinary or pharmaceutical compositions containing at least one compound of formula (I), optionally in salt form alone or in combination with one or more compatible and veterinary or pharmaceutically acceptable carriers, such as diluents or excipients, or other agent. Compositions are provided that contain a derivative of formula (I) or a salt thereof and a suitable excipient, carrier or diluent. The composition may also be in a variety of forms, which include, but are not limited to, oral preparations, injectable preparations and topical, dermal or subcutaneous preparations.

The composition may be in a form suitable for oral administration, for example, as dietary supplements, lozenges, lozenges, chewable tablets, tablets, hard or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, dispersible powders or granules, syrups or elixirs. Compositions intended for oral administration can be prepared by any method known in the art for the preparation of veterinary or pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of the following: sweeteners, bittering agents, flavoring agents agents, coloring agents and preservatives to produce attractive and palatable preparations.

Lozenges are solid compositions containing one or more active ingredients, intended to be slowly dissolved or disintegrated in the mouth by passive retention in the mouth or active processing by sucking or chewing. They can be used for systemic exposure if the drug is absorbed through the lining of the cheek or esophagus, or is swallowed. In particular, soft lozenges can be chewed or allowed to dissolve slowly in the mouth. These dosage forms have the advantage that they are flavored and therefore easy to administer to humans and animals; their composition is easy to change and select specifically for a given patient; with their help it is possible to deliver precise quantities of the active ingredient into the oral cavity and digestive system; and they ensure the interaction of the drug with the oral cavity and esophagus for an extended period of time.

Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for tablet formulation. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders, for example starch, gelatin or acacia; and lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide prolonged action over a long period of time.

Oral preparations may be hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. Capsules may also be soft gelatin capsules in which the active ingredient is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oily vehicle such as peanut oil, liquid paraffin, or olive oil.

The compositions may also be in the form of an oil-in-water or water-in-oil emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be natural phosphatides, for example soy, lecithin and esters or partial esters formed from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners, bittering agents, flavoring agents and preservatives.

In one embodiment of the formulation, the composition is in the form of a microemulsion. Microemulsions are well suited for use as a liquid carrier. Microemulsions are four-component systems containing an aqueous phase, an oil phase, a surfactant and a co-surfactant. They are translucent and isotropic liquids. Microemulsions consist of a stable dispersion of microdroplets of an aqueous phase in an oil phase or, conversely, microdroplets of an oil phase in an aqueous phase. The size of these microdroplets is less than 200 nm (from 1000 to 100,000 nm for an emulsion). The interfacial film consists of alternating surfactant (SA) and co-surfactant (Co-SA) molecules, which, due to the decrease in interfacial tension, ensures the spontaneous formation of a microemulsion. In one embodiment of the oil phase, the oil phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or, alternatively, from mixtures of such compounds. In one embodiment of the oil phase, the oil phase consists of triglycerides; in another embodiment of the oil phase triglycerides are medium chain triglycerides, for example, C ₈ -C ₁₀ caprylic/capric acid triglycerides. In another embodiment, the oil phase content in % v/v. is in a range selected from the group consisting of: from about 2 to about 15%; from about 7 to about 10%; and from about 8 to about 9% v/v. in terms of microemulsion. The aqueous phase includes, for example, water or glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. In one embodiment of glycol derivatives, the glycol is selected from the group consisting of the following: propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, and mixtures thereof. Typically the aqueous phase is from about 1 to about 4% v/v. in terms of microemulsion. Microemulsion surfactants include diethylene glycol monoethyl ether, propylene glycol dimonomethyl ether, polyglycosylated C ₈ -C ₁₀ glycerides or polyglyceryl 6-dioleate. In addition to these surfactants, co-surfactants include short chain alcohols such as ethanol and propanol. Some compounds are included in the three components discussed above, for example, an aqueous phase, a surfactant and a co-surfactant. However, the experienced practitioner is well aware that different compounds should be used in different components of the same drug. In one embodiment, in the amount of surfactant/co-surfactant, the ratio of the amount of co-surfactant to the amount of surfactant is from about 1/7 to about 1/2.

In another embodiment, the amount of cosurfactant in the microemulsion is from about 25 to about 75% v/v. surfactant and from about 10 to about 55% v/v. co-surfactant.

Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent such as beeswax, paraffin wax or cetyl alcohol. Sweeteners such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents can be added to form a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid or other known preservatives.

Aqueous suspensions may contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; The dispersing or wetting agents may be a natural phosphatide, such as lecithin, or a condensation product of an alkylene oxide with fatty acids, such as polyoxyethylene stearate, or a condensation product of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with partial esters formed from fatty acids and hexitol, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters formed from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening and/or bittering agents, such as those mentioned above.

Dispersible powders and granules, suitable for preparing an aqueous suspension by the addition of water, contain the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Additional excipients may also be contained, such as sweeteners, bittering agents, flavoring agents and coloring agents.

Syrups and elixirs can be prepared with sweeteners such as glycerin, propylene glycol, sorbitol or sucrose. Such preparations may also contain a softening agent, a preservative, a flavoring agent(s) and a coloring agent(s).

The compositions may be in the form of a sterile aqueous or oily suspension for injection. This suspension can be prepared by known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable diluents and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Co-solvents such as ethanol, propylene glycol or polyethylene glycols can also be used. Preservatives such as phenol or benzyl alcohol can be used.

In addition, sterile fixed oils are commonly used as a solvent or suspending medium. For this purpose, any light, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injection preparations.

Topical, cutaneous, and subcutaneous preparations may include emulsions, creams, ointments, gels, or pastes.

Organic solvents that can be used in the present invention include, but are not limited to: acetyltributyl citrate, fatty acid esters such as dimethyl ether, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethyl acetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethyl acetamide, propylene glycol dimonomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (for example, N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.

The solvent or diluent for the compositions of the present invention may include vegetable oils such as, but not limited to, soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grape seed oil, sunflower oil, etc. . P.; mineral oils such as, but not limited to, petroleum jelly, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons, or alternatively, for example, medium chain triglycerides (such as C ₈ -C ₁₂ ).

Dosage forms may contain from about 0.5 mg to about 5 g of active agent.

In one embodiment of the present invention, the active agent is contained in the formulation at a concentration of about 0.05 to 10% w/v.

The compounds of formula (I) can be used individually or as preparations or formulations thereof in combinations.

The compounds of formula (I) proposed in the present invention can be combined with one or more agents having the same range of activity, for example, to increase activity, or with substances having a different spectrum of activity, for example, to expand the range of activity. The compounds of formula (I) have been found to have activity as JAK inhibitors. Thus, the compounds of the present invention can also be combined with other agents that inhibit JAK activity. Such JAK inhibitors may include small molecules, nucleic acids, eg, JAK antisense nucleic acids, amino acids, peptides, carbohydrates, and anti-JAK antibodies. Such agents are preferably combined with a pharmaceutically acceptable solvent or delivery vehicle. Examples of anti-JAK antibodies include, for example, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, Fab, F(ab') ₂ and Fab expression library fragments, scFV molecules and antigenic determinant binding fragments thereof. Antisense oligonucleotides targeting the JAK gene or mRNA to inhibit its expression are prepared using standard techniques (see, for example, Agrawal et al., Methods in Molecular Biology: Protocols for Oligonucleotides and Analogs , Vol. 20, (1993)). For anti-JAK antibodies, the preferred dose is usually 0.2 mg/kg to 20 mg/kg body weight. Generally, partially humanized antibodies and full human antibodies have a longer half-life in the human body than other antibodies. Accordingly, smaller doses and less frequent administration are possible. Modifications such as lipidation can be used to stabilize antibodies and increase uptake and tissue penetration. The antibody lipidation technique is described in Cruikshank et al., J. Acquired Immune Deficiency Syndromes Hum. Retrovirol. 14: 193, (1997).

The compounds of formula (I) of the present invention can be combined with one or more agents that modulate the mammalian immune system or anti-inflammatory agents. These agents may include, but are not limited to, cyclosporine A, such as Sandimmune® or Neoral®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualine, mycophenolate, such as Cellcept®, azathioprine, such as Imuran®, daclizumab , such as Zenapax®, OKT3, such as Orthocolon®, Atgam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids, such as prednisolone or dexamethasone. These agents may be administered as part of preparations or separate dosage forms, by the same or different routes of administration, and in the same or different modes of administration, in accordance with standard pharmaceutical practice known to one skilled in the art.

A pharmaceutical preparation containing compounds of formula (I) for administration to a human or other mammal is preferably in unit dosage form, in which the preparation is divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form may be a packaged preparation containing individual quantities of the drug, such as packaged tablets, capsules and powders in vials or ampoules. In addition, the unit dosage form may be the capsule, tablet, or lozenge itself, or may be an appropriate quantity of these packaged forms.

The amount of active component in a single dose of the drug can be varied or set equal to from about 0.1 mg to about 1000 mg depending on the specific application and activity of the active component. The composition may also contain other compatible therapeutic agents if desired.

When used therapeutically for the treatment or relief of pruritus associated with allergic dermatitis and atopic dermatitis in humans or other mammals, the compounds used in the method of treatment are administered at an initial dose of from about 0.1 mg/kg to about 100 mg/kg per interval, from about 0.1 mg/kg to about 50.0 mg/kg per interval, from about 0.1 mg/kg to about 10.0 mg/kg per interval, from about 0.1 mg/kg to about 5.0 mg/kg per interval, from about 0.1 mg/kg to about 2.5 mg/kg per interval, from about 0.1 mg/kg to about 2.0 mg/kg per interval, from about 0 .1 mg/kg to about 1.0 mg/kg per interval, about 0.4 mg/kg to about 1.0 mg/kg per interval, or about 0.4 mg/kg to about 0.6 mg/ kg per interval. Preferred intervals may be daily, weekly, monthly, quarterly, semi-annually or annually. Dosages may vary depending on the requirements of the patient, for example, the weight of the human or mammal being treated, the severity of the pathological condition being treated, the route of administration and the potency of the compound(s) used. Determination of the appropriate dosage and route of administration in a particular case is within the competence of the practitioner. Typically, treatment is started with smaller doses that are less than the optimal dose of the compound, which can be increased in small steps until the optimal effect is achieved for the specific characteristics of the pathological condition. For convenience, if desired, the full daily dose can be divided and administered in portions throughout the day.

In therapeutic use, the compounds of formula (I) are useful for the preparation of a medicinal product for the treatment of lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease , Alzheimer's disease, leukemia, osteoarthritis, anti-pruritus, chronic respiratory disease and other indications where immunosuppression/immunomodulation is desired.

The compounds of formula (I) can be used in particular in the fields of veterinary medicine, animal husbandry and, in particular, warm-blooded vertebrates, including companion animals such as dogs and cats, horses, livestock and poultry.

The compounds of the present invention, their stereoisomers and their veterinary or pharmaceutically acceptable salts, and compositions containing the compounds of the present invention together with at least one other veterinary agent are particularly valuable for the control of pruritus and atopic dermatitis in animals. companions, especially in dogs and cats, livestock and birds.

Any of the compounds of the present invention, or a suitable combination of a compound of the present invention, and optionally with at least one additional veterinary agent, can be administered directly to the animal and/or indirectly by introducing it into the local environment in which the animal is located ( such as bedding, fencing, etc.). Direct administration includes contact of the animal's skin, fur or feathers with the compound(s) or administration through feed or by injection of the compounds into the animal.

It is believed that the compound of formula (I), its stereoisomer and its veterinary acceptable salt in combination with at least one additional veterinary agent described in the present invention is valuable for the treatment and control of various symptoms associated with pruritus and atopic dermatitis.

The present invention also relates to a method of administering a compound of the present invention, alone or in combination with at least one additional veterinary agent and optionally a veterinarily acceptable excipient, diluent or carrier, to an animal in good health, comprising administering to said animal to weaken or eliminating symptoms associated with itching and atopic dermatitis.

The present invention clearly includes the compounds listed in Table 1. A composition containing a therapeutically acceptable amount of any of these compounds is also within the scope of the present invention. The composition may further contain a veterinarily acceptable excipient, diluent, carrier, or a mixture thereof. Such a composition may be administered to an animal in need thereof to treat or control pruritus or atopic dermatitis. The composition may further contain an additional veterinary agent described in the present invention.

Table 1 Example Connection name 1 N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 2 N-ethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 3 6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-propylspiro[3.3]heptane-2-sulfonamide 4 N-isopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 5 N-cyclopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 6 6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(2,2,2-trifluoroethyl)spiro[3.3]heptane-2-sulfonamide 7 N-isobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 8 N-tert-butyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 9 N-cyclobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 10 N-cyclopentyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide eleven N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide 12 2-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide 13 4-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide 14 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]-4-(trifluoromethyl)benzenesulfonamide 15 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]methanesulfonamide 16 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]ethanesulfonamide 17 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide 18 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-2-sulfonamide 19 2-methyl-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide 20 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]cyclopentanesulfonamide 21 3,3,3-trifluoro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide 22 N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)methanesulfonamide 23 N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)ethanesulfonamide 24 N-methyl-6-[methyl(9H-purin-6-yl)amino]spiro[3.3]heptane-2-sulfonamide 25 N-methyl-6-[methyl(1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 26 (enantiomer A)-N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 27 (enantiomer B)-N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 28 6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 29 N,N-dimethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide thirty N-methyl-N-(2-pyrrolidin-1-ylsulfonylspiro[3.3]heptan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Experimental techniques

EXAMPLES

The following examples provide a more detailed description of the conditions for obtaining the compounds proposed in the present invention. However, it should be understood that the present invention, as fully described and set forth in the claims, is not limited to the details of the following schemes or production modes.

Synthesis

In general, the compounds of the present invention can be prepared, isolated, or obtained by any procedure apparent to those skilled in the art. Typical preparation procedures are illustrated in the diagrams below.

Scheme 1 (example 1 as illustrative):

Example 1

Compound 1: N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

Intermediate 1: 6-(methylamino)spiro[3.3]heptan-2-ol. Tert-butyl-N-(2-hydroxyspiro[3.3]heptan-6-yl)carbamate (16.0 g, 70 mmol) and toluene (200 ml) were added to a 1 L flask. Red-Al (116 mL, 420 mmol, 70% in toluene) was added dropwise over 2 h and the internal temperature was maintained below 35°C. After addition, the mixture was slowly heated to 130°C and stirred at this temperature for approximately 4 hours. It was then cooled to <5°C. The reaction was stopped by adding a saturated solution of Na ₂ SO ₄ (~200 ml) dropwise. The internal temperature was maintained below 20°C. The solid was filtered and the aqueous solution was extracted with DCM (3×200 ml). The combined solution was dried over MgSO ₄ . Filtration and concentration in vacuo gave a viscous oil (9.0 g, 75%). ¹ H NMR (400 MHz, methanol- d 4) δ ppm 1.69-1.88 (m, 4 H) 2.09-2.37 (m, 8 H) 2.97-3.05 (m, 0.5 H) 3.23-3.32 (m, 8 H) 3.36-3.40 (m, 1 H) 3.42-3.48 (m, 1 H) 3.57 -3.62 (m, 4 H) 3.99-4.07 (m, 0.5 H). LCMS (M/Z): 142 (M+H).

Intermediate 2: 6-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]spiro[3.3]heptan-2-ol.

DIPEA (32 mL, 180 mmol) and 4-chloro- 7- (p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine (18.4 g, 60 mmol). The mixture was heated at 110°C for 1 day. The solvent was removed in vacuo. The residue was purified on an ISCO column (330 g eluting with EtOAc and heptane). Concentration gave an almost white solid (17.0 g, 79.4%). ¹ H NMR (400 MHz, DMSO- d 6) δ ppm 1.82 (ddd, J =15.03, 10.93, 7.81 Hz, 2 H) 2.06-2.24 (m , 5 H) 2.29-2.40 (m, 4 H) 3.10-3.14 (m, 3 H) 3.18-3.27 (m, 1 H) 3.90-3.99 (m, 1 H) 4.88 (d, J =6.25 Hz, 1 H) 4.97 (br t, J =8.59 Hz, 1 H) 6.85 (d, J =4.10 Hz, 1 H) 7.39 (m, J =8.00 Hz, 2 H) 7.57 (d, J =4.10 Hz, 1 H) 7.93 (m, J =8.20 Hz, 2 H) 8.19 (s, 1 H); LCMS (M/Z): 413 (M+H).

Intermediate 3: [6-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]spiro[3.3]heptan-2-yl]-4-methylbenzenesulfonate. 6-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]spiro[3.3]heptan-2-ol (~22.3 g, 54.1 mmol), DCM (200 ml), DMAP (1.31 g, 10.8 mmol), Et ₃ N (15.3 ml, 108.2 mmol) and TsCl (11.9 g, 62 .2 mmol). The reaction was carried out at room temperature for approximately 20 hours monitored by LCMS, then the mixture was treated with water (100 ml). The aqueous solution was extracted with DCM (100 ml×2). The combined organic solution was dried over Na ₂ SO ₄ . After filtration and concentration, a light brown solid (38.3 g) was obtained. The crude material was purified using ISCO (330 g column) and eluted with EtOAc and heptane. A light yellow solid was obtained (29.4 g, 96%). ¹ H NMR (400 MHz, DMSO- d 6) δ ppm) 1.20 (s, 1 H) 1.99-2.25 (m, 7 H) 2.32 (s, 4 H) 2 .40 (s, 4 H) 3.09 (s, 3 H) 4.69 (t, J =7.22 Hz, 1 H) 4.92 (s, 1 H) 5.72 (s, 1 H ) 6.84 (d, J =4.10 Hz, 1 H) 7.36-7.47 (m, 5 H) 7.56 (d, J =4.30 Hz, 1 H) 7.75 ( d, J =8.40 Hz, 2 H) 7.92 (d, J =8.40 Hz, 2 H) 8.17 (s, 1 H); LCMS (M/Z): 567 (M+H).

Intermediate 4: S-[6-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]spiro[3.3]heptan-2-yl]ethanethioate. Into a 1 L round bottom flask containing the compound 6-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]spiro[3.3]heptan-2-yl]-4 -methylbenzenesulfonate (29.4 g, ∼51.9 mmol), DMSO (200 ml) and potassium thioacetate (∼33.1 g, 289 mmol) were added. The reaction mixture was heated at 60°C for 20 hours and monitored by LCMS. It was then treated with 5% NaHCO ₃ (200 ml) and extracted with EtOAc (3×200 ml). The combined organic solution was dried over Na ₂ SO ₄ . After filtration and concentration, a light brownish solid was obtained (25.3 g, ~100%). LCMS (M/Z): 471 (M+H). It was used in the next step as is without further purification.

Intermediate 5: 6-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]spiro[3.3]heptane-2-sulfonic acid. S-[6-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino was added to a 1 L three-neck flask equipped with a thermometer, a dropping funnel, and a nitrogen supply pipe. ]spiro[3.3]heptan-2-yl]ethanethioate (~9.8 g, ~20 mmol) and formic acid (80 ml). H ₂ O ₂ (30% in water, ~25 ml) was then added over 1.5 hours. It was cooled in an ice water bath as necessary to maintain the temperature below 35°C. After addition, the reaction mixture was cooled to room temperature and stirred at room temperature for 30 minutes. After cooling to 0-5°C, the reaction was stopped with NaHSO ₃ and Na ₂ S ₂ O ₅ (33% in water, ~100 ml) added in portions, maintaining the temperature below 35°C. NaOH aqueous solution (33%) was added at 0-5°C until pH=4-5 (maintained internal temperature <35°C). The resulting white solid was filtered and pump dried overnight. A tan solid was obtained (~16.6 g, contains salts, 60% purity). ¹ H NMR (400 MHz, methanol- d 4) δ ppm 2.21-2.39 (m, 4 H) 2.40 (s, 3 H) 2.42-2.50 (m, 3 H) 2.51-2.57 (m, 1 H) 3.22-3.24 (s, 3 H) 3.51 (quintet, J = 8.36 Hz, 1 H) 4.92-5, 01 (m, 1 H) 6.85 (d, J =4.15 Hz, 1 H) 7.37 (d, J =8.54 Hz, 2 H) 7.56 (d, J =4.15 Hz, 1 H) 7.95-8.00 (m, 2 H) 8.20 (s, 1 H) 8.42 (s, 2 H, HCO ₂ Na); LCMS (M/Z): 477 (M+H).

N-Methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide.

Compound 1. Intermediate 5,6-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]spiro[3.3]heptane-2-sulfonic acid (~476 mg , crude, contains salts, ~0.66 mmol) was suspended in DCM (4 ml). SOCl ₂ (4 ml) was then added, followed by 4 drops of DMF. The reaction mixture was then refluxed for 4 hours (heating block temperature was 55-60°C. The reaction mixture was then cooled to room temperature. Dry toluene was added to the solution. The solvent was removed in vacuo. The residue was taken up in THF (2 ml) and excess CH ₃ NH ₂ (2M in THF, 4 ml) was added. The reaction mixture was stirred overnight. The reaction mixture was then treated with water (~10 ml) and extracted with EtOAc (3x20 ml). After removal of the solvent, the residue was further purified on a C18 ISCO column (50 g) and eluted with MeOH and water to provide a white solid (~274 mg, ~85%) after removal of the solvent.

LiOH.H ₂ O (419 mg, 10 mmol) was added to a solution of sulfonamide (274 mg, ~0.54 mmol) in isopropanol (4 ml) and water (3 ml). The mixture was stirred at 50-55°C for 4 hours and at room temperature overnight. After removing the solvent, the residue was dissolved in water (~2 ml) and MeOH (~1 ml). It was purified on a C18 ISCO column (50 g) and eluted with MeOH and water. Concentration gave a white solid (128 mg, 71%). ¹ H NMR (400 MHz, methanol- d 4) δ ppm 2.27-2.42 (m, 4 H) 2.42-2.61 (m, 4 H) 2.68 (s, 3 H) 3.27 (s, 3 H) 3.86 (quintet, J =8.25 Hz, 1 H) 5.05 (quintet, J =8.54 Hz, 1 H) 6.61 (d, J =3.51 Hz, 1 H) 7.07 (d, J =3.51 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 336 (M+H).

The following compounds were also prepared using similar procedures.

Example 2:

Compound 2: N-ethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

N-ethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 2: ¹ H NMR (400 MHz, methanol -d 4) δ ppm 1.15 (t, J =7.22 Hz, 3 H) 2.26-2.60 (m, 9 H) 3.07 (q, J =7.22 Hz, 2 H) 3.82 (quintet, J =8.30 Hz, 1 H) 4.99-5.13 (m, 1 H) 6.61 (d, J =3.51 Hz, 1 H) 7.08 (d , J =3.71 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 350 (M+H).

Example 3:

Compound 3: 6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-propylspiro[3.3]heptane-2-sulfonamide

6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-propylspiro[3.3]heptane-2-sulfonamide 3: ¹ H NMR (400 MHz, methanol -d 4) δ ppm 0.93 (t, J =7.32 Hz, 3 H) 1.53 (sxt, J =7.26 Hz, 2 H) 2.26-2.57 (m, 8 H) 2 .98 (t, J =7.13 Hz, 2 H) 3.75-3.89 (m, 1 H) 4.96-5.12 (m, 1 H) 6.61 (d, J =3 .71 Hz, 1 H) 7.08 (d, J =3.71 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 364 (M+H).

Example 4:

Compound 4: N-isopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

N-isopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 4: ¹ H NMR (400 MHz, methanol -d 4) δppm 1.17 (d, J =6.64 Hz, 6 H) 2.23-2.60 (m, 8 H) 3.51 (dt, J =13.18, 6.49 Hz, 1 H) 3.72-3.87 (m, 1 H) 5.00-5.13 (m, 1 H) 6.61 (d, J =3.71 Hz, 1 H) 7.08 (d , J =3.51 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 364 (M+H).

Example 5:

Compound 5: N-cyclopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

N-cyclopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 5: ¹ H NMR (400 MHz, methanol -d 4) δ ppm 0.52-0.72 (m, 4 H) 2.25-2.65 (m, 10 H) 3.93 (quintet, J = 8.30 Hz, 1 H) 4.98 -5.13 (m, 1 H) 6.62 (d, J =3.71 Hz, 1 H) 7.08 (d, J =3.51 Hz, 1 H) 8.07 (s, 1 H ); LCMS (M/Z): 362 (M+H).

Example 6:

Compound 6: 6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(2,2,2-trifluoroethyl)spiro[3.3]heptane-2-sulfonamide

6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(2,2,2-trifluoroethyl)spiro[3.3]heptane-2-sulfonamide 6: ¹ H NMR ( 400 MHz, methanol- d 4) δ ppm 2.24-2.61 (m, 8 H) 3.72 (q, J =9.18 Hz, 2 H) 3.84 (quintet, J = 8.25 Hz, 1 H) 4.98-5.13 (m, 1 H) 6.61 (d, J =3.71 Hz, 1 H) 7.08 (d, J =3.71 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 404 (M+H).

Example 7:

Compound 7: N-isobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

N-isobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 7: ¹ H NMR (400 MHz, methanol -d 4) δ ppm 0.92 (d, J =6.83 Hz, 6 H) 1.71 (dt, J =13.47, 6.74 Hz, 1 H) 2.28-2.57 (m , 8 H) 2.83 (d, J =6.83 Hz, 2 H) 3.81 (t, J =8.30 Hz, 1 H) 4.98-5.15 (m, 1 H) 6 .61 (d, J =3.51 Hz, 1 H) 7.08 (d, J =3.71 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 378 (M+H).

Example 8:

Compound 8: N-tert-butyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

N-tert-butyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 8: ¹ H NMR (400 MHz, methanol- d 4) δ ppm 1.34 (s, 9 H) 2.31-2.43 (m, 4 H) 2.47-2.61 (m, 4 H) 3.80 (quintet, J = 8.29 Hz, 1 H) 5.04-5.13 (m, 1 H) 6.65 (d, J =3.66 Hz, 1 H) 7.11 (d, J =3.66 Hz, 1 H) 8.11 (s, 1 H); LCMS (M/Z): 378 (M+H).

Example 9:

Compound 9: N-cyclobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

N-cyclobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 9: ¹ H NMR (400 MHz, methanol -d 4) δ ppm 1.53-1.72 (m, 2 H) 1.99 (ddd, J =10.92, 9.21, 1.83 Hz, 2 H) 2.28-2.47 ( m, 8 H) 2.48-2.56 (m, 3 H) 2.86 (s, 1 H) 3.30-3.31 (m, 3 H) 3.73 (t, J =8, 29 Hz, 1 H) 3.84 (dd, J =8.78, 7.81 Hz, 1 H) 4.91-5.12 (m, 1 H) 6.65 (d, J =3.66 Hz, 1 H) 7.11 (d, J =3.66 Hz, 1 H) 8.11 (s, 1 H); LCMS (M/Z): 376 (M+H).

Example 10:

Compound 10: N-cyclopentyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

N-cyclopentyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 10: ¹ H NMR (400 MHz, methanol -d 4) δ ppm 1.46-1.64 (m, 5 H) 1.68-1.77 (m, 2 H) 1.90-2.00 (m, 2 H) 2.33-2, 44 (m, 4 H) 2.47-2.61 (m, 4 H) 3.66-3.73 (m, 1 H) 3.84 (quintet, J = 8.29 Hz, 1 H) 5 .04-5.13 (m, 1 H) 6.65 (d, J =3.66 Hz, 1 H) 7.11 (d, J =3.66 Hz, 1 H) 8.11 (s, 1H); LCMS (M/Z): 390 (M+H).

Example 11:

Compound 11: N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide

Scheme 2 (example 11, as illustrative):

Intermediate 1: tert-butyl-N-[6-(methylamino)spiro[3.3]heptan-2-yl]carbamate. To a solution of tert-butyl-N-(2-oxospiro[3.3]heptan-6-yl)carbamate (2.08 g, 9.2 mmol) in THF (50 ml) was added MeNH ₂ (13 ml, 26 mmol). The mixture was stirred at approximately -20°C for 3 hours and then at room temperature over the weekend. After cooling to approximately -20°C and stirring for 2 hours, NaBH(OAc) ₃ (6.32 g, 30 mmol) was added. The mixture was stirred for 1 hour and treated with 10% NaHCO ₃ (30 ml). It was then treated with 10% NaOH to pH= ~11. It was extracted with DCM (3×40 ml). The combined organic solution was dried over Na ₂ SO ₄ . After filtration and concentration, the product was obtained as a colorless oil (~2.40 g, 100%). LCMS (M/Z): 241 (M+H). The substance was used immediately in the next step without purification.

Intermediate 2: tert-butyl-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]carbamate. Add tert-butyl-N-[6-(methylamino)spiro[3.3]heptan-2-yl]carbamate (0.96 g, 4.0 mmol, crude), 4-chloro-7H-pyrrolo to a microwave-safe vessel [2,3-d]pyrimidine (0.61 g, 4.0 mmol), DIPEA (1.03 ml, 8.0 mmol) and CH ₃ CN (6 ml). The mixture was heated at 100°C for 1 hour in a microwave oven (75 W and 250 lbf/in ² ). The reaction mixture was cooled to room temperature and kept. The solid (product) was filtered and washed with CH ₃ CN. The filtrate was concentrated and dried in vacuum. The combined solids were an off-white solid (~0.66 g, 46%). ¹ H NMR (400 MHz, methanol- d 4) δ ppm 1.41 (s, 9 H) 1.89-2.08 (m, 2 H) 2.20-2.37 (m, 4 H) 2.38-2.57 (m, 2 H) 3.27 (s, 3 H) 3.94 (br. s., 1 H) 4.97-5.15 (m, 1 H) 6 .60 (d, J =3.71 Hz, 1 H) 7.07 (d, J =3.71 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 358 (M+H).

Intermediate 3: N2-methyl-N2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)spiro[3.3]heptane-2,6-diamine. Into a 40 ml vessel containing tert-butyl-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]carbamate (~ 18 mg, 0.05 mmol) MeOH (0.5 ml) was added, then 4M HCl in dioxane (1 ml). The mixture was stirred at RT for 1 hour. Concentration gave the product as a white solid (~13 mg, ~89%). LCMS (M/Z): 258 (M+H). The mixture was used immediately without purification.

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide 11. Into a 40 ml vessel containing N2-methyl- N2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)spiro[3.3]heptane-2,6-diamine (~13 mg, 0.051 mmol) added DMF (1.5 ml), DMAP (~ 6.1 mg, 0.050 mmol), DIPEA (~87 µl, 0.50 mmol) and PhSO ₂ Cl (~13 mg in 0.13 ml DMF, 0.075 mmol). The mixture was stirred at room temperature for 30 minutes while being monitored by LCMS. After a further 30 min the mixture was treated with water (0.2 ml), DIPEA was removed in vacuo and the remaining solution in DMF was chromatographed on a C18 ISCO column (50 g), eluting with MeOH and water. After concentration and lyophilization, the product was obtained as a white solid (~11 mg, 52%). ¹ H NMR (400 MHz, methanol- d 4) δ ppm 1.75-1.95 (m, 2 H) 2.01-2.41 (m, 6 H) 3.22 (s, 3 H) 3.66 (t, J =8.00 Hz, 1 H) 4.91-5.04 (m, 1 H) 6.56 (d, J =3.51 Hz, 1 H) 7.05 (d, J =3.51 Hz, 1 H) 7.50-7.68 (m, 3 H) 7.80-7.88 (m, 2 H) 8.04 (s, 1 H); LCMS (M/Z): 398 (M+H).

The following compounds were prepared using similar procedures.

Example 12:

Compound 12: 2-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide

2-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide 12: ¹ H NMR (400 MHz, methanol- d 4) δ ppm 1.94-2.09 (m, 3 H) 2.12-2.37 (m, 5 H) 3.21 (s, 3 H) 3.65 (quintet , J =8.20 Hz, 1 H) 4.90-5.03 (m, 1

H) 6.56 (d, J =3.51 Hz, 1 H) 7.05 (d, J =3.51 Hz, 1 H) 7.42-7.53 (m, 1 H) 7.58 (d, J =3.71 Hz, 2 H) 8.00-8.09 (m, 2 H); LCMS (M/Z): 432 (M+H).

Example 13:

Compound 13: 4-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide

4-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide 13: ¹ H NMR (400 MHz, methanol- d 4) δppm 1.73-1.96 (m, 2 H) 2.04-2.28 (m, 4 H) 2.28-2.42 (m, 2 H) 3, 22 (s, 3 H) 3.67 (quintet, J =8.15 Hz, 1 H) 4.91-5.06 (m, 1 H) 6.56 (d, J =3.71 Hz, 1 H) 7.06 (d, J =3.51 Hz, 1 H) 7.57 (d, J =8.59 Hz, 2 H) 7.81 (d, J =8.59 Hz, 2 H) 8.04(s, 1H); LCMS (M/Z): 432 (M+H).

Example 14:

Compound 14: N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]-4-(trifluoromethyl)benzenesulfonamide

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]-4-(trifluoromethyl)benzenesulfonamide 14: ¹ H NMR (400 MHz, methanol- d 4) δ ppm 1.79-1.97 (m, 2 H) 2.07-2.29 (m, 4 H) 2.29-2.42 (m, 2 H ) 3.22 (s, 3 H) 3.72 (quintet, J =8.15 Hz, 1H) 4.92-5.04 (m, 1 H) 6.57 (d, J =3.71 Hz , 1 H) 7.05 (d, J =3.51 Hz, 1 H) 7.88 (d, J =8.20 Hz, 2 H) 7.99-8.07 (m, 3 H); LCMS (M/Z): 466 (M+H).

Example 15:

Compound 15: N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]methanesulfonamide

Scheme 3 (example 15, as illustrative):

Intermediate 1: tert-butyl-N-[2-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]spiro[3.3]heptan-6-yl] carbamate Add tert-butyl-N-[6-(methylamino)spiro[3.3]heptan-2-yl]carbamate (0.48 g, 2.0 mmol, crude), 4-chloro-7-( p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidine (0.61 g, 2.0 mmol), DIPEA (0.5 ml) and CH ₃ CN (5 ml). The mixture was heated at 100°C for 1 hour in a microwave oven (75 W and 250 lbf/in ² ). It was then cooled to room temperature. After removal of the solvent, it was purified on an ISCO silica column and eluted with DCM and MeOH. After concentration, an almost white solid was obtained (~0.64 g, 62.7%). LCMS (M/Z): 512 (M+H).

Intermediate 2: N2-methyl-N2-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]spiro[3.3]heptane-2,6-diamine. Into a 40 ml vessel containing tert-butyl-N-[2-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]spiro[3.3]heptane-6 -yl]carbamate (~1.24 g, 2.2 mmol), MeOH (1 ml) was added, then 4M HCl in dioxane (4 ml). The mixture was stirred at room temperature for 1 hour. Concentration gave the product as a light yellow solid (1.12 g, ~100%). LCMS (M/Z): 412 (M+H). The mixture was used immediately without purification.

Intermediate 3: N-[2-[methyl-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]spiro[3.3]heptan-6-yl]methanesulfonamide. Into a 40 ml vessel containing N2-methyl-N2-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]spiro[3.3]heptane-2,6-diamine (~20 mg , 0.05 mmol) DCM (1.5 ml), DMAP (~6.1 mg, 0.05 mmol), DIPEA (~87 μl, 0.05 mmol) and MeSO ₂ Cl (2 drops) were added. The mixture was stirred at room temperature for 2 hours. After removal of the solvent, the crude material (~20 mg, ~100%) was immediately used in the next step. LCMS (M/Z): 490 (M+H).

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]methanesulfonamide 15. To a sulfonamide solution (~20 mg, ~0. 05 mmol) in isopropanol (1 ml) and water (1 ml) was added LiOH.H ₂ O (42 mg, 1 mmol). The mixture was stirred at 50-55°C for 2 hours and at room temperature overnight. After removal of the solvent, it was purified on a C18 ISCO column (50 g) and eluted with MeOH and water. Concentration gave a white solid (1.5 mg, 9.0%). ¹ H NMR (400 MHz, methanol- d 4) δppm 1.20 (d, J =6.83 Hz, 1 H) 2.00-2.15 (m, 2 H) 2.20-2 .52 (m, 5 H) 2.55-2.67 (m, 1 H) 2.87 (s, 3 H) 3.75-3.86 (m, 1 H) 4.99-5.15 (m, 1 H) 6.61 (d, J =3.71 Hz, 1 H) 7.08 (d, J =3.71 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 336 (M+H).

The following compounds were prepared using similar procedures.

Example 16:

Compound 16: N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]ethanesulfonamide

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]ethanesulfonamide 16. ¹ H NMR (400 MHz, methanol- d 4 ) δppm 1.29 (t, J =7.42 Hz, 3 H) 2.01-2.15 (m, 2 H) 2.23-2.48 (m, 5 H) 2.53 -2.66 (m, 1 H) 2.97 (q, J =7.42 Hz, 2 H) 3.22-3.28 (m, 3 H) 3.73-3.82 (m, 1 H) 5.02-5.11 (m, 1 H) 6.61 (d, J =3.51 Hz, 1 H) 7.08 (d, J =3.51 Hz, 1 H) 8.07 (s, 1H); LCMS (M/Z): 350 (M+H).

Example 17:

Compound 17: N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide 17. ¹ H NMR (400 MHz, methanol- d 4) δppm 1.04 (t, J =7.42 Hz, 3 H) 1.72-1.82 (m, 2 H) 2.01-2.15 (m, 2 H ) 2.23-2.48 (m, 5 H) 2.56-2.63 (m, 1 H) 2.91-2.97 (m, 2 H) 3.22-3.27 (m, 3 H) 3.73-3.82 (m, 1 H) 5.02-5.12 (m, 1 H) 6.61 (d, J =3.71 Hz, 1 H) 7.08 (d , J =3.71 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 364 (M+H).

Example 18:

Compound 18: N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-2-sulfonamide

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-2-sulfonamide 18. ¹ H NMR (400 MHz, methanol- d 4) δppm 1.22-1.36 (m, 6 H) 2.08-2.20 (m, 2 H) 2.26-2.49 (m, 5 H) 2, 54-2.72 (m, 1 H) 3.04 (s, 1 H) 3.12 (quintet, J =6.83 Hz, 1 H) 3.34-3.47 (m, 1 H) 3 .71-3.87 (m, 1 H) 5.10 (ddd, J =9.45, 7.75, 1.83 Hz, 1 H) 6.64 (d, J =3.69 Hz, 1 H) 7.11 (d, J =3.42 Hz, 1 H) 8.10 (s, 1 H); LCMS (M/Z): 364 (M+H).

Example 19:

Compound 19: 2-methyl-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide

2-methyl-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide 19. ¹ H NMR (400 MHz, methanol- d 4) δ ppm 1.11 (dd, J =6.83, 0.73 Hz, 6 H) 2.06-2.24 (m, 3 H) 2.26 -2.42 (m, 4 H) 2.45-2.51 (m, 1 H) 2.63 (ddd, J =10.98, 7.07, 5.61 Hz, 1 H) 2.89 (d, J =6.34 Hz, 2 H) 3.30-3.31 (m, 3 H) 3.77-3.85 (m, 1 H) 5.06-5.14 (m, 1 H) 6.64 (d, J =3.66 Hz, 1 H) 7.11 (d, J =3.42 Hz, 1 H) 8.10 (s, 1 H); LCMS (M/Z): 378 (M+H).

Example 20:

Compound 20: N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]cyclopentanesulfonamide

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]cyclopentanesulfonamide 20. ¹ H NMR (400 MHz, methanol -d 4 ) δ ppm 1.59-1.73 (m, 2 H) 1.73-1.84 (m, 2 H) 1.88-2.05 (m, 4 H) 2.05-2 .21 (m, 3 H) 2.27-2.42 (m, 4 H) 2.44-2.50 (m, 1 H) 2.55-2.71 (m, 2 H) 3.27 -3.31 (m, 3 H) 3.34-3.40 (m, 1 H) 3.40-3.51 (m, 1 H) 3.79-3.87 (m, 1 H) 5 .05-5.15 (m, 1 H) 6.61-6.67 (m, 1 H) 7.11 (d, J =3.66 Hz, 1 H) 8.08-8.12 (m , 1H); LCMS (M/Z): 390 (M+H).

Example 21:

Compound 21: 3,3,3-trifluoro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1 -sulfonamide

3,3,3-trifluoro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide 21 ^.1 H NMR (400 MHz, methanol- d 4) δ ppm 2.04-2.18 (m, 2 H) 2.27-2.44 (m, 4 H) 2.47-2, 52 (m, 1 H) 2.59-2.71 (m, 3 H) 3.17-3.28 (m, 2 H) 3.30-3.31 (m, 3 H) 3.81- 3.89 (m, 1 H) 5.06-5.15 (m, 1 H) 6.64 (d, J =3.66 Hz, 1 H) 7.11 (d, J =3.42 Hz , 1 H) 8.10 (s, 1 H); LCMS (M/Z): 418 (M+H).

Example 22:

Compound 22: N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)methanesulfonamide

Scheme 4 (example 22, as illustrative):

Intermediate 1: 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine. To a cooled (0°C) suspension of NaH (1.56 g, 39.1 mmol, 60% in mineral oil) in DMA (40 ml) a solution of 4-chloro-7H-pyrrolo[2,3-d ]pyrimidine (5.00 g, 32.6 mmol) in DMA (40 ml) at a rate to control excess gas formation. After addition by cannula was completed, the reaction mixture was stirred in an ice bath for 30 min, then a solution of SEMCl (6.92 mL, 39.1 mmol) in DMA (20 mL) was added dropwise. After the dropwise addition was complete, the reaction mixture was removed from the ice bath and stirred at room temperature for 1 hour. The reaction mixture was slowly poured into water (100 ml) and the mixture was extracted with 3×150 ml EtOAc. The combined organic fractions were washed with 1×100 ml saturated aqueous NaCl, dried over Na ₂ SO ₄ filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (330 g, Isco column, 0 to 25% EtOAc in heptane for 35.4 min) to give 8.23 g (89%) 4-chloro-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine in the form of a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.66 (s, 1H), 7.85 (d, J =3.7 Hz, 1H), 6.69 (d, J =3.7 Hz, 1H), 5.62 (s, 2H), 3.52-3.46 (m, 2H), 0.82-0.75 (m, 2H), -0.12 - -0.16 ( m, 9H). LC/MS RT=1.49 min, 284.2 [M+H] ⁺ .

Intermediate 2: 6-(methylamino)spiro[3.3]heptan-2-ol. To a cooled (13°C) suspension of tert-butyl (6-hydroxyspiro[3.3]heptan-2-yl)carbamate (2.50 g, 11.0 mmol) in toluene (26 ml) in a 0.25 round bottom three-neck flask l, equipped with a reflux condenser, N ₂ supply pipe, membrane and thermocouple insertion channel, a solution of REDAl (19.0 ml, 68.4 mmol, 3.60 M) in toluene was added dropwise over 25 min, maintaining the internal temperature below 30°C. After addition was complete, the reaction mixture was refluxed for 1 hour, then cooled to 2°C. The reaction was stopped by slowly adding saturated aqueous Na ₂ SO ₄ solution (40 ml). The resulting mixture was filtered using a Buchner funnel and the solids were washed with 10 ml DCM. The organic layer was separated and the aqueous layer was extracted with 4×20 ml DCM. The combined organic fractions were dried over MgSO ₄ , filtered and concentrated in vacuo to give 1.08 g (70%) 6-(methylamino)spiro[3.3]heptan-2-ol as a colorless oil. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 4.08 (quintet, J = 7.4 Hz, 1H), 3.10-2.98 (m, 1H), 2.43-2.34 (m, 1H), 2.31-2.12 (m, 6H), 1.95-1.84 (m, 2H), 1.77 (td, J =8.4, 10.9 Hz, 2H ). LC/MS RT=1.49 min, 284.2 [M+H] ⁺ .

Intermediate 3: 6-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-ol . A mixture of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.17 g, 7.65 mmol), 6-(methylamino)spiro[3.3 ]heptan-2-ol (1.08 g, 7.65 mmol) and EtN(i-Pr) ₂ (4.00 ml, 22.9 mmol) in n-butanol (15 ml) were heated at 110°C in for 18 hours. The solution was cooled to room temperature, concentrated in vacuo and the resulting residue was chromatographed on silica gel (120 g, Isco column, 0 to 100% EtOAc in heptane over 36 min, then 100% EtOAc over 10 min) to give 1.30 g (44%) 6-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptane -2-ol as a yellowish-brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.13 (s, 1H), 7.29 (d, J =3.7 Hz, 1H), 6.61 (d, J =3.7 Hz, 1H), 5.47 (s, 2H), 5.16-5.05 (m, 1H), 4.90 (d, J =6.4 Hz, 1H), 4.03-3.93 (m, 1H), 3.48-3.42 (m, 2H), 3.18 (s, 3H), 2.44-2.36 (m, 1H), 2.26-2.16 (m , 4H), 2.16-2.08 (m, 1H), 1.91-1.79 (m, 2H), 0.82-0.75 (m, 2H), -0.08 - -0 .14 (m, 9H). LC/MS RT=0.90 min, 389.2 [M+H] ⁺ .

Intermediate 4: 6-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl -4-methylbenzenesulfonate. To a solution of 6-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-ol (1 .30 g, 3.35 mmol), DMAP (82.0 mg, 0.669 mmol) and NEt ₃ (1.50 ml, 10.7 mmol) in DCM (17 ml) was added TsCl (1.08 g, 5. 69 mmol). The reaction mixture was stirred at room temperature for 16 hours, then the reaction mixture was poured into water (15 ml). The organic layer was separated and the aqueous layer was extracted with 3×10 ml EtOAc. The combined organic layers were washed with 1×10 ml saturated aqueous NaHCO ₃ solution, 1×10 ml saturated aqueous NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (40 g, Isco column, 0 to 75% EtOAc in heptane for 19 min) to give 1.70 g (94%) 6-(methyl(7-((2-(trimethylsilyl)ethoxy )methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl-4-methylbenzenesulfonate as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.12 (s, 1H), 7.76 (d, J =8.4 Hz, 2H), 7.46 (d, J =8.2 Hz, 2H), 7.28 (d, J =3.7 Hz, 1H), 6.60 (d, J =3.7 Hz, 1H), 5.46 (s, 2H), 5.04 ( t, J =8.1 Hz, 1H), 4.77-4.66 (m, 1H), 3.48-3.41 (m, 2H), 3.14 (s, 3H), 2.45 -2.39 (m, 4H), 2.29-2.09 (m, 6H), 2.05 (dd, J =7.5, 12.0 Hz, 1H), 0.81-0.75 (m, 2H), -0.10 - -0.14 (m, 9H). LC/MS RT=1.55 min, 543.2 [M+H] ⁺ .

Intermediate 5: 6-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptane-2-carbonitrile . A mixture of 6-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl-4- methylbenzenesulfonate (0.300 g, 0.553 mmol) and KCN (108 mg, 1.66 mmol) were diluted with anhydrous DMSO (2 ml) and the reaction mixture was heated at 90×C for 27 hours. The reaction mixture was allowed to cool to room temperature, poured into water (10 ml) and extracted with 4x5 ml EtOAc. The combined organic fractions were washed with 1×3 ml water, 1×3 ml saturated aqueous NaCl, dried over Na ₂ SO ₄ filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (24 g, Isco column, 0 to 100% EtOAc in heptane for 15 min) to give 115 mg (52%) 6-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptane-2-carbonitrile as a tan solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.14 (s, 1H), 7.30 (d, J =3.7 Hz, 1H), 6.63 (d, J =3.7 Hz, 1H), 5.47 (s, 2H), 5.12-5.01 (m, 1H), 3.48-3.42 (m, 2H), 3.24 (t, J =8, 4 Hz, 1H), 3.18 (s, 3H), 2.57-2.50 (m, 1H), 2.44-2.21 (m, 7H), 0.81-0.76 (m , 2H), -0.12 (s, 9H). LC/MS RT=1.09 min, 398.3 [M+H] ⁺ .

Intermediate 6: N-(6-(aminomethyl)spiro[3.3]heptan-2-yl)-N-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-amine. To a cooled (0°C) solution of 6-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptane -2-carbonitrile (115 mg, 0.289 mmol) in THF (2.4 ml) was added LAH (27 mg, 0.72 mmol). The reaction mixture was stirred for 2 hours at 0°C, then the reaction was stopped with Na ₂ SO ₄ ⋅10H ₂ O (350 mg, added in portions). Stirring was continued until gas evolution ceased and the mixture was diluted with DCM (10 ml) and filtered through celite using a Buchner funnel. The mother liquor was concentrated in vacuo to obtain 115 mg of N-(6-(aminomethyl)spiro[3.3]heptan-2-yl)-N-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-amine as a colorless oil, which was used without further purification. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 8.13 (s, 1H), 7.19 (d, J =3.7 Hz, 1H), 6.67 (d, J =3.7 Hz, 1H), 5.53 (s, 2H), 5.04 (quintet, J =8.5 Hz, 1H), 3.54-3.48 (m, 2H), 3.27 (s, 3H ), 2.63 (d, J =6.8 Hz, 2H), 2.48-2.40 (m, 1H), 2.33-2.24 (m, 4H), 2.15-2, 06 (m, 1H), 1.74 (dd, J =6.8, 12.1 Hz, 1H), 1.61-1.53 (m, 2H), 0.87-0.80 (m, 2H), -0.08 - -0.12 (m, 9H). LC/MS RT=0.61 min, 402.2 [M+H] ⁺ .

Intermediate 7: N-((6-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptane -2-yl)methyl)methanesulfonamide. To a solution of N-(6-(aminomethyl)spiro[3.3]heptan-2-yl)-N-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine -4-amine (57 mg, 0.14 mmol) and NEt ₃ (59 ml, 0.43 mmol) in DCM (1.4 ml) was added methanesulfonyl chloride (13 ml, 0.17 mmol). The reaction mixture was stirred for 2.75 hours, then it was concentrated in vacuo and the residue was chromatographed on silica gel (12 g, Isco column, 0 to 100% EtOAc in heptane for 16 minutes) to give 38 mg (56%) N- ((6-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl )methanesulfonamide as a white solid. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 8.14 (s, 1H), 7.21 (d, J =3.7 Hz, 1H), 6.69 (d, J =3.7 Hz, 1H), 5.53 (s, 2H), 5.06-4.95 (m, 1H), 3.55-3.48 (m, 2H), 3.27 (s, 3H), 3 .05 (d, J =7.2 Hz, 2H), 2.92-2.87 (m, 3H), 2.49-2.36 (m, 2H), 2.35-2.25 (m , 4H), 2.11 (ddd, J =3.5, 8.0, 11.5 Hz, 1H), 1.95-1.78 (m, 2H), 0.87-0.81 (m , 2H), -0.07 - -0.11 (m, 9H). LC/MS RT=1.08 min, 480.2 [M+H] ⁺ .

N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)methanesulfonamide 22. To a solution of N-((6- (methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)methanesulfonamide (38 mg, 0.079 mmol) in DMF (1 ml) was added ethylenediamine (11 ml, 0.16 mmol) and a solution of TBAF (0.16 ml, 0.16 mmol, 1 M) in THF. The reaction mixture was heated at 60°C for 24 h, then additional TBAF (0.32 mL, 0.32 mmol, 1 M) in THF was added. The temperature of the reaction mixture was raised to 90°C and stirred for another 72 hours, then the solution was concentrated in vacuo and the resulting residue was chromatographed on a C18 reverse phase column (43 g, C18 Isco column, 100% water 1 for min, then from 0 to 100% MeOH in water over 15 min) to obtain 18 mg (64%) N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3] heptan-2-yl)methyl)methanesulfonamide 22 as a white solid. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 8.07 (s, 1H), 7.07 (d, J =3.7 Hz, 1H), 6.60 (d, J =3.7 Hz, 1H), 5.05 (quintet, J =8.6 Hz, 1H), 3.27 (s, 3H), 3.05 (d, J =7.2 Hz, 2H), 2.90 ( s, 3H), 2.48-2.36 (m, 2H), 2.34-2.24 (m, 4H), 2.11 (ddd, J = 3.4, 8.1, 11.6 Hz, 1H), 1.92 (dd, J =7.4, 10.9 Hz, 1H), 1.82 (dd, J =7.7, 11.8 Hz, 1H). LC/MS RT=0.32 min, 350.2 [M+H] ⁺

The following compounds were prepared using similar procedures.

Example 23:

Compound 23: N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)ethanesulfonamide

N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)ethanesulfonamide 23. ¹ H NMR (400 MHz, methanol -d ₄ ) δ = 8.07 (s, 1H), 7.07 (d, J =3.7 Hz, 1H), 6.60 (d, J =3.5 Hz, 1H), 5.05 (quintet, J =8.6 Hz, 1H), 3.27 (s, 3H), 3.06-2.98 (m, 4H), 2.47-2.36 (m, 2H), 2, 35-2.24 (m, 4H), 2.11 (ddd, J =3.7, 8.1, 11.5 Hz, 1H), 1.91 (dd, J =7.3, 10.8 Hz, 1H), 1.81 (dd, J =7.5, 11.6 Hz, 1H), 1.29 (t, J =7.3 Hz, 3H). LC/MS RT=0.39 min, 364.2 [M+H] ⁺ .

Example 24:

Compound 24: N-methyl-6-[methyl(9H-purin-6-yl)amino]spiro[3.3]heptane-2-sulfonamide

Scheme 5 (example 24, as illustrative)

Intermediate 1: Benzyl-N-(2-hydroxyspiro[3.3]heptan-6-yl) -N -methylcarbamate. Benzyl chloroformate (1.50 ml, 10.5 mmol) was added with stirring to a solution of 6-(methylamino)spiro[3.3]heptan-2-ol (1.59 g, 10.5 mmol), an aqueous solution of sodium carbonate (21, 1 ml, 21.1 mmol 1 N solution) and EtOAc (10.5 ml) at 0°C. After addition was complete, the ice water bath was removed and the reaction mixture was stirred at ambient temperature for 4 hours, then the layers were separated and the aqueous layer was washed with EtOAc (2 x 10 mL). The organic layers were combined, washed with brine (1×10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give a colorless oil (2.46 g, 85%). ¹ H NMR (400 MHz, chloroform- d ): δ ppm 1.91 (dt, J =11.42, 6.98 Hz, 2H), 2.03 (s, 1H), 2.05- 2.21 (m, 4H), 2.27 (dt, J =11.66, 5.98 Hz, 1H), 2.43-2.51 (m, 1H), 2.82 (s, 3H) , 4.18 (quintet, J =7.22 Hz, 1H), 5.10 (s, 2H), 7.31-7.38 (m, 5H); m/z 276 [M+H] ⁺ .

Intermediate 2: [6-[Benzyloxycarbonyl(methyl)amino]spiro[3.3]heptan-2-yl]-4-methylbenzenesulfonate. p-Toluenesulfonyl chloride (2.09 g, 11.0 mmol) was added to the solution of benzyl-N-(2-hydroxyspiro[3.3]heptan-6-yl) -N -methylcarbamate (2.35 g, 8.55 mmol) with stirring ), triethylamine (2.66 ml, 19.1 mmol), DMAP (233 mg, 1.91 mmol) and CH ₂ Cl ₂ (35 ml). The reaction mixture was stirred for 18 hours, then the solution was poured into water (50 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×50 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography using a gradient of 0 to 75% EtOAc in heptane to give the title compound as a colorless oil (3.14 g, 86%). ¹ H NMR (400 MHz, chloroform- d ): δ ppm 2.17-2.34 (m, 3H), 2.37-2.64 (m, 6H), 2.78 (d, J =5.27 Hz, 3H), 3.18 (s, 3H), 3.74 (quintet, J =8.30 Hz, 1H), 3.95 (q, J =5.08 Hz, 1H), 4.94-5.06 (m, 1H), 6.59 (d, J =4.10 Hz, 1H), 7.27 (s, 2H), 7.44 (d, J =4.10 Hz , 1H), 8.03 (d, J =8.39 Hz, 2H), 8.37 (s, 1H); m/z 430 [M+H] ⁺ .

Intermediate 3: S -[6-[Benzyloxycarbonyl(methyl)amino]spiro[3.3]heptan-2-yl]ethanethioate. Potassium thioacetate (6.62 g, 58.0 mmol) was added with stirring to a solution of [6-[benzyloxycarbonyl(methyl)amino]spiro[3.3]heptan-2-yl]-4-methylbenzenesulfonate (5.00 g, 11. 6 mmol) and DMSO (50 ml). The outside temperature was raised to 60°C and the heterogeneous solution initially became homogeneous. After 17 hours at 60°C, the solution was cooled and the reaction mixture was diluted with EtOAc (50 ml) and aqueous NaHCO ₃ solution (75 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×50 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography using a gradient of 0 to 40% EtOAc in heptane to give the title compound as a colorless oil (3.26 g, 84%). ¹ H NMR (400 MHz, chloroform- d ): δ ppm 1.98-2.20 (m, 5H), 2.25 (s, 3H), 2.29-2.44 (m, 2H ), 2.56 (ddd, J =11.47, 7.66, 3.90 Hz, 1H), 2.81 (s, 3H), 3.93 (quintet, J =8.35 Hz, 1H) , 4.15-4.64 (m, 1H), 5.09 (s, 2H), 7.26-7.37 (m, 4H); m/z 334 [M+H] ⁺ .

Intermediate 4: Benzyl-N-(2-chlorosulfonylspiro[3.3]heptan-6-yl) -N -methylcarbamate. A solution of S- [6-[benzyloxycarbonyl(methyl)amino]spiro[3.3]heptan-2-yl]ethanethioate and acetonitrile (11 ml) was slowly added dropwise to the NCS solution (2.87 g, 20.9 mmol) with stirring. , a mixture of acetic acid:H ₂ O (0.80 ml of a 1:1 solution by volume) and acetonitrile (12 ml) at ambient temperature at such a rate that the internal temperature of the solution does not exceed 30 ° C. After 15 min, the mixture was diluted with EtOAc (80 ml), washed with saturated aqueous NaHCO ₃ (1 x 20 ml), washed with brine (1 x 20 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and purified by chromatography on silica gel using a gradient from 0 to 40% EtOAc in heptane to give the title compound as a white solid (1.53 g, 61%). ^1H NMR (400 MHz, chloroform- d ): δ ppm 2.17-2.26 (m, 2H), 2.27-2.38 (m, 2H), 2.45 (ddd, J =12.45, 8.74, 3.22 Hz, 1H), 2.57-2.65 (m, 1H), 2.66-2.81 (m, 3H), 2.82 (s, 3H ), 4.29 (quintet, J =8.20 Hz, 1H), 4.35-4.55 (m, 1H), 5.10 (s, 2H), 7.28-7.38 (m, 6H); m/z 358 [M+H] ⁺ .

Intermediate 5: Benzyl-N-methyl- N- [2-(methylsulfamoyl)spiro[3.3]heptan-6-yl]carbamate. Methylamine (10.7 ml, 4.28 mmol 2M solution in THF) was added dropwise to a solution of benzyl-N-(2-chlorosulfonylspiro[3.3]heptan-6-yl) -N -methylcarbamate (1.53 g, 4. 28 mmol) and THF (12.2 ml) at 0°C. The reaction mixture was allowed to warm to ambient temperature with stirring overnight. After 17 hours, the solution was poured into water (50 ml) and extracted with EtOAc (3×50 ml). Organic extracts were combined, washed with brine (1×30 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane to obtain the title compound as a white solid substances (1.19 g, 79%). ^1H NMR (400 MHz, chloroform- d ): δ ppm 2.09-2.17 (m, 2H), 2.18-2.34 (m, 3H), 2.35-2.43 (m, 1H), 2.44-2.55 (m, 2H), 2.76 (d, J =5.47 Hz, 3H), 2.81 (s, 3H), 3.70 (quintet, J =8.39 Hz, 1H), 3.97 (q, J =4.95 Hz, 1H), 5.09 (s, 2H), 7.28-7.38 (m, 5H); m/z 353 [M+H] ⁺ .

Intermediate 6: N -Methyl-6-(methylamino)spiro[3.3]heptane-2-sulfonamide. Wet 5% Pd/C (700 mg) was placed into a 500 mL round bottom flask that had been purged with nitrogen; a small amount of EtOAc was used to rinse the neck of the flask. Benzyl-N-methyl- N- [2-(methylsulfamoyl)spiro[3.3]heptan-6-yl]carbamate (700 mg, 1.99 mmol) and EtOH (70 ml) were added. The air was pumped out and replaced with hydrogen. After 18 hours, the atmosphere was replaced with nitrogen and the mixture was filtered through a pad of celite, eluting with more EtOAc. The filtrate was concentrated to give the title compound as a white solid (395 mg, 91%). ¹ H NMR (400 MHz, methanol- d 4): δ ppm 1.78-1.90 (m, 2H), 2.20-2.32 (m, 5H), 2.35-2, 48 (m, 4H), 2.65 (s, 3H), 3.05-3.16 (m, 1H), 3.81 (quintet, J = 8.30 Hz, 1 H); m/z 219 [M+H] ⁺ .

Compound 24: N-methyl-6-[methyl(9H-purin-6-yl)amino]spiro[3.3]heptane-2-sulfonamide.

In a 5 mL Wheaton flask, 6-chloro-9H-purine (0.34 mmol, 87.0 mg) and N-methyl-6-(methylamino)spiro[3.3]heptane-2-sulfonamide (0.34 mmol, 52 .0 mg) was dissolved in n-butanol (3.0 ml). N,N-diisopropylethylamine (0.29 ml, 1.7 mmol) was added to it. The reaction mixture was stirred at 80°C for 16 hours. Cooled and the reaction mixture was concentrated. The crude mixture was triturated with acetonitrile (2×2.0 ml) to obtain 67 mg of product (85% purity). It was further purified by preparative HPLC using water/methanol as eluent to obtain a product of 93% purity. LC-MS 337 (M+H); ¹ H-NMR (400 MHz, DMSO-d6) δ ppm 2.11-2.43 (m, 8 H) 2.49-2.58 (m, 3 H) 3.31-3.36 (m, 2 H) 3.69-3.89 (m, 1 H) 5.24-6.04 (m, 1 H) 6.62 -6.93 (m, 1 H) 7.88-8 .12 (m, 1 H) 8.13-8.29 (m, 1 H) 11.86-13.35 (m, 1 H);

The following compounds were prepared using similar procedures.

Example 25:

Compound 25: N-methyl-6-[methyl(1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

N-methyl-6-[methyl(1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide. LC-MS 337 (M+H); ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.08-2.44 (m, 7 H) 2.51-2.58 (m, 3 H) 3.17-3.24 ( m, 3 H) 3.60-3.92 (m, 1 H) 4.68-5.48 (m, 1 H) 6.40 -

7.01 (m, 1 H) 8.16 (d, J=18.35 Hz, 2 H) 12.55-13.69 (m, 1 H).

Examples 26 and 27:

Compounds 26 and 27: Separation of enantiomers of N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide.

The racemic substance was dissolved in MeOH. Separation of enantiomers A and B was carried out on a semipreparative Chiral Tech Chiralpak IF column (30×250 mm, 5 µm) eluting in isocratic mode with a solvent (70% EtOH and 30% hexane). Enantiomer A was collected between 11.1 and 12.1 min. Enantiomer B was collected from 12.7 to 14.1 min. Enantiomers A and B were analyzed on a Chiral Tech Chiralpak IF-3 analytical column (4.6 x 150 mm, 3 μm) eluting in isocratic mode with solvent (60% EtOH and 40% hexane).

Compound 26: Enantiomer A: ¹ H NMR (400 MHz, methanol-d4) δ ppm 2.30-2.41 (m, 4 H) 2.44-2.59 (m, 4 H) 2, 68 (s, 3 H) 3.27 (s, 3 H, overlapped with MeOH-d4) 3.87 (quintet, J=8.30 Hz, 1 H) 5.01-5.10 (m, 1 H ) 6.61 (d, J=3.71 Hz, 1 H) 7.08 (d, J=3.71 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 336 (M+H); retention time on Chiralpak IF-3 column: 6.56 min.

Compound 27: Enantiomer B: ¹ H NMR (400 MHz, methanol-d4) δ ppm 2.30-2.41 (m, 4 H), 2.44-2.59 (m, 4 H) 2 .68 (s, 3 H) 3.27 (s, 3 H, overlapped with MeOH-d4) 3.87 (quintet, J=8.30 Hz, 1 H) 5.01-5.10 (m, 1 H) 6.61 (d, J=3.51 Hz, 1 H) 7.08 (d, J=3.71 Hz, 1 H) 8.07 (s, 1 H); LCMS (M/Z): 336 (M+H); Chiralpak IF-3 column retention time: 8.59 min (broad peak).

Using methods similar to those given in the previous examples, the following was obtained.

Example 28:

Compound 28: 6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide: ¹ H NMR (400 MHz, methanol-d4) δ ppm 8 .07 (s, 1H), 7.08 (d, J=3.7 Hz, 1H), 6.62 (d, J=3.7 Hz, 1H), 5.13-5.00 (m, 1H), 3.83-3.72 (m, 1H), 3.28 (s, 3H, overlapped with MeOH-d4), 2.63-2.22 (m, 9H); LCMS (M/Z): 322 (M+H).

Example 29:

Compound 29: N,N-dimethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide

N,N-dimethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide: ¹ H NMR (400 MHz, methanol-d4) δ ppm 8.07 (s, 1H), 7.08 (d, J=3.5 Hz, 1H), 6.62 (d, J=3.7 Hz, 1H), 5.13- 5.01 (m, 1H), 3.93 (t, J=8.4 Hz, 1H), 3.28 (s, 3H), 2.82 (s, 6H), 2.65-2.46 (m, 4H), 2.41-2.26 (m, 4H); LCMS (M/Z): 350 (M+H).

Example 30:

Compound 30: N-methyl-N-(2-pyrrolidin-1-ylsulfonylspiro[3.3]heptan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

N-methyl-N-(2-pyrrolidin-1-ylsulfonylspiro[3.3]heptan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine: ¹ H NMR (400 MHz, methanol-d4 ) δ ppm 8.08 (br s, 1H), 7.08 (d, J=3.5 Hz, 1H), 6.62 (d, J=3.7 Hz, 1H), 5, 16-4.95 (m, 1H), 3.96 (quintet, J=8.4 Hz, 1H), 3.27 (s, 3H, overlapped with MeOH-d4), 2.69-2.21 ( m, 8H), 1.97-1.83 (m, 4H); LCMS (M/Z): 376 (M+H).

Abbreviations:

DCM=dichloromethane

DMA=dimethylacetamide

DMF=dimethylformamide

DMAP=4-dimethylaminopyridine

LAH=lithium aluminum hydride

NaH=sodium hydride

REDAl=sodium bis(2-methoxyethoxy)aluminum hydride

SEMCl=2-(Trimethylsilyl)ethoxymethyl chloride

TBAF=tetrabutyl ammonium fluoride

THF=tetrahydrofuran

TsCl=p-toluenesulfonyl chloride

Study

The biological activity of the compounds proposed in the present invention was studied using the methods described below.

Representative compounds were screened for activity against Jak1 using Thermo Fisher Scientific using their Z'-Lyte™ protocol described below. Screening for selectivity with respect to other kinases can be performed using similar methods.

Z′-LYTE Assay Conditions: Test compounds were screened in 1% DMSO (final) wells. Three concentrations (10, 100 and 1000 nM) of the test compounds were used for screening.

Peptide/kinase mixtures: All peptide/kinase mixtures are diluted to 2× working concentration in a suitable kinase buffer (for JAK1, a 2× JAK1/Tyr 06 mixture was prepared in 50 mM HEPES pH 6.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA, 0.02% NaN3 The final 10 µl kinase reaction mixture contained 21.2-91.5 ng JAK1 and 2 µM Tyr 06 in 50 mM HEPES pH 7.0, 0.01% BRIJ -35, 10 mM MgCl2, 1 mM EGTA, 0.01% NaN3 After incubating the kinase reaction mixture for 1 hour, add 5 µl of a 1:128 dilution of developing reagent A.).

ATP Solution: All ATP solutions are diluted to 4× working concentration in kinase buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA).

ATP: The apparent Km value was previously determined using Z'-LYTE analysis.

10× New PKC lipid mixture: 2 mg/ml phosphatidylserine, 0.2 mg/ml DAG in 20 mM HEPES, pH 7.4, 0.3% CHAPS.

To prepare 5 ml of 10× new PKC lipid mixture:

1. Place 10 mg of phosphatidylserine (Avanti Polar Lipids Part# 8400032C or 840039C) and 1 mg of DAG (Avanti Polar Lipids Part# 800811C) into a glass test tube.

2. Chloroform is removed from the lipid mixture by evaporation in a nitrogen stream until a thin transparent film is formed. Continuous rotation of the tube at an angle to provide maximum surface area of the lipid solution promotes the thinnest film possible.

3. Add 5 ml of resuspension buffer, 20 mM HEPES, 0.3% CHAPS, pH 7.4 to the dried lipid mixture

4. Gently heat to 50-60°C for 1-2 minutes and shake at short intervals until the lipids dissolve to form a clear or slightly cloudy solution. Lipids usually go into solution after 2-3 heating/shaking cycles.

5. For use, an aliquot in one volume is cooled to room temperature and stored at -20°C.

Bar-coded Corning Assay Protocol, Low Volume NBS, Black 384-Well Plate (Corning Cat. #4514)

1. 100 nl - 100× test compound in 100% DMSO

2. 2.4 µl - kinase buffer

3. 5 µl - 2× peptide/kinase mixture

4. 2.5 µl - 4× ATP solution

5. Shake the tablet for 30 s

6. The reaction mixture with the kinase is incubated for 60 minutes at room temperature

7. 5 µl - Developing reagent solution

8. Shake the tablet for 30 s

9. Incubate the development reaction for 60 minutes at room temperature

10. Read the fluorescence signal of the plates on the reader and analyze the data.

Table: Data Summary Compound Connection name Inhibition, %, at 10 nM Inhibition, %, at 100 nM Inhibition, %, at 1000 nM 1 N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 71 92 96 2 N-ethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 52 90 98 3 6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-propylspiro[3.3]heptane-2-sulfonamide 57 92 98 4 N-isopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 23 75 95 5 N-cyclopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 61 94 99 6 6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(2,2,2-trifluoroethyl)spiro[3.3]heptane-2-sulfonamide 63 93 96 7 N-isobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 42 88 97 8 N-tert-butyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 37 82 94 9 N-cyclobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 64 93 99 10 N-cyclopentyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 52 84 97 eleven N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide eleven 81 95 12 2-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide 15 60 90 13 4-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide 27 77 95 14 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]-4-(trifluoromethyl)benzenesulfonamide 1 56 92 15 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]methanesulfonamide 31 78 95 16 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]ethanesulfonamide 28 76 96 17 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide 38 83 95 18 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-2-sulfonamide 23 71 94 19 2-methyl-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide 27 73 94 20 N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]cyclopentanesulfonamide 33 82 97 21 3,3,3-trifluoro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide 46 85 98 22 N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)methanesulfonamide 76 96 96 23 N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)ethanesulfonamide 66 94 97 24 N-methyl-6-[methyl(9H-purin-6-yl)amino]spiro[3.3]heptane-2-sulfonamide 4 21 72 25 N-methyl-6-[methyl(1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 2 4 19 26 (enantiomer A)-N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 77 96 98 27 (enantiomer B)-N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 12 52 89 28 6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 13 60 94 29 N,N-dimethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide 55 92 98 thirty N-methyl-N-(2-pyrrolidin-1-ylsulfonylspiro[3.3]heptan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 43 89 99

Embodiments of the present invention include:

1. Compound of formula I or pharmaceutical or veterinary salt thereof

Formula I,

Where

X is N, CH or CR ³ ;

Y is N, CH or CR ³ ;

R ¹ means (CH ₂ ) _n SO ₂ N(R ² ) ₂ , (CH ₂ ) _m NHSO ₂ R ² , (CH ₂ ) _n CON(R ² ) ₂ or (CH ₂ ) _m NHCOR ²

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, 3 or 4;

each R ² is independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or

two R ² may combine with the nitrogen atom to which they are attached to form an unsubstituted or substituted 5- to 7-membered ring, which may include one or more additional heteroatoms selected from the group consisting of N, O or S, and which may include one or more multiple bonds;

And

each R ³ is independently C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, hydroxy, C _1-6 alkoxy, C _1-6 haloalkyloxy group, C _1-6 alkylsulfonyl, C _1-6 thioalkyl, mercapto group, halogen, nitro group, cyano group, amino group, C _1-6 alkylamino group, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl,

if X is CR ³ and Y is CR ³ , each CR ³ can combine with the atoms to which they are attached to form a fused 5- to 7-membered ring.

2. The compound according to paragraph 1, where R ¹ means (CH ₂ ) _n SO ₂ NHR ² or (CH ₂ ) _m NHSO ₂ R ² _.

3. The compound according to paragraph 1 or 2, where R ¹ means (CH ₂ ) _n SO ₂ NHR ² _.

4. Connection according to one of paragraphs 1-3, where n is 0.

5. Connection according to one of paragraphs 1-3, where n is 1.

6. A compound according to any of paragraphs 1-5, wherein R ² is C _1-6 alkyl, unsubstituted or substituted cycloalkyl, C _1-6 haloalkyl, or unsubstituted or substituted aryl.

7. The compound of paragraph 6, wherein said cycloalkyl or aryl is substituted by one or more of the following: halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl , C _2-6 haloalkynyl, CN, NO ₂ , NH ₂ , N(C _1-6 alkyl) ₂ , OH or OC _1-6 alkyl.

8. The compound according to paragraph 1 or 2, where R ¹ means (CH ₂ ) _m NHSO ₂ R ² .

9. Connection according to one of paragraphs 1, 2 or 8, where m is 0.

10. Connection according to one of paragraphs 1, 2 or 9, where m is 1.

11. A compound according to any of paragraphs 1, 2 or 8-10, where R ² is C _1-6 alkyl, unsubstituted or substituted cycloalkyl, C _1-6 haloalkyl, or unsubstituted or substituted aryl.

12. The compound of paragraph 11, wherein said cycloalkyl or aryl is substituted by one or more of the following: halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl , C _2-6 haloalkynyl, CN, NO ₂ , NH ₂ , N(C _1-6 alkyl) ₂ , OH or OC _1-6 alkyl.

13. A compound according to any of paragraphs 1-12, where X is CH.

14. A compound according to any of paragraphs 1-13, where Y is CH.

15. A compound as defined in any one of paragraphs 1-12, wherein one or more of X and Y is CR ³ , wherein each R ³ is halogen, cyano or C _1-6 alkyl.

16. A connection selected from the group consisting of:

N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-ethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-propylspiro[3.3]heptane-2-sulfonamide;

N-isopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-cyclopropyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(2,2,2-trifluoroethyl)spiro[3.3]heptane-2-sulfonamide;

N-isobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-tert-butyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-cyclobutyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-cyclopentyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide;

2-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide;

4-chloro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]benzenesulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]-4-(trifluoromethyl)benzenesulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]methanesulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]ethanesulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-2-sulfonamide;

2-methyl-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propane-1-sulfonamide;

N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]cyclopentanesulfonamide;

3,3,3-trifluoro-N-[2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptan-6-yl]propan-1-sulfonamide;

N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)methanesulfonamide;

N-((6-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)methyl)ethanesulfonamide;

N-methyl-6-[methyl(9H-purin-6-yl)amino]spiro[3.3]heptane-2-sulfonamide;

(enantiomer A)-N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

(enantiomer B)-N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide;

N,N-dimethyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide; And

N-methyl-N-(2-pyrrolidin-1-ylsulfonylspiro[3.3]heptan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

or its veterinary or pharmaceutical salt.

17. A composition containing a compound according to any of paragraphs 1-16 and a pharmaceutically or veterinarily acceptable carrier.

18. A combination containing a compound according to any of paragraphs 1-16 and one or more other pharmaceutically or veterinary active substances.

19. A method for treating itching or atopic dermatitis, comprising:

administering to a subject in need thereof an effective amount of a compound of any one of paragraphs 1-16.

20. The method of paragraph 19, where the subject is a mammal.

21. The method of paragraph 20, wherein the mammal is selected from the group consisting of the following: humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, livestock mammals, domestic mammals or mammals -satellites.

22. The compound according to any of paragraphs 1-16 for use in medicine.

23. A compound according to any one of paragraphs 1 to 16 for the preparation of a medicament for the treatment of itching or atopic dermatitis.

24. Use of a compound according to any of paragraphs 1-16 for the treatment of itching or atopic dermatitis.

All publications, patents and patent applications cited herein are incorporated herein by reference to the provisions to which such citation is made.

The test compounds in the experiments described in the present invention were used in free form or in salt form.

The particular responses observed may vary according to and depending on the particular active compound selected and whether carriers are contained, as well as the type of formulation and mode of administration used, and such expected changes or differences in results are contemplated by the practice of the present invention.

Although specific embodiments of the present invention are illustrated and described in detail in the present invention, the present invention is not limited thereto. The above detailed description is presented as representative of the present invention and should not be construed as constituting any limitation of the present invention. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the present invention are intended to be included within the scope of the appended claims.

Claims (9)

1. A connection that is: N-methyl-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]spiro[3.3]heptane-2-sulfonamide. 2. A composition for the treatment of itching and atopic dermatitis, comprising an effective amount of a compound according to claim 1 and a pharmaceutically or veterinarily acceptable carrier. 3. A combination for the treatment of itching and atopic dermatitis, containing an effective amount of a compound according to claim 1 and one or more other pharmaceutically or veterinary active substances. 4. A method of treating itching and atopic dermatitis, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1. 5. The method of claim 4, wherein the subject is a mammal. 6. The method of claim 5, wherein the mammal is selected from the group consisting of the following: humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, livestock mammals, domestic mammals, or companion mammals. 7. The compound according to claim 1 for the preparation of a medicinal product for the treatment of itching and atopic dermatitis. 8. Use of a compound according to claim 1 for the treatment of itching and atopic dermatitis.