CN1756553A - 2-cyanopyrrolopyrimidines and pharmaceutical uses thereof - Google Patents

Abstract

The invention relates to pyrrolo pyrimidines of formula (I), wherein Y represents -(CH2)t-O- or -(CH2)r-S-, p is 1 or 2, r is 1, 2 or 3, t is 1, 2 or 3, or Y is -(CH2)j- or -CH=CH-, j is 1 or 2; p is 1 or 2, or Y is -(CH2)f-, f is 1 or 2, p is 1, and the further radicals and symbols have the meaning as defined herein; their preparation, their use as pharmaceuticals, pharmaceutical compositions containing them, the use of such a compound for the manufacture of a pharmaceutical preparation for the treatment of neuropathic pain and to a method for the treatment of such a disease in animals, especially in humans.

Description

2-cyanopyrrolopyrimidines and their pharmaceutical uses

The present invention relates to novel pyrrolopyrimidine-2-carbonitrile derivatives, their preparation, their use as medicaments, pharmaceutical compositions containing them, the use of such compounds in the preparation of pharmaceutical preparations for the treatment of neuropathic pain and their use in animals In particular, methods of treating such diseases in humans.

Cathepsin S is a member of the lysosomal cysteine cathepsin family such as cathepsins B, K, L, and S, which are associated with inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors ( especially tumor invasion or tumor metastasis), coronary artery disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune disease, respiratory disease, infectious disease, and immune-mediated disease (including graft rejection), including a variety of conditions.

Surprisingly, it has now been found that the pyrrolopyrimidine-2-carbonitrile derivatives described herein have advantageous pharmacological properties, inhibiting eg cathepsin S activity. The pyrrolopyrimidine-2-carbonitrile derivatives of formula I are therefore suitable for use in the treatment of diseases in which inhibition of cathepsin S activity can have a beneficial effect.

The pyrrolopyrimidine-2-carbonitrile derivatives of the formula I are especially suitable for the treatment and prophylaxis of neuropathic pain.

Accordingly, the present invention provides pyrrolopyrimidines of formula I:

in:

Y stands for -(CH ₂ ) _t -O- or -(CH ₂ ) _r -S-,

p is 1 or 2,

r is 1, 2 or 3,

t is 1, 2 or 3,

R ₁ stands for

(a) phenyl that is unsubstituted or mono-, di- or trisubstituted by:

(α) Halogen, carboxyl, alkoxy, nitro, alkyl-C(O)-NH-, cycloalkyl-C(O)-NH-, alkyl-C(O)-N(alkyl) -, formyl, alkyl-C(O)-, alkyl-S(O) ₂ -NH-, CF ₃ -alkyl-S(O) ₂ -NH-, pyrrolidinylcarbonyl, piperidinylcarbonyl , Morpholinylcarbonyl, N-alkylpiperazinylcarbonyl, piperidinyl, 1-(alkylcarbonyl)piperidinyl, 1,2,3,6-tetrahydropyridyl, alkylcarbonyl 1,2, 3,6-tetrahydropyridyl, piperazinyl, alkylpiperazinyl, alkylcarbonylpiperazinyl, cycloalkylcarbonylpiperazinyl, alkoxycarbonylpiperazinyl, alkyl-SO ₂ -piperazinyl Base, diazepanyl, alkylcarbonyldiazepanyl, 2-oxo-1-pyrrolidinyl, 3,3-di-alkyl-2-oxo-1-pyrrolidinyl;

(β) R ₃ -alkyl, wherein R ₃ represents hydrogen, hydroxyl, carboxyl, alkyl-N(alkyl)-, alkyl-NH-, 1-pyrrolidinyl, 1-piperidinyl, 4-alkane Base-1-piperazinylcarbonyl, 2,4-dioxa-5,5-(di-alkyl)-oxazolidin-3-yl, R ₄ R ₅ NC(O)-, wherein R ₄ and _R independently of each other represent hydrogen or alkyl; or

(γ) R ₆ R ₇ NC(O)-, wherein R ₆ and R ₇ independently represent hydrogen, alkyl, cycloalkylalkyl, CF ₃ -alkyl or pyridylalkyl;

(b) pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen or alkyl, wherein said alkyl is mono-, di- or trisubstituted by halogen;

(c) pyrimidinyl;

(d) indolyl mono- or disubstituted by alkyl-C(O)-NH-alkyl;

(e) 2-(Alkyl)-benzothiazolyl;

(f) groups of the subformula Ia:

wherein _R is hydrogen, halogen or alkyl, _R is hydrogen or alkyl, and m is 1, 2, 3 or 4;

or

(g) groups of the subformula Ib:

wherein R ₁₀ is hydrogen, halogen or alkyl, R ₁₁ is hydrogen or alkyl, and n is 1, 2, 3 or 4; R ₂ represents alkyl, which is unsubstituted or substituted by: unsubstituted or cycloalkyl mono- or disubstituted by halogen, or phenyl mono- or disubstituted by halogen;

Provided that if Y is O and R _is selected from 3-pyridyl, 4-pyridyl, 5-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-chloro-4-pyridyl, 2- Trifluoromethyl-4-pyridyl, 2-difluoromethyl-4-pyridyl, 4-acetyl-1-piperazinyl-phenyl, 4-methyl-1-piperazinyl-methyl- phenyl, then _R does not represent 1,1-dimethylethyl, and

with the proviso that if Y is S and _R is 4-pyridyl, then _R does not represent 1,1-dimethylethyl;

or

Y is -(CH ₂ ) _j - or -CH=CH-,

j is 1 or 2;

p is 1 or 2,

R ₁ stands for

(a) thienyl, thiazolyl, 1-piperidinyl-carbonyl, or

(b) Unsubstituted or mono-, di- or trisubstituted phenyl by:

(i) alkoxy, _H2NC (O)-, 4-(alkylcarbonyl) 1-piperazinyl, 2-oxo-1-pyrrolidinyl or halogen;

(ii) R ₁₂ -OC(O)-, wherein R ₁₂ is hydrogen or alkyl, or

(iii) R ₁₃ NH-, wherein R ₁₃ represents hydrogen or a group R ₁₄ -alkyl-Z-, wherein Z is CO, SO or SO ₂ and R ₁₄ represents hydrogen, trifluoromethyl or alkoxy,

(iv) R ₁₅ -alkyl, wherein R ₁₅ represents hydrogen, hydroxyl, alkoxy, 1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolidine-2,5-dione-1- Base, 5,5-di-alkyl-oxazolidin-2,4-dione-3-yl or alkyl-N(R ₁₆ )-, wherein R ₁₆ represents hydrogen or alkyl; and

_R2 stands for

(a) Alkyl, which is unsubstituted or substituted by alkenyl, indanyl, cycloalkyl unsubstituted or mono- or disubstituted by halogen or alkyl, cycloalkenyl, unsubstituted Phenyl substituted or mono- or disubstituted by halogen or alkyl;

(b) cycloalkyl; or

(c) alkylcarbonyl;

with the proviso that if Y is _CH2 , _R1 represents 4-chlorophenyl and p is 1, then _R2 does not represent 1,1-dimethylethyl, 1-methylethyl, cyclopropyl, cyclohexyl, 2-methyl-propyl or 2-ethyl-propyl; provided that if p is ₁ , Y is CH and _R represents thienyl, phenyl, methoxyphenyl, propoxyphenyl, 4 -Fluorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-butylphenyl, hydroxymethylphenyl, 4-(5,5-dimethyl-oxazolidine-2,4 -diketo-3-yl-methyl)-phenyl, 4-(methylsulfonylamino)-phenyl, 4-(n-butylsulfonylamino)-phenyl, 4-(ethylsulfonylamino )-phenyl, 4-(n-propylsulfonylamino)-phenyl, 4-(isopropylsulfonylamino)-phenyl, 4-aminophenyl, 4-(acetylamino)-phenyl, 4-(butyrylamino)-phenyl or 4-(diethylaminomethyl)-phenyl, then _R does not represent 1,1-dimethylethyl;

and with the proviso that if p is 1, Y is CH _{and R} represents phenyl which is unsubstituted or substituted by 4-acetyl-1-piperazinyl, then _R does not represent 1-methylethyl;

or

Y is -(CH ₂ ) _f -,

f is 1 or 2,

p is 1,

R ₁ stands for

(a) 1,2,3,6-tetrahydropyridin-1-yl, alkyl-1,2,3,6-tetrahydropyridin-1-yl, di-alkyl-1,2,3,6 -tetrahydropyridin-1-yl, halo-1,2,3,6-tetrahydropyridin-1-yl, phenyl-1,2,3,6-tetrahydropyridin-1-yl, imidazolyl, Alkyl imidazolyl, di-haloimidazolyl, imidazolidin-2,5-dione-1-yl, 5,5-dialkyl-oxazolidin-2,4-dione-3-yl, alkane Imidazolidin-2,5-dione-1-yl, trifluoromethyl-3,4-pyrrolin-1-yl, pyrrolidinyl, alkyl 1-pyrrolidinyl, di-alkylpyrrolidinyl , alkoxypyrrolidinyl, alkyl 2-oxo-1-pyrrolidinyl, di-alkyl 2-oxo-1-pyrrolidinyl, halogenated 1-pyrrolidinyl, di-halogenated 1- Pyrrolidinyl, di-halogenated 1-piperidinyl, triazolyl, nitrotriazolyl, phenylimidazolyl, tetrazolyl, benzo[b]imidazolyl, (1-(alkyl-SO ₂ )-4-piperidinyl)-2,3-dihydro-2-oxo-benzo[b]imidazolyl, 3-(alkylcarbonyl-4-piperidinyl)-2,3-dihydro- 2-oxo-benzo[b]imidazolyl, indolyl, halogenated 1-indolyl, 1,3-dihydro-2-isoindolyl, 2,3-dihydro-1-indolyl Base, 2,3-dihydro-2-oxo-benzo[b]thiazolyl, two-alkoxy 1,2,3,4-tetrahydroquinoline, alkoxy-1,2,3, 4-Tetrahydroisoquinoline;

(b) Groups of substructure Ic:

It is attached to the molecule through a nitrogen atom, where

X is -O-, -(CH ₂ ) _s -CR ₁₇ R ₁₈ -or -NR ₁₈ , wherein

s is 0, 1 or 2, R and R are _{independently} selected from hydrogen, halogen, hydroxy _, alkyl, phenylalkylcarbonyl, carbamoyl, N-phenylcarbamoyl, cyano, pyridyl, Piperidinyl and phenyl unsubstituted or mono- or disubstituted by halogen or alkoxy, or, if X is CR ₁₇ R ₁₈ , R ₁₇ and R ₁₈ together form an oxo group or the group HO-C (O)-CH=, and R ₂₃ , R ₂₄ , R ₂₅ and R ₂₆ are independently selected from hydrogen and alkyl;

(c) The group of the substructure Id:

It is attached to the molecule through a nitrogen atom, where

k is 0, 1 or 2, A is _CH2 or a bond, B is _CH2 or carbonyl, D is _CH2 or carbonyl, E is _CH2 or _NR22 , G is _CH2 or a bond, Q is _CH2 or carbonyl , T is CH ₂ or NR ₂₉ , R ₁₉ represents hydrogen, alkyl, phenylalkyl, alkylcarbonyl or alkyl-SO ₂ -, R ₂₂ is hydrogen

Or alkyl and R ₂₉ is phenyl;

(d) Groups of substructure Ie:

It is attached to the molecule through a nitrogen atom, where

R ₂₇ is alkyl or alkylcarbonyl and R ₂₈ is hydrogen, alkoxy or halogen; or

(e) NR ₂₀ R ₂₁ , wherein R ₂₀ and R ₂₁ are independently selected from hydrogen, alkyl, unsubstituted or hydroxy

Mono- or disubstituted cycloalkyl; and phenyl that is unsubstituted or mono- or disubstituted by 1,2,3-thiadiazolyl, with the proviso that R ₂₀ and R ₂₁ cannot represent hydrogen at the same time; and

_R represents alkyl, which is unsubstituted or substituted by: cycloalkyl which is unsubstituted or mono- or disubstituted by halogen; or phenyl which is mono- or disubstituted by halogen;

with the proviso that _R does not represent 1,1-dimethylethyl in the following cases:

(a) R ₁ is benzo[b]imidazol-1-yl, 1-imidazolyl, 4,5-dichloro-1-imidazolyl, 2-(C ₁ -C ₄ alkyl)-1-imidazolyl , imidazolidine-2,5-dione-1-yl, 5,5-dimethyl-oxazolidine-2,4-dione-3-yl, 1H-1,2,3-triazole-1 -yl, 2H-1,2,3-triazol-2-yl, 3-nitro-1H-1,2,4-triazol-1-yl, 2H-tetrazol-2-yl or 1H-tetra Azol-1-yl, or R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is NR ₁₈ and R ₁₈ is hydrogen, methyl, ethyl, acetyl, 4-pyridyl, 1 - piperidinyl, phenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl or chlorophenyl;

(b) R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is -(CH ₂ ) _s -CR ₁₇ R ₁₈ -, s is 0, and R ₁₇ and R ₁₈ are selected from hydroxyl and Phenyl monosubstituted by chlorine or _R and _R are selected from hydrogen, methoxyphenyl and N-phenyl-carbamoyl; or

(c) R ₁ is a group of substructure Id, k is 1, A is a bond, E is NR ₂₂ , R ₂₂ is hydrogen, G, Q and T are CH ₂ , B and D are carbonyl and R ₁₉ is methyl radical, n-propyl or isobutyl;

Provided that if R ₁ is a group of substructure Id, k is 1, A is a bond, E is NR ₂₂ , R ₂₂ is hydrogen, G, Q and T are CH ₂ , B and D are carbonyl and R ₁₉ is methyl group, or if R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is -(CH ₂ ) _r CR ₁₇ R ₁₈ -, s is 0, and R ₁₇ and

_R18 is selected from hydrogen and phenyl monosubstituted by methoxy, then _R2 does not represent 2-methylpropyl; and with the proviso that if _R1 is a group of substructure Ic, _R23 to _R26 are hydrogen, X is NR ₁₈ and R ₁₈

is methoxyphenyl or ethoxyphenyl, or X is CR ₁₇ R ₁₈ and R ₁₇ and R ₁₈ are selected from hydrogen and methoxyphenyl, then _R does not represent 1-methylethyl;

or its N-oxide or tautomer,

Or such salts of pyrrolopyrimidines, N-oxides or tautomers thereof.

Unless otherwise indicated, the generic terms used above and below preferably have the following meanings in this disclosure:

When the plural form is used to refer to a compound, salt, etc., the singular compound, salt, etc. is also meant. Halogen or halo is especially fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

Alkoxy is especially methoxy, ethoxy, propoxy or n-pentyloxy, also benzyloxy or halogen-lower alkoxy, such as trifluoromethoxy or 1,1,2,2 - tetrafluoroethoxy. Preferably, alkoxy is methoxy, ethoxy or propoxy.

Alkyl is especially an alkyl group containing from 1 and including 1 to 7 and including 7, preferably from 1 and including 1 to 4 and including 4 carbon atoms , which is linear or branched; preferably, the alkyl group is methyl, ethyl, propyl such as n-propyl or isopropyl, butyl such as n-butyl, sec-butyl, isobutyl or tert Butyl, 3-methyl-butyl or 2,2-dimethyl-butyl.

Alkenyl is preferably a chain containing from 2 and including 7 and including 7 carbon atoms, preferably from 2 and including 2 and including 4 and including 4 carbon atoms Alkenyl, which is straight chain or branched. Alkenyl is preferably allyl, butenyl such as 2-butenyl, methyl-butenyl such as 3-methyl-2-butenyl or dimethyl-butenyl such as 2,2- Dimethyl-4-butenyl.

Cycloalkyl is in particular C ₃ -C ₈ cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Cycloalkenyl is in particular C ₅ -C ₈ cycloalkenyl, for example cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl.

In view of the close relationship between the novel compounds in free form and their salt forms including, for example, those salts useful as intermediates in the purification or identification of novel compounds, where appropriate, supra and hereinafter Any reference to a free compound should be understood as referring also to the corresponding salt.

Salt forms are, for example, acid addition salts, preferably acid addition salts of compounds of the formula I having a basic nitrogen atom with organic or inorganic acids, especially pharmaceutically acceptable salts. Suitable inorganic acids are, for example, hydrohalic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, such as acetic acid, propionic acid, caprylic acid, capric acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid , pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexane Formic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid , Ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methyl sulfuric acid, Ethylsulfuric acid, laurylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid or other organic protic acids such as ascorbic acid.

For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts such as picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds (which may be used in pharmaceutical formulations) are used and these are therefore preferred.

The compounds of the invention display valuable pharmacological properties in mammals and are especially useful as inhibitors of cathepsin S. Inhibition of cathepsin S by the compounds of the invention can be demonstrated in vitro by measuring the inhibition of eg recombinant human cathepsin S (in vitro cathepsin S assay).

In vitro assays were performed using recombinant human cathepsin S in clear flat-bottomed 96-well microtiter plates (Greiner GmbH, Germany) at ambient temperature. Constant enzyme and different substrate concentrations ( The substrate is Z-Leu-Leu-4-methylcoumaryl (coumaryl)-7-amide (Bachem (Switzerland)) to determine the inhibition of human cathepsin S. By adding various concentrations of the corresponding substrate The assay was started by adding an enzyme solution (13-fold higher than the final concentration of recombinant human cathepsin S) to the reaction mixture with the compound. A substrate concentration of 3.4-17 μΜ was used. Recombinant human cathepsin S was used at a final concentration of 0.04 nM. Test compounds were used at a concentration of 0.4-2 times the IC50 of the compound for the enzyme being determined. Relative fluorescence was measured for 30 minutes and initial velocity was obtained from each development curve. Inhibition patterns and _Ki values were determined by Dixon plot analysis.

Compounds of the invention generally have an _IC50 for inhibiting human cathepsin S of less than about 100 nM to about 1 nM or less, preferably about 5 nM or less, eg about 0.5 nM.

In view of their activity as cathepsin S inhibitors, the compounds of formula I are especially useful in mammals as agents for the treatment and prophylaxis of diseases and medical conditions associated with elevated levels of cathepsin S activity. These diseases include chronic neuropathic pain, examples of which are e.g. diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, painful diabetic polyneuropathy, post-stroke pain (central pain), amputation Posterior pain, myolopathic or radiculopathic pain (eg, spinal stenosis, arachnoiditis, root mantle fibrosis), atypical facial pain, and causalgia-like syndrome ( complex regional pain syndrome), autoimmune diseases including but not limited to juvenile diabetes and multiple sclerosis, allergic diseases including but not limited to asthma, and allograft immune responses including but not limited to organ transplants Rejection.

Beneficial effects are evaluated in in vitro and in vivo pharmacological assays well known in the art and described herein. The above-mentioned properties can be confirmed in in vitro and in vivo tests, it is advantageous to use organs and tissues of mammals, such as rats, mice, dogs, rabbits, monkeys or isolated as well as natural or prepared by recombinant techniques, for example. Enzyme products. The compounds of the invention can be applied in vitro in the form of solutions, such as preferably aqueous solutions or suspensions, and can be used enterally or parenterally in vivo, for example in the form of suspensions or in the form of aqueous solutions or in the form of solid capsules or tablets, advantageously Oral application. Dosages in vitro may range from about 10 ^"5 to 10 ^"9 molar. The dosage in vivo may be about 0.1 to 100 mg/kg depending on the route of administration.

The efficacy of the compounds of the invention in the treatment of chronic inflammatory pain or neuropathic pain can be determined using the following in vivo animal models.

Chronic Inflammatory Pain Model:

Complete Freund's adjuvant-induced mechanical hyperalgesia can be used as a model of chronic inflammatory pain (Stein, C. et al. Pharmacol. Biochem. Behav. (1988) 31:445-451). In this model, typically male Sprague-Dawley or Wistar rats (200-250 g) receive an intraplantar injection of 25 μl of complete Freund's adjuvant in one hind paw. Significant inflammation was present in this hind foot. When mechanical hyperalgesia is considered fully established, drugs are generally administered 24 hours after the onset of inflammation to assess efficacy.

Chronic Neuropathic Pain Models:

Two animal models of chronic neuropathic pain involving some form of peripheral nerve injury are available. In the Seltzer model (Seltzer et al. (1990) Pain 43:205-218), rats are anesthetized and a small incision is made along the middle of one thigh (usually the left) to expose the sciatic nerve. Carefully separate the nerve from the surrounding connective tissue at a location close to the trochanter just distal to the point where the posterior biceps semitendinosus nerve exits the common sciatic nerve. Insert a 7-0 silk suture into the nerve with a 3/8 bent back-cut microneedle and tie tightly so that the dorsal 1/3 to 1/2 of the nerve's thickness is secured within the tie. The muscle and skin are closed with sutures and clips, and the wound is dusted with antibiotic powder. In mock animals, the sciatic nerve was exposed but not ligated, and the wound was closed as in non-mock animals.

In the chronic confinement injury (CCI) model (Bennett, G.J. and Xie, Y.K. Pain (1988) 33:87-107), rats are anesthetized and a small incision is made along the middle of one thigh (usually the left) to expose the sciatic nerve. The nerve was separated from the surrounding connective tissue and four 4/0 chrmic gut ligatures were tied loosely around the nerve, about 1 mm between each, so that the ligature just limited the nerve surface only. The wound was closed with sutures and clips as described above. In mock animals, the sciatic nerve was exposed but not ligated, and the wound was closed as in non-mock animals.

Unlike the Seltzer and CCI models, the Chung model involves ligation of the spinal nerves (Kim, S.O. and Chung, J.M. Pain (1992):50:355-363). In this model, rats are anesthetized and placed in a prone position, and an incision is made on the left side of the spine at the L4-S2 level. Deep dissection through the paraspinal muscles and separation of the muscles from the spinal processes at the L4-S2 level will expose part of the sciatic nerve, whose branches form the L4, L5, and L6 spinal nerves. The L6 transverse process was carefully removed using small rongeurs to allow visualization of these spinal nerves. The L5 spinal nerve was isolated and ligated tightly with 7-0 silk suture. The wound was closed with a single muscle suture (6-0 silk) and one or two skin closure clips and dusted with antibiotic powder. In mock animals, the L5 nerve was exposed but not ligated and the wound was closed as previously described.

behavior index

In all chronic pain models (inflammatory and neuropathic), mechanical hyperalgesia was assessed by measuring the paw withdrawal threshold of both hindpaws to increasing pressure stimuli with an Analgesymeter (Ugo-Basile, Milan). Mechanical allodynia was assessed by measuring the paw withdrawal threshold to innocuous mechanical stimuli applied with von Frey hairs to the plantar surfaces of both hind feet. Thermal hyperalgesia was assessed by measuring paw withdrawal latencies to noxious thermal stimuli applied on the plantar surface of each hind paw. For all models, mechanical hyperalgesia and allodynia and thermal hyperalgesia occurred within 1-3 days after surgery and persisted for at least 50 days. For the assays described herein, drugs can be administered before or after surgery to assess their effect on the development of hyperalgesia, particularly about 14 days after surgery, in order to determine their ability to reverse established hyperalgesia.

The percent reversal of hyperalgesia was calculated as follows:

In the experiments described herein, Wistar rats (male) were used in the pain model described above. Rats weigh approximately 120-140 grams at the time of surgery. All operations were performed under enflurane/ _O2 inhalational anesthesia. In all cases, the wounds were closed after surgery and the animals were allowed to recover. In all pain models used, overt mechanical and thermal hyperalgesia and allodynia occurred after several days in all non-simulated manipulated animals, with a decrease in pain threshold and hindpaw response to touch, pressure, or heat stimuli The reflex paw withdrawal response increases. After surgery, the animals also showed characteristic changes in the affected feet. In most animals, the toes of the affected hind foot merge together and the foot is turned slightly to one side; in some rats, the toes also curl downward. Gait changes in ligated rats, but lameness was uncommon. Some rats were observed to lift the affected hind paw from the floor of the cage and exhibit an unusual stiff extension of the hind paw when held. Rats tend to be very sensitive to touch and may vocalize. Otherwise, the general health of the rats was good.

The efficacy of the compounds of the present invention in treating osteoarthritis can be determined in a model such as the aforementioned (Colombo et al. Arth. Rheum. 1993 26, 875-886) rabbit partial lateral meniscectomy model or a model similar thereto. The efficacy of compounds in the model can be quantified using histological scoring as previously described (O'Byrne et al. Inflamm Res 1995, 44, S117-S118).

The compound of formula I can be administered alone or in combination with one or more other therapeutic agents, and possible combination therapy can be administered in a fixed combination or staggered or independently of each other. , or administering a fixed combination in combination with one or more other therapeutic agents.

The present invention relates especially to pyrrolopyrimidines of formula I, wherein:

Y stands for -(CH ₂ ) _t -O- or -(CH ₂ ) _r -S-,

p is 1,

R ₁ stands for

(a) phenyl that is unsubstituted or mono- or disubstituted by:

(α) Halogen, carboxyl, C ₁ -C ₄ alkoxy, nitro, C ₁ -C ₄ alkyl-C(O)-NH-, C ₃ -C ₄ cycloalkyl-C(O)-NH -, C ₁ -C ₄ alkyl-C(O)-N(C ₁ -C ₄ alkyl)-, formyl, C ₁ -C ₄ alkyl-C(O)-, C ₁ -C ₄ alkane Base-S(O) ₂ -NH-, CF ₃ -C ₁ -C ₃ Alkyl-S(O) ₂ -NH-, 1-pyrrolidinyl-carbonyl, 1-piperidinyl-carbonyl, 4-morphine Linyl-carbonyl, 4-(C ₁ -C ₄ alkyl)-1-piperazinylcarbonyl, 4-piperidinyl, 1-piperidinyl, 1-(C ₁ -C ₄ alkyl-carbonyl)- 4-piperidyl, 1,2,3,6-tetrahydro-4-pyridyl, 1-(C ₁ -C ₄ alkyl-carbonyl)-1,2,3,6-tetrahydro-4-pyridine Base, 1-piperazinyl, 4-(C ₁ -C ₄ alkyl)-1-piperazinyl, 4-(C ₁ -C ₄ alkyl-carbonyl)-1-piperazinyl, 4-(C ₃ -C ₅ cycloalkyl-carbonyl)-1-piperazinyl, 4-(C ₁ -C ₄ alkoxy-carbonyl)-1-piperazinyl, 4-(C ₁ -C ₄ alkyl-SO ₂ )-1-piperazinyl, 1,4-diazepan-1-yl, 4-(C ₁ -C ₄ alkyl-carbonyl)-1,4-diazepan-1-yl , 2-oxo-1-pyrrolidinyl, 3,3-di-(C ₁ -C ₄ alkyl)-2-oxo-1-pyrrolidinyl;

(β) R ₃ -C ₁ -C ₄ alkyl, wherein R ₃ represents hydrogen, hydroxyl, carboxyl, C ₁ -C ₄ alkyl-N(C ₁ -C ₄ alkyl)-, C ₁ -C ₄ alkane -NH-, 1-pyrrolidinyl, 1-piperidinyl, 4-(C ₁ -C ₄ alkyl)-1-piperazinylcarbonyl, 2,4-dioxa-5,5-(di -C ₁ -C ₄ alkyl)-oxazolidin-3-yl,

R ₄ R ₅ NC(O)-, wherein R ₄ and R ₅ independently represent hydrogen or C ₁ -C ₄ alkyl; or (γ)R ₆ R ₇ NC(O)-, wherein R ₆ and R ₇ independently of each other represent hydrogen, C ₁ -C ₄ alkyl, C ₅ -C ₇ cycloalkyl-C ₁ -C ₄ alkyl, CF ₃ -C ₁ -C ₃ alkyl or pyridyl-C ₁ -C ₄ Alkyl; (b) pyridyl, which is unsubstituted or mono- or disubstituted by halogen or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is di- or trisubstituted by halogen;

(c) pyrimidinyl;

(d) indolyl monosubstituted by C ₁ -C ₄ alkyl-C(O)-NH-C ₁ -C ₄ alkyl;

(e) 2-(C ₁ -C ₄ alkyl)-benzothiazolyl;

(f) the group of subformula Ia

wherein _R is hydrogen, _R is hydrogen, and m is 2 or 3; or

(g) the group of subformula Ib

wherein R ₁₀ is hydrogen, R ₁₁ is hydrogen, and n is 2 or 3;

R ₂ represents C ₁ -C ₅ alkyl, which is unsubstituted or substituted by: cycloalkyl which is unsubstituted or disubstituted by halogen, or phenyl which is mono- or disubstituted by halogen;

Provided that if Y is O and R _is selected from 3-pyridyl, 4-pyridyl, 5-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-chloro-4-pyridyl, 2- Trifluoromethyl-4-pyridyl, 2-difluoromethyl-4-pyridyl, 4-acetyl-1-piperazinyl-phenyl, 4-methyl-1-piperazinyl-methyl- phenyl, then _R does not represent 1,1-dimethylethyl, and

with the proviso that if Y is S and R is ₄ -pyridyl, then _R does not represent 1,1-dimethylethyl; and tautomers thereof and such pyrropyrimidines or tautomers thereof of salt.

Furthermore, the present invention relates in particular to pyrrolopyrimidines of the formula I, in which:

Y is _CH2 or -CH=CH-,

p is 1 or 2,

R ₁ stands for

(a) thienyl, thiazolyl, 1-piperidinyl-carbonyl, or

(b) Unsubstituted or mono- or disubstituted phenyl by:

(i) C ₁ -C ₄ alkoxy, H ₂ NC(O)-, 4-(C ₁ -C ₄ alkyl-carbonyl)-1-piperazinyl, 2-oxo-1-pyrrolidinyl or halogen;

(ii) R ₁₂ -OC(O)-, wherein R ₁₂ is hydrogen or C ₁ -C ₄ alkyl, or

(iii) R ₁₃ NH-, wherein R ₁₃ represents hydrogen or the group R ₁₄ -C ₁ -C ₄ alkyl-Z-, wherein Z is CO or SO ₂ and R ₁₄ represents hydrogen, trifluoromethyl or C ₁ -C ₄ alkoxy,

(iv) R ₁₅ -C ₁ -C ₄ alkyl, wherein R ₁₅ represents hydrogen, hydroxyl, lower alkoxy, 1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolidine-2,5 -diketone-1-yl, 5,5-dimethyl-oxazolidin-2,4-diketone-3-yl or C ₁ -C ₄ alkyl-N(R ₁₆ )-, wherein R ₁₆ represents hydrogen or C ₁ -C ₄ alkyl; and

_R2 stands for

(a) C ₁ -C ₇ alkyl, which is unsubstituted or substituted by: C ₂ -C ₃ alkenyl, indanyl, unsubstituted or by halogen or C ₁ -C ₄ alkyl Disubstituted C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkenyl, unsubstituted or mono- or disubstituted phenyl by halogen or C ₁ -C ₄ alkyl;

(b) C ₃ -C ₇ cycloalkyl; or

(c) C ₁ -C ₄ alkylcarbonyl;

with the proviso that if Y is _CH2 , _R1 represents 4-chlorophenyl and p is 1, then _R2 does not represent 1,1-dimethylethyl, 1-methylethyl, cyclopropyl, cyclohexyl, 2-methyl-propyl or 2-ethyl-propyl;

with the proviso that if p is 1, Y is CH _{and R} represents thienyl, phenyl, methoxyphenyl, propoxyphenyl, 4-fluorophenyl, 4-methylphenyl, 4-ethyl Phenyl, 4-butylphenyl, hydroxymethylphenyl, 4-(5,5-dimethyl-oxazolidine-2,4-dione-3-yl-methyl)-phenyl, 4 -(methylsulfonylamino)-phenyl, 4-(n-butylsulfonylamino)-phenyl, 4-(ethylsulfonylamino)-phenyl, 4-(n-propylsulfonylamino)- Phenyl, 4-(isopropylsulfonylamino)-phenyl, 4-aminophenyl, 4-(acetylamino)-phenyl, 4-(butyrylamino)-phenyl or 4-(diethyl Baseaminomethyl)-phenyl, then _R does not represent 1,1-dimethylethyl;

And with the proviso that if p is 1, Y is CH2 _{and R1} represents phenyl which is unsubstituted or substituted by 4-acetyl-1-piperazinyl, then _R2 does not represent 1-methylethyl.

Furthermore, the present invention relates in particular to pyrrolopyrimidines of the formula I, in which:

Y is _CH2 ,

p is 1,

R ₁ stands for

(a) 1,2,3,6-tetrahydropyridin-1-yl, 4-(C ₁ -C ₄ alkyl)-1,2,3,6-tetrahydropyridin-1-yl, 4,5 -Di(C ₁ -C ₄ alkyl)-1,2,3,6-tetrahydropyridin-1-yl, 5-chloro-1,2,3,6-tetrahydropyridin-1-yl, 4- Phenyl-1,2,3,6-tetrahydropyridin-1-yl, 1-imidazolyl, 2-(C ₁ -C ₄ alkyl)-1-imidazolyl, 4,5-dihalo-1 -imidazolyl, imidazolidin-2,5-dione-1-yl, 5,5-dimethyl-oxazolidin-2,4-dione-3-yl, 3-(C ₁ -C ₄ alkane Base)-imidazolidine-2,5-dione-1-yl, 3-trifluoromethyl-3,4-pyrrolin-1-yl, 1-pyrrolidinyl, 3-C ₁ -C ₄ alkyl -1-pyrrolidinyl, 3,3-di-(C ₁ -C ₄ alkyl)-1-pyrrolidinyl, 3-C ₁ -C ₄ alkoxy-1-pyrrolidinyl, 3-C ₁ -C ₄ alkyl-2-oxo-1-pyrrolidinyl, 3,3-di-(C ₁ -C ₄ alkyl)-2-oxo-1-pyrrolidinyl, 3-halo-1 -pyrrolidinyl, 3,3-di-halo-1-pyrrolidinyl, 3,3-di-halo-1-piperidinyl, 1H-1,2,3-triazol-1-yl, 2H -1,2,3-triazol-2-yl, 1H-1,2,4-triazol-1-yl, 3-nitro-1H-1,2,4-triazol-1-yl, 2 -Phenyl-1-imidazolyl, 2H-tetrazol-2-yl, 1H-tetrazol-1-yl, benzo[b]imidazol-1-yl, 3-(1-(C ₁ -C ₄ alkane Base-SO ₂ )-4-piperidinyl)-2,3-dihydro-2-oxo-benzo[b]imidazol-1-yl, 3-(1-C ₁ -C ₄ alkylcarbonyl- 4-piperidinyl)-2,3-dihydro-2-oxo-benzo[b]imidazol-1-yl, 1-indolyl, 6-halo-1-indolyl, 1,3 -Dihydro-2-isoindolyl, 2,3-dihydro-1-indolyl, 2,3-dihydro-2-oxo-benzo[b]thiazol-3-yl, 6,7 -Di-(C ₁ -C ₄ alkoxy)-1,2,3,4-tetrahydroquinoline, 6-C ₁ -C ₄ alkoxy-1,2,3,4-tetrahydroisoquinoline Line, 7-C ₁ -C ₄ alkoxy-1,2,3,4-tetrahydroisoquinoline;

(b) Groups of substructure Ic

It is attached to the molecule through a nitrogen atom, where

X is -O-, -(CH ₂ ) _s -CR ₁₇ R ₁₈ -or -NR ₁₈ , wherein

S is 0 or 1, R and R are _{independently} selected from hydrogen, halogen, hydroxyl, _{C 1 -C 4} alkyl, phenyl-C ₁ -C ₄ alkyl-carbonyl, carbamoyl, N-phenyl -carbamoyl, cyano, 4-pyridyl, 1-piperidinyl and phenyl unsubstituted or monosubstituted by halogen or C ₁ -C ₄ alkoxy, or, if X is CR ₁₇ R ₁₈ , _R17 and _R18 together form an oxo group or group

HO-C(O)-CH=, and

R ₂₃ , R ₂₄ , R ₂₅ and R ₂₆ are independently selected from hydrogen and C ₁ -C ₄ alkyl;

(c) The group of the substructure Id:

It is attached to the molecule through a nitrogen atom, where

k is 0 or 1, A is _CH2 or bond, B is _CH2 or carbonyl, D is _CH2 or carbonyl, E is _CH2 or _NR22 , G is _CH2 or bond, Q is _CH2 or carbonyl, T is CH ₂ or NR ₂₉ , R ₁₉ represents hydrogen, C ₁ -C ₄ alkyl, phenyl- _{C 1} -C ₄ alkyl, C ₁ -C ₄ alkylcarbonyl or C ₁ -C ₄ alkyl -SO ₂ -, R ₂₂ is hydrogen and R ₂₉ is phenyl;

(d) Groups of substructure Ie

It is attached to the molecule through a nitrogen atom, where

R ₂₇ is C ₁ -C ₄ alkyl or C ₁ -C ₄ alkylcarbonyl and R ₂₈ is hydrogen, C ₁ -C ₄ alkoxy or halogen;

or

(e) NR ₂₀ R ₂₁ , wherein R ₂₀ and R ₂₁ are independently selected from hydrogen, C ₁ -C ₄ alkyl, unsubstituted or C ₃ -C ₇ cycloalkyl monosubstituted by hydroxyl; and unsubstituted or phenyl monosubstituted by 1,2,3-thiadiazol-4-yl, with the proviso that _R20 and _R21 cannot represent hydrogen at the same time; and

R ₂ represents C ₁ -C ₈ alkyl, which is unsubstituted or substituted by: C ₃ -C ₇ cycloalkyl which is unsubstituted or disubstituted by halogen; benzene which is mono- or disubstituted by halogen base;

with the proviso that _R does not represent 1,1-dimethylethyl in the following cases:

(a) R ₁ is benzo[b]imidazol-1-yl, 1-imidazolyl, 4,5-dichloro-1-imidazolyl, 2-(C ₁ -C ₄ alkyl)-1-imidazolyl , imidazolidine-2,5-dione-1-yl, 5,5-dimethyl-oxazolidine-2,4-dione-3-yl, 1H-1,2,3-triazole-1 -yl, 2H-1,2,3-triazol-2-yl, 3-nitro-1H-1,2,4-triazol-1-yl, 2H-tetrazol-2-yl or 1H-tetra Azol-1-yl, or R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is NR ₁₈ and R ₁₈ is hydrogen, methyl, ethyl, acetyl, 4-pyridyl, 1 - piperidinyl, phenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl or chlorophenyl;

(b) R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is -(CH ₂ ) _s -CR ₁₇ R ₁₈ -, s is 0, and R ₁₇ and R ₁₈ are selected from hydroxyl and Phenyl monosubstituted by chlorine or _R and _R are selected from hydrogen, methoxyphenyl and N-phenyl-carbamoyl; or

(c) R ₁ is a group of substructure Id, k is 1, A is a bond, E is NR ₂₂ , R ₂₂ is hydrogen, G, Q and T are CH ₂ , B and D are carbonyl and R ₁₉ is methyl radical, n-propyl or isobutyl;

Provided that if R ₁ is a group of substructure Id, k is 1, A is a bond, E is NR ₂₂ , R ₂₂ is hydrogen, G, Q and T are CH ₂ , B and D are carbonyl and R ₁₉ is methyl group, or if R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is -(CH ₂ ) _s -CR ₁₇ R ₁₈ -, s is 0, and R ₁₇ and

_R18 is selected from hydrogen and phenyl monosubstituted by methoxy, then _R2 does not represent 2-methylpropyl; and with the proviso that if _R1 is a group of substructure Ic, _R23 to _R26 are hydrogen, X is NR ₁₈ and R ₁₈ is methoxyphenyl or ethoxyphenyl, or X is CR ₁₇ R ₁₈ and R ₁₇ and R ₁₈ are selected from hydrogen and methoxyphenyl, then R ₂ does not represent 1- methyl ethyl;

or its tautomer,

Or a salt of such pyrrolopyrimidine or a tautomer thereof.

Therefore, in another aspect, the present invention provides:

A compound of formula I for use as a medicine;

A pharmaceutical composition comprising a compound of formula I as an active ingredient;

A method of treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin S is involved, the method comprising administering to the patient an effective amount of a compound of formula I, and

Use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of a disease or medical condition in which cathepsin S is involved.

Compounds of formula I wherein Y represents -(CH ₂ ) _t -O- or (CH ₂ ) _r -S- and t, r, R ₁ , R ₂ and p have the meanings given above for compounds of formula I may be obtained, for example, by Prepared as follows:

Alcohol or thiol of formula II,

R ₁ -(Y) _p -H (II)

wherein Y represents -(CH ₂ ) _r -O- or (CH ₂ ) _r -S- and t, r and R ₁ have the meanings given above for compounds of formula I,

Alkylation with pyrrolopyrimidines of formula III

wherein _R has the meanings given above for compounds of formula I and Hal represents halogen, preferably bromine, wherein the starting compounds of formulas II and III may also have functional groups in protected form, if necessary, and/or in salt form, Provided that a salt-forming group is present and a reaction in the form of a salt is possible; wherein any protecting group in the protected derivative of the compound of formula I is removed;

And, if desired, converting an available compound of formula I into another compound of formula I or its N-oxide, converting a free compound of formula I into a salt, converting an available salt of a compound of formula I into a free Compound or another salt, and/or separation of a mixture of isomers of a compound of formula I into individual isomers.

Detailed description of the alkylation:

In the more detailed description of the methods below, t, r, _R1 and _R2 are as defined for the compounds of formula I, unless otherwise stated.

Alkylation of an alcohol or thiol of formula II with an alkyl halide of formula III can be accomplished by standard methods known in the art, for example by dissolving the two compounds in a suitable solvent such as dimethylacetamide or dimethylacetamide. In base formamide by adding a suitable base such as carbonate such as potassium carbonate, react at 0°C to the reflux temperature of the solvent used, preferably from about 10°C to about 35°C, for about 15 minutes to 48 hours, preferably 2 hours to 12 hours .

protecting group

If one or more other functional groups such as carboxyl, hydroxyl, amino or sulfhydryl groups are protected or need to be protected in compounds of formula II or III because they should not take part in the reaction, these are commonly used in the synthesis of peptide compounds, cephalosporins Those groups of mycocins and penicillins as well as nucleic acid derivatives and sugars.

Protecting groups may already be present in the precursors and should protect the relevant functional groups against undesired side reactions such as acylation, etherification, esterification, oxidation, solvolysis and similar reactions. Protecting groups are characterized in that they can be removed easily, i.e. without undesired side reactions, usually by solvolysis, reduction, photolysis or by enzymatic activity, e.g. under conditions similar to physiological conditions , protecting groups are also characterized by their absence in the final product. Those skilled in the art know or can readily determine which protecting groups are suitable for the reactions described above and below.

The protection of such functional groups by such protecting groups, the protecting groups themselves and their removal reactions are described, for example, in standard reference works, such as J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, "The Peptides"; Volume 3 (Editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, "Methoden der organischen Chemie" (Methods in Organic Chemistry ), Houben Weyl, 4th Edition, Vol. 15/I, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jescheit, "Aminosuren, Peptide, Proteine" (amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Carbohydrate chemistry: monosaccharides and their derivatives), Georg Thieme Verlag, Stuttgart 1974.

Other method steps

Salts of compounds of the formula I having salt-forming groups can be prepared in a manner known per se. Thus, acid addition salts of compounds of formula I can be obtained by treatment with an acid or a suitable anion exchange reagent. Salts with two acid molecules (e.g. dihydrohalide salts of compounds of formula I) can also be converted into salts with one acid molecule per compound (e.g. monohydrohalide salts); this can be done by heating to melt or by, for example, This is accomplished by heating in solid form under high vacuum at elevated temperature, eg 130 to 170° C., such that one molecule of acid is liberated from each molecule of compound of formula I.

Salts can generally be converted into the free compounds, for example, by treatment with a suitable basic substance, such as an alkali metal carbonate, alkali metal bicarbonate or alkali metal hydroxide, usually potassium carbonate or sodium hydroxide.

General method conditions

All process steps described here can be carried out under known reaction conditions, preferably under those conditions specifically mentioned; solvents or diluents, preferably, for example, inert to the reagents used and soluble in the absence or usual presence Their solvents or diluents; absence or presence of catalysts, condensing agents or neutralizing agents such as ion exchangers, usually cation exchangers, e.g. in the H ⁺ form, depending on the reaction and/or the reactants type; at reduced, normal or elevated temperature, for example at -100°C to about 190°C, preferably at about -80°C to about 150°C, for example at -80 to -60°C, at room temperature, at - At 20 to 40° C. or at the boiling point of the solvent used; at atmospheric pressure or in a closed vessel, preferably under pressure; and/or under an inert atmosphere such as argon or nitrogen.

All starting compounds and transition substances can be present as salts if they contain salt-forming groups. Salts may also be present during the reaction of the compounds, as long as the reaction is not disturbed thereby.

Solvents suitable for the reaction can be selected from, unless otherwise stated in the process description, including, for example, water; esters, typically lower alkyl-lower alkanoates, such as diethyl acetate; ethers, typically are aliphatic ethers, such as diethyl ether, or cyclic ethers, such as tetrahydrofuran; liquid aromatic hydrocarbons, usually benzene or toluene; alcohols, usually methanol, ethanol, or 1- or 2-propanol; nitriles, usually acetonitrile; Hydrocarbons, usually dichloromethane; amides, usually dimethylformamide; bases, usually heterocyclic nitrogen bases, such as pyridine; carboxylic acids, usually lower alkanecarboxylic acids, such as acetic acid; carboxylic anhydrides, usually lower Alkanoic anhydrides, such as acetic anhydride; cyclic, linear or branched hydrocarbons, usually cyclohexane, hexane or isopentane, or mixtures of these solvents, for example aqueous solutions. The solvent mixtures can also be employed in work-up, for example by chromatography or partitioning.

Compounds of formula I, including their salts, may also be obtained in the form of hydrates, or their crystals may include, for example, the solvent used for crystallization (in solvated form).

In a preferred embodiment, the compounds of formula I are prepared according to the methods and method steps defined in the examples or methods and method steps analogous thereto.

The dosage of the active ingredient will depend on many factors including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition being treated; the route of administration; the renal and hepatic function of the patient and the particular compound used. A typical physician, clinician or veterinarian can readily determine and prescribe the effective amount of drug required to prevent, counter or arrest the development of the condition. Optimal precision in achieving drug concentrations within the range that produces efficacy without toxicity requires a dosing regimen based on the kinetics of the drug at the target site. This includes consideration of drug distribution, equilibration and elimination.

The dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered to a warm-blooded animal such as a human having a body weight of about 70 kg is preferably from about 3 mg to about 5 g, more preferably from about 10 mg to about 1.5 g, most preferably from about 100 mg to about 1000 mg per person per day , preferably divided into 1-3 single doses for administration, these single doses may for example be of equal size. Typically, children receive half the adult dose.

The present invention also relates to pharmaceutical compositions comprising an effective amount, in particular for the treatment of one of the above-mentioned disorders, of a compound of formula I or its N-oxide or tautomer and suitable for topical, enteral, e.g. Pharmaceutically acceptable carriers, which may be organic or inorganic, solid or liquid, are administered orally or rectally or parenterally. For oral administration are especially tablets or gelatin capsules comprising the active ingredient together with diluents such as lactose, dextrose, mannitol and/or glycerol, and/or lubricants and/or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starches such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone and, if desired, Disintegrants such as starch, agar, alginic acid or its salts such as sodium alginate, and/or effervescent mixtures, or absorbents, dyes, flavors and sweeteners. It is also possible to use the pharmacologically active compounds according to the invention in the form of compositions which can be administered parenterally or in the form of infusion solutions. The pharmaceutical composition may be sterilized and/or may contain excipients, such as preservatives, stabilizers, wetting and/or emulsifying agents, solubilizers, salts for adjusting the osmotic pressure and/or buffers. If desired, the pharmaceutical composition of the present invention may contain other pharmacologically active substances, said composition being prepared by methods known per se, for example by conventional mixing, granulating, shaping, dissolving or lyophilizing methods, and comprising about 1% to 95%, especially about 1% to about 20%, of one or more active ingredients.

Starting materials

Novel starting materials and/or intermediates and processes for their preparation are also subjects of the present invention. In preferred embodiments, such starting materials are used, and reaction conditions are selected such that preferred compounds are obtained.

The starting materials of formula II and III are known, commercially available or can be synthesized analogously or according to methods known in the art or described in the examples.

In particular, pyrrolopyrimidines of formula III can be prepared by the following reaction sequence

wherein _R2 has the meanings given above for compounds of formula I, and Hal represents halogen.

In the first step, the pyrimidine of formula IV

Reaction with an amine of formula V,

R ₂ -CH ₂ -NH ₂ (V)

wherein _R has the meanings provided in compounds of formula I above,

The reaction method is a known method, for example, at a temperature of about -10°C to about +10°C, such as about 0°C, the amine of formula V is added dropwise to the pyrimidine of formula IV in a suitable solvent such as C ₁ -C ₃ alcohol , and allowing the solution to react at a temperature of about 15°C to about 30°C, for example about 20°C, for about 3 to 12 hours to obtain the pyrimidine of formula VI

wherein _R2 has the meanings provided for the compounds of formula I above.

In a second step, a pyrimidine of formula VI, wherein _R has the meaning given above for the compound of formula I, is reacted with a cyanide such as potassium cyanide or sodium cyanide in a suitable solvent in a manner known per se to give 2-cyano-pyrimidine derivatives of formula VII,

wherein _R2 has the meanings provided for the compounds of formula I above.

In a second step, _{a 2} -cyano-pyrimidine derivative of formula VII in which R has the meaning given above for a compound of formula I is combined with a compound of formula VIII

where PG represents a suitable protecting group that is stable under the coupling reaction conditions,

Reaction in a suitable solvent such as dimethylformamide, for example in the presence of a palladium-(II) catalyst, cuprous iodide-(I) and a suitable base such as a trialkylamine such as triethylamine affords compounds of formula IX 2-cyano-pyrimidine derivatives,

wherein _R2 has the meanings given above for compounds of formula I, and PG represents a protecting group.

Cyclization of ₂ -cyano-pyrimidine derivatives of formula IX, wherein R has the meanings given above for compounds of formula I and PG represents a protecting group, can be achieved, for example, at temperatures between about 80°C and about 120°C, for example At a temperature of about 100°C, 1,8-diazabicyclo[5.4.0]undec-7-ene is added to a 2-cyano-pyrimidine derivative of formula IX in a suitable solvent such as dimethylformaldehyde In solution in the amide, the mixture is maintained at about this temperature for about 0.5 to 2 hours, for example 1 hour, to give a protected hydroxymethylpyrrolopyrimidine of formula X,

wherein _R2 has the meanings given above for compounds of formula I and PG represents a protecting group.

The protecting group PG can be removed under conditions known per se to give unprotected hydroxymethylpyrrolopyrimidines of formula XI,

wherein _R2 has the meanings provided for the compounds of formula I above. The hydroxymethylpyrrolopyrimidines of formula XI can be converted to the desired pyrrolopyrimidines of formula III by standard substitution reactions in which the hydroxyl group is replaced by a halogen group.

Alternatively, 2-cyano-pyrimidine derivatives of formula VII

wherein _R has the meanings provided in compounds of formula I above,

Compounds of formula XII can be reacted under suitable conditions known per se, such as those used for the preparation of compounds of formula IX mentioned above

wherein R ₁ , Y and p have the meanings given above for compounds of formula I to give compounds of formula XIII,

wherein R ₁ , R ₂ , Y and p have the meanings provided for compounds of formula I above.

Cyclization of 2-cyano-pyrimidine derivatives of formula XIII wherein R ₁ , R ₂ , Y and p have the meanings provided above for compounds of formula I can be achieved, for example, by: at about 80°C to about 120°C , for example at a temperature of about 100° C., 1,8-diazabicyclo[5.4.0]undec-7-ene is added to a 2-cyano-pyrimidine derivative of formula XIII in a suitable solvent such as dimethyl In a solution in methyl formamide, and maintaining the mixture at about this temperature for about 0.5 to 2 hours, for example 1 hour, the protected hydroxymethylpyrrolopyrimidine of formula I is obtained directly.

Particularly preferred compounds according to the invention are the compounds of the examples.

The present invention relates to methods of inhibiting cathepsin S in mammals and treating conditions associated with cathepsin S, such as those described herein, with compounds of formula I and their pharmaceutically acceptable salts or pharmaceutical compositions thereof. Disorders, such as chronic inflammatory or neuropathic pain.

In particular, the present invention relates to a method of selectively inhibiting cathepsin S activity in a mammal, the method comprising administering to the mammal in need thereof a compound of formula I in a cathepsin S inhibiting effective amount.

More particularly, the present invention relates to a method of treating chronic inflammatory or neuropathic pain (and the other diseases mentioned above) in a mammal comprising administering to the mammal in need thereof a corresponding effective amount of a compound of formula I.

Example

The following examples illustrate the invention without limiting its scope.

Temperatures are measured in degrees Celsius. Reactions were carried out at room temperature unless otherwise stated. The structures of final products, intermediates and starting materials are confirmed by standard analytical methods such as microanalysis and spectroscopic characteristics (eg MS, IR, NMR).

abbreviation

Abbreviations used are conventional abbreviations in the art, and specifically, have the meanings given below.

Ac acetyl

aq.

Boc tert-butoxycarbonyl

conc. thick

DABCO 1,4-diazabicyclo[2.2.2]octane

DEAD Diethyl azodicarboxylate

DMF Dimethylformamide

DMSO Dimethyl Sulfoxide

Et ethyl

FC Flash Chromatography

Me methyl

min minutes

MS mass spectrometry

NMR nuclear magnetic resonance

Ph phenyl

RP-HPLC reversed phase high pressure liquid chromatography

rt room temperature

sat. Saturated

soln. solution

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TsOH Toluenesulfonic acid

Example A: 6-bromomethyl-2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine

A solution of CBr ₄ (56.1 g, 0.17 mol) in dry CH ₂ Cl ₂ (150 ml) was added dropwise to the product of step A.5 (20.65 g, 84.8 mmol) and Ph _3P (44.2 g, 0.17 mol) in solution in dry _{CH2Cl2 (} 150 ml). After stirring at 0°C for 30 minutes, the mixture was warmed to room temperature and stirred for 3 hours. The mixture was diluted with _CH2Cl2 ( _300ml ), washed with saturated aqueous _NaHCO3 (150ml) and brine (150ml) and dried ( _MgSO4 ). The organic layer was treated with _SiO2 (70 g), evaporated and the residue loaded on a silica gel column. The title compound was obtained as a yellow solid by FC (800 g silica gel; hexane/EtOAc 7:4); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.98-1.11 (m, 2H), 1.18-1.45 (m, 5H ), 1.64-1.89 (m, 6H), 4.40 (t, 2H), 4.68 (s, 2H), 6.70 (s, 1H), 8.95 (s, 1H).

Step A.1 : (5-Bromo-2-chloro-pyrimidin-4-yl)-(2-cyclohexyl-ethyl)-amine

2-Cyclohexyl-ethylamine (40.3 g, 320 mmol) was added dropwise to a solution of 5-bromo-2,4-dichloropyrimidine (51 g, 224 mmol) in MeOH (200 ml) at 0 °C during 20 minutes. in solution. After stirring at 0°C for 20 minutes, the mixture was warmed to room temperature, stirred for 11 hours and evaporated. The residue was suspended in _{200ml CH2Cl2} , washed with water and brine, dried ( _MgSO4 ) and evaporated. The residue was chromatographed on a silica gel column (hexane/EtOAc 5:1) to give the title product; ¹ H-NMR (400MHz, CDCl ₃ ) δ0.90-1.01(m, 2H), 1.10-1.41(m , 5H), 1.55 (q, 2H), 1.61-1.80 (m, 4H), 3.52 (q, 2H), 5.43 (brs, 1H), 8.09 (s, 1H).

Step A.2 : 5-Bromo-4-(2-cyclohexyl-ethylamino)-pyrimidine-2-carbonitrile

To an aqueous solution (5 ml) of NaCN (1.27 g, 25.9 mmol) was added successively DMSO (50 ml), DABCO (0.24 g, 2.16 mmol) and the product of step A.1 (6.9 g, 21.6 mmol) at room temperature. The mixture was stirred at 60 °C for 11 h, poured into ice water, extracted with EtOAc, dried ( _MgSO4 ) and evaporated. The residue is chromatographed on a silica gel column (Hexane/EtOAc 4:1) to give the title product.

Step A.3 : 2-cyano-4-(2-cyclohexyl-ethyl)amino-5-[3-(tetrahydro-2H-pyran-2-yloxy)-prop-1-ynyl ]-pyrimidine

A solution of the product of step A.2 (25.0 g, 89.9 mmol) and 2-prop-2-ynyloxy-tetrahydropyran (13.6 ml, 97.02 mmol) in dry DMF (420 ml) was added at room temperature Treated with _Et3N (56.5ml, 40.5mmol), CuI (0.78mg, 4.05mmol) and ( _Ph3P ) _2PdCl2 ( _1.4g , 2.02mmol). The mixture was stirred at 70°C for 3 hours, poured into ice water, extracted with EtOAc, washed with brine, dried ( _MgSO4 ) and evaporated. The residue was chromatographed on a silica gel column (1800 g silica gel; hexane/EtOAc 2:1) to obtain the title compound; ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.90-1.02 (m, 2H), 1.10- 1.40(m, 5H), 1.48-1.91(m, 12H), 3.49-3.60(m, 3H), 3.84-3.92(m, 1H), 4.54(s, 2H), 4.86(t, 1H), 5.88( brt, 1H), 8.19 (s, 1H).

Step A.4 : 7-(2-Cyclohexyl-ethyl)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ol

A solution of the product from step A.3 (23.1 g, 62.69 mmol) in dry DMF (400 ml) was treated with DBU (11.3 ml, 75.23 mmol) at room temperature, stirred at 100°C for 1 hour, poured into ice water, Extracted with EtOAc, washed with _H2O , dried ( _MgSO4 ) and evaporated. The residue was chromatographed on a silica gel column (hexane/EtOAc 5:1) to give the title compound; ¹ H-NMR (400 MHz, CDCl ₃ ) δ0.93-1.08 (m, 2H), 1.12-1.40 (m , 5H), 1.48-1.91(m, 12H), 3.54-3.62(m, 1H), 3.82-3.91(m, 1H), 4.38(t, 2H), 4.70(d, 1H), 4.73(t, 1H ), 4.94(d, 1H), 6.61(s, 1H), 8.91(s, 1H).

Step A.5 : 7-(2-Cyclohexyl-ethyl)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ol

A solution of the product from step A.4 (21.4 g, 58.08 mmol) in MeOH (200 ml) was treated with TsOH· _H2O (1.1 g, 5.78 mmol) at room temperature, stirred for 11 hours and evaporated. The residue was diluted with _CH2Cl2 and washed with _water and saturated aqueous _NaHCO3 . The organic extracts were dried ( _MgSO4 ) and concentrated. Chromatography of the residue on a silica gel column affords the title compound.

Example B:

Compounds of formula 1 identified below in Table 1 were obtained by repeating the procedure described under Example A using appropriate starting materials and conditions.

Table 1

Example C: Phenol Derivatives

Example C.1 : 3-fluoro-4-hydroxy-N-propyl-benzamide

To a solution of 3-fluoro-4-hydroxybenzoic acid (5 g, 32 mmol) and propylamine (3.1 ml, 38 ml) in DMF (250 ml) was added HOAt (5.2 g, 38 mmol) and WSCl.HCl ( 7.2 g, 38 mmol). The reaction mixture was stirred at room temperature for 15 hours, quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with _H2O , brine and dried over magnesium sulfate. Chromatography on silica gel (eluent: dichloromethane and 3% MeOH in dichloromethane) gave 4.8 g of the desired product; Rf = 0.76 (dichloromethane:MeOH = 8:2).

Example C.2 : 3-Hydroxy-N-propyl-benzamide

To a solution of 3-hydroxy-benzoic acid (430mg, 3.6mmol) in THF (5ml) was added _SOCl2 (0.4ml) and DMF (2 drops). The reaction mixture was stirred overnight at room temperature. The mixture was split in half and _Et3N (0.42ml) and the corresponding amine were added to the mixture. After the mixture was stirred overnight at room temperature, it was diluted with water. The mixture was extracted with EtOAc, the combined organic extracts were washed with _brine , dried over _Na2SO4 , filtered and concentrated to give the product.

Example D

Example D.1 : (4-Hydroxy-phenyl)-piperidin-1-yl-methanone

To a toluene solution (6 mL) was added trimethylaluminum (1M in hexane, 3 mL), piperidine (3 mmol) at room temperature. The mixture was stirred at room temperature for 0.3 hours. Add ethyl 4-hydroxybenzoate and stir at 100°C for 1 hour. The reaction mixture was diluted with water and 8N aqueous KOH was added. Then, the reaction mixture was acidified with concentrated aqueous HCl and extracted with dichloromethane (3 times). The combined organic layers were washed with water and brine, dried over _MgSO4 and concentrated in vacuo to afford the title compound.

Example D.2 : 4-Hydroxy-N-pyridin-3-ylmethyl-benzamide

To a solution of DMF/ _H2O (20 mL/7 mL) was added 4-benzyloxy-benzoic acid (1 g), 3-methyl-aminopyridine (710 mg), HOAt (715 mg), WSCD HCl (1 g). The mixture was stirred at room temperature for 3 hours and diluted with ice water. The white precipitate was collected by filtration. To a solution of the above product in methanol was added Pd/C, and the mixture was stirred under _H2 atmosphere for 12 h. The reaction mixture was filtered through a pad of celite and concentrated to give the title compound.

Embodiment E: azepine (azepin) derivatives

Example E.1 : 7-Methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one and 7-methoxy-1,3,4,5- Tetrahydro-benzo[b]azepin-2-one

To a heated solution of 6-methoxy-1-tetalone (1 g) in trichloroacetic acid (10 g) was added sodium azide (553 mg) at 70°C, and the mixture was kept under stirring for 4 hr. The reaction mixture was diluted with ice water and neutralized with potassium carbonate, extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated aqueous NaCl, dried over _MgSO4 , and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give 7-methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (later) in 49% yield, 7-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was obtained in 27% yield.

Example E.2 : 7-Hydroxy-2,3,4,5-tetrahydro-benzo[clazepin-1-one

To a solution of 7-methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (520 mg) in dichloromethane (3 mL) was added Boron tribromide in dichloromethane (1M in dichloromethane), stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and neutralized with aqueous sodium bicarbonate. The white precipitate in the mixture was collected by filtration. The precipitate was dried in vacuo to afford the title compound.

Example F: Synthesis of 4-pyrrolidinyl-phenol derivatives

A mixture of 4-amino-2-fluoro-phenol (3.4mmol) and γ-butyrolactone (3.57mmol) and 90ml concentrated HCl was heated to 190°C and stirred for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with THF and aqueous NaHCO ₃ , extracted with AcOEt and dried over Na ₂ SO ₄ . 1-(3-Fluoro-4-hydroxy-phenyl)-pyrrolidin-2-one was obtained by flash chromatography on silica gel with AcOEt-hexane (3:1) as eluent.

Example G: Synthesis of 4-pyrrolidinyl-phenol derivatives

4-iodophenol (1.0 mmol) was dissolved in 3 ml of dioxane. To this solution were added 3,3-dimethyl-pyrrolidin-2-one (1.2 mmol), K ₂ CO ₃ (2.0 mmol) and N,N′-dimethylethylenediamine at room temperature. The reaction mixture was heated and stirred under _N2 at 110 °C for 14 hours, then filtered through celite. The resulting mixture was diluted with AcOEt and aqueous NaHCO ₃ , extracted with AcOEt, dried over Na ₂ SO ₄ . 1-(4-Hydroxy-phenyl)-3,3-dimethyl-pyrrolidin-2-one was obtained as a brown solid by flash chromatography using AcOEt-hexane (3:1) as eluent.

Example H: 4-(4-Hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester

A solution of the product from Step H.1 (2 g) in 1M HCl in EtOAc was stirred at reflux for 0.5 h and concentrated in vacuo. The residue was suspended in ether and the white powder was collected by filtration. To a solution of the powder in methanol (100 mL) was added Pd/C (10% w/w, 200 mg) and stirred under H2 atmosphere for 18 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give crude product. To a solution of the crude product (300 mg) in DMF was added _Boc2O (305 mg) and Et3N and stirred at room temperature for 5 hours. The reaction mixture was diluted with _H2O and extracted with EtOAc (2x). The organic layers were combined, washed sequentially with _H2O , aqueous NaCl, dried over _MgSO4 and concentrated in vacuo. The residue was purified by column chromatography to obtain pure product; Rf = 0.56 (n-Hexane:EtOAc = 1:1).

Step H.1 : 1-Benzyl-4-(4-benzyloxy-phenyl)-piperidin-4-ol

To a solution of 1-benzyloxy-4-bromo-benzene (5 g) in tetrahydrofuran (100 mL) was added n-butyllithium (1.6M in hexane, 13 mL) at -78°C and heated at -78°C Stirring was continued for 0.5 hours. To this mixture was added 1-benzyl-piperidin-4-one in tetrahydrofuran (3.6 g in 20 mL) at -78°C and kept stirring at -78°C for 1.5 hours. The reaction mixture was diluted with aqueous _NH4Cl , then extracted with EtOAc. The organic layer was washed sequentially with _H2O and aqueous NaCl, dried over _MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography to obtain pure product; Rf = 0.15 (n-Hexane:EtOAc = 1:1).

Example I: tert-butyl 4-(4-hydroxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate

To a solution of the product from Example H (2 g) in methanol (50 ml) was added Pd/C (10% w/w, 200 mg) and stirred under _H2 atmosphere for 9 hours. The reaction mixture was filtered through a pad of celite. HCl (1M in EtOH, 50ml) was added to the filtrate and stirred at reflux. The reaction mixture was concentrated in vacuo to give crude product. To a solution of the crude product in MeOH/THF/ _H2O (10ml/5ml/10ml) was added _NaHCO3 (until pH = 9), _Boc2O at 0°C and kept stirring at 0°C for 1 hour. The reaction mixture was evaporated, neutralized with aqueous citric acid, extracted with EtOAc (3 times). The organic layers were combined, washed sequentially with _H2O , aqueous NaCl, dried over _MgSO4 and concentrated. The residue was purified by column chromatography to give pure product; Rf = 0.60 (n-Hexane:EtOAc = 1:1).

Example J: 1-[4-(3-Fluoro-4-hydroxy-phenyl)-piperazin-1-yl]-ethanone

To a solution of the product from step J.1 (1 g) in methanol (100 mL) was added Pd/C (10% w/w on charcoal, 0.1 g) and stirred under _H2 atmosphere for 11 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give the title compound; Rf=0.23 (dichloromethane:methanol=9:1).

Step J.1 : 1-[4-(4-Benzyloxy-3-fluoro-phenyl)-piperazin-1-yl]-ethanone

Under _N atmosphere, 1-benzyloxy-4-bromo-2-fluoro-benzene (1 g), 1-acetylpiperazine (0.55 g) and sodium tert-butoxide (0.51 g) in toluene (70 mL) Tri-o-tolyl-phosphine (0.05 g) and Pd ₂ (dba) ₃ (0.16 g) were added to the solution in , and stirred under reflux for 4 hours. The reaction mixture was diluted with _H2O and extracted with EtOAc. The organic layer was washed sequentially with _H2O and aqueous sodium chloride, dried over _MgSO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography to obtain pure product; Rf=0.29 (dichloromethane:methanol=9:1).

Example K: tert-butyl 4-(3-fluoro-4-hydroxy-phenyl)-piperazine-1-carboxylate

To a solution of the product from step K.1 (2.8 g) in methanol (100 mL) was added Pd/C (10% w/w on charcoal) and stirred under _H2 atmosphere for 12 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give the title product; Rf = 0.13 (n-hexane:EtOAc = 4:1).

Step K.1 : tert-butyl 4-(4-benzyloxy-3-fluoro-phenyl)-piperazine-1-carboxylate

Under _N atmosphere, 1-benzyloxy-4-bromo-2-fluoro-benzene (3 g), piperazine-1-carboxylic acid tert-butyl ester (2.36 g) and sodium tert-butoxide (1.54 g) in toluene Tris-o-tolyl-phosphine (0.163 g) and Pd ₂ (dba) ₃ (0.49 g) were added to a solution in (210 ml), and stirred at 80° C. for 11 hours. The reaction mixture was diluted with _H2O , extracted with EtOAc. The organic layer was washed sequentially with _H2O and aqueous sodium chloride, dried over _MgSO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give the pure title product;

Rf=0.19 (n-Hexane:EtOAc=4:1).

Example L: (4-prop-2-ynyl-phenyl)-methanol

To a suspension of Mg powder (19.3 mmol) and a tablet of iodine in THF (10 ml) was added (4-bromo-benzyloxy)-trimethyl-silane (16.0 mmol) and the mixture was stirred at 85 °C for 0.5 h. Copper(I) bromide (1.60 mmol) was added at room temperature, followed by methoxypropadiene (16.0 mmol) in THF (10 ml) at 0°C and the mixture was stirred at room temperature for 5 hours. The mixture was poured into saturated ammonium chloride and extracted with AcOEt. The organic layer was washed with 1N HCl solution, _H2O and brine, dried over _MgSO4 and concentrated. Chromatography on silica gel (n-hexane:AcOEt=1:9) affords the title compound; Rf=0.4 ( _{CH2Cl2: AcOEt} =3:2).

Example M: 1-Chloro-4-prop-2-ynyl-benzene

A mixture of methyl propargyl ether (50.0 g, 714 mmol) and t-BuOK (4.0 g, 36 mmol) was refluxed under _N2 for 1 h. Distillation of the mixture yielded methoxypropadiene (50 g, quantitative) as a colorless oil. At 0°C under N ₂ , to the solution of methoxypropadiene (42ml, 50mmol) and CuBr (720mg, 5mmol) in 200ml ether was added dropwise 1M p-chlorophenylmagnesium bromide in ether solution (50ml, 50mmol). After stirring at room temperature for 1 hour, 150 ml of saturated NH ₄ Cl solution was added, the mixture was extracted with ether and washed with saturated NaHCO ₃ solution. _The organic layer was dried over _Na2SO4 and concentrated. The residue was purified by column chromatography eluting with hexane only to afford 1-chloro-4-prop-2-ynyl-benzene as a yellow oil.

Example N: 1-fluoro-4-prop-2-ynyl-benzene

1-Fluoro-4-prop-2-ynyl-benzene was synthesized from p-fluorophenylmagnesium bromide and methoxypropadiene following the procedure described under Example M.

Example O: 1-(4-prop-2-ynyl-phenyl)-pyrrolidin-2-one

4-Prop-2-ynyl-aniline (2.0 mmol) and g-butyrolactone (2.0 mmol) in concentrated HCl were heated to 190°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was diluted with aqueous NaHCO ₃ , extracted with AcOEt and dried over Na ₂ SO ₄ . 1-(4-Propan-2-ynyl-phenyl)-pyrrolidin-2-one was obtained by flash chromatography on silica gel with AcOEt-hexane (1:1) as eluent.

Example P: 6-(4-Chloro-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

5-Bromo-2,4-dichloropyrimidine was dissolved in _NH3 /MeOH and stirred at room temperature, and the solvent was removed under reduced pressure. The resulting solid was washed with _H2O and dried in vacuo to afford 5-bromo-2-chloro-pyrimidin-4-ylamine as a white solid in quantitative yield. The white solid was dissolved in DMSO/ _H2O . DABCO and NaCN were added to the solution, and the resulting mixture was heated to 60 °C. The reaction mixture was diluted with water and extracted with AcOEt. The combined organic extracts were dried _{over Na2SO4} . Flash chromatography on silica gel eluting with AcOEt-hexanes afforded 4-amino-5-bromo-pyrimidine-2-carbonitrile as a white solid. To a solution of the above product in DMF _was added 1-chloro-4-prop-2-ynyl-benzene, ( _PPh3 ) _2PdCl2 and CuI under _N2 . The resulting solution was stirred at 80° C., and then aqueous NH ₄ Cl was added to the mixture. After stirring for a further 1 h, the mixture was extracted twice with AcOEt. The combined organic extracts were washed with aqueous NaHCO ₃ and dried over Na ₂ SO ₄ . The title compound was obtained by flash chromatography on silica gel eluting with AcOEt-hexane.

Example Q: 5-iodo-3,3-dimethyl-pent-1-ene

3,3-Dimethyl-pent-4 _- en-1-ol (0.77 mmol) was dissolved in 10 ml _CH2Cl2 , then the solution was cooled to 0°C. To the cooled solution were added PPh ₃ (0.92 mmol), pyridine (0.85 mmol) and iodine (0.92 mmol), followed by stirring at 0° C. to room temperature for 16 hours. After addition of _{aqueous Na2SO3} , the mixture was extracted twice with _Et2O . The combined organic extracts were washed with _H2O and _dried over _Na2SO4 . Flash chromatography on silica gel eluting with n-hexane affords the iodide as a colorless oil.

Example R: 1-(2-Bromo-ethyl)-4-methyl-benzene

To a solution of 2-p-tolyl-ethanol (1 g, 7.30 mmol) in _CH2Cl2 was added _PPh3 (1.94 g, 7.40 mmol) and NBS (1.32 g, _7.40 mmol) at -15 °C. The reaction mixture was stirred overnight at -15°C to room temperature. The reaction was quenched by adding saturated aqueous NaHCO ₃ and the resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic extracts were washed with brine and dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to obtain the title compound.

Example S: (3-Bromo-propyl)-cyclopropane

To a solution of 3-cyclopropyl-propan-1-ol (530 mg, 5.30 mmol) in CH ₂ Cl ₂ (10 ml) at -20°C was added PPh ₃ (1.42 g, 5.40 mmol) and NBS (960 mg , 5.40 mmol). The reaction mixture was stirred overnight at -20°C to room temperature. The reaction was quenched by adding water and _the resulting mixture was extracted with _CH2Cl2 . The combined organic extracts were washed with _brine , dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography ( _Et2O ) to afford the title compound.

Example T: 2-Hydroxymethyl-indane

To a solution of indane-2-carboxylic acid (1 g, 6.20 mmol) in THF (10 ml) was added _LiAlH4 (266 mg, 7 mmol) in portions at 0°C. The reaction mixture was stirred at 0°C to room temperature for 3.5 hours. The reaction was quenched by adding water and the resulting mixture was extracted with _Et2O . The combined organic extracts were washed with brine, dried over _Na2SO4 , filtered and concentrated _in vacuo to afford the title compound.

Example U: 1-piperidin-1-yl-pent-4-yn-1-one

To a solution of 4-pentynoic acid (512mg, 0.53mmol) in benzene (10ml) was added (COCl) ₂ (1ml). After stirring at room temperature for 5.5 hours, the reaction mixture was concentrated in vacuo to afford the corresponding acid chloride, which was used in subsequent reactions without further purification. To a solution of piperidine (890mg, 10.5mmol) in benzene (3ml) was added a solution of the acid chloride in benzene (2ml). The reaction mixture was stirred at room temperature for 2 hours, diluted with EtOAc. The mixture was washed with 1M aqueous KHSO ₄ , water, saturated aqueous NaHCO ₃ , water and brine. The organic layer was dried over _Na2SO4 , filtered and concentrated in vacuo to afford the title compound _.

Example V: 2-But-3-ynyl-thiazole

To a suspension of NaH (60%, 424 mg, 10.6 mmol) in THF (5 ml) at 0°C was added (EtO) ₂ P(O)CH ₂ CO ₂ Et (2.6 g, 11.6 mmol) in THF (8ml). After stirring at 0°C for 30 minutes, to this solution was added a solution of 2-formylthiazole (1 g, 8.84 mmol) in THF (8 ml). The reaction mixture was stirred at 0°C to room temperature for 13 hours. After removing most of the solvent in vacuo, the residue was diluted with ether, washed with 1M aqueous KHSO ₄ , water and brine. The organic layer was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc=5:1) to obtain unsaturated ester.

To a solution of the unsaturated ester (1.16 g, 6.33 mmol) in EtOH (15 mL) was added 10% palladium on carbon (100 mg). The black slurry was stirred at room temperature under 1 atm _H2 for 22 hours. The reaction mixture was filtered through a pad of Celite (rinsed with EtOH) and the filtrate was concentrated in vacuo to give the saturated ester.

To a solution of the above saturated ester (1.15 g, 6.21 mmol) in _CH2Cl2 (10 ml) was added DIBAL (0.95M in _hexane , 6.6 ml, 6.27 mmol) dropwise at -78 °C. After stirring at -78 °C for 20 min, the reaction was stopped by adding 1 M aqueous KHSO ₄ . _The resulting mixture was extracted with _CH2Cl2 (x3). The combined organic extracts were washed with saturated aqueous NaHCO ₃ , water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=2:1) to give the corresponding alcohol.

To a solution of the above alcohol (211 mg, 1.47 mmol) in _CH2Cl2 (5 ml) was added Dess _- Martin periodinane (750 mg, 1.76 mmol). The reaction mixture was stirred at room temperature _for 30 minutes and quenched by adding _{aqueous Na2S2O3} . The mixture was extracted with diethyl ether, the organic layer was washed with water and saturated aqueous NaHCO ₃ , dried over MgSO ₄ , filtered and concentrated in vacuo to give the corresponding aldehyde which was used directly in the next step without further purification.

To a solution of _TMSCHN2 (2.0M in hexane, 0.6ml, 1.20mmol) in THF (3ml) was added n-BuLi (1.58M in hexane, 0.76ml, 1.20mmol) dropwise at -78°C ). After stirring at -78°C for 30 minutes, to this solution was added a solution of the above aldehyde (140 mg, 0.99 mmol) in THF (2 ml). The reaction mixture was stirred at -78°C to room temperature for 2.5 hours. After diluting with ether, the mixture was washed with saturated aqueous _NH4Cl , water and brine. The organic layer was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=5:1) to obtain the title compound.

Example W: 1-(3-Bromo-benzyl)-pyrrolidin-2-one

To a solution of pyrrolidin-2-one (1.03 g, 12.1 mmol) in DMF (30 ml) was added NaH (60%, 540 mg, 13.5 mmol) at 0°C. The reaction mixture was stirred at 0 °C for 20 minutes, then allowed to warm to room temperature for 40 minutes. To this solution was added 1-bromo-3-bromomethyl-benzene (2.45 g, 9.8 mmol) at 0°C. The reaction mixture was stirred at 0 °C for 15 minutes, then allowed to warm to room temperature for 13 hours. After diluting with ether, the mixture was washed with 1M aqueous KHSO ₄ , water, saturated aqueous NaHCO ₃ , water and brine. The organic layer was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1 to 1:2) to obtain the title compound.

Example X: 1-Bromo-3-methoxymethyl-benzene

To a solution of (3-bromo-phenyl)-methanol (1 g, 5.35 mmol) in THF (10 ml) was added NaH (60%, 257 mg, 6.43 mmol) at 0°C. After 13 minutes, MeI (1 ml, 16.1 mmol) was added to the mixture. The reaction mixture was stirred at 0 °C for 10 minutes, then allowed to warm to room temperature for 50 minutes. The reaction was quenched by the addition of 1M aqueous KHSO ₄ , and the mixture was diluted with ether. After separation of the resulting two phases, the organic layer was washed with brine. The organic layer was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=10:1) to obtain the title compound.

Example YA: tert-butyl 4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carboxylate

To a suspension of 1-phenyl-1,3,8-triaza-spiro[4.5]decane-4-one (1.0 g, 4.32 mmol) in dichloromethane (10 ml) at ambient temperature Saturated sodium bicarbonate solution (10ml) and di-tert-butyl dicarbonate (1.04g, 4.76mmol) in dichloromethane (5ml) were added. The reaction mixture was stirred for 1 h, quenched with _H2O , and extracted with ethyl acetate. The combined extracts were washed with H ₂ O and brine, dried over sodium sulfate and evaporated to give the title compound; Rf=0.90 (CH ₂ Cl _{2 :} MeOH=20:1) ¹ H-NMR (400 MHz, CDCl ₃ )δ : 1.51(s, 9H), 1.63-1.71(m, 2H), 2.50-2.65(m, 2H), 3.50-3.65(m, 2H), 3.97-4.10(m, 2H), 4.75(s, 2H) , 6.74-6.76 (m, 2H), 6.84-6.88 (m, 1H), 7.01 (brs, 1H), 7.23-7.27 (m, 2H).

Example YB: 3-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl Base]-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester

To a solution of 6-chloromethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (600mg, 1.98mmol) in DMF (7ml) 4-Oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (657 mg, 1.98 mmol) and sodium hydride (101 mg, 2.53 mmol) were added. The mixture was stirred at room temperature under nitrogen atmosphere for 14 hours. The reaction mixture was diluted with water and extracted with AcOEt (2x). The combined organic layers were washed with water and brine, dried over _MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to obtain the title compound; Rf=0.25 (n-hexane:AcOEt=1:1). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.97-1.49 (m, 7H), 1.50 (s, 9H), 1.56-1.82 (m, 8H), 2.45-2.60 (m, 2H), 3.50-3.65 ( m, 2H), 4.09-4.14(m, 2H), 4.33-4.36(m, 2H), 4.64(s, 2H), 4.87(s, 2H), 6.72-6.74(m, 2H), 6.86-6.90( m, 1H), 7.20-7.24 (m, 2H), 8.94 (s, 1H).

Example YC: 7-(2-Cyclohexyl-ethyl)-6-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-3- Methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetate

To 3-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-4-oxo-1-phenyl - To a solution of tert-butyl 1,3,8-triaza-spiro[4.5]decane-8-carboxylate (340mg, 0.56mmol) in dichloromethane (5ml) was added trifluoroacetic acid (5ml). After stirring at room temperature for 1 hour, the solvent was evaporated to give the title compound; Rf=0.10 ( _{CH2Cl2 :} MeOH=20:1). ¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.98-1.38 (m, 5H), 1.65-1.83 (m, 8H), 1.98-2.09 (m, 2H), 2.71-2.80 (m, 2H), 3.53- 3.56(m, 2H), 3.94-4.02(m, 2H), 4.38-4.42(m, 2H), 4.73(s, 2H), 4.91(s, 2H), 6.71(s, 1H), 6.88-6.90( m, 2H), 7.01-7.04 (m, 1H), 7.28-7.32 (m, 2H), 7.85 (brs, 1H), 8.25 (brs, 1H), 9.08 (s, 1H).

Example YD: 4-{7-[2-(4-chloro-phenyl)-ethyl]-2-cyano-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl tert-butyl)-piperazine-1-carboxylate

To 6-bromomethyl-7-[2-(4-chloro-phenyl)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (1.0g, 2.66mmol) in DMF To a solution in (10 mL) was added piperazine-1-carboxylic acid tert-butyl ester (545 mg, 2.93 mmol) and potassium carbonate (515 mg, 3.72 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 14 hours. The reaction mixture was diluted with water and extracted with AcOEt (2x). The combined organic layers were washed with water and brine, dried over _MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to obtain the title compound; Rf=0.20 (n-hexane:AcOEt=2:1). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45 (s, 9H), 2.36-2.38 (m, 4H), 3.12-3.15 (m, 2H), 3.39-3.43 (m, 6H), 4.58-4.62 ( m, 2H), 6.48 (s, 1H), 7.01-7.03 (m, 2H), 7.24-7.26 (m, 2H), 8.90 (s, 1H).

Example YE: 5-(3-Azepan-1-yl-prop-1-ynyl)-4-(2-cyclohexyl-ethylamino)-pyrimidine -2-carbonitrile

A solution of B (0.49 mmol) and C (0.73 mmol) in DMF (5 ml) was treated with Et ₃ N (2.18 mmol), CuI (0.05 mmol) and (Ph ₃ P) ₂ PdCl ₂ (0.03 mmol) at room temperature solution. The mixture was stirred at 80 °C for 2 hours, poured into ice water, extracted with EtOAc, washed with brine and dried ( _MgSO4 ). The residue was purified by silica gel column chromatography (AcOEt) to obtain the title compound as an orange solid; ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.91-1.04 (m, 2H), 1.12-1.38 (m, 3H), 1.49-1.79 (m, 16H), 2.74 (t, 4H), 3.54 (t, 2H), 3.67 (s, 1H), 5.77 (brs. 1H), 8.18 (s, 1H). Rf 0.12 (Hexane/EtOAc 1:3).

Example ZA: 8-Benzyl-2,8-diaza-spiro[4.5]decane-1,3-dione

To a solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (400 ml) was added ethyl cyano-acetate (50.6 ml, 0.48 mol) and acetic acid ( 18.2ml, 0.32mol). The reaction mixture was refluxed for 4 hours, quenched with ice water and extracted with ether. The combined extracts were washed with _H2O , brine and dried over sodium sulfate to afford (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester in quantitative yield. Rf = 0.53 (n-hexane:AcOEt = 1:1). ¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.30-1.37 (m, 3H), 2.58 (dd, 2H), 2.64 (dd, 2H), 2.79 (dd, 2H), 3.15 (dd, 2H), 3.55 (s, 2H), 4.23-4.32 (m, 2H), 7.21-7.36 (m, 5H).

To a solution of ethyl (1-benzyl-piperidin-4-ylidene)-cyano-acetate (112.9 g, 0.40 mol) in EtOH (500 ml) and H ₂ O (100 ml) at ambient temperature Potassium cyanide (64.6 g, 0.99 mol) was added. The reaction mixture was stirred at 65 °C for 24 hours. After removal of EtOH, _H2O was added to the residue. The aqueous phase was extracted with ether. The combined extracts were washed with _H2O and brine, dried over sodium sulfate and evaporated to give 1-benzyl-4-cyanomethyl-piperidine-4-carbonitrile; Rf = 0.38 (n-Hexane:AcOEt = 1 : 1). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.76-1.81 (m, 2H), 2.10-2.05 (m, 2H), 2.23-2.39 (m, 2H), 2.69 (s, 2H), 2.90-2.94 ( m, 2H), 3.56 (s, 2H), 7.21-7.38 (m, 5H).

Acetic acid (56.8ml) and sulfuric acid (11.8ml) were added to 1-benzyl-4-cyanomethyl-piperidine-4-carbonitrile (27.2g, 0.114mmol) at ambient temperature. The reaction mixture was stirred at 125 °C for 1 h, cooled to room temperature and added to saturated aqueous NaOH to adjust to pH 6.0. The mixture was extracted with dichloromethane. The combined extracts were washed with _H2O and brine, dried over sodium sulfate and evaporated to give the title compound; Rf = 0.40 ( _{CH2Cl2 :MeOH} = 10:1). ¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.52-1.57(m, 2H), 2.02-2.17(m, 4H), 2.59(s, 2H), 2.86-2.90(m, 2H), 3.52(s, 2H), 7.21-7.28 (m, 2H), 7.30-7.37 (m, 3H), 7.92 (brs, 1H).

Example ZB: 8-Benzyl-2,8-diaza-spiro[4.5]decane

To a solution of lithium aluminum hydride (3.63 g, 95.6 mmol) in THF (100 ml) was slowly added a solution of the product of Example ZA (8.23 g, 31.8 mol) in THF (60 ml) at ambient temperature. The reaction mixture was refluxed for _{6 hours and quenched with Na2SO410H2O at} 0 °C. The inorganics were removed by filtration and the THF was evaporated to give the title compound; Rf = 0.10 (ethyl acetate only).

Example ZC: 2,8-Diaza-spiro[4.5]decane-1,3-dione hydrochloride

To a solution of the product from example ZA (1.04 g, 4.02 mol) and Pd(OH) ₂ (8.5 g) in a 200 ml flask was added EtOH (80.5 ml) at ambient temperature. The reaction mixture was stirred under _H2 at room temperature for 15 hours. The catalyst was removed by filtration and EtOH was evaporated to give 2,8-diaza-spiro[4.5]decane-1,3-dione in quantitative yield.

To a solution of 2,8-diaza-spiro[4.5]decane-1,3-dione in EtOH (20ml) was added 1M HCl in dioxane (10ml). After stirring at room temperature for 1 hour, the solvent was evaporated to give the title compound; ¹ H-NMR (400MHz, DMSO-d ₆ )δ: 1.76-1.79(m, 2H), 1.90-2.00(m, 2H), 2.68(s , 2H), 2.88-2.96 (m, 2H), 3.20-3.28 (m, 2H), 8.76 (brs, 1H), 9.01 (brs, 1H), 11.25 (brs, 1H).

Example ZD: tert-butyl 8-benzyl-2,8-diaza-spiro[4.5]decane-2-carboxylate

To a solution of the product of Example ZB (5.06 g, 21.9 mmol) in dichloromethane (50 ml) at ambient temperature was added 1 N NaOH (50 ml) and di-tert-butyl dicarbonate (6.14 g, 28.1 mmol) in Solution in dichloromethane (10ml). The reaction mixture was stirred for 5 hours, quenched with _H2O and extracted with ethyl acetate. The combined extracts were washed with H ₂ O and brine, dried over sodium sulfate and evaporated to give the title compound; ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 (s, 9H), 1.50-1.70 (m, 6H ), 2.25-2.40 (m, 2H), 2.45-2.55 (m, 2H), 3.10-3.40 (m, 4H), 3.50 (s, 2H), 7.24-7.31 (m, 5H).

Example ZE: tert-butyl 2,8-diaza-spiro[4.5]decane-2-carboxylate

To a solution of the product from Example zD (7.95 g, 24.0 mol) and Pd(OH) ₂ (2.4 g) in a 200 ml flask was added EtOH (96 ml) and acetic acid (1.2 ml) at ambient temperature. The reaction mixture was stirred under _H2 at room temperature for 15 hours. The catalyst was removed by filtration and the EtOH was evaporated to give the title compound; Rf = 0.05 (ethyl acetate only).

Example ZF: 8-Methanesulfonyl-2,8-diaza-spiro[4.5]decane hydrochloride

To a solution of the product of Example ZE (1.12 g, 4.66 mol) in dichloromethane (10 ml) was added triethylamine (3.88 ml) and methanesulfonyl chloride (1.08 ml, 14 mmol) at 0°C. The reaction mixture was stirred overnight, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with H ₂ O, brine, and dried over sodium sulfate to give crude tert-butyl 8-methylsulfonyl-2,8-diaza-spiro[4.5]decane-2-carboxylate; Rf = 0.7 ( _{CH2Cl2 :} MeOH=10:1).

To a solution of the ester (1.32g) in ethyl acetate (10ml) was added 1M HCl in ethyl acetate (20ml). After stirring at room temperature for 2 hours, the solvent was evaporated to give the title compound; ¹ H-NMR (400MHz, DMSO-d ₆ )δ: 1.62-1.68(m, 4H), 1.78-1.82(m, 2H), 2.87(s , 3H), 2.98-3.12 (m, 6H), 3.20-3.23 (m, 2H), 9.49 (brs, 1H), 9.59 (brs, 1H).

Example ZG: 1-(2,8-Diaza-spiro[4.5]dec-8-yl)-ethanone hydrochloride

To a solution of the product of Example ZE (1.12 g, 4.66 mol) in dichloromethane (10 ml) was added triethylamine (3.88 ml) and acetic anhydride (1.32 ml, 14 mmol) at 0°C. The reaction mixture was stirred overnight, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with _H2O , brine, and dried over sodium sulfate to give crude tert-butyl 8-acetyl-2,8-diaza-spiro[4.5]decane-2-carboxylate; Rf=0.6 ( _{CH2Cl2 :} MeOH=10:1).

To a solution of the ester (1.34g) in ethyl acetate (10ml) was added 1M HCl in ethyl acetate (20ml). After stirring at room temperature for 2 hours, the solvent was evaporated to obtain the title compound as a solid; ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.44-1.59 (m, 4H), 1.76-1.83 (m, 2H), 2.07 (s, 3H), 2.96-3.06 (m, 2H), 3.16-3.24 (m, 4H), 3.38-3.56 (m, 2H), 9.55 (brs, 1H), 9.67 (brs, 1H).

Example ZH: 5-fluoro-1,3-dihydro-indol-2-one

To a solution of 2,4-difluoronitro-benzene (127 g, 0.79 mol) and dimethyl malonate (210.9 g, 1.59 mol) in DMF (800 ml) was added potassium carbonate (220.6 g, 1.59 mol). The reaction mixture was stirred at 70 °C for 12 hours. The reaction mixture was added to toluene (639ml) and 12N HCl (1200ml) and extracted with ethyl acetate. The combined extracts were washed with _H2O and brine, dried over sodium sulfate and evaporated to give dimethyl 2-(5-fluoro-2-nitro-phenyl)-malonate; Rf = 0.5 (n-hexane :AcOEt=2:1).

To the crude ester and 5% Pd-C (10.8 g) in a 2 L flask was added MeOH (600 ml) at ambient temperature. The reaction mixture was stirred under _H2 at room temperature for 15 hours. The catalyst was removed by filtration and MeOH was evaporated to give methyl 5-fluoro-2-oxo-2,3-dihydro-1H-indole-3-carboxylate; Rf=0.10 (n-hexane:ethyl acetate=1:1) .

To a solution of crude methyl 5-fluoro-2-oxo-2,3-dihydro-1H-indole-3-carboxylate in MeOH (800ml) at ambient temperature was added 6N HCl (415ml , 1.92mol). The reaction mixture was stirred at 80 °C for 5 hours. After cooling to room temperature, 8N KOH (438ml, 1.82mol) was added to the reaction mixture. The reaction mixture was stirred at 40°C for 30 minutes. 12N HCl (66.5ml) was added to the reaction mixture. MeOH was evaporated and white powder was filtered off; Rf = 0.25 (n-Hexane:AcOEt = 1:1). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.54 (s, 2H), 6.78-6.81 (m, 1H), 6.90-6.98 (m, 2H), 8.34 (brs, 1H).

Embodiment ZI

To a solution of the product from Example ZH (1.5 g, 10 mmol) in THF (160 ml) was added NaHMDS solution (1M in THF) (50 ml, 50 mmol) at -78°C. After stirring at -78°C for 30 minutes, ethyl-bis-(2-chloro-ethyl)-amine (47.3 g, 0.18 mol) in THF (176 ml) was added and the reaction mixture was stirred at room temperature for 15 hours , quenched with saturated ammonium chloride and ice water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated. Ethyl acetate was added to the residue, and powder was obtained by filtration; Rf=0.10 (CH ₂ Cl ₂ :MeOH=30:1).

Example ZJ: 2-fluoro-4-methoxy-1-nitro-benzene

To a solution of 3-fluoro-4-nitro-phenol (25.3 g, 0.16 mol) in acetone (160 ml) was added potassium carbonate (41.7 g, 0.30 mol) and iodomethane (20.0 ml, 0.32 mol) at ambient temperature mol). The reaction mixture was stirred at 40 °C for 3 hours. After cooling to room temperature, dichloromethane was added to the reaction mixture, which was filtered and evaporated. Dichloromethane was added to the residue, the combined extracts were washed with H ₂ O and brine, dried over sodium sulfate and evaporated to give the title compound; ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (s, 3H ), 6.72-6.79 (m, 2H), 8.06-8.13 (m, 1H).

Example ZK: 5-Methoxy-1,3-dihydro-indol-2-one

To the solution of 2-fluoro-4-methoxy-1-nitro-benzene (84.1 g, 0.49 mol) and dimethyl malonate (129.9 g, 0.98 mol) in DMF (490 ml) at ambient temperature Potassium carbonate (135.9 g, 0.98 mol) was added to the solution. The reaction mixture was stirred at 70 °C for 12 hours. The reaction mixture was added to toluene (393ml) and 12N HCl (123ml), and extracted with ethyl acetate. The combined extracts were washed with _H2O and brine, dried over sodium sulfate and evaporated to give dimethyl 2-(5-methoxy-2-nitro-phenyl)-malonate; Rf = 0.8( n-Hexane:AcOEt=1:1).

To the ester and 5% Pd-C (7.0 g) in a 1 L flask was added MeOH (490 ml) at ambient temperature. The reaction mixture was stirred under _H2 at room temperature for 15 hours. The catalyst was removed by filtration and MeOH was evaporated to give methyl 5-methoxy-2-oxo-2,3-dihydro-1H-indole-3-carboxylate; Rf=0.10 (n-hexane:ethyl acetate=1: 1).

To a solution of crude methyl 5-methoxy-2-oxo-2,3-dihydro-1H-indole-3-carboxylate in MeOH (0320ml) was added 6N HCl (255ml, 1.92mol). The reaction mixture was stirred at 70 °C for 3 hours. After cooling to room temperature, 8N KOH (269ml, 1.82mol) was added to the reaction mixture. The reaction mixture was stirred at 40°C for 30 minutes. 12N HCl (41 ml) was added to the reaction mixture. Evaporate MeOH and filter out the white powder to obtain the title compound; Rf=0.25 (n-Hexane:AcOEt=1:1); ¹ H-NMR (400MHz, CDCl ₃ )δ: 3.51(s, 2H), 3.78(s, 3H ), 6.72-6.85 (m, 3H), 7.60 (brs, 1H).

Example ZL

To a solution of the product from Example ZK (1.06 g, 6.49 mmol) in THF (13 ml) was added NaHMDS solution (1M in THF) (32.5 ml, 32.5 mmol) at -78°C. After stirring at -78°C for 30 minutes, methyl-bis-(2-chloro-ethyl)-amine hydrochloride (1.37 g, 7.14 mol) was added, and the reaction mixture was stirred at room temperature for 13.5 hours, washed with saturated chlorine Ammonium chloride and ice water were used to quench the reaction and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated. Diethyl ether was added to the residue, and the powder was obtained by filtration; Rf=0.10 (CH ₂ Cl ₂ :MeOH=30:1). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.66-1.78 (m, 4H), 2.28 (s, 3H), 2.44-2.47 (m, 2H), 2.71-2.77 (m, 2H), 3.70 ( s, 3H), 6.74 (s, 2H), 7.01 (s, 1H), 10.15 (brs, 1H).

Example ZM

To a solution of 1,3-dihydro-indol-2-one (8-79 g, 66 mmol) in THF (50 ml) was added LiHMDS solution (1M in THF) (200 ml, 200 mmol) at -78°C. After stirring at -78°C for 30 minutes, bis-(2-chloro-ethyl)-carbamate tert-butyl ester (17.5 g, 72.6 mol) was added, and the reaction mixture was stirred at room temperature for 21 hours, washed with saturated ammonium chloride Quench with ice water and extract with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated to give crude product. Rf = 0.25 (CH ₂ Cl ₂ :MeOH = 30:1). ¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 1.43(s, 9H), 1.63-1.70(m, 4H), 3.57-3.71(m, 4H), 6.84-6.86(m, 1H), 6.95- 6.97 (m, 1H), 7.17-7.19 (m, 1H), 7.42-7.44 (m, 1H), 10.40 (brs, 1H).

To a solution of the crude product in ethyl acetate (20ml) was added 1M HCl in ethyl acetate (20ml). After stirring at room temperature for 2 hours, the solvent was evaporated. Diethyl ether was added to the residue, and the powder was obtained by filtration; Rf=0.05 (ethyl acetate only); ¹ H-NMR (400MHz, DMSO-d ₆ )δ: 1.87-1.90 (m, 2H), 2.04-2.11 (m , 2H), 3.24-3.27(m, 2H), 3.45-3.49(m, 2H), 6.88-6.89(m, 1H), 7.00-7.04(m, 1H), 7.21-7.29(m, 2H), 9.04 (brs, 1H), 10.57 (brs, 1H).

Example ZN

To a solution of the product from Example ZM (422mg, 1.76mol) in dichloromethane (5ml) was added triethylamine (1.2ml) and acetic anhydride (0.33ml, 3.53mmol) at 0°C. The reaction mixture was stirred for 2 hours, quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over _MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=5:1) to obtain the product; Rf=0.6 (CH ₂ Cl ₂ :MeOH=10:1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.79-1.95(m, 4H), 2.20(s, 3H), 3.68-3.74(m, 1H), 3.80-3.87(m, 1H), 3.98-4.22(m, 2H), 6.90-6.92(m, 1H ), 7.03-7.07 (m, 1H), 7.22-7.26 (m, 2H), 8.06 (brs, 1H).

Example ZO

To a solution of 1,3-dihydro-indol-2-one (2.66 g, 20 mmol) in THF (40 ml) was added NaHMDS solution (1M in THF) (100 ml, 100 mmol) at -78°C. After stirring at -78°C for 30 minutes, ethyl-bis-(2-chloro-ethyl)-amine hydrochloride (4.54 g, 22 mol) was added, and the reaction mixture was stirred at room temperature for 18 hours, then washed with saturated chloride Ammonium and ice water were quenched and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over _MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=5:1) to give the product; Rf=0.25 (CH ₂ Cl ₂ :MeOH=30:1).

Example ZP: 4,4-difluoropiperidine hydrochloride

To a solution of tert-butyl 4-oxo-piperidine-1-carboxylate (1 g) in _CH2Cl2 (10 mL) at ₀ °C was added [di(2-methoxyethyl)amino]tris Sulfur fluoride (1.85 mL), stirred at room temperature for 1.5 hours. The reaction mixture was poured into aqueous NaHCO ₃ and extracted with dichloromethane. The organic layer was washed sequentially with _H2O and aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography to give a colorless oil.

To a solution of the oil in _Et2O (10 mL) was added HCl in EtOAc (4N, 5 mL) and stirred at room temperature for 1 h. The white precipitate in the reaction mixture was collected by filtration to give pure product; 1H NMR (DMSO-d6, δ (ppm)); 2.23-2.2.36 (m, 4H), 3.17-3.28 (m, 4H), 9.54 ( brs, 2H).

Example ZQ: 3-(S)-fluoro-pyrrolidine hydrochloride

[Bis( _{2 -} methoxyethyl) Amino]sulfur trifluoride (236uL), stirred at room temperature for 1 hour. The reaction mixture was poured into aqueous NaHCO ₃ and extracted with Et ₂ O. The organic layer was washed sequentially with _H2O and aqueous NaCl, dried over _MgSO4 and concentrated in vacuo. The residue was purified by column chromatography to give a colorless oil.

The oil was dissolved in 4N HCl in dioxane (5 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to afford the title compound.

Example ZR: 3,3-Difluoropiperidine hydrochloride

To a solution of 1-benzyl-piperidin-3-one (1 g) in _CH2Cl2 (10 mL) at ₀ °C was added [bis(2-methoxyethyl)amino]sulfur trifluoride (1.84 mL), stirred at room temperature for 1.5 hours. The reaction mixture was poured into aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed sequentially with _H2O and aqueous NaCl, dried over _MgSO4 and concentrated in vacuo. The residue was purified by column chromatography to give a colorless oil. The oil in HCl in EtOH/MeOH (50 mL) and Pd/C (5% w/w on charcoal, 100 mg) was stirred under _H2 atmosphere for 22 h. The reaction mixture was filtered through a pad of celite. To the filtrate was added HCl in EtOAc, then concentrated in vacuo to afford the title compound.

Example ZS: 3,3-Difluoro-pyrrolidine

To a solution of tert-butyl 3-oxo-pyrrolidine-1-carboxylate (1 g) in _CH2Cl2 (10 mL) at ₀ °C was added [di(2-methoxyethyl)amino]tris Sulfur fluoride (2 mL), stirred at room temperature for 1 hour. The reaction mixture was poured into aqueous NaHCO ₃ and extracted with Et ₂ O. The organic layer was washed sequentially with _H2O and aqueous NaCl, dried over _MgSO4 and concentrated in vacuo. The residue was purified by column chromatography to give a colorless oil. To a solution of the oil in _Et2O (10 mL) was added HCl in EtOAc (4N, 5 mL) and stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in _Et2O . The white precipitate in _Et2O was collected by filtration to afford the title compound.

Example ZT: 3-(R)-fluoro-pyrrolidine hydrochloride

[Bis( _{2 -} methoxyethyl) Amino]sulfur trifluoride (236uL), stirred at room temperature for 1 hour. The reaction mixture was poured into aqueous NaHCO ₃ and extracted with Et ₂ O. The organic layer was washed sequentially with _H2O and aqueous NaCl, dried over _MgSO4 and concentrated in vacuo. The residue was purified by column chromatography to give a colorless oil. The oil was dissolved in 4N HCl in dioxane (5 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to afford the title compound.

Example ZU: 7-methoxy-3,4-dihydro-2H-isoquinolin-1-one

Sodium azide (1.8 g) was added to a heated solution of 6-methoxy-indan-1-one (3 g) in trichloroacetic acid (30 g) at 70° C., and the mixture was kept under stirring. 12 hours. The reaction mixture was diluted with ice water and neutralized with potassium carbonate, extracted with ethyl acetate (2 times). The organic layer was washed sequentially with H ₂ O and saturated aqueous NaCl, dried over MgSO ₄ , and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound; 1H NMR (CDCl3, δ (ppm)); 2.86 (dd, 2H), 3.45-3.50 (m, 2H), 3.78 (s, 3H), 6.36 (brs, 1H), 6.92-6.95 (m, 1H), 7.06 (d, 1H), 7.52 (d, 1H).

Example ZV: 7-Methoxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride

To a solution of 7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (200 mg) in THF (8 mL) was added LiAlH4 (76 mg), stirred at reflux for 3 hours and diluted with THF . Sodium sulfate decahydrate was added to the reaction mixture and filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was dissolved in _Et2O , then to _Et2O was added HCl in EtOAc. The white precipitate was collected by filtration to give the title compound; 1H NMR (CDCl3, δ (ppm)); 2.92 (dd, 2H), 3.30-3.35 (m, 2H), 3.72 (s, 3H), 4.18-4.23 (m , 2H), 6.81-6.86 (m, 2H), 7.12 (d, 1H), 9.45 (brs, 2H).

Example ZW: 4-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid

To a suspension of 1-piperidin-4-yl-1,3-dihydro-benzimidazol-2-one (1.0 g, 4.6 mmol) in dichloromethane (10 ml) was added Saturated sodium bicarbonate solution (10ml) and di-tert-butyl dicarbonate (1.1g, 5.06mmol) in dichloromethane (5ml). The reaction mixture was stirred for 1 hour, quenched with _H2O and extracted with ethyl acetate. The combined extracts were washed with _H2O and brine, dried over sodium sulfate and evaporated to give the title compound; Rf = 0.90 ( _CH2Cl2 : _MeOH = 20:1). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.60 (s, 9H), 1.82-1.85 (m, 2H), 2.31-2.36 (m, 2H), 2.84-2.90 (m, 2H), 4.25-4.45 ( m, 2H), 4.47-4.51 (m, 2H), 7.04-7.14 (m, 4H), 9.43 (brs, 1H).

Example ZX: 4-{3-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl Base]-2-oxo-2,3-dihydro-benzimidazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 6-chloromethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (600mg, 1.98mmol) in DMF (7ml) 4-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (628 mg, 1.98 mmol) and sodium hydride (106 mg, 2.65 mmol) were added. The mixture was stirred at room temperature under nitrogen atmosphere for 14 hours. The reaction mixture was diluted with water and extracted with AcOEt (2x). The combined organic layers were washed with water and brine, dried over _MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to obtain the title compound; Rf=0.30 (n-hexane:AcOEt=1:1); ¹ H-NMR (400MHz, CDCl ₃ )δ: 0.92 -0.97(m, 2H), 1.00-1.34(m, 3H), 1.50(s, 9H), 1.53-1.85(m, 10H), 2.30-2.41(m, 2H), 2.85-2.91(m, 2H) , 4.31-4.54(m, 5H), 5.29(s, 2H), 6.54(s, 1H), 6.96-6.98(m, 1H), 7.02-7.12(m, 2H), 7.17-7.19(m, 1H) , 8.88 (s, 1H).

Example ZY: 7-(2-cyclohexyl-ethyl)-6-(2-oxo-3-piperidin-4-yl-2,3-dihydro-benzimidazole-1- Methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetate

To 4-{3-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-2-oxo-2 , To a solution of tert-butyl 3-dihydro-benzimidazol-1-yl}-piperidine-1-carboxylate (512 mg) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml). After stirring at room temperature for 1 hour, the solvent was evaporated to give the title compound; Rf=0.10 ( _{CH2Cl2 :} MeOH=20:1). ¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.95-1.03 (m, 2H), 1.17-1.35 (m, 4H), 1.59-1.79 (m, 7H), 2.14-2.17 (m, 2H), 2.86- 3.01(m, 2H), 3.29-3.32(m, 2H), 3.77-3.80(m, 2H), 4.43-4.47(m, 2H), 4.79-4.85(m, 1H), 5.36(s, 2H), 6.55 (s, 1H), 7.03-7.23 (m, 3H), 7.46-7.47 (m, 1H), 8.27 (brs, 1H), 8.36 (brs, 1H), 8.99 (s, 1H).

Example 1: 7-[2-(4-chloro-phenyl)-ethyl]-6-(2,4-difluoro-phenoxymethyl)-7H-pyrrolo[2 Pyrimidine-2-carbonitrile

6-Bromomethyl-7-[2-(4-chloro-phenyl)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (Example A; 0.1 g, 0.27 mmol) and 2,4-difluorophenol (35mg, 0.27mmol) were dissolved in DMF (10ml), and potassium carbonate (75mg, 0.54mmol) was added to the solution. The reaction mixture was stirred at room temperature for 15 hours, quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried over _MgSO4 (or _Na2SO4 ) and _concentrated . Chromatography on silica gel afforded the desired product; _Rf = 0.30 (n-hexane: ethyl acetate = 1:1). ¹ H-NMR (400MHz, CDCl ₃ ) δ: 3.18(t, 2H), 4.63(t, 2H), 4.93(s, 2H), 6.63(s, 1H), 6.67-6.95(m, 3H), 7.02 (d, 2H), 7.22 (d, 2H), 8.97 (s, 1H).

Example 2-49

Compounds of Formula 2 below, identified in Table 2 below, were obtained by repeating the procedure described in Example 1 using appropriate starting materials (including those of Examples A and B) and conditions.

Table 2

Example 50: 4-{7-[2-(4-Chloro-phenyl)-ethyl]-2-cyano-7H-pyrrolo[2,3-d]pyrimidine-6- methoxy}-3-fluoro-N-propyl-benzamide

6-Bromomethyl-7-[2-(4-chloro-phenyl)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (Example A, 3.8g, 10.1 mmol) and 3-fluoro-4-hydroxy-N-propyl-benzamide (2.0 g, 10.1 mmol) were dissolved in DMF (220 ml), and potassium carbonate (2.8 g, 20.2 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 3 hours, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated. Chromatography on silica gel (eluent; n-hexane: ethyl acetate=4: 1, 2: 1, 1: 1, 1: 2) gave a yellow product, which was recrystallized with acetonitrile to give a light yellow powder; Rf = 0.30 (n-hexane: ethyl acetate = 1:1); ¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.99(s, 3H), 1.65(q, 2H), 3.18(t, 2H), 3.41(q , 2H), 4.60(t, 2H), 4.97(s, 2H), 5.94-6.05(br, 1H), 6.77(s, 1H), 6.97-6.99(m, 3H), 7.26-7.31(m, 2H ), 7.50-7.58 (m, 2H), 8.97 (s, 1H).

Examples 51 to 68

Compounds of Formula 2 below, identified in Table 3 below, were obtained by repeating the procedure described in Example 50 using appropriate starting materials (including those prepared in Example C) and conditions.

table 3

Examples 69 to 81

Compounds of Formula 2 below, identified in Table 4 below, were obtained by repeating the procedure described in Example 50 using appropriate starting materials (including those prepared in Example D) and conditions.

Table 4

Examples 82 to 87

Compounds of Formula 2 identified below in Table 5 were obtained by repeating the procedure described in Example 50 using appropriate starting materials (including those prepared in Example E) and conditions.

table 5

Example 88: 7-[2-(4-Chloro-phenyl)-ethyl]-6-(2-fluoro-4-formyl-phenoxymethyl)-7H-pyrrole And[2,3-d]pyrimidine-2-carbonitrile

To 6-bromomethyl-7-[2-(4-chloro-phenyl)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (Example B2, 500mg) in DMF (5 mL) were added 3-fluoro-4-hydroxybenzaldehyde (224 mg) and potassium carbonate (276 mg), followed by stirring for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography to obtain the title compound; Rf = 0.25 (n-hexane; EtOAc = 1:1); ¹ H NMR (DMSO-d6, δ (ppm); 3.19 (dd, 2H), 4.60 (dd , 2H), 5.00(s, 2H), 6.72(s, 1H), 6.98(dd, 2H), 7.06(dd, 1H), 7.22(d, 2H), 7.65-7.69(m, 2H), 9.01( s, 1H), 9.90 (s, 1H).

Example 89: 4-{7-[2-(4-Chloro-phenyl)-ethyl]-2-cyano-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl Oxy}-3-fluoro-benzoic acid

At 0°C, to 7-[2-(4-chloro-phenyl)-ethyl]-6-(2-fluoro-4-formyl-phenoxymethyl)-7H-pyrrolo[2, 3-d] To a solution of pyrimidine-2-carbonitrile (example 88, 480 mg), NaClO ₄ (298 mg) in THF (10 mL) was added NH ₂ SO ₃ H (160 mg) in H ₂ O at room temperature Stir for 3 hours. The reaction mixture was diluted with _H2O and extracted with EtOAc. The organic layer was washed sequentially with _H2O and aqueous sodium chloride, dried over _MgSO4 and concentrated in vacuo. The crude product was washed with Et ₂ O to give the title compound; Rf=0.08 (n-Hexane:EtOAc=1:1); ¹ H NMR (DMSO-d6, δ(ppm): 3.13 (dd, 2H), 4.61 (dd, 2H), 5.54(s, 2H), 7.01(s, 1H), 7.08-7.10(m, 2H), 7.22-7.25(m, 2H), 7.45-7.49(m, 1H), 7.71-7.74(m, 1H), 7.80-7.82 (m, 1H), 9.16 (s, 1H), 13.00 (brs, 1H).

Example 90: 4-{7-[2-(4-Chloro-phenyl)-ethyl]-2-oxyl-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl Oxy}-3-fluoro-N,N-dipropyl-benzamide

At 0°C, 4-{7-[2-(4-chloro-phenyl)-ethyl]-2-cyano-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethoxy To a solution of )-3-fluoro-benzoic acid (60 mg) in pyridine (1 mL) was added POCl ₃ (15 uL) and stirring was continued at 0° C. for 1 hour. Di-n-propylamine (17 uL) was added to the reaction mixture and stirred at 0 °C for 1 h, diluted with _H2O and extracted with EtOAc. The organic layer was washed sequentially with _H2O and aqueous sodium chloride, dried over _MgSO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give the title compound; Rf = 0.13 (n-Hexane:EtOAc = 1:1); ¹ H NMR (CDCl ₃ , δ(ppm)); 0.88-1.04 (m, 6H), 1.65 -1.85(m, 4H), 3.18-3.61(m, 6H), 4.70(dd, 2H), 5.05(s, 2H), 6.76(s, 1H), 7.02-7.10(m, 3H), 7.20-7.31 (m, 4H), 9.08 (s, 1H).

Example 91: 6-[4-(5,5-Dimethyl-2,4-dioxo-oxazolidin-3-ylmethyl)-phenoxymethyl Base]-7-(3-ethyl-heptyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

To 7-(3-ethyl-heptyl)-6-(4-formyl-phenoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (720mg, 1.90mmol) To a solution in MeOH (30ml) and THF (30ml) was added _NaBH4 (100mg, 2.60mmol) in portions. The reaction mixture was stirred at room temperature for 4 hours and most of the solvent was removed in vacuo. The residue _was diluted with water and extracted with _CH2Cl2 . The combined organic extracts were washed with _brine , dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the alcohol 7-(3-ethyl-heptyl)-6-(4-hydroxymethyl-phenoxymethyl)-7H-pyrrolo[2,3-d] Pyrimidine-2-carbonitrile. To a solution of the alcohol (140mg, 0.36mmol), 5,5-dimethyl-oxazolidinedione (46mg, 360mmol) and _Ph3P (105mg, 0.40mmol) in THF (2ml) was added DEAD (0.25ml, 0.46mmol). The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by RP-HPLC to give the title compound; Rf 0.38 (n-hexane:EtOAc=1:1); ¹ H-HMR (400 MHz) δ0.92-1.00 (m, 2H), 1.18-1.25 ( m, 3H), 1.30-1.40(m, 1H), 1.58(s, 6H), 1.68-1.78(m, 7H), 4.35-4.39(m, 2H), 4.62(s, 2H), 5.22(s, 2H), 6.71 (s, 1H), 6.95 (dd, 2H), 7.37 (dd, 2H), 8.96 (s, 1H).

Example 92:

6-Bromomethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (Example A, 0.23 mmol) was dissolved in 2 ml DMF. To this solution was added 1-(4-hydroxy-phenyl)-3,3-dimethyl-pyrrolidin-2-one (0.25 mmol) and _K2CO3 (0.27 _mmol ) at room temperature. After 1.5 hours, the reaction mixture _was diluted with _H2O , extracted twice with AcOEt, and dried over _Na2SO4 . The product was obtained by flash chromatography on silica gel eluting with AcOEt-hexane (1:2) (see Table 6 below for physical data).

Examples 93 to 96

Compounds of Formula 2 below, identified in Table 6 below, were obtained by repeating the procedure described in Example 92 using appropriate starting materials (including those prepared in Examples F and G) and conditions.

Table 6

Example 97: 2,2,2-Trifluoro-ethanesulfonic acid {4-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d] Pyrimidin-6-ylmethoxy]-phenyl}-amide

Dissolve 6-(4-amino-phenoxymethyl)-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.21mmol) in 2ml _{CH2Cl2 .} To this solution were added 2,2,2-trifluoro-ethanesulfonyl chloride (0.25 mmol) and pyridine (0.25 mmol) at room temperature. After 0.5 h, the reaction mixture _was diluted with _H2O , extracted twice with _Et2O , dried over _Na2SO4 . The title product was obtained by silica gel flash chromatography using AcOEt-hexane (1:1) as eluent; Rf 0.18 (n-hexane:AcOEt=2:1); ¹ H-HMR (400MHz, CDCl3) δ: .0.93 -1.02(m, 2H), 1.10-1.28(m, 3H), 1.29-1.39(m, 1H), 1.65-1.79(m, 5H), 3.73-3.79(q, 2H), 4.37-4.41(m, 2H), 5.24 (s, 2H), 6.63 (br s, 1H), 6.74 (s, 1H), 7.01-7.03 (m, 2H), 7.27 (d, 2H), 8.98 (s, 1H).

Example 98: 6-[4-(4-Acetyl-piperazin-1-yl)-phenoxymethyl]-7-(2-cyclopentyl-ethyl)-7H- Pyrrolo[2,3-d]pyrimidine-2-carbonitrile

5-Bromo-4-(2-cyclopentyl-ethylamino)-pyrimidine-2-carbonitrile (0.46mmol) and 1-[4-(4-prop-2-ynyloxy-phenyl)- Piperazin-1-yl]-ethanone (0.41 mmol) was dissolved in 4 ml DMF. The mixture was degassed by evaporation and purged several times with nitrogen with stirring. (Ph ₃ P) ₂ PdCl ₂ (0.021 mmol), CuI (0.041 mmol) and Et ₃ N (0.82 mmol) were added and the reaction was heated at 80° C. under nitrogen for 9 hours. After cooling the mixture to room temperature, the mixture was extracted twice with AcOEt, the combined organic layers were washed with brine several times, dried over _Na2SO4 and concentrated under reduced pressure _. A solid was obtained by flash chromatography on silica gel. This solid was dissolved in 3ml DMF. DBU (60ml) was added to the solution, which was then heated at 100°C for 1.5 hours. After cooling the mixture to room temperature, the mixture was concentrated under reduced pressure. Flash chromatography on silica gel gave the title compound as a yellow solid; Rf 0.13 (AcOEt); ¹ H-HMR (400 MHz, CDCl3) δ: .1.14-1.16 (m, 2H), 1.49-1.65 (m, 4H), 1.78 -1.88(m, 5H), 2.14(s, 3H), 3.04-3.10(m, 4H), 3.62(t, 2H), 3.77(t, 2H), 4.39(t, 2H), 5.20(s, 2H ), 6.70 (s, 1H), 6.74 (d, 2H), 7.03 (d, 2H), 8.95 (s, 1H).

Examples 99 to 103

Compounds of Formula 2 below, identified in Table 7 below, were obtained by repeating the procedure described in Example 98 using appropriate starting materials (including some of the materials prepared in Examples A to G) and conditions.

Table 7

Example 104: 4-[2-Cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethoxy Base]-N-(2,2,2-trifluoro-ethyl)-benzamide

At 0°C, 4-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethoxy]-benzoic acid ( 51 mg, 0.13 mmol) and 2,2,2-trifluoroethylamine (25 mg, 0.25 mmol) in DMF (3 ml) were added HOAt (26 mg, 0.19 mmol) and WSCI.HCl (36 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 15 hours, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined extracts were washed with _H2O , brine and dried over magnesium sulfate. The crude product was purified by reverse phase HPLC and fractions were collected and evaporated. Saturated sodium bicarbonate was added for neutralization, and the aqueous phase was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to give the desired product; Rf = 0.76 (n-hexane: ethyl acetate = 1:2); ¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.94 -0.99(m, 2H), 1.11-1.39(m, 4H), 1.61-1.84(m, 7H), 4.09-4.17(m, 2H), 4.37-4.40(m, 2H), 5.39(s, 2H) , 6.27-6.30 (br, 1H), 6.76 (s, 1H), 7.07 (d, 2H), 7.82 (d, 2H), 8.97 (s, 1H).

Examples 105 to 106

Compounds of Formula 2 below, identified in Table 8 below, were obtained by repeating the procedure described in Example 104 using appropriate starting materials (including some of the materials prepared in Examples A to G) and conditions.

Table 8

Example 107A: {4-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl-methanol Oxy]-phenyl}-tert-butyl carbamate

6-Chloromethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and (4-hydroxy- Phenyl)-tert-butyl carbamate was reacted to give the title compound; R _f =0.16 (n-Hexane:AcOEt=3:1). NMR (400MHz, CDCl ₃ , δ) 0.92-1.05(m, 2H), 1.15-1.40(m, 4H), 1.51(s, 9H), 1.60-1.84(m, 7H), 4.38(t, 2H), 5.30 (s, 2H), 6.38 (br s, 2H), 6.70 (s, 2H), 6.92 (d, 2H), 7.31 (d, 2H), 8.95 (s, 1H).

Example 107B: N-{4-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl Methoxy]-phenyl}-propionamide

Treatment of Example 107A with TFA in dichloromethane afforded the amine 6-(4-amino-phenoxymethyl)-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2, 3-d] pyrimidine-2-carbonitrile. To a solution of the amine (0.18 mmol) in dichloromethane (10 ml) was added propionyl chloride (0.62 mmol) and triethylamine (0.97 mmol) dropwise at 0°C. The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic layer was washed with water and brine, dried over _MgSO4 and concentrated in vacuo. Purification of the residue by HPLC with reverse phase column (0.1% TFA in _H2O and 0.1% TFA in MeCN) afforded the title compound; Rf (n-Hexane:AcOEt=1:1): 0.15; ¹ H -HMR (400MHz) δ: .0.92-1.04(m, 2H), 1.11-1.40(m, 7H), 1.62-1.81(m, 7H), 2.38(q, 2H), 4.38(t, 2H), 5.21 (s, 2H), 6.71 (s, 2H), 6.94 (d, 2H), 7.05 (br s, 1H), 7.47 (d, 2H), 8.86 (s, 1H).

Examples 108 and 109

Compounds of Formula 2 below, identified in Table 9 below, were obtained by repeating the procedure described in Examples 107A and 107B using appropriate starting materials (including some of the materials prepared in Examples A to G) and conditions.

Table 9

Example 110: 7-[2-(4-Chloro-phenyl)-ethyl]-6-(3-fluoro-4-nitro-phenoxymethyl)-7H-pyrrolo [2,3-d]pyrimidine-2-carbonitrile

6-Bromomethyl-7-[2-(4-chloro-phenyl)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine-2- Nitrile and 3-fluoro-4-nitro-phenol were reacted to give the title compound; Rf 0.43 (n-hexane:AcOEt=1:1); ¹ H-HMR (400MHz) δ: .3.16(t, 2H), 4.56( t, 2H), 4.84(s, 2H), 6.71(s, 1H), 6.74(s, 1H), 6.76(s, 1H), 6.91(d, 2H), 7.22(d, 2H), 8.14(t , 1H), 9.03 (s, 1H).

Example 111: N-(4-{7-[2-(4-Chloro-phenyl)-ethyl]-2-cyano-7H-pyrrolo[2,3-d]pyrimidine-6- methoxy}-2-fluoro-phenyl)-acetamide

Reduction of the compound of Example 110 by hydrogenation with 10% Pd-C under a hydrogen atmosphere gave the amine 7-[2-(4-chloro-phenyl)-ethyl]-6-(3-fluoro-4-amino -phenoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile. The amine was acetylated with acetyl chloride by the same procedure as above to obtain the title compound; Rf0.14 (n-hexane:AcOEt=1:1); ¹ H-HMR (CDCl ₃ , 400MHz)δ: .2.22 (s, 3H), 3.15(t, 2H), 4.56(t, 2H), 4.83(s, 2H), 6.65-6.71(m, 3H), 6.95(d, 2H), 7.18(br s, 1H) , 7.21 (d, 2H), 8.18 (t, 1H), 8.99 (s, 1H).

Examples 112 to 119

Compounds of Formula 2 identified below in Table 10 were obtained by repeating the procedure described in Examples 110 and 111 using appropriate starting materials (including some of the materials prepared in Examples A to G) and conditions.

Table 10

Example 120: 7-[2-(4-Chloro-phenyl)-ethyl]-6-(2-fluoro-4-propylaminomethylphenoxymethyl Base)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

Treatment of 6-(4-chloromethyl-2-fluoro-phenoxymethyl)-7-[2-(4-chloro-phenyl)-ethyl]-7H-pyrrolo with potassium carbonate in DMF [2,3-d]pyrimidine-2-carbonitrile and propylamine to give 7-[2-(4-chloro-phenyl)-ethyl]-6-(2-fluoro-4-propylaminomethyl-benzene Oxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile; Rf0.10 (n-hexane: AcOEt=1:2); ¹ H-HMR (CDCl ₃ , 400MHz)δ: . 0.92(t, 3H), 1.49-1.59(m, 2H), 2.62(t, 2H), 3.18(t, 2H), 3.77(s, 2H), 4.61(t, 2H), 4.95(s, 2H) , 6.65 (s, 1H), 6.91 (t, 1H), 6.98-7.08 (m, 3H), 7.11-7.21 (m, 3H), 8.97 (s, 1H).

Examples 121 to 130

Compounds of Formula 2 identified below in Table 11 were obtained by repeating the procedure described in Example 120 using appropriate starting materials (including some of the materials prepared in Examples A to G) and conditions.

Table 11

Example 131: 7-(2-Cyclohexyl-ethyl)-6-[4-(4-propionyl-piperazin-1-yl)-phenoxymethyl]-7H- Pyrrolo[2,3-d]pyrimidine-2-carbonitrile

6-Chloromethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile was reacted with 4-(4- Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester reaction to give 4-{4-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3- d] pyrimidin-6-ylmethoxy]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester. The Boc group was deprotected by treating the ester with TFA, and the deprotected piperazine derivative was acylated with propionyl chloride according to the same procedure described in Example 107B to afford the title compound; ¹ H-HMR(CDCl ₃ , 400MHz) δ0.58 (CH ₂ Cl ₂ :MeOH=9:1); 0.93-1.03(m, 2H), 1.15-1.43(m, 7H), 1.59-1.81(m, 7H), 2.39(q , 2H), 3.07(brs, 4H), 3.62(brt, 2H), 3.78(brt, 2H), 4.39(t, 2H), 5.19(s, 2H), 6.69(s, 1H), 6.92(s, 4H), 8.95 (s, 1H).

Examples 132 to 139

Compounds of Formula 2 below, identified in Table 12 below, were obtained by repeating the procedure described in Example 131 using appropriate starting materials (including some of the materials prepared in Examples A to G) and conditions.

Table 12

(R" stands for cyclohexylethyl)

Examples 140 to 147

By repeating the procedure described in Examples 131 and 107B (removal of the boc group) using appropriate starting materials, including some of the materials prepared in Examples H to K, the following formula 2, identified in Table 13 below, was obtained compound of.

Table 13

Example 148: 6-[4-(4-Acetyl-piperazin-1-yl)-2-fluoro-phenoxymethyl]-7-[2-(4-chloro-phenyl)- Ethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

At 0°C, to 7-[2-(4-chloro-phenyl)-ethyl]-6-(2-fluoro-4-piperazin-1-yl-phenoxymethyl)-7H-pyrrole Et ₃ N (55 uL) and acetyl chloride (11.3 uL) were added to a solution of [2,3-d]pyrimidine-2-carbonitrile (80 mg) in CH ₂ Cl ₂ , and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography to obtain the product; Rf=0.27 (dichloromethane:methanol=10:1); ¹ HNMR (CDCl3, δ(ppm)): 2.14 (s, 3H), 3.06-3.12 (m, 4H), 3.18(dd, 2H), 3.61(dd, 2H), 3.76(dd, 2H), 4.63(dd, 2H), 4.90(s, 2H), 6.58-6.62(m, 2H), 6.70(dd , 1H), 6.87(t, 1H), 6.99-7.02(m, 2H), 7.19-7.22(m, 2H), 8.96(s, 1H).

Examples 149 to 156

Compounds of Formula 2 below, identified in Table 14 below, were obtained by repeating the procedure described in Example 148 using appropriate starting materials, including some of the materials prepared in Examples A to K.

Table 14

Example 157: 7-[2-(4-Chloro-phenyl)-ethyl]-6-[4-(4-ethyl-piperazin-1-yl)-2-fluoro-phenoxymethyl Base]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

To 7-[2-(4-chloro-phenyl)-ethyl]-6-(2-fluoro-4-piperazin-1-yl-phenoxymethyl)-7H-pyrrolo[2,3 -d] To a solution of pyrimidine-2-carbonitrile (80 mg) in DMF were added iodoethane (12.8 uL) and potassium carbonate (55 mg), and stirred at 60°C for 11 hours. Solids in the reaction mixture were filtered off. The filtrate was loaded on HPLC to give pure product; Rf = 0.15 (n-hexane:EtOAc = 1:1) HCl salt; ¹ H NMR (DMSO-d6), δ.(ppm): 1.28 (t, 3H), 3.04 -3.17(m, 8H), 3.50-3.53(m, 2H), 3.65-3.75(m, 2H), 4.60(dd, 2H), 5.31(s, 2H), 6.75-6.78(m, 1H), 6.93 (s, 1H), 6.99 (dd, 1H), 7.09 (d, 2H), 7.20-7.26 (m, 3H), 9.14 (s, 1H), 10.70 (brs, 1H).

Examples 158 to 160

Compounds of Formula 2 below, identified in Table 15 below, were obtained by repeating the procedure described in Example 157 using appropriate starting materials, including some of the materials prepared in Examples A to K.

Table 15

Example 161: 7-[2-(4-Chloro-phenyl)-ethyl]-6-(4-methoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidine Pyridine-2-carbonitrile

To 6-bromomethyl-7-[2-(4-chloro-phenyl)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (110mg, 0.293mmol) and p-methyl To a solution of oxyphenylboronic acid (98mg, 0.645mmol) in THF (1.5ml) was added _Cs2CO3 ( _143mg , 0.439mmol) and Pd( _dppf ) _Cl2.CH2Cl2 ( _24mg , 0.029mmol) . The reaction mixture was stirred at 60°C under nitrogen atmosphere for 1 hour. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. Purification of the residue by silica gel column chromatography (n-hexane:EtOAc=4:1 to 3:1) afforded the product; Rf 0.46 (n-hexane:AcOEt=1:1); ¹ H NMR (CDCl ₃ ), δ( ppm): 0.95(t, 2H), 3.75(s, 3H), 3.80(s, 3H), 4.36(t, 2H), 6.23(s, 1H), 6.87(d, 2H), 6.89(d, 2H ), 6.98 (d, 2H), 7.24 (d, 2H), 8.85 (s, 1H).

Examples 162 to 170

Compounds of Formula 2 below, identified in Table 16 below, were obtained by repeating the procedure described in Example 161 using appropriate starting materials, including some of the materials prepared in Examples A to K.

Table 16

Example 171: 6-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-7-(2-cyclohexyl-ethyl)-7H-pyrrolo [2,3-d]pyrimidine-2-carbonitrile

Palladium acetate (6.7mg), (di-tert-butylphosphino)biphenyl (18mg), _Cs2CO3 (120mg) and _Et3N ( _51.4ml ) in degassed dioxane (1.3ml) 6-(4-Chloro-benzyl)-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (100 mg) and 1-acetyl Piperazine (40, 4 mg), stirred at reflux for 18 hours. The reaction mixture was diluted with _H2O and extracted with EtOAc. The organic layer was washed sequentially with _H2O , aqueous NaCl, and concentrated in vacuo. Purification of the residue by HPLC gave pure product; Rf = 0.47 (dichloromethane: methanol = 9: 1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.88-0.98 (m, 2H), 1.14-1.32 (m , 4H), 1.49-1.73(m, 7H), 2.14(s, 3H), 3.14-3.20(m, 4H), 3.61-3.67(m, 2H), 3.77-3.82(m, 2H), 4.10(s , 2H), 4.17-4.21 (m, 2H), 6.30 (s, 1H), 6.91-6.95 (m, 2H), 7.11 (d, 2H), 8.83 (s, 1H).

Example 172: 7-(2-Cyclohexyl-ethyl)-6-(4-hydroxymethyl-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2- Nitrile

5-Bromo-4-(2-cyclohexyl-ethylamino)-pyrimidine-2-carbonitrile (1.03 mmol), (4-prop-2-ynyl-phenyl)-methanol in DMF (20 ml) (4.10 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol), copper(I) iodide (0.10 mmol) and triethylamine (5.15 mmol) were stirred at 75°C for 3 hours. After the reaction mixture was treated with saturated ammonium chloride, the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The crude product was subjected to silica gel column chromatography and eluted with the following solvent: n-hexane:AcOEt=3:7 (v/v). The latter effluent was evaporated to remove the solvent and dried in vacuo to obtain the title compound, Rf=0.22 (n-hexane:AcOEt=1:1); ¹ HNMR (CDCl ₃ ), δ.(ppm): 0.89-1.32 (m, 6H), 1.50-1.58(m, 3H), 1.64(t, 1H), 1.62-1.78(m, 4H), 4.18(s, 2H), 4.19(t, 2H), 4.72(d, 2H), 6.31 (s, 1H), 7.20 (d, 2H), 7.36 (d, 2H), 8.84 (s, 1H).

Example 173: 4-[2-Cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]- benzoic acid

7-(2-cyclohexyl-ethyl)-6-(4-hydroxymethyl-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.88mmol), TMPO (0.088 mmol) and sodium phosphate buffer (pH 6.8) (3 ml) were dissolved in MeCN (10 ml). To this solution were added _NaClO2 (3.52mmol) in water (3ml) and 8.5% aqueous NaOCl (0.04mmol). The mixture was stirred at 35°C under nitrogen atmosphere for 2 days. The reaction mixture was diluted with _{CH2Cl2 and} water and extracted with _CH2Cl2 ( _2x ). The combined organic layers were washed with water and brine, dried over _MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt) to obtain the title compound; Rf=0.17 (n-hexane:AcOEt=2:3); ¹ H NMR (CDCl ₃ ), δ.(ppm): 0.87-1.32 (m, 6H), 1.54-1.77(m, 7H), 4.20(t, 2H), 4.26(s, 2H), 6.34(s, 1H), 7.32(d, 2H), 8.09(d, 2H), 8.87(s , 1H).

Example 174: 4-[2-Cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]- benzamide

4-[2-Cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-benzoic acid (0.23 mmol) was dissolved in CH ₂ Cl ₂ (15ml). To this solution was added (COCl) ₂ (2.27 mmol) and DMF (1 drop) at 0°C. The mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. The reaction mixture was evaporated and the residue was dissolved in Et2O ( _2ml )-AcOEt (5ml). To this solution was added _NH4OH (5ml) at 0°C. The mixture was stirred at room temperature under nitrogen atmosphere for 11 h, the reaction mixture was diluted with AcOEt and water and extracted with AcOEt (2x). The combined organic layers were washed with water and aqueous protective NaHCO ₃ , then dried over MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt) to obtain the title compound; Rf=0.16 (n-hexane:AcOEt=2:3); ¹ H NMR (CDCl ₃ ), δ.(ppm): 0.87-1.33 (m, 6H), 1.54-1.79(m, 7H), 4.19(t, 2H), 4.24(s, 2H), 5.71(brs, 1H), 6.02(brs, 1H), 6.32(s, 1H), 7.30(d , 2H), 7.82 (d, 2H), 8.86 (s, 1H).

Examples 175 to 178

Compounds of Formula 2 identified below in Table 17 were obtained by repeating the procedure described in Examples 172 to 174 using appropriate starting materials, including some of the materials prepared in Examples A to K.

Table 17

Example 179: 7-(2-Cyclohexyl-ethyl)-6-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-7H-pyrrolo [2,3-d]pyrimidine-2-carbonitrile

5-Bromo-4-(2-cyclohexyl-ethylamino)-pyrimidine-2-carbonitrile (0.3mmol) and 1-(4-prop-2-ynyl-phenyl)-pyrrolidin-2-one (0.3mmol) was dissolved in 3ml DMF. The mixture was degassed by evaporation and purged several times with nitrogen with stirring. (Ph ₃ P)PdCl ₂ (0.015 mmol), CuI (0.03 mmol) and Et ₃ N (0.6 mmol) were added and the reaction was heated at 80° C. under nitrogen atmosphere for 16 hours. After cooling the mixture to room temperature, the aqueous layer was extracted twice with AcOEt, the combined organic extracts were washed several times with brine, dried over _Na2SO4 and concentrated under reduced pressure _. The title compound was obtained as a yellow solid by flash chromatography on silica gel using AcOEt-hexane (1:1) as eluent; ¹ H NMR (CDCl ₃ ), δ. (ppm): 0.91-1.01 (m, 2H) , 1.14-1.28(m, 4H), 1.66-1.76(m, 7H), 2.14-2.22(m, 2H), 2.63(t, 2H), 3.86(t, 2H), 4.15(s, 2H), 4.17 -4.21 (m, 2H), 6.30 (s, 1H), 7.20 (d, 2H), 7.61-7.63 (m, 2H), 8.84 (s, 1H).

Examples 180 to 193

Compounds of Formula 2 below, identified in Table 18 below, were obtained by repeating the procedure described in Example 179 using appropriate starting materials, including some of the materials prepared in Examples M to O.

Table 18

Example 194: 6-(4-Chloro-benzyl)-7-(2-p-tolyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2- Nitrile

To a solution of 6-(4-chloro-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (68 mg, 250 mmol) in DMF (3 ml) was added K ₂ CO ₃ (40 mg, 0.29 mmol) and 1-(2-bromo-ethyl)-4-methyl-benzene (100 mg, 0.50 mmol). The reaction mixture was stirred overnight at room temperature. After pouring into water, the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with _brine , dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=3:1) to obtain the title compound; ¹ H NMR (CDCl ₃ ), δ.(ppm): 2.33 (s, 3H), 2.99 (t, 2H) , 3.63(s, 2H), 4.37(t, 2H), 6.12(s, 1H), 6.81(d, 2H), 6.95(d, 2H), 7.07(d, 2H), 7.30(d, 2H), 8.84 (s, 1H).

Examples 195 to 200

Compounds of Formula 2 below, identified in Table 19 below, were obtained by repeating the procedure described in Example 194 using appropriate starting materials, including some of the materials prepared in Examples P to S.

Table 19

Example 201: 6-(4-Chloro-benzyl)-7-(2-cyclopentyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

To 6-(4-chloro-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (270mg, 1.00mmol), 2-cyclopentylethanol (140mg, 1.20mmol) and Ph ₃ To a solution of P (310 mg, 1.20 mmol) in THF (3 ml) was added DEAD (190 mg, 1.10 mmol) dropwise. The reaction mixture was stirred overnight at room temperature under nitrogen atmosphere. After concentration, the residue was purified by silica gel column chromatography (n-hexane:AcOEt=3:1), followed by RP-HPLC purification to obtain the title compound; ¹ H NMR (CDCl ₃ ), δ.(ppm): 1.09-1.12 (m, 2H), 1.24-1.70(m, 7H), 1.74-1.80(m, 2H), 4.16(s, 2H), 4.17(t, 2H), 6.30(s, 1H), 7.14(d, 2H ), 7.33 (d, 2H), 8.85 (s, 1H).

Examples 202 to 210

Compounds of Formula 2 identified below in Table 20 were obtained by repeating the procedure described in Example 201 using appropriate starting materials, including some of the materials prepared in Examples P to T.

Table 20

Example 211: 7-(3,3-Dimethyl-butyl)-6-styryl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

7-(3,3-Dimethyl-butyl)-6-hydroxymethyl _- 7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile was dissolved in _CH2Cl2 . To this solution was added Dess-Martin periodinane at 0°C, and the resulting solution was stirred. After dilution with _H2O , the mixture was extracted twice with AcOEt and washed with brine. 7-(3,3-Dimethyl-butyl)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine-2 was obtained by silica gel flash chromatography using AcOEt-hexane as eluent - Nitrile. The aldehyde was dissolved in THF. To this solution were added benzyl-diethylphosphonate and sodium hydride, and the resulting solution was stirred. The reaction was quenched by adding _H2O , and the mixture was extracted twice with AcOEt. The combined organic extracts were washed with _brine , dried over _Na2SO4 , filtered and concentrated in vacuo. The title compound was obtained by flash chromatography on silica gel with AcOEt-hexane as eluent. ¹ H NMR (CDCl ₃ ), δ.(ppm): 0.99 (s, 9H), (m, 2H), 3.80 (q, 2H), 4.16-4.21 (m, 4H), 6.34 (s, 1H), 7.24-7.26 (m, 4H), 8.87 (s, 1H).

Example 212: 7-(3,3-Dimethyl-butyl)-6-phenethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

The product of Example 211 was dissolved in MeOH. The solution was degassed by evaporation and purging several times with nitrogen with stirring. Pd/C (mmol) was added and the mixture was degassed by evaporation and purged several times with nitrogen with stirring. The suspension was vigorously stirred under hydrogen. After 2 hours, the mixture was filtered through celite and the filtrate was concentrated. The title compound was obtained by flash chromatography on silica gel with AcOEt-hexane as eluent. ¹ H NMR (CDCl ₃ ), δ (ppm): 1.03(s, 9H), 1.55-1.59(m, 2H), 3.12(s, 4H), 4.15-4.20(m, 2H), 6.43(s, 1H ), 7.19-7.21 (m, 1H), (m, 2H), 8.85 (s, 1H).

Example 213

Compounds of Formula 2 identified below in Table 21 were obtained by repeating the procedure described in Examples 211 and 212 using appropriate starting materials, including some of the materials prepared in Examples P to T.

Table 21

(R" stands for 3,3-dimethyl-1-butyl)

Example 214: 6-(4-Amino-benzyl)-7-(3,3-dimethyl-butyl)-7H-pyrrolo[2,3-d]pyrimidine-2- Nitrile

Dissolve 5-bromo-4-(3,3-dimethyl-butylamino)-pyrimidine-2-carbonitrile and (4-prop-2-ynyl-phenyl)-carbamic acid tert-butyl ester in DMF . The mixture was degassed by evaporation and purged several times with nitrogen with stirring. (Ph ₃ P)PdCl ₂ , CuI and Et ₃ N were added and the reaction was heated at 80° C. under nitrogen. After cooling the mixture to room temperature, the aqueous layer was extracted twice with AcOEt, the combined organic extracts were washed several times with brine, dried over _Na2SO4 and concentrated under reduced pressure _. The yellow solid was dissolved _{in CH2Cl2} . TFA was added dropwise to this solution, and the resulting solution was stirred for several hours. After dilution with _H2O , the mixture was extracted twice with AcOEt and the combined organic phases were washed with brine. The title compound was obtained as a yellow solid by flash chromatography on silica gel with AcOEt-hexane as eluent; ¹ H NMR (CDCl ₃ ), δ.(ppm): 1.00 (s, 9H), 3.67 (s, 2H) , 4.06 (s, 2H), 4.16-4.20 (m, 2H), 6.31 (s, 1H), 6.65-6.67 (m, 2H), 6.97 (d, 2H), 8.83 (s, 1H).

Example 215: 6-(4-Amino-benzyl)-7-(3,3-dimethyl-butyl)-7H-pyrrolo[2,3-d]pyrimidine-2- Nitrile

The amine _from Example 214 was dissolved in _CH2Cl2 . To this solution was added 2-methoxy-ethanesulfonyl chloride and pyridine at room temperature. After stirring at room temperature for several hours, the reaction mixture was diluted with _H2O . The mixture was extracted twice with _AcOEt and the combined organic extracts were dried over _Na2SO4 . The title compound was obtained by silica gel flash chromatography using AcOEt-hexane as eluent; ¹ H NMR (CDCl ₃ ), δ.(ppm): 0.99(s, 9H), 3.22(t, 2H), 3.43(s , 3H), 3.84(t, 2H), 4.16-4.21(m, 4H), 6.33(s, 1H), 6.44(s, 1H), 7.17(d, 2H), 7.23-7.26(m, 2H), 8.86 (s, 1H).

Examples 216 to 218

Compounds of Formula 3 below, identified in Table 22 below, were obtained by repeating the procedure described in Examples 214 and 215 using appropriate starting materials, including some of the materials prepared in Examples A to T.

Table 22

Example 219: 3-[2-Cyano-7-(3,3-dimethyl-butyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl base]-benzoic acid

Dissolve 7-(3,3-dimethyl-butyl)-6-(3-formyl-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in THF/H ₂ O, react it with NaClO ₂ and NH ₂ SO ₃ H in THF/H ₂ O at 0°C; ¹ H NMR (CDCl ₃ ), δ (ppm): 0.98 (s, 9H), 1.40- 1.45(m, 2H), 4.26-4.30(m, 2H), 4.50(s, 2H), 6.65(s, 1H), 7.57-7.64(m, 2H), 7.95-7.96(m, 2H), 9.13( s, 1H).

Example 220: 7-[2-(4-Chloro-phenyl)-ethyl]-6-[3-(2,5-dioxo-imidazolidin-1-ylmethyl)-benzyl Base]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

To 7-[2-(4-chloro-phenyl)-ethyl]-6-(3-hydroxymethyl-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (31mg , 0.077mmol) in _CH2Cl2 ( _0.5ml ) were added _Ph3P (24mg, 0.092mmol) and _CBr4 (33mg, 0.093mmol). After stirring at room temperature for 30 minutes, additional _Ph3P (29 mg, 0.11 mmol) and _CBr4 (40 mg, 0.12 mmol) were added. The reaction mixture was stirred at room temperature for 20 minutes and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=5:1) to give the corresponding bromide.

To a solution of the bromide (14mg, 0.030mmol) in DMF (0.3ml) was added hydantoin (4mg, 0.040mmol) and _K2CO3 ( _5mg , 0.036mmol). The reaction mixture was stirred at room temperature for 16 hours. After dilution with EtOAc, the mixture was washed with water and brine. The organic layer was dried over _Na2SO4 , filtered and concentrated _in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=2:3 to 1:2) to obtain the title compound; ¹ H NMR (CDCl ₃ ), δ.(ppm): 2.95 (t, 2H), 3.79 ( s, 2H), 3.96(s, 2H), 4.34(t, 2H), 4.65(s, 2H), 5.23(s, 1H), 6.24(s, 1H), 6.87(d, 2H), 6.97(d , 1H), 7.17(s, 1H), 7.18(d, 2H), 7.28-7.35(m, 2H), 8.87(s, 1H).

Examples 221 to 225

Compounds of Formula 2 below, identified in Table 23 below, were obtained by repeating the procedure described in Example 220 using appropriate starting materials, including some of the materials prepared in Examples P to T.

Table 23

Example 226: 6-(4-Chloro-3-hydroxymethyl-benzyl)-7-[2-(4-chloro-phenyl)-ethyl]-7H-pyrrolo [2,3-d]pyrimidine-2-carbonitrile

To (5-bromo-2-chloro-phenyl)-methanol (272mg, 1.23mmol) and bis(pinacolate)diboron (bis(pinacolate)diboron) (343mg, 1.35mmol) in DMSO (7ml) To the solution were added KOAc (362mg, 3.69mmol) and Pd( _dppf ) _Cl2.CH2Cl2 ( _50mg , 0.062mmol). The reaction mixture was stirred at 80°C under nitrogen atmosphere for 9 hours. After diluting with ether, the mixture was washed with water (x2) and brine. The organic layer was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=5:1) to give the corresponding boronic ester. To 6-bromomethyl-7-[2-(4-chloro-phenyl)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (88mg, 0.234mmol) and the To a solution of boroester (126mg, 0.469mmol) in THF ( _1.5ml ) was added _Cs2CO3 (115mg, 0.353mmol) and Pd( _dppf ) _Cl2.CH2Cl2 ( _19mg , 0.023mmol). The reaction mixture was stirred at 60°C under nitrogen atmosphere for 1 hour. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=2:1) to give the title compound; Rf=0.25 (n-hexane:AcOEt=1:1); ¹ H NMR (CDCl ₃ ), δ.(ppm) : 1.98(t, 1H), 3.00(t, 2H), 3.73(s, 2H), 4.38(t, 2H), 4.77(d, 2H), 6.19(s, 1H), 6.87(dd, 2H), 6.92 (dd, 1H), 7.22-7.25 (m, 3H), 7.32 (d, 1H), 8.86 (s, 1H).

Examples 227 to 228

Compounds of Formula 2 below, identified in Table 24 below, were obtained by repeating the procedure described in Example 226 using appropriate starting materials, including some of the materials prepared in Examples A to T.

Table 24

Example 229: 7-(2-Cyclohexyl-ethyl)-6-(3-oxo-3-piperidin-1-yl-propyl)-7H-pyrrolo [2,3-d]pyrimidine-2-carbonitrile

To a solution of alkyne (71 mg, 0.43 mmol) and cyanopyrimidine (110 mg, 0.36 mmol) in DMF (2 ml) was added _Et3N (0.15 ml, 1.08 mmol), CuI (6.8 mg, 0.036 mmol) and Pd ( _Ph3P ) _2Cl2 ( ₁₃ mg, 0.019 mmol). The flask was evacuated and filled with nitrogen, followed by stirring at 80°C for 2 hours. After dilution with EtOAc, the mixture was washed with water (x2) and brine. The organic layer was dried over _Na2SO4 , filtered and concentrated _in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=2:1) to obtain a coupled product.

To a solution of the above product (133 mg) in DMF (1 ml) was added 2 drops of DMF. The reaction mixture was stirred at 100°C for 2.5 hours. After dilution with EtOAc, the mixture was washed with 1M aqueous KHSO ₄ and brine. The organic layer was dried over _Na2SO4 , filtered and concentrated _in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=2:1 to 1:1), followed by RP-HPLC to give the title compound; ¹ H NMR (CDCl ₃ ), δ.(ppm): 0.95-1.05 (m, 2H), 1.14-1.26(m, 3H), 1.29-1.37(m, 1H), 1.54-1.75(m, 11H), 1.80-1.83(m, 2H), 2.81(t, 2H), 3.19 (t, 2H), 3.45 (t, 2h), 3.59 (t, 2H), 4.32 (t, 2H), 6.37 (s, 1H), 8.83 (s, 1H).

Example 230

Compounds of Formula 2 below, identified in Table 24 below, were obtained by repeating the procedure described in Example 229 using appropriate starting materials, including some of the materials prepared in Examples A to V.

Table 24

Example 231: 7-[2-(4-Chloro-phenyl)-ethyl]-6-(3-methoxymethyl-benzyl)-7H-pyrrolo[2,3-d] Pyrimidine-2-carbonitrile

To a solution of 1-bromo-3-methoxymethyl-benzene (286 mg, 1.42 mmol) and diboron (397 mg, 1.56 mmol) in DMSO (8 ml) was added KOAc (419 mg, 4.27 mmol) and Pd( _dppf ) _Cl2.CH2Cl2 (58 _mg , 0.071 mmol). The reaction mixture was stirred at 80°C under nitrogen atmosphere for 1 hour. After diluting with ether, the mixture was washed with water (x2) and brine. The organic layer was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc=10:1) to give the corresponding boronic ester.

To 6-bromomethyl-7-[2-(4-chloro-phenyl)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (83mg, 0.221mmol) and the above boron To a solution of the _ester (110 mg, 0.443 mmol) in _THF (1.6 ml) was added _Cs2CO3 (108 mg, 0.331 mmol), benzyl alcohol ₍ 0.046 mmol, 0.445 mmol) and Pd(dppf) _Cl2.CH2Cl2 (18 mg, 0.022 mmol). The reaction mixture was stirred at 60 °C under nitrogen for 1 hour. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=4:1), followed by RP-HPLC to obtain the title compound; ¹ H NMR (CDCl ₃ ), δ.(ppm): 1.94-2.01 (m, 2H ), 2.42(t, 2H), 2.96(t, 2H), 3.24(t, 2H), 3.77(s, 2H), 4.36(t, 2H), 4.42(s, 2H), 6.20(s, 1H) , 6.88(d, 2H), 6.97-6.98(m, 2H), 7.17(d, 1H), 7.17(d, 2H), 7.31(t, 1H), 8.86(s, 1H).

Example 232

Compounds of Formula 2 below, identified in Table 25 below, were obtained by repeating the procedure described in Example 230 using appropriate starting materials, including some of the materials prepared in Examples A to X.

Table 25

Example 233: 7-(2-Cyclohexyl-ethyl)-6-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-7H-pyrrole And[2,3-d]pyrimidine-2-carbonitrile

Mix 6-bromomethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (80mg, 0.23mmol) and 4-phenyl-piperidine- 4-Alcohol (41.8mg, 0.23mmol) was dissolved in DMF (2ml), and potassium carbonate (63.6mg, 0.46mmol) was added to the solution. The reaction mixture was stirred at room temperature for 3 hours, quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated. The crude product was purified by reverse phase HPLC and fractions were collected and evaporated. Saturated sodium bicarbonate was added for neutralization, and the aqueous phase was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to give the title compound; Rf = 0.30 (n-hexane: ethyl acetate = 1:1); ¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.02- 1.05(m, 2H), 1.23-1.40(m, 3H), 1.71-1.86(m, 9H), 2.10-2.19(m, 2H), 2.61(t, 2H), 2.77-2.79(m, 2H), 3.78(s, 2H), 4.43-4.47(m, 2H), 6.54(s, 1H), 7.28(t, 1H), 7.37(t, 2H), 7.49(d, 2H), 8.88(s, 1H) .

Examples 234 to 296

Compounds of Formula 2 below, identified in Table 26 below, were obtained by repeating the procedure described in Example 233 using appropriate starting materials, including some of the materials prepared in Examples A to X.

Table 26

Example 297: 7-(2-Cyclohexyl-ethyl)-6-(4-hydroxy-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d] Pyrimidine-2-carbonitrile

Reduction of 7-(2-cyclohexyl-ethyl)-6-(4-oxo-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine with sodium borohydride in methanol -2-carbonitrile to give the corresponding alcohol; Rf=0.15 (n-hexane:AcOEt=1:2). NMR (400MHz, CDCl ₃ , δ) 0.94-1.09(m, 2H), 1.15-1.42(m, 4H), 1.52-1.78(m, 11H), 1.80-1.94(m, 4H), 2.21-2.29(m , 2H), 2.74-2.78 (m, 2H), 3.67 (s, 2H), 4.42 (t, 2H), 6.49 (s, 1H), 8.87 (s, 1H).

Example 298: 6-(8-Acetyl-2,8-diaza-spiro[4.5]dec-2-ylmethyl)-7-(3,3-dimethyl-butane Base)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

To 6-bromomethyl-7-(3,3-dimethyl-butyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (440mg, 1.37mmol) in DMF (5ml) 1-(2,8-diaza-spiro[4.5]dec-8-yl)-ethanone hydrochloride (Example ZG, 300 mg, 1.37 mmol) and K ₂ CO ₃ (568 mg, 4.11 mmol) and triethylamine (5ml). The mixture was stirred at room temperature under nitrogen atmosphere for 11 hours. The reaction mixture was diluted with water and extracted with AcOEt (2x). The combined organic layers were washed with water and brine, dried over _MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to obtain the title compound; Rf=0.30 (n-hexane:AcOEt=1:1); ¹ H-NMR (400MHz, CDCl ₃ )δ: 1.05 (s, 9H), 1.53-1.72 (m, 8H), 2.07 (s, 3H), 2.40-2.48 (m, 2H), 2.60-2.69 (m, 2H), 3.35-3.45 (m, 2H), 3.60 -3.67 (m, 1H), 3.74-3.82 (m, 2H), 4.40-4.44 (m, 2H), 6.49 (s, 1H), 8.87 (s, 1H).

Examples 299 to 330

Compounds of Formula 2 identified below in Table 27 were obtained by repeating the procedure described in Example 298 using appropriate starting materials, including some of the materials prepared in Examples A to X and ZA to ZV.

Table 27

Example 331: 6-[3-(1-Acetyl-piperidin-4-yl)-2-oxo-2,3-dihydro-benzimidazol-1-ylmethyl Base]-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

At 0°C, to 7-(2-cyclohexyl-ethyl)-6-(2-oxo-3-piperidin-4-yl-2,3-dihydro-benzimidazol-1-ylmethyl To a solution of -7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetate (141 mg, 0.29 mol) in dichloromethane (2 ml) was added triethylamine (395 μl) and ethyl Anhydride (60 μl, 0.63 mmol). The reaction mixture was stirred overnight at room temperature, quenched with ice water and extracted with ethyl acetate. The combined extracts were washed with _H2O , brine and dried over sodium sulfate. The title compound was obtained by silica gel chromatography; Rf=0.30 (n-hexane:AcOEt=1:1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.95-1.33 (m, 5H), 1.53-1.96 (m, 8H ), 2.20(s, 3H), 2.32-2.41(m, 2H), 2.66-2.72(m, 1H), 3.22-3.29(m, 1H), 4.01-4.11(m, 1H), 4.40-4.44(m , 2H), 4.54-4.60(m, 1H), 4.87-4.91(m, 1H), 5.29(s, 2H), 6.54(s, 1H), 6.96-7.17(m, 4H), 8.88(s, 1H ).

Example 332: 7-(2-Cyclohexyl-ethyl)-6-[3-(1-methanesulfonyl-piperidin-4-yl)-2-oxo-2,3-di Hydrogen-benzimidazol-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

At 0°C, to 7-(2-cyclohexyl-ethyl)-6-(2-oxo-3-piperidin-4-yl-2,3-dihydro-benzimidazol-1-ylmethyl To a solution of -7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetate (141 mg, 0.29 mol) in dichloromethane (2 ml) was added triethylamine (395 μl) and ethyl Anhydride (60 μl, 0.77 mmol). The reaction mixture was stirred overnight at room temperature, quenched with ice water and extracted with ethyl acetate. The combined extracts were washed with _H2O , brine and dried over sodium sulfate. The title compound was obtained by chromatography on silica gel; Rf = 0.30 (n-hexane:AcOEt = 1:1). ¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.93-1.01 (m, 2H), 1.13-1.33 (m, 3H), 1.54-1.78 (m, 8H), 1.95-2.04 (m, 2H), 2.52- 2.63(m, 2H), 2.87-2.93(m, 5H), 4.03-4.06(m, 2H), 4.40-4.44(m, 2H), 4.50-4.56(m, 1H), 5.29(s, 2H), 6.53 (s, 1H), 6.97-7.24 (m, 4H), 8.88 (s, 1H).

Example 333: 6-(8-Acetyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl Base)-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

At 0°C, to 7-(2-cyclohexyl-ethyl)-6-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl To a solution of methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetate (142 mg, 0.28 mol) in dichloromethane (2 ml) was added triethylamine (395 μl) and Acetic anhydride (54 μl, 0.57 mmol). The reaction mixture was stirred overnight at room temperature, quenched with ice water and extracted with ethyl acetate. The combined extracts were washed with _H2O , brine and dried over sodium sulfate. The title compound was obtained by chromatography on silica gel; Rf = 0.30 (n-hexane:AcOEt = 1:1). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.97-1.40 (m, 6H), 1.64-1.82 (m, 9H), 2.14 (s, 3H), 2.37-2.44 (m, 2H), 3.40-3.48 ( m, 1H), 3.74-3.79(m, 1H), 3.93-4.01(m, 1H), 4.34-4.38(m, 2H), 4.56-4.66(m, 3H), 4.87(s, 2H), 6.61( s, 1H), 6.74-6.76 (m, 2H), 6.91-6.95 (m, 1H), 7.23-7.25 (m, 2H), 8.94 (s, 1H).

Example 334: 7-[2-(4-Chloro-phenyl)-ethyl]-6-(4-phenylacetyl-piperazin-1-ylmethyl)-7H- Pyrrolo[2,3-d]pyrimidine-2-carbonitrile

To 4-{7-[2-(4-chloro-phenyl)-ethyl]-2-cyano-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl}-piperazine- To a solution of tert-butyl 1-carboxylate (125mg, 0.26mmol) in dichloromethane (1ml) was added trifluoroacetic acid (1ml). After stirring at room temperature for 30 minutes, the solvent was evaporated to give 7-[2-(4-chloro-phenyl)-ethyl]-6-piperazin-1-ylmethyl-7H-pyrrolo[2,3- d] Pyrimidine-2-carbonitrile trifluoroacetate; Rf = 0.10 (CH ₂ Cl ₂ :MeOH = 10:1).

At 0°C, to 7-[2-(4-chloro-phenyl)-ethyl]-6-piperazin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2- To a solution of nitrile trifluoroacetate in pyridine (5 ml) was added phenylacetyl chloride (172 μl, 1.30 mmol). The reaction mixture was stirred at 80°C for 6 hours, quenched with ice water and extracted with ethyl acetate. The combined extracts were washed with _H2O , brine and dried over sodium sulfate. The title compound was obtained by chromatography on silica gel; Rf = 0.30 (n-hexane:AcOEt = 1:1). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.18-2.21 (m, 2H), 2.37-2.39 (m, 2H), 3.09-3.13 (m, 2H), 3.32 (s, 2H), 3.40-3.48 ( m, 2H), 3.63-3.65(m, 2H), 3.72(s, 2H), 4.55-4.59(m, 2H), 6.44(s, 1H), 6.96-6.98(m, 2H), 7.21-7.33( m, 7H), 8.89 (s, 1H).

Example 335: 6-(2-Acetyl-2,8-diaza-spiro[4.5]dec-8-ylmethyl)-7-(2-cyclohexyl-ethyl Base)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

To a solution of 6-bromomethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (290mg, 0.84mmol) in DMF (1.7ml) To tert-butyl 2,8-diaza-spiro[4.5]decane-2-carboxylate (201 mg, 0.84 mmol) and potassium carbonate (138 mg, 1.0 mmol) were added. The mixture was stirred at room temperature under nitrogen atmosphere for 14 hours. The reaction mixture was diluted with water and extracted with AcOEt (2x). The combined organic layers were washed with water and brine, dried over _MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to obtain 8-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d ]pyrimidin-6-ylmethyl]-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester; Rf=0.45 (n-hexane:AcOEt=1:1).

To 8-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-2,8-diaza-spiro [4.5] To a solution of tert-butyl decane-2-carboxylate (300mg, 0.59mmol) in dichloromethane (5ml) was added trifluoroacetic acid (3ml). After stirring at room temperature for 1.5 hours, the solvent was evaporated to give 7-(2-cyclohexyl-ethyl)-6-(2,8-diaza-spiro[4.5]dec-8-ylmethanol in quantitative yield yl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetate; Rf=0.10 (CH ₂ Cl _{2 :} MeOH=10:1).

At 0°C, to 7-(2-cyclohexyl-ethyl)-6-(2,8-diaza-spiro[4.5]dec-8-ylmethyl)-7H-pyrrolo[2,3 -d] To a solution of pyridine-2-carbonitrile trifluoroacetate in pyridine (5ml) was added acetic anhydride (0.28ml, 2.90mmol). The reaction mixture was stirred overnight at room temperature, quenched with ice water and extracted with ethyl acetate. The combined extracts were washed with _H2O , brine and dried over sodium sulfate. The title compound was obtained by chromatography on silica gel; Rf = 0.30 (n-hexane:AcOEt = 1:1). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.00-1.84 (m, 17H), 2.04 (s, 3H), 2.33-2.56 (m, 4H), 3.25-3.35 (m, 2H), 3.47-3.53 ( m, 2H), 3.66-3.69 (m, 2H), 4.38-4.43 (m, 2H), 6.49 (s, 1H), 8.87 (s, 1H).

Example 336: 7-(2-Cyclohexyl-ethyl)-6-indol-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2- Nitrile

To 7-(2-cyclohexyl-ethyl)-6-(2,3-dihydro-indol-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile ( To a solution of NVP-TAC583, 167mg, 0.481mmol) in toluene (1.5ml) was added MnO2 (487mg). After 1 hour, additional MnO2 (430 mg) was added and the mixture was stirred at room temperature for 36 hours. To this mixture was added additional MnO2 (430 mg) and the resulting mixture was heated at 50°C for 2 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=5:1) to obtain the title compound; 1H NMR (400MHz, DMSO-d6) δ0.77-0.84 (m, 2H), 1.06-1.14 (m, 4H ), 1.24-1.30(m, 2H), 1.60-1.63(m, 5H), 4.29(t, 2H), 5.84(s, 2H), 6.38(s, 1H), 6.56(d, 1H), 7.06( t, 1H), 7.14 (t, 1H), 7.44 (d, 1H), 7.55 (d, 1H), 7.60 (d, 1H), 9.05 (s, 1H); Rf 0.47 (n-hexane: EtOAc=1: 1).

Example 337: 7-(2-Cyclohexyl-ethyl)-6-(6-fluoro-indol-1-ylmethyl)-7H-pyrrolo[2,3-d] Pyrimidine-2-carbonitrile

To a solution of 6-fluoro-1H-indole (147 mg, 1.09 mmol) in THF (3.7 ml) was added NaH (60%, 48 mg, 1.20 mmol) at 0°C. After stirring at 0°C for 20 minutes, to the mixture was added propargyl bromide (0.1 ml, 1.33 mmol), and the mixture was stirred at 0°C to room temperature for 11 hours. The reaction was quenched by adding water and the mixture was extracted with ether. The combined organic extracts were washed with water and brine. The organic layer was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=10:1) to give propargyl indole.

To the above propargyl indole (82mg, 0.473mmol) and 5-bromo-4-(2-cyclohexyl-ethylamino)-pyrimidine-2-carbonitrile (140mg, 0.453mmol) in DMF (1.7ml) _Et3N (0.19ml, 1.37mmol), CuI (9.0mg, 0.047mmol) and Pd( _Ph3P ) _2Cl2 ( _16mg , 0.023mmol) were added to the solution. The flask was evacuated and filled with nitrogen, followed by stirring at 80°C for 70 minutes. After dilution with EtOAc, the mixture was washed with water (x2) and brine. The organic layer was dried over _Na2SO4 , filtered and concentrated _in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=4:1) to obtain a coupled product.

To a solution of the product (105 mg) in DMF (1 ml) was added 1 drop of DMF. The reaction mixture was stirred at 100°C for 30 minutes. After dilution with EtOAc, the mixture was washed with 1M aqueous KHSO ₄ and brine. The organic layer was dried over _Na2SO4 , filtered and concentrated _in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=4:1 to 1:1), then triturated with ether-n-hexane to give the title compound; 1H NMR (400MHz, DMSO-d6) δ0.75-0.83( m, 2H), 1.04-1.14(m, 4H), 1.22-1.28(m, 2H), 1.59-1.61(m, 5H), 4.27(t, 2H), 5.80(s, 2H), 6.39(s, 1H), 6.57(t, 1H), 6.91(dt, 1H), 7.41(d, 1H), 7.46(dd, 1H), 7.59(dd, 1H), 9.05(s, 1H); Rf 0.55 (n-hexane :EtOAc=1:1).

Example 338: 7-[2-(4-Chloro-2-fluoro-phenyl)-ethyl]-6-(3-trifluoromethyl-2,5-dihydro-pyrrol-1-yl Methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

To a solution of tert-butyl 3-oxo-pyrrolidine-1-carboxylate (2.71 g, 14.7 mmol) in THF (50 ml) was added _CF3TMS (2.4 ml, 16.2 mmol) followed by TBAF at 0°C (1.0M in THF, 0.8ml, 0.8mmol). The reaction mixture was stirred at 0°C for 20 minutes, then at room temperature for 9 hours. The reaction was quenched by adding saturated aqueous _NH4Cl and TBAF. The mixture was extracted with ether, and the combined organic extracts were washed with 1M aqueous KHSO ₄ , water and brine. The organic layer was dried over _MgSO4 , filtered and concentrated in vacuo to give the product.

To a solution of the above product in pyridine (50ml) was added _SOCl2 (5ml). The reaction mixture was stirred at 100°C for 15 minutes, then diluted with ether. The mixture was washed with 1M aqueous KHSO ₄ , water, saturated aqueous NaHCO ₃ , water and brine. The organic layer was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=20:1) to obtain tert-butyl 3-trifluoromethyl-2,5-dihydro-pyrrole-1-carboxylate.

The above ester (105mg, 0.443mmol) was treated with 4N HCl-EtOAc (1ml) and the mixture was concentrated in vacuo to give the hydrochloride salt.

To a solution of 6-bromomethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (76mg, 0.193mmol) in DMF (1.0ml) The above hydrochloride and K ₂ CO ₃ (138 mg, 1.00 mmol) were added to . The reaction mixture was stirred at room temperature for 11 hours. After dilution with EtOAc, the mixture was washed with water (x2) and brine. The organic layer was dried over _Na2SO4 , filtered and concentrated _in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=4:1 to 3:1) to give the title compound; Rf 0.47 (n-hexane:AcOEt=1:1); 1H NMR (400MHz, CDCl3) δ.3.19 (t, 2H), 3.60-3.64(m, 4H), 3.81(s, 2H), 4.62(t, 2H), 6.31(q, 1H), 6.52(s, 1H), 6.96-7.08(m, 3H ), 8.91(s, 1H).

Example 339: 7-[2-(4-Chloro-2-fluoro-phenyl)-ethyl]-6-(3-trifluoromethyl-pyrrolidin-1-ylmethyl Base)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile

A mixture of 3-trifluoromethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (764 mg, 3.22 mmol) and 10% palladium on carbon (460 mg) in EtOH (10 ml) was heated under 1 atm H _2. Stir at room temperature for 19 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=15:1) to obtain the product.

The above product was treated with 4N HCl-EtOAc at room temperature for 1 hour to give the hydrochloride salt.

To a solution of 6-bromomethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (75mg, 0.190mmol) in DMF (1.0ml) The above hydrochloride (62 mg, 0.353 mmol) and K ₂ CO ₃ (176 mg, 1.27 mmol) were added to . The reaction mixture was stirred at room temperature for 6.5 hours. After dilution with EtOAc, the mixture was washed with water (x2) and brine. The organic layer was dried over _Na2SO4 , filtered and concentrated _in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=4:1 to 3:1) to give the title compound; Rf 0.36 (n-hexane:AcOEt=1:1); 1H NMR (400MHz, CDCl3) δ.1.91 -1.99(m, 1H), 2.02-2.11(m, 1H), 2.55-2.67(m, 3H), 2.78(t, 1H), 2.82-2.92(m, 1H), 3.16(t, 2H), 3.63 (d, 2H), 4.61 (t, 2H), 6.49 (s, 1H), 6.97-7.08 (m, 3H), 8.90 (s, 1H).

Example 340: 1-[2-Cyano-7-(3-ethyl-heptyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]- Piperidine-4-carboxylic acid phenylamide

To a solution of piperidine-4-carboxylic acid (1 g, 7.7 mmol) in 1,4-dioxane (10 ml), water (5 ml) and 1 N aqueous NaOH (8 ml) was added Boc ₂ O (1.86 g, 8.5 mmol) ) in 1,4-dioxane (5ml). The reaction mixture was stirred overnight at room temperature, then acidified by the addition of 10% aqueous citric acid. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine. The organic layer was dried over _Na2SO4 , filtered and concentrated in vacuo to give the desired _acid .

To a solution of the above acid (1.64g, 7.2mmol), aniline (745mg, 8mmol) and HOBt (990mg, 7.3mmol) in DMF (10ml) was added WSCD (1.13g, 7.3mmol). The reaction mixture was stirred overnight at room temperature. After pouring into water, the mixture was extracted with EtOAc. The combined organic extracts were washed with _brine , dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by HPLC (n-Hexane-EtOAc) to give the desired amide.

To a solution of the above amide (1.63g, 5.4mmol) in 1,4-dioxane (5ml) and THF (10ml) was added 4N HCl-dioxane (5ml). The reaction mixture was stirred overnight at room temperature. The resulting white precipitate was collected by filtration, washed with ether and dried to give the desired hydrochloride.

To a solution of 6-chloromethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (85mg, 0.28mmol) in DMF (3ml) The above hydrochloride (72mg, 0.30mmol) and _K2CO3 ( _83mg , 0.60mmol) were added. The reaction mixture was stirred overnight at room temperature. After pouring into water, the mixture was extracted with EtOAc. The combined organic extracts were washed with _brine , dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by RP-HPLC to obtain the title compound; Rf 0.53 (CH ₂ Cl ₂ :acetone=9:1); 1H-NMR (400 MHz, CDCl3) δ.0.98-1.08 (m, 2H), 1.18-1.27 ( m, 3H), 1.30-1.42(m, 1H), 1.67-1.78(m, 4h), 1.82-1.97(m, 7H), 2.13-2.18(m, 2H), 2.25-2.31(m, 1H), 2.96(d, 2H), 3.70(s, 2H), 4.42-4.46(m, 2H), 6.51(s, 1H), 7.11(br, 2H), 7.32(t, 2H), 7.50(d, 2H) , 8.88 (s, 1H).

Example 341: 6-Azepan-1-ylmethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d] Pyrimidine-2-carbonitrile

5-(3-Azepan-1-yl-prop-1-ynyl)-4-(2-cyclohexyl-ethylamino)-pyrimidine-2 was treated with DBU (0.40 mmol) at room temperature - A solution of nitrile (0.27mmol) in DMF (10ml), stirred at 100°C for 3h, poured into water, extracted with EtOAc, washed with _H2O , dried ( _MgSO4 ) and evaporated. The residue was purified by silica gel column chromatography (AcOEt) to give the title compound; 1H-NMR (400MHz, CDCl3) δ.0.97-1.06(m, 2H), 1.15-1.42(m, 4H), 1.68(brs, 8H) , 1.58-1.85 (m, 7H), 2.64 (brs, 4H), 3.79 (s, 2H), 4.46 (t, 2H), 6.48 (s, 1H), 8.86 (s, 1H).

Example 342

Compounds of Formula 2 identified below in Table 28 were obtained by repeating the procedure described in Example 341 using appropriate starting materials, including some of the materials prepared in Examples A to ZZ.

Table 28

Example 343: 7-(2-Cyclohexyl-ethyl)-6-((R)-3-methoxy-pyrrolidin-1-ylmethyl)-7H-pyrrole And[2,3-d]pyrimidine-2-carbonitrile

(R)-3-Methoxy-pyrrolidine hydrochloride (Step 343.3, 46 mg, 0.34 mmol) and 6-bromomethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2 ,3-d]pyrimidine-2-carbonitrile (117mg, 0.34mmol) was dissolved in DMF (2ml), and potassium carbonate (130mg, 1.02mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated. The title compound was obtained by silica gel chromatography (eluent; n-hexane:ethyl acetate=4:1, 2:1, 1:1); Rf=0.30 (n-hexane:ethyl acetate=1:2); ¹ H -NMR (400MHz, CDCl ₃ ) δ: 0.95-1.04 (m, 2H), 1.16-1.38 (m, 5H), 1.52-1.53 (m, 2H), 1.64-1.87 (m, 9H), 2.02-2.11 ( m, 1H), 2.52-2.60(m, 2H), 2.67-2.71(m, 1H), 2.79-2.83(m, 1H), 3.81-3.82(d, 2H), 3.91-3.96(m, 1H), 4.37-4.41 (m, 2H), 6.51 (s, 1H), 8.87 (s, 1H).

Step 343.1: (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester

To (R)-1-benzyl-pyrrolidin-3-ol (1.5 g, 8.24 mol), di-tert-butyl dicarbonate (2.2 g, 9.9 mmol) and 5% To Pd/C (0.2g) was added MeOH:ethyl acetate (10ml:10ml). The reaction mixture was stirred under _H2 at room temperature for 15 hours. The catalyst was removed by filtration and the MeOH and ethyl acetate were evaporated to give the crude product as an oil. Chromatography on silica gel (eluent; dichloromethane and 2% MeOH in dichloromethane) gave the title compound; Rf = 0.45 (dichloroethane:MeOH = 9:1).

Step 343.2 : (R)-3-Methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester

To a suspension of NaH (98 mg, 2.46 mmol) in DMF (10 ml) was sequentially added (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (460 mg, 2.46 mmol) at 0°C. To this mixture was added iodomethane (0.19ml, 3.0mmol) at 0°C, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with ice water and extracted with AcOEt. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to give the title compound; Rf = 0.45 (n-hexane: ethyl acetate = 2:1).

Step 343.3 : (R)-3-Methoxy-pyrrolidine hydrochloride

(R)-tert-butyl 3-methoxy-pyrrolidine-1-carboxylate (0.2 g, 0.99 mmol) was dissolved in 4N HCl in dioxane (0.75 ml, 3.0 mmol) at 0°C. The mixture was stirred overnight at room temperature for 1 hour. After removal of the solvent, the oily residue was dried to give crude (R)-3-methoxy-pyrrolidine hydrochloride.

Example 344

Compounds of Formula 2 below, identified in Table 29 below, were obtained by repeating the procedure described in Example 343 using appropriate starting materials, including some of the materials prepared in Examples A to ZZ.

Table 29

Example 345: Softamine Capsules

5000 soft gelatin capsules were prepared as follows, each capsule containing as active ingredient 0.05 g of one of the compounds of formula I mentioned in the preceding examples:

combination

Active ingredient 250g

Lauroglycol 2 L

Preparation method: The powdered active ingredient is suspended in ^{Lauroglycol®} (propylene glycol laurate, Gattefossé S.A., Saint Priest, France) and ground in a wet mill to obtain a particle size of about 1 to 3 μm. 0.419 g portions of the mixture were then filled into soft gelatin capsules using a capsule filling machine.

Example 346: Biological activity

The following are some exemplary _IC50's for the inhibition of human cathepsin by compounds of formula I determined in the in vitro cathepsin S assay described herein:

Table 30 Example IC50(μmol/l) 54 0.032 169 0.030 175 0.0051 179 0.035 193 0.0041 278 0.033 335 0.048

Claims (7)

1. Pyrrolopyrimidines of formula I: in: Y stands for -(CH ₂ ) _t -O- or -(CH ₂ ) _r -S-, p is 1 or 2, r is 1, 2 or 3, t is 1, 2 or 3, R ₁ stands for (h) phenyl that is unsubstituted or mono-, di- or trisubstituted by: (α) Halogen, carboxyl, alkoxy, nitro, alkyl-C(O)-NH-, cycloalkyl-C(O)-NH-, alkyl-C(O)-N(alkyl) -, formyl, alkyl-C(O)-, alkyl-S(O) ₂ -NH-, CF ₃ -alkyl-S(O) ₂ -NH-, pyrrolidinylcarbonyl, piperidinylcarbonyl , Morpholinylcarbonyl, N-alkylpiperazinylcarbonyl, piperidinyl, 1-(alkylcarbonyl)piperidinyl, 1,2,3,6-tetrahydropyridyl, alkylcarbonyl 1,2, 3,6-tetrahydropyridyl, piperazinyl, alkylpiperazinyl, alkylcarbonylpiperazinyl, cycloalkylcarbonylpiperazinyl, alkoxycarbonylpiperazinyl, alkyl-SO ₂ -piperazinyl Base, diazepanyl, alkylcarbonyldiazepanyl, 2-oxo-1-pyrrolidinyl, 3,3-di-alkyl-2-oxo-1-pyrrolidinyl; (β) R ₃ -alkyl, wherein R ₃ represents hydrogen, hydroxyl, carboxyl, alkyl-N(alkyl)-, alkyl-NH-, 1-pyrrolidinyl, 1-piperidinyl, 4-alkane Base-1-piperazinylcarbonyl, 2,4-dioxa-5,5-(di-alkyl)-oxazolidin-3-yl, R ₄ R ₅ NC(O)-, wherein R ₄ and _R independently of each other represent hydrogen or alkyl; or (γ) R ₆ R ₇ NC(O)-, wherein R ₆ and R ₇ independently represent hydrogen, alkyl, cycloalkylalkyl, CF ₃ -alkyl or pyridylalkyl; (i) pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen or alkyl, wherein said alkyl is mono-, di- or trisubstituted by halogen; (j) pyrimidinyl; (k) indolyl mono- or disubstituted by alkyl-C(O)-NH-alkyl; (l) 2-(alkyl)-benzothiazolyl; (m) groups of the subformula Ia:

wherein _R is hydrogen, halogen or alkyl, _R is hydrogen or alkyl, and m is 1, 2, 3 or 4; or (n) groups of the subformula Ib:

wherein R ₁₀ is hydrogen, halogen or alkyl, R ₁₁ is hydrogen or alkyl, and n is 1, 2, 3 or 4; R ₂ represents alkyl, which is unsubstituted or substituted by: unsubstituted of either halogen mono- or di- Substituted cycloalkyl, or phenyl mono- or disubstituted by halogen; Provided that if Y is O and R _is selected from 3-pyridyl, 4-pyridyl, 5-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-chloro-4-pyridyl, 2- Trifluoromethyl-4-pyridyl, 2-difluoromethyl-4-pyridyl, 4-acetyl-1-piperazinyl-phenyl, 4-methyl-1-piperazinyl-methyl- phenyl, then _R does not represent 1,1-dimethylethyl, and with the proviso that if Y is S and _R is 4-pyridyl, then _R does not represent 1,1-dimethylethyl; or Y is -(CH ₂ ) _j - or -CH=CH-, j is 1 or 2; p is 1 or 2, R ₁ stands for (c) thienyl, thiazolyl, 1-piperidinyl-carbonyl, or (d) phenyl that is unsubstituted or mono-, di- or trisubstituted by: (i) alkoxy, _H2NC (O)-, 4-(alkylcarbonyl) 1-piperazinyl, 2-oxo-1-pyrrolidinyl or halogen; (ii) R ₁₂ -OC(O)-, wherein R ₁₂ is hydrogen or alkyl, or (iii) R ₁₃ NH-, wherein R ₁₃ represents hydrogen or a group R ₁₄ -alkyl-Z-, wherein Z is CO, SO or SO ₂ and R ₁₄ represents hydrogen, trifluoromethyl or alkoxy, (iv) R ₁₅ -alkyl, wherein R ₁₅ represents hydrogen, hydroxyl, alkoxy, 1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolidine-2,5-dione-1- Base, 5,5-di-alkyl-oxazolidin-2,4-dione-3-yl or alkyl-N(R ₁₆ )-, wherein R ₁₆ represents hydrogen or alkyl; and _R2 stands for (a) Alkyl, which is unsubstituted or substituted by alkenyl, indanyl, cycloalkyl unsubstituted or mono- or disubstituted by halogen or alkyl, cycloalkenyl, unsubstituted Phenyl substituted or mono- or disubstituted by halogen or alkyl; (b) cycloalkyl; or (c) alkylcarbonyl; with the proviso that if Y is _CH2 , _R1 represents 4-chlorophenyl and p is 1, then _R2 does not represent 1,1-dimethylethyl, 1-methylethyl, cyclopropyl, cyclohexyl, 2-methyl-propyl or 2-ethyl-propyl; with the proviso that if p is 1, Y is CH _{and R} represents thienyl, phenyl, methoxyphenyl, propoxyphenyl, 4-fluorophenyl, 4-methylphenyl, 4-ethyl Phenyl, 4-butylphenyl, hydroxymethylphenyl, 4-(5,5-dimethyl-oxazolidine-2,4-dione-3-yl-methyl)-phenyl, 4 -(methylsulfonylamino)-phenyl, 4-(n-butylsulfonylamino)-phenyl, 4-(ethylsulfonylamino)-phenyl, 4-(n-propylsulfonylamino)- Phenyl, 4-(isopropylsulfonylamino)-phenyl, 4-aminophenyl, 4-(acetylamino)-phenyl, 4-(butyrylamino)-phenyl or 4-(diethyl Baseaminomethyl)-phenyl, then _R does not represent 1,1-dimethylethyl; and with the proviso that if p is 1, Y is CH _{and R} represents phenyl which is unsubstituted or substituted by 4-acetyl-1-piperazine, then _R does not represent 1-methylethyl; or Y is -(CH ₂ ) _f -, f is 1 or 2, p is 1, R ₁ stands for (a) 1,2,3,6-tetrahydropyridin-1-yl, alkyl-1,2,3,6-tetrahydropyridin-1-yl, di-alkyl-1,2,3,6 -tetrahydropyridin-1-yl, halo-1,2,3,6-tetrahydropyridin-1-yl, phenyl-1,2,3,6-tetrahydropyridin-1-yl, imidazolyl, Alkyl imidazolyl, di-haloimidazolyl, imidazolidin-2,5-dione-1-yl, 5,5-dialkyl-oxazolidin-2,4-dione-3-yl, alkane Imidazolidin-2,5-dione-1-yl, trifluoromethyl-3,4-pyrrolin-1-yl, pyrrolidinyl, alkyl 1-pyrrolidinyl, di-alkylpyrrolidinyl , alkoxypyrrolidinyl, alkyl 2-oxo-1-pyrrolidinyl, di-alkyl 2-oxo-1-pyrrolidinyl, halogenated 1-pyrrolidinyl, di-halogenated 1- Pyrrolidinyl, di-halogenated 1-piperidinyl, triazolyl, nitrotriazolyl, phenylimidazolyl, tetrazolyl, benzo[b]imidazolyl, (1-(alkyl-SO ₂ )-4-piperidinyl)-2,3-dihydro-2-oxo-benzo[b]imidazolyl, 3-(alkylcarbonyl-4-piperidinyl)-2,3-dihydro- 2-oxo-benzo[b]imidazolyl, indolyl, halogenated 1-indolyl, 1,3-dihydro-2-isoindolyl, 2,3-dihydro-1-indolyl Base, 2,3-dihydro-2-oxo-benzo[b]thiazolyl, two-alkoxy 1,2,3,4-tetrahydroquinoline, alkoxy-1,2,3, 4-Tetrahydroisoquinoline; (b) Groups of substructure Ic: It is attached to the molecule through a nitrogen atom, where X is -O-, -(CH ₂ ) _s -CR ₁₇ R ₁₈ -or -NR ₁₈ , wherein s is 0, 1 or 2, R and R are _{independently} selected from hydrogen, halogen, hydroxy _, alkyl, phenylalkylcarbonyl, carbamoyl, N-phenylcarbamoyl, cyano, pyridyl, Piperidinyl and phenyl unsubstituted or mono- or disubstituted by halogen or alkoxy, or, if X is CR ₁₇ R ₁₈ , R ₁₇ and R ₁₈ together form an oxo group or the group HO-C (O)-CH=, and R ₂₃ , R ₂₄ , R ₂₅ and R ₂₆ are independently selected from hydrogen and alkyl; (c) The group of the substructure Id:

It is attached to the molecule through a nitrogen atom, where k is 0, 1 or 2, A is _CH2 or a bond, B is _CH2 or carbonyl, D is _CH2 or carbonyl, E is _CH2 or _NR22 , G is _CH2 or a bond, Q is _CH2 or carbonyl , T is CH ₂ or NR ₂₉ , R ₁₉ represents hydrogen, alkyl, phenylalkyl, alkylcarbonyl or alkyl-SO ₂ -, R ₂₂ is hydrogen or alkyl and R ₂₉ is phenyl; (d) Groups of substructure Ie: It is attached to the molecule through a nitrogen atom, where R ₂₇ is alkyl or alkylcarbonyl and R ₂₈ is hydrogen, alkoxy or halogen; or (e) NR ₂₀ R ₂₁ , wherein R ₂₀ and R ₂₁ are independently selected from hydrogen, alkyl, unsubstituted or cycloalkyl mono- or disubstituted by hydroxyl; and unsubstituted or substituted by 1,2,3 - thiadiazolyl mono- or disubstituted phenyl, with the proviso that R ₂₀ and R ₂₁ cannot represent hydrogen at the same time; and _R represents alkyl, which is unsubstituted or substituted by: cycloalkyl which is unsubstituted or mono- or disubstituted by halogen; or phenyl which is mono- or disubstituted by halogen; with the proviso that _R does not represent 1,1-dimethylethyl in the following cases: (a) R ₁ is benzo[b]imidazol-1-yl, 1-imidazolyl, 4,5-dichloro-1-imidazolyl, 2-(C ₁ -C ₄ alkyl)-1-imidazolyl , imidazolidine-2,5-dione-1-yl, 5,5-dimethyl-oxazolidine-2,4-dione-3-yl, 1H-1,2,3-triazole-1 -yl, 2H-1,2,3-triazol-2-yl, 3-nitro-1H-1,2,4-triazol-1-yl, 2H-tetrazol-2-yl or 1H-tetra Azol-1-yl, or R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is NR ₁₈ and R ₁₈ is hydrogen, methyl, ethyl, acetyl, 4-pyridyl, 1 - piperidinyl, phenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl or chlorophenyl; (b) R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is -(CH ₂ ) _s -CR ₁₇ R ₁₈ -, s is 0, and R ₁₇ and R ₁₈ are selected from hydroxyl and Phenyl monosubstituted by chlorine or _R and _R are selected from hydrogen, methoxyphenyl and N-phenyl-carbamoyl; or (c) R ₁ is a group of substructure Id, k is 1, A is a bond, E is NR ₂₂ , R ₂₂ is hydrogen, G, Q and T are CH ₂ , B and D are carbonyl and R ₁₉ is methyl radical, n-propyl or isobutyl; Provided that if R ₁ is a group of substructure Id, k is 1, A is a bond, E is NR ₂₂ , R ₂₂ is hydrogen, G, Q and T are CH ₂ , B and D are carbonyl and R ₁₉ is methyl or if R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is -(CH ₂ ) _s -CR ₁₇ R ₁₈ -, s is 0, and R ₁₇ and R ₁₈ are selected from hydrogen and phenyl monosubstituted by methoxy, then R does not represent ₂ -methylpropyl; and with the proviso that if R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is NR ₁₈ and R ₁₈ is methoxyphenyl or ethoxyphenyl, or X is CR ₁₇ R ₁₈ and R ₁₇ and R ₁₈ are selected from hydrogen and methoxyphenyl, then R ₂ does not represent 1-methylethyl; or its N-oxide or tautomer, Or such salts of pyrrolopyrimidines, N-oxides or tautomers thereof. 2. The pyrrolopyrimidine of formula I according to claim 1, in: Y represents -CH ₂ -O- or -CH ₂ -S-, p is 1, R ₁ stands for (o) phenyl that is unsubstituted or mono- or disubstituted by: (α) Halogen, carboxyl, C ₁ -C ₄ alkoxy, nitro, C ₁ -C ₄ alkyl-C(O)-NH-, C ₃ -C ₄ cycloalkyl-C(O)-NH -, C ₁ -C ₄ alkyl-C(O)-N(C ₁ -C ₄ alkyl)-, formyl, C ₁ -C ₄ alkyl-C(O)-, C ₁ -C ₄ alkane Base-S(O) ₂ -NH-, CF ₃ -C ₁ -C ₃ Alkyl-S(O) ₂ -NH-, 1-pyrrolidinyl-carbonyl, 1-piperidinyl-carbonyl, 4-morphine Linyl-carbonyl, 4-(C ₁ -C ₄ alkyl)-1-piperazinylcarbonyl, 4-piperidinyl, 1-piperidinyl, 1-(C ₁ -C ₄ alkyl-carbonyl)- 4-piperidyl, 1,2,3,6-tetrahydro-4-pyridyl, 1-(C ₁ -C ₄ alkyl-carbonyl)-1,2,3,6-tetrahydro-4-pyridine Base, 1-piperazinyl, 4-(C ₁ -C ₄ alkyl)-1-piperazinyl, 4-(C ₁ -C ₄ alkyl-carbonyl)-1-piperazinyl, 4-(C ₃ -C ₅ cycloalkyl-carbonyl)-1-piperazinyl, 4-(C ₁ -C ₄ alkoxy-carbonyl)-1-piperazinyl, 4-(C ₁ -C ₄ alkyl-SO ₂ )-1-piperazinyl, 1,4-diazepan-1-yl, 4-(C ₁ -C ₄ alkyl-carbonyl)-1,4-diazepan-1-yl , 2-oxo-1-pyrrolidinyl, 3,3-di-(C ₁ -C ₄ alkyl)-2-oxo-1-pyrrolidinyl; (β) R ₃ -C ₁ -C ₄ alkyl, wherein R ₃ represents hydrogen, hydroxyl, carboxyl, C ₁ -C ₄ alkyl-N(C ₁ -C ₄ alkyl)-, C ₁ -C ₄ alkane -NH-, 1-pyrrolidinyl, 1-piperidinyl, 4-(C ₁ -C ₄ alkyl)-1-piperazinylcarbonyl, 2,4-dioxa-5,5-(di -C ₁ -C ₄ alkyl)-oxazolidin-3-yl, R ₄ R ₅ NC (O)-, wherein R ₄ and R ₅ independently represent hydrogen or C ₁ -C ₄ alkyl; or (γ) R ₆ R ₇ NC(O)-, wherein R ₆ and R ₇ independently represent hydrogen, C ₁ -C ₄ alkyl, C ₅ -C ₇ cycloalkyl-C ₁ -C ₄ alkyl, CF ₃ -C ₁ -C ₃ alkyl or pyridyl-C ₁ -C ₄ alkyl; (p) pyridyl, which is unsubstituted or mono- or disubstituted by halogen or C ₁ -C ₄ alkyl, wherein said C ₁ -C ₄ alkyl is di- or trisubstituted by halogen; (q) pyrimidinyl; (r) indolyl monosubstituted by C ₁ -C ₄ alkyl-C(O)-NH-C ₁ -C ₄ alkyl; (s) 2-(C ₁ -C ₄ alkyl)-benzothiazolyl; (t) the group of subformula Ia wherein _R is hydrogen, _R is hydrogen, and m is 2 or 3; or (u) the group of subformula Ib wherein R ₁₀ is hydrogen, R ₁₁ is hydrogen, and n is 2 or 3; R ₂ represents C ₁ -C ₅ alkyl, which is unsubstituted or substituted by: C ₅ -C ₇ cycloalkyl unsubstituted or disubstituted by halogen, or mono- or disubstituted by halogen phenyl; Provided that if Y is O and R _is selected from 3-pyridyl, 4-pyridyl, 5-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-chloro-4-pyridyl, 2- Trifluoromethyl-4-pyridyl, 2-difluoromethyl-4-pyridyl, 4-acetyl-1-piperazinyl-phenyl, 4-methyl-1-piperazinyl-methyl- phenyl, then _R does not represent 1,1-dimethylethyl, and with the proviso that if Y is S and _R is 4-pyridyl, then _R does not represent 1,1-dimethylethyl; or Y is _CH2 or -CH=CH-, p is 1 or 2, R ₁ stands for (e) thienyl, thiazolyl, 1-piperidinyl-carbonyl, or (f) phenyl that is unsubstituted or mono- or disubstituted by: (i) C ₁ -C ₄ alkoxy, H ₂ NC(O)-, 4-(C ₁ -C ₄ alkyl-carbonyl)-1-piperazinyl, 2-oxo-1-pyrrolidinyl or halogen; (ii) R ₁₂ -OC(O)-, wherein R ₁₂ is hydrogen or C ₁ -C ₄ alkyl, or (iii) R ₁₃ NH-, wherein R ₁₃ represents hydrogen or the group R ₁₄ -C ₁ -C ₄ alkyl-Z-, wherein Z is CO or SO ₂ and R ₁₄ represents hydrogen, trifluoromethyl or C ₁ -C ₄ alkoxy, (iv) R ₁₅ -C ₁ -C ₄ alkyl, wherein R ₁₅ represents hydrogen, hydroxyl, lower alkoxy, 1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolidine-2,5 -diketone-1-yl, 5,5-dimethyl-oxazolidin-2,4-diketone-3-yl or C ₁ -C ₄ alkyl-N(R ₁₆ )-, wherein R ₁₆ represents hydrogen or C ₁ -C ₄ alkyl; and _R2 stands for (a) C ₁ -C ₇ alkyl, which is unsubstituted or substituted by: C ₂ -C ₃ alkenyl, indanyl, unsubstituted or by halogen or C ₁ -C ₄ alkyl Disubstituted C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkenyl, unsubstituted or mono- or disubstituted phenyl by halogen or C ₁ -C ₄ alkyl; (b) C ₃ -C ₇ cycloalkyl; or (c) C ₁ -C ₄ alkylcarbonyl; with the proviso that if Y is _CH2 , _R1 represents 4-chlorophenyl and p is 1, then _R2 does not represent 1,1-dimethylethyl, 1-methylethyl, cyclopropyl, cyclohexyl, 2-methyl-propyl or 2-ethyl-propyl; with the proviso that if p is 1, Y is CH _{and R} represents thienyl, phenyl, methoxyphenyl, propoxyphenyl, 4-fluorophenyl, 4-methylphenyl, 4-ethyl Phenyl, 4-butylphenyl, hydroxymethylphenyl, 4-(5,5-dimethyl-oxazolidine-2,4-dione-3-yl-methyl)-phenyl, 4 -(methylsulfonylamino)-phenyl, 4-(n-butylsulfonylamino)-phenyl, 4-(ethylsulfonylamino)-phenyl, 4-(n-propylsulfonylamino)- Phenyl, 4-(isopropylsulfonylamino)-phenyl, 4-aminophenyl, 4-(acetylamino)-phenyl, 4-(butyrylamino)-phenyl or 4-(diethyl Baseaminomethyl)-phenyl, then _R does not represent 1,1-dimethylethyl; and with the proviso that if p is 1, Y is CH _{and R} represents phenyl which is unsubstituted or substituted by 4-acetyl-1-piperazinyl, then _R does not represent 1-methylethyl; or Y is _CH2 , p is 1, R ₁ stands for (a) 1,2,3,6-tetrahydropyridin-1-yl, 4-(C ₁ -C ₄ alkyl)-1,2,3,6-tetrahydropyridin-1-yl, 4,5 -Di(C ₁ -C ₄ alkyl)-1,2,3,6-tetrahydropyridin-1-yl, 5-chloro-1,2,3,6-tetrahydropyridin-1-yl, 4- Phenyl-1,2,3,6-tetrahydropyridin-1-yl, 1-imidazolyl, 2-(C ₁ -C ₄ alkyl)-1-imidazolyl, 4,5-dihalo-1 -imidazolyl, imidazolidin-2,5-dione-1-yl, 5,5-dimethyl-oxazolidin-2,4-dione-3-yl, 3-(C ₁ -C ₄ alkane Base)-imidazolidine-2,5-dione-1-yl, 3-trifluoromethyl-3,4-pyrrolin-1-yl, 1-pyrrolidinyl, 3-C ₁ -C ₄ alkyl -1-pyrrolidinyl, 3,3-di-(C ₁ -C ₄ alkyl)-1-pyrrolidinyl, 3-C ₁ -C ₄ alkoxy-1-pyrrolidinyl, 3-C ₁ -C ₄ alkyl-2-oxo-1-pyrrolidinyl, 3,3-di-(C ₁ -C ₄ alkyl)-2-oxo-1-pyrrolidinyl, 3-halo-1 -pyrrolidinyl, 3,3-di-halo-1-pyrrolidinyl, 3,3-di-halo-1-piperidinyl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, 1H-1,2,4-triazol-1-yl, 3-nitro-1H-1,2,4-triazol-1-yl, 2-phenyl-1-imidazolyl, 2H-tetrazol-2-yl, 1H-tetrazol-1-yl, benzo[b]imidazol-1-yl, 3-(1-(C ₁ -C ₄ Alkyl-SO ₂ )-4-piperidinyl)-2,3-dihydro-2-oxo-benzo[b]imidazol-1-yl, 3-(1-C ₁ -C ₄ alkylcarbonyl -4-piperidinyl)-2,3-dihydro-2-oxo-benzo[b]imidazol-1-yl, 1-indolyl, 6-halo-1-indolyl, 1, 3-dihydro-2-isoindolyl, 2,3-dihydro-1-indolyl, 2,3-dihydro-2-oxo-benzo[b]thiazol-3-yl, 6, 7-di-(C ₁ -C ₄ alkoxy)-1,2,3,4-tetrahydroquinoline, 6-C ₁ -C ₄ alkoxy-1,2,3,4-tetrahydroiso Quinoline, 7-C ₁ -C ₄ alkoxy-1,2,3,4-tetrahydroisoquinoline; (b) Groups of substructure Ic It is attached to the molecule through a nitrogen atom, where X is -O-, -(CH ₂ ) _s -CR ₁₇ R ₁₈ -or -NR ₁₈ , wherein S is 0 or 1, R and R are _{independently} selected from hydrogen, halogen, hydroxyl, _{C 1 -C 4} alkyl, phenyl-C ₁ -C ₄ alkyl-carbonyl, carbamoyl, N-phenyl -carbamoyl, cyano, 4-pyridyl, 1-piperidinyl and phenyl unsubstituted or monosubstituted by halogen or C ₁ -C ₄ alkoxy, or, if X is CR ₁₇ R ₁₈ , R ₁₇ and R ₁₈ together form an oxo group or group HO-C(O)-CH=, and R ₂₃ , R ₂₄ , R ₂₅ and R ₂₆ are independently selected from hydrogen and C ₁ -C ₄ alkyl; (c) The group of the substructure Id It is attached to the molecule through a nitrogen atom, where k is 0 or 1, A is _CH2 or bond, B is _CH2 or carbonyl, D is _CH2 or carbonyl, E is _CH2 or _NR22 , G is _CH2 or bond, Q is _CH2 or carbonyl, T is CH ₂ or NR ₂₉ , R ₁₉ represents hydrogen, C ₁ -C ₄ alkyl, phenyl- _{C 1} -C ₄ alkyl, C ₁ -C ₄ alkylcarbonyl or C ₁ -C ₄ alkyl -SO ₂ -, R ₂₂ is hydrogen and R ₂₉ is phenyl; (d) Groups of substructure Ie It is attached to the molecule through a nitrogen atom, where R ₂₇ is C ₁ -C ₄ alkyl or C ₁ -C ₄ alkylcarbonyl and R ₂₈ is hydrogen, C ₁ -C ₄ alkoxy or halogen; or (e) NR ₂₀ R ₂₁ , wherein R ₂₀ and R ₂₁ are independently selected from hydrogen, C ₁ -C ₄ alkyl, unsubstituted or C ₃ -C ₇ cycloalkyl monosubstituted by hydroxyl; and unsubstituted or phenyl monosubstituted by 1,2,3-thiadiazol-4-yl, with the proviso that _R20 and _R21 cannot represent hydrogen at the same time; and R ₂ represents C ₁ -C ₈ alkyl, which is unsubstituted or substituted by: C ₃ -C ₇ cycloalkyl which is unsubstituted or disubstituted by halogen; benzene which is mono- or disubstituted by halogen base; with the proviso that _R does not represent 1,1-dimethylethyl in the following cases: (a) R ₁ is benzo[b]imidazol-1-yl, 1-imidazolyl, 4,5-dichloro-1-imidazolyl, 2-(C ₁ -C ₄ alkyl)-1-imidazolyl , imidazolidine-2,5-dione-1-yl, 5,5-dimethyl-oxazolidine-2,4-dione-3-yl, 1H-1,2,3-triazole-1 -yl, 2H-1,2,3-triazol-2-yl, 3-nitro-1H-1,2,4-triazol-1-yl, 2H-tetrazol-2-yl or 1H-tetra Azol-1-yl, or R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is NR ₁₈ and R ₁₈ is hydrogen, methyl, ethyl, acetyl, 4-pyridyl, 1 - piperidinyl, phenyl, methoxyphenyl, ethoxyphenyl, fluorophenyl or chlorophenyl; (b) R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is -(CH ₂ ) _s -CR ₁₇ R ₁₈ -, s is 0, and R ₁₇ and R ₁₈ are selected from hydroxyl and Phenyl monosubstituted by chlorine or _R and _R are selected from hydrogen, methoxyphenyl and N-phenyl-carbamoyl; or (c) R ₁ is a group of substructure Id, k is 1, A is a bond, E is NR ₂₂ , R ₂₂ is hydrogen, G, Q and T are CH ₂ , B and D are carbonyl and R ₁₉ is methyl group, n-propyl or isobutyl; provided that if R ₁ is a group of substructure Id, k is 1, A is a bond, E is NR ₂₂ , R ₂₂ is hydrogen, G, Q and T are CH ₂ , B and D are carbonyl and R ₁₉ is methyl, or if R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ are hydrogen, X is -(CH ₂ ) _s -CR ₁₇ R ₁₈ -, s is 0 , and R ₁₇ and R ₁₈ are selected from hydrogen and phenyl monosubstituted by methoxy, then R ₂ does not represent 2-methylpropyl; and with the proviso that if R ₁ is a group of substructure Ic, R ₂₃ to R ₂₆ is hydrogen, X is NR ₁₈ and R ₁₈ is methoxyphenyl or ethoxyphenyl, or X is CR ₁₇ R ₁₈ and R ₁₇ and R ₁₈ are selected from hydrogen and methoxyphenyl, then R ₂ does not represent 1-methylethyl; or its tautomer, Or a salt of such pyrrolopyrimidine or a tautomer thereof. 3. Pyrrolopyrimidines of the formula I according to claim 1 or 2 or N-oxides or tautomers thereof or pharmaceutically acceptable salts of such compounds for use in a method of treatment of the human or animal body. 4. Use of the pyrrolopyrimidine of formula I according to claim 1 or 2 or its N-oxide or tautomer or a pharmaceutically acceptable salt of such compounds in the preparation of a pharmaceutical product for the treatment of neuropathic pain. 5. A method of treating neuropathic pain comprising administering a pyrrolopyrimidine of formula I according to claim 1 or 2, or an N-oxide or Tautomers, or pharmaceutically acceptable salts, N-oxides or tautomers thereof. 6. A pharmaceutical preparation comprising the pyrrolopyrimidine of formula I according to claim 1 or 2 or its N-oxide or tautomer or a pharmaceutically acceptable salt of such a compound or a hydrate or solvate thereof , and at least one pharmaceutically acceptable carrier. 7. Process for preparing pyrrolopyrimidines of formula I

in: Y stands for -(CH ₂ ) _t -O- or -(CH ₂ ) _r -S-, p is 1 or 2, r is 1, 2 or 3, t is 1, 2 or 3, R ₁ stands for (v) unsubstituted or mono-, di- or trisubstituted phenyl by: (α) Halogen, carboxyl, alkoxy, nitro, alkyl-C(O)-NH-, cycloalkyl-C(O)-NH-, alkyl-C(O)-N(alkyl) -, formyl, alkyl-C(O)-, alkyl-S(O) ₂ -NH-, CF ₃ -alkyl-S(O) ₂ -NH-, pyrrolidinylcarbonyl, piperidinylcarbonyl , Morpholinylcarbonyl, N-alkylpiperazinylcarbonyl, piperidinyl, 1-(alkylcarbonyl)piperidinyl, 1,2,3,6-tetrahydropyridyl, alkylcarbonyl 1,2, 3,6-tetrahydropyridyl, piperazinyl, alkylpiperazinyl, alkylcarbonylpiperazinyl, cycloalkylcarbonylpiperazinyl, alkoxycarbonylpiperazinyl, alkyl-SO ₂ -piperazinyl Base, diazepanyl, alkylcarbonyldiazepanyl, 2-oxo-1-pyrrolidinyl, 3,3-di-alkyl-2-oxo-1-pyrrolidinyl; (β) R ₃ -alkyl, wherein R ₃ represents hydrogen, hydroxyl, carboxyl, alkyl-N(alkyl)-, alkyl-NH-, 1-pyrrolidinyl, 1-piperidinyl, 4-alkane Base-1-piperazinylcarbonyl, 2,4-dioxa-5,5-(di-alkyl)-oxazolidin-3-yl, R ₄ R ₅ NC(O)-, wherein R ₄ and _R independently of each other represent hydrogen or alkyl; or (γ) R ₆ R ₇ NC(O)-, wherein R ₆ and R ₇ independently represent hydrogen, alkyl, cycloalkylalkyl, CF ₃ -alkyl or pyridylalkyl; (w) pyridyl, which is unsubstituted or mono-, di- or trisubstituted by halogen or alkyl, wherein said alkyl is mono-, di- or trisubstituted by halogen; (x) pyrimidinyl; (y) indolyl mono- or disubstituted by alkyl-C(O)-NH-alkyl; (z) 2-(alkyl)-benzothiazolyl; (aa) a group of the subformula Ia:

wherein _R is hydrogen, halogen or alkyl, _R is hydrogen or alkyl, and m is 1, 2, 3 or 4; or (bb) a group of the subformula Ib:

wherein R ₁₀ is hydrogen, halogen or alkyl, R ₁₁ is hydrogen or alkyl, and n is 1, 2, 3 or 4; _R represents alkyl, which is unsubstituted or substituted by cycloalkyl which is unsubstituted or mono- or disubstituted by halogen, or phenyl which is mono- or disubstituted by halogen; Provided that if Y is O and R _is selected from 3-pyridyl, 4-pyridyl, 5-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-chloro-4-pyridyl, 2- Trifluoromethyl-4-pyridyl, 2-difluoromethyl-4-pyridyl, 4-acetyl-1-piperazinyl-phenyl, 4-methyl-1-piperazinyl-methyl- phenyl, then _R does not represent 1,1-dimethylethyl, and with the proviso that if Y is S and _R is 4-pyridyl, then _R does not represent 1,1-dimethylethyl; wherein the alcohol or thiol of formula II, R ₁ -(Y) _p -H (II) wherein Y represents -(CH ₂ ) _t -O- or (CH ₂ ) _r -S- and t, r and R ₁ have the meanings given above for compounds of formula I, Alkylation with pyrrolopyrimidines of formula III

wherein _R has the meanings given above for compounds of formula I and Hal represents halogen, preferably bromine, wherein the starting compounds of formulas II and III may also have functional groups in protected form, if necessary, and/or in salt form, Provided that a salt-forming group is present and a reaction in the salt form is possible; wherein any protecting group in the protected derivative of the compound of formula I is removed; And, if desired, converting an available compound of formula I into another compound of formula I or its N-oxide, converting a free compound of formula I into a salt, converting an available salt of a compound of formula I into a free Compound or another salt, and/or separation of a mixture of isomers of a compound of formula I into individual isomers.