Phosphorus derivatives as kinase inhibitors

Abstract

To provide a new group of phosphorus compounds effective for treating cancers and other diseases.SOLUTION: A compound represented by the following formula: A therapeutic agent for non-small cell lung cancer, which is an ALK inhibitor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to a novel class of phosphorus compounds and their use in the treatment of cancer and other diseases. do. [Background technology]

[0002] Protein kinases play a central role in regulating diverse cellular processes and are essential for all cellular functions. Kinases are a large group of proteins that maintain the regulation of the body. The list does not include: ALK, abl, Akt, bcr-abl, Blk, Brk, c -kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK 5, CDK6, CDK7, CDK8, CDK9, CDK10, bRaf, cRaf1, C SK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Pak, fes, FG FR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, fl t-3, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak1, Ja k2, Jak3, KDR, Lck, Lyn, FAK, MEK, p38, PDGFR, PI K, PKC, PYK2, ros, tie, tie2, Pim-1, P13k, TRK and Abnormal protein kinase activity can lead to life-threatening conditions such as psoriasis. It has been implicated in several diseases ranging from minor illnesses to extremely serious illnesses such as cancer.

[0003] Considering the large number of protein kinases and the large number of protein kinase-related diseases, These compounds are useful as protein kinase inhibitors and therefore act as inhibitors of protein tyrosine kinases. and to provide a novel class of highly selective compounds useful in the treatment of related diseases. There is always a demand for it.

[0004] This invention relates to a novel class of phosphorus compounds and their use in the treatment of cancer and other diseases. do. Summary of the Invention

[0005] 1. General Description of the Compounds of the Invention The compounds of the present invention are effective in treating cancer, especially lymphomas, solid tumors, and leukemias. including advanced cancer and those resistant or refractory to one or more other treatments. and the use thereof in pharmaceutical compositions and methods for the treatment of cancer, including cases of , can have a wide range of useful biological and pharmacological activities.

[0006] The present invention relates to compounds represented by the following general formula I, and their tautomers and pharmaceutically acceptable salts thereof: Salts and solvates are included.

[0007] [ka]

[0008] During the ceremony, X 1 is NR b1 or CR b and; X 2 is NR c1 or CR c and; X 3 is NR d1 or CR d and; X 4 is NR e1 or CR e and; Ring A is aryl, or N, O and S(O) r containing 1 to 4 heteroatoms selected from a 5- or 6-membered heteroaryl ring; R a , R b , R c , R d , and R e Each occurrence of represents independently a halogen, -CN, or -N O2, -R 1 , -OR 2 , -O-NR 1 R 2 , -NR 1 R 2 , -NR 1 -NR 1 R 2 , -NR 1 -O R 2 , -C(O)YR 2 , -OC(O)YR 2 , -NR 1 C(O)YR 2 , -SC(O)YR 2 , -NR 1 C(=S)YR 2 , -OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 1 )YR 2 , -YC (=N-OR 1 )YR 2 , -YC(=N-NR 1 R 2 )YR 2 , -YP(=O)(YR 3 )(YR 3 ), -S i(R 3a )3, -NR 1 SO2R 2 , -S(O) r R 2 , -SO2NR 1 R 2 , and -NR 1 SO2NR 1 R 2 and R b1 , R c1 , R d1 and R e1does not exist, and each Y is independent and a single bond, -O-, -S-, or -NR 1 -or; R b , R b1 , R c , R c1 , R d , R d1 , R e and R e1 Two adjacent permutations chosen from group or two adjacent R a The moieties, along with the atoms to which they are attached, are N, O, and S(O). r and 1 to 4 R f Partially substituted, saturated, may form a partially saturated or unsaturated 5-, 6- or 7-membered ring; Each R f The moieties may independently be halogen, =O, =S, -CN, -NO2, -R 1 , -OR 2 , -O-NR 1 R 2 , -NR 1 R 2 , -NR 1 -NR 1 R 2 , -NR 1 -OR 2 , -C(O)YR 2 ,- OC(O)YR 2 , -NR 1 C(O)YR 2 , -SC(O)YR 2 , -NR 1 C(=S)YR 2 , -OC (=S)YR 2 , -C(=S)YR 2 , -YC(=NR 1 )YR 2 , -YC(=N-OR 1 )YR 2 ,- YC(=N-NR 1 R 2 )YR 2, -YP(=O)(YR 3 )(YR 3 ), -Si(R 3a )3, -NR 1 S O2R 2 , -S(O) r R 2 , -SO2NR 1 R 2 , and -NR 1 SO2NR 1 R 2 Selected from the group consisting of or two adjacent R f The moieties, together with the atoms to which they are attached, are N, O and and S(O) r Optionally substituted, containing 0 to 4 heteroatoms selected from may form a saturated, partially saturated or unsaturated 5-, 6- or 7-membered ring; R a , R b , R c , R d , R e , R f , R b1 , R c1 , R d1 , and R e1 At least one of If it exists, -P(=O)(R 3 )2 or containing it, or a ring component As -P(=O)(R 3 is or includes a ring system containing a )- moiety; r is 0, 2 or 2; s is 1, 2, 3, 4 or 5; n is 0 or 1; Each occurrence of Y is independently a single bond, -O-, -S-, or -NR 1 - and; R 1 and R 2 Each occurrence of represents independently H, alkyl, alkenyl, alkynyl, cyclohexyl, alkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, hetero selected from heterocyclic groups (=heterocycles) and heteroaryls; R 3 Each occurrence of is independently alkyl, alkenyl, alkynyl, or cycloalkyl. , cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic groups and heterocyclic groups. or two adjacent R 3 The moieties together contain a phosphorus atom may form a ring system having R 3a Each occurrence of is independently alkyl, alkenyl, alkynyl, cycloalkynyl, or cycloalkyl. aryl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic groups and selected from heteroaryl; Or, each NR 1 R 2 The moieties are N, O and S(O) r 0 to 2 additional heterocyclic groups selected from optionally substituted, saturated, partially saturated or unsaturated 5, 6 or may be a seven-membered ring; The above alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl, The alkynyl, aryl, heteroaryl, and heterocyclic moieties are optionally substituted. That's fine.

[0009] Each of the above definitions is further elaborated and exemplified below, and unless otherwise specified, This also applies when the 2. Specific classes of compounds and their uses, general description One class of compounds of particular interest for use in the present invention is X 2 is CR c and X 3 but CR d and X 4 is CR e a compound of general formula I as described in Part 1 above, Compounds of this type are exemplified by compounds of the following general formula IA:

[0010] [ka]

[0011] During the ceremony, X 1 is N or CR b and rings A and R a , R b , R c , R d , R e , n and s are As defined in general formula I.

[0012] One class of compounds of interest includes those in which ring A is phenyl. Another class of compounds of interest is compounds in which Ring A is a 5- or 6-membered heteroaryl. Examples include:

[0013] Another class of compounds of particular interest for use in the present invention is X 1 is CR b The above general formula This type of compound is represented by the general formula IB. Illustrated.

[0014] [ka]

[0015] A subclass of interest includes compounds of formula IB where n is zero. Another subclass of interest includes compounds of formula IB where n is 1. Another subclass of interest includes compounds of formula IB where ring A is phenyl.

[0016] Another class of compounds of particular interest is X 1as described above in Part 1 where N This type of compound is represented by the general formula IA. This type of compound is represented by the following general formula IC. Examples are given below.

[0017] [ka]

[0018] A subclass of interest includes compounds of the general formula IC where n is zero. Another subclass of interest includes compounds of the general formula IC where n is 1. Another subclass of interest includes compounds of formula IC where ring A is phenyl.

[0019] In the general formulas IB and IC, s, R a , R b , R c , R d and R e is in general formula I As defined above. In particular embodiments of the foregoing classes and subclasses, R a One of -P(=O)(R 3 )2 groups or containing them. 3 ) containing two groups a Examples of the alkyl group include, but are not limited to, -(CH2) m -P(=O)(R 3 )2, -(CH2) m -N R 1 -P(=O)(R 3 )2, -(CH2) m -OP(=O)(R 3 )2, -(CH2) m -NR 1 -(CH2) m -P(=O)(R 3 )2, -(CH2) m -NR 1 -C(O)O-(CH2)m -P(=O)(R 3 )2, -(CH 2) m -C(O)-(CH2) m -P(=O)(R 3 )2, -(CH2) m -C(O)NR 1 -(CH2) m -P(= O)(R 3 ) 2 (wherein m is 0, 1, 2, 3 or 4).

[0020] Representative examples of this type of compound are compounds of the general formula IA below.

[0021] [ka]

[0022] In some embodiments, R a is a part of the cyclic structure -P(=O)(R 3 )2 substituents. For example, two R 3 The groups can be taken together to form a ring system that includes a phosphorus atom, where , which ring system is an optionally substituted 5-, 6-, or 7-membered saturated ring; and The ring system is optionally N, O and S(O) r containing one heteroatom selected from In some embodiments, R a is a group represented by any of the following formulae or contains such a group: There is.

[0023] [ka]

[0024] Illustrative of this class are compounds of the general formula IA, including:

[0025] [ka]

[0026] In another example, R a is a ring component -P(=O)(R 3 is a ring system containing a )-moiety, For example, an optionally substituted 5-, 6- or 7-membered saturated ring; Contains one phosphorus atom and optionally N, O and S(O) r One selected item In some embodiments, R a is a group represented by one of the following formulas: or contains the group.

[0027] [ka]

[0028] - Illustrative of this class are compounds of the general formula IA, including:

[0029] [ka]

[0030] In one subspecies of interest, R a One of them is -(CH2) m -P(=O)(R 3 )2. This kind is exemplified by compounds of the following general formula II:

[0031] [ka]

[0032] In the formula, R 3 , R a ,n,ring A,X 1 , X 2 , X 3 and X 4is as defined above in general formula I and m is 0, 1, 2, 3 or 4. One class of compounds of particular interest for use in the present invention are those compounds represented by general formula II above. In the compound, X 2 is CR c and X 3 is CR d and X 4 is CR e This is what is This class is exemplified by the compound of formula IIA:

[0033] [ka]

[0034] In the formula, R 3 , R a , ring A, n, X 1 , R c , R d and R e is as defined above in general formula I and m is 0, 1, 2, 3 or 4. One subclass of interest is the compound of formula II or formula IIA where m is 0. In another subspecies, m is 1.

[0035] Another subclass of interest is the compounds of formula II or formula IIA where X is N. be. Another subspecies of interest is X where CR b A compound represented by general formula II or general formula IIA, It is a thing.

[0036] Another subclass of interest is that class or subclass of compounds where n is 0. where n is 1. One class of compounds of particular interest is the compound of general formula IIA, in which ring A is phenyl. It is a mixture.

[0037] A non-limiting example of this embodiment is a compound represented by the general formula IIA below:

[0038] [ka]

[0039] In one embodiment, R c1 , R d1 , R c and R d Two adjacent substituents selected from Five-, six-, or seven-membered saturated, partially saturated, or unsaturated rings together with the atoms to which they are attached Forming ring B, this ring B is 1 to 4 R f and N, O and S(O) r Choose from This class of compounds contains 0 to 4 heteroatoms. This is further exemplified.

[0040] [ka]

[0041] In the formula, R a , Rf, ring A, n, s, X 1 , X 2 , X 3 and X 4 is as described in general formula I and t is 1, 2, 3 or 4. One class of compounds of particular interest for use in the present invention is represented by the general formula III, as shown above. In the compound represented by the formula: X 2 is CR c and X 3 is CR d and X 4 is CR e and R c and R dThe moieties, together with the atoms to which they are attached, may be 5-, 6-, or 7-membered saturated rings, Compounds that form a partially saturated or unsaturated ring B. This type has the following general formula III This is exemplified by the compound represented by A.

[0042] [ka]

[0043] In the formula, R a , X 1 , ring A, n, s, t, X 1 , R e and R f is as described above in general formula III That is exactly what happened. In certain embodiments, one R a -P(=O)(R 3 )2 or contains it, or is a ring component -P(=O)(R 3 )-containing ring system or containing the moiety ( For example, -(CH2) m -P(=O)(alkyl)2, where m is 0, 1, 2, 3 or 4, and Other examples of phosphorus-containing substituents include those listed above, including cyclic ones. In another particular embodiment, R f but P(=O)(R 3 )2 or containing -P(=O)(R 3 ) is or includes a ring system containing a - moiety (e.g., -(CH) m -P(=O)(Archi m is 0, 1, 2, 3, or 4, as well as phosphorus-containing rings, including the cyclic rings listed above. Other examples of substituents).

[0044] One class of compounds of particular interest is of the general formula III or IIIA, where Ring A is phenyl. The compound shown is: Illustrative of this type of compound is the compound of formula IIIA below:

[0045] [ka]

[0046] Another example of this type of compound is the compound represented by the following general formula III:

[0047] [ka]

[0048] In another embodiment, R d1 , R e1 , R d and R d Two adjacent substituents selected from Five-, six-, or seven-membered saturated, partially saturated, or unsaturated rings together with the atoms to which they are attached Forms a ring C, and this ring C is bound to 1 to 4 R f and N, O and S(O) r Choose from This class contains 0 to 4 heteroatoms. Examples are given below.

[0049] [ka]

[0050] In the formula, rings A, R a , Rf, s, n, X 1 , X 2 , X 3 and X 4 is as defined in general formula I and t is 1, 2, 3 or 4. Representative examples of this type are compounds of formula IV below:

[0051] [ka]

[0052] One class of compounds of particular interest for use in the present invention is represented by general formula IV, as shown above: In the compound shown, X 1 is CR b and X 2 is CR c and X 3 is CR d and X 4 is CR e and R d and R e The moieties, together with the atoms to which they are attached, may be 5, 6 or These are compounds that form a seven-membered saturated, partially saturated or unsaturated ring C. This type includes the following: This is exemplified by a compound of general formula IVA:

[0053] [ka]

[0054] In the formula, ring A, ring C, R a ,s,n,R b , R c , R f and t is defined above in general formula IV That's exactly what I did. In certain aspects of this embodiment, one R a But -P(=O)(R 3 )2 or it Contains or contains -P(=O)(R 3 a ring system containing a - moiety or This includes.

[0055] In another aspect of this embodiment, R f One of them is P(=O)(R 3 )2 or containing it, or is a ring component -P(=O)(R 3is or includes a ring system containing a )-moiety. In another aspect of this embodiment, R c P(=O)(R 3 )2 or containing the ring As a component -P(=O)(R 3 is or includes a ring system containing a )-moiety.

[0056] One class of compounds of particular interest is represented by the general formula IV or IVA, where Ring A is phenyl. It is a compound that can be Illustrative of this type of compound is the compound of formula IVA below:

[0057] [ka]

[0058] In another embodiment, R b , R c , R b1 and R c1 Two adjacent substituents selected from Five-, six-, or seven-membered saturated, partially saturated, or unsaturated rings together with the atoms to which they are attached Forming a ring D, the ring D is composed of 1 to 4 R f Substituted with N, O and S(O) groups r Choose from This group is represented by the following general formula V: Examples are given below.

[0059] [ka]

[0060] In the formula, R a , s, n, X 1 , X 2 , X 3 ,X 4 and R f is as defined above in general formula I and t is 1, 2, 3, or 4. An example of this type of compound is the compound represented by the following general formula V:

[0061] [ka]

[0062] One class of compounds of particular interest for use in the present invention is represented by general formula V, as shown above: In the compound, X 1 is CR b and X 2 is CR c and X 3 is CR d and X 4 is CR e and R b and R b together with the atoms to which they are attached form a 5, 6 or 7 membered Compounds that form a saturated, partially saturated or unsaturated ring D. This class is one of the following: This is exemplified by compounds of formula IVA.

[0063] [ka]

[0064] In the formula, R a , s, n, t, ring A, ring D, R d , R e and R f is defined above in general formula V That's exactly what I did. In certain aspects of this embodiment, one R a But -P(=O)(R 3 )2 or it Contains or contains -P(=O)(R 3 a ring system containing a - moiety or This includes.

[0065] In another aspect of this embodiment, R f One of them is P(=O)(R 3 )2 or contains it, or or -P(=O)(R 3 is or comprises a ring system containing a - moiety .

[0066] One class of compounds of particular interest is represented by the general formula V or VA, where ring A is phenyl. It is a compound. Illustrative of this type of compound are compounds of the general formula VA below:

[0067] [ka]

[0068] The present invention also relates to compounds of the general formula VI:

[0069] [ka]

[0070] During the ceremony, X 1 is NR b1 or CR b and; X 3 is NR d1 or CR d and; X 4 is NR e1 or CR e and; Ring A is aryl, or N, O and S(O) r containing 1 to 4 heteroatoms selected from a 5- or 6-membered heteroaryl ring; Ring E is an aryl ring, a carbocycle, or independently of the carbon atoms O, N, and S(O) r Selected from and 1 to 4 heteroatoms, and a 5-, 6-, or 7-membered heterocyclic ring or heteroaryl ring. and ring E is optionally fused with a 5-, 6-, or 7-membered saturated, partially saturated, or unsaturated ring. and ring E has 1 to 7 R on a carbon atom or heteroatom. g substituted by a group are.

[0071] L is a single bond, O(CH2) y , N.R. 4 (CH2) y , S(O) r (CH2) y , (CH2) y , (CH2) y S O2NR 4 , (CH2) y NR 4 SO2, (CH2) y CH=CH, (CH2) y C≡C,

[0072] [ka]

[0073] (CH2) y C(O)NR 4 , (CH2) y NR 4 C(O) and y is 0, 1, 2, 3, or 4; p is 1, 2, 3, 4, 5, 6, or 7; r is 0, 1, or 2; R 4 is H or Al The linker L may be included in either direction.

[0074] R a , R b , R d and R e is independently halogen, -CN, -NO2, -R 1 , -OR 2 , -O-NR 1 R 2 , -NR 1 R 2 , -NR1 -NR 1 R 2 , -NR 1 -OR 2 , -C( O)YR 2 , -OC(O)YR 2 , -NR 1 C(O)YR 2 , -SC(O)YR 2 , -NR 1 C(=S) YR 2 , -OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 1 )YR 2 , -YC(=NO R 1 )YR 2 , -YC(=N-NR 1 R 2 )YR 2 , -YP(=O)(YR 3 )(YR 3 ), -Si(R 3a ) 3, -NR 1 SO2R 2 , -S(O) r R 2 , -SO2NR 1 R 2 , and -NR 1 SO2NR 1 R 2 twist and R b1 , R d1 and R e1 is not present, each Y is independently a single bond, -O-, -S- or -NR 1 -or; R b , R b1 , R d , R d1 , R e and R e1 two adjacent substituents or two adjacent substituents selected from Adjacent R a The moieties, along with the atoms to which they are attached, are N, O, and S(O). r Selected from Contains 0 to 4 heteroatoms and 1 to 4 R f Partially substituted saturated, partially saturated or may form an unsaturated 5-, 6- or 7-membered ring; Each R f The moieties may independently be halogen, =O, =S, -CN, -NO2, -R 1 , -OR 2 , -O-NR 1 R 2 , -NR 1 R 2 , -NR 1 -NR 1 R 2 , -NR 1 -OR 2 , -C(O)YR 2 ,- OC(O)YR 2 , -NR 1 C(O)YR 2 , -SC(O)YR 2 , -NR 1 C(=S)YR 2 , -OC (=S)YR 2 , -C(=S)YR 2 , -YC(=NR 1 )YR 2 , -YC(=N-OR 1 )YR 2 ,- YC(=N-NR 1 R 2 )YR 2 , -YP(=O)(YR 3 )(YR 3 ), -Si(R 3a )3, -NR 1 S O2R 2 , -S(O) r R 2 , -SO2NR 1 R 2 , and -NR 1 SO2NR 1 R 2 Selected from the group consisting of or two adjacent R fThe moieties, together with the atoms to which they are attached, are N, O and and S(O) r Optionally substituted, containing 0 to 4 heteroatoms selected from may form a saturated, partially saturated or unsaturated 5-, 6- or 7-membered ring; Each R g The moieties are independently halogen, =O, =S, -CN, -NO2, -R 1 , -OR 2 ,- O-NR 1 R 2 , -NR 1 R 2 , -NR 1 -NR 1 R 2 , -NR 1 -OR 2 , -C(O)YR 2 , -O C(O)YR 2 , -NR 1 C(O)YR 2 , -SC(O)YR 2 , -NR 1 C(=S)YR 2 , -OC( =S)YR 2 , -C(=S)YR 2 , -YC(=NR 1 )YR 2 , -YC(=N-OR 1 )YR 2 , -Y C(=N-NR 1 R 2 )YR 2 , -YP(=O)(YR 3 )(YR 3 ), -Si(R 3a )3, -NR 1 SO2 R 2 , -S(O) r R 2 , -SO2NR 1 R 2 , and -NR 1 SO2NR 1 R 2 Selected from the group consisting of wherein each Y is independently a single bond, —O—, —S—, or —NR 1 - and;, and R a , R b , R d , R e or R g At least one of, if present, -P(=O)(R 3 )2 or containing -P(=O)(R 3 )-containing ring systems is or contains; r is 0, 1 or 2; s is 1, 2, 3, 4 or 5; n is 0 or 1; p is 1, 2, 3 or 4; Each occurrence of Y is independently a single bond, -O-, -S-, or -NR 1 - and; R 1 and R 2 Each occurrence of represents independently H, alkyl, alkenyl, alkynyl, cyclohexyl, alkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, hetero selected from cyclic groups and heteroaryl; R 3 Each occurrence of is independently alkyl, alkenyl, alkynyl, or cycloalkyl. , cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic groups and heterocyclic groups. or two adjacent R 3 The moieties together contain a phosphorus atom may form a ring system having R 3a Each occurrence of is independently alkyl, alkenyl, alkynyl, cycloalkynyl, or cycloalkyl. aryl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic groups and selected from heteroaryl; Or, each NR 1 R 2The moieties are N, O and S(O) r 0 to 2 additional heteroatoms selected from containing 5, 6 or more optionally substituted saturated, partially saturated or unsaturated may be a seven-membered ring; The above alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl, Each of the alkynyl, aryl, heteroaryl, and heterocycle moieties is optionally substituted. It may be replaced.

[0075] In one embodiment, in compounds of general formula VI, R a One of them is -P(=O)(R 3 )2 or contains In another embodiment, in compounds of formula VI, R g One of them is -P(=O)(R 3 )2 is or contains

[0076] In one embodiment, in compounds of formula VI, L is a single bond. Non-limiting examples of compounds include the following:

[0077] [ka]

[0078] In another embodiment, in the compound of formula VI, L is NR 4 (CH2) y One In a specific embodiment, L is NR 4 In another embodiment, L is NR 4 (CH2) 1-3 is Non-limiting examples of the linker L are NHCH2CH2, NHCH2, NH, and NCH3. Non-limiting examples of this type of compound include the following compounds:

[0079] [ka]

[0080] In another embodiment, in the compound of formula VI, L is O(CH2) y This type of compound Non-limiting examples of the compounds include the following compounds:

[0081] [ka]

[0082] In another embodiment, in the compound of formula VI, L is (CH2) y C(O)NR 4 or (CH2) y N R 4 C(O). Non-limiting examples of this type of compound include the following compounds:

[0083] [ka]

[0084] In another embodiment, in the compound of formula VI, L is S(CH2) y This type of compound Non-limiting examples of the compounds include the following compounds:

[0085] [ka]

[0086] In yet another embodiment, in the compound of formula VI, ring E is selected from 1 to 5 R g Substituted with a group Non-limiting examples of this class of compounds include the following classes of compounds: It can be obtained.

[0087] [ka]

[0088] In another embodiment, in the compound of formula VI, ring E is a carbon atom and O, N and S(O) r and 1 to 3 heteroatoms independently selected from Ring E is a ring having 1 to 7 R on a carbon atom or heteroatom. g Substituted by a group Substituent R g It goes without saying that the total number of valences cannot exceed the normal number of available valences. Non-limiting examples of compounds of this type are compounds of general formula VI in which ring E is of the following type:

[0089] [ka]

[0090] A non-limiting example is a compound of the formula:

[0091] [ka]

[0092] In another embodiment, in the compound of formula VI, ring E is a carbocyclic ring, and ring E is 1 ~7 R g A non-limiting example of this type of compound is shown in the formula: It is a compound that can be

[0093] [ka]

[0094] In another aspect of the above embodiment, ring E is a ring consisting of a carbon atom and O, N, and S(O) r Selected independently from and 1 to 3 heteroatoms. For example, ring E is a 5-membered heteroaryl containing carbon atoms and 1 to 3 nitrogen atoms. Non-limiting examples of compounds of this type are those in which ring E is of the following type: do.

[0095] [ka]

[0096] In some embodiments, ring E has the formula:

[0097] [ka]

[0098] Another interesting one is R g Ga-R 1 and -C(O)YR 2 The aforementioned Another interesting subclass is R g Aryl, heteroaryl, substituted aryl Non-limiting examples of substituted alkyl are: -(CH2) z C(=O)NR 1 R 2 , -(CH2) z NHC(=O)R 2 , -(CH2) z NR 1 R 2 , -(C H2) z C(=O)OR 1 , -(CH2) z Heterocycle, -(CH2) z Aryl and -(CH2) z Heteroa alkyl, where z is 1, 2, 3, or 4, and alkyl is linear (i.e., unbranched). or acyclic), branched, and cyclic alkyl groups, and alkyl, aryl, hydroxyl, The heteroaryl and heterocyclic groups may be optionally substituted.

[0099] Substituent R g Specific examples of such rings E containing include, but are not limited to, the following: Examples include:

[0100] [ka]

[0101] A non-limiting example of this class of compounds is a compound of the formula:

[0102] [ka]

[0103] In another embodiment, Ring E is a 5-membered heteroaryl ring containing carbon atoms and 1 to 3 nitrogen atoms. The heteroaryl ring is connected to the core moiety via a nitrogen atom. In one preferred form of this embodiment, L is a single bond or (CH2) y is.

[0104] Another interesting species is R g Ga-R 1 , -OR 2 , -P(=O)(R 3 )2, -NR 1 R 2 , -C(O )YR 2 , -NR 1 C(O)YR 2 , -NR 1 SO2R 2 , -S(O) r R 2 , -SO2NR 1 R 2 , and -NR 1 SO2NR1 R 2 Another interesting compound is a compound of the above type selected from the group consisting of: In terms of rank, R g is an aryl, heteroaryl, substituted alkyl or heterocyclic group. It is a compound similar to R g A non-limiting example of is -(CH2) y C(=O)NR 1 R 2 , -(CH2) y N HC(=O)R 2 , -(CH2) y NR 1 R 2 , -(CH2) y Heterocycle, -(CH2) y Aryl, -(C H2) y Heteroaryl, -NH-aryl, -NH-heteroaryl and -NH heterocycle where y is 0, 1, 2, 3, or 4, and the alkyl is linear (i.e., unbranched or It includes alkyl, aryl, heterocyclic, branched, and cyclic alkyl groups. The aryl and heterocyclic groups may be optionally substituted.

[0105] A non-limiting example of such a compound is a compound in which ring E is a triazole having the formula: Certain compounds of general formula VI are mentioned.

[0106] [ka]

[0107] In another embodiment, ring E is a pyrazole of the formula:

[0108] [ka]

[0109] In another aspect of the above embodiment, ring E is a tetrazole of the formula:

[0110] [ka]

[0111] In another embodiment, ring E contains carbon atoms and 1 to 3 heteroatoms selected from N and O. A non-limiting example is one in which ring E is of the type shown below: The compound is represented by the general formula VI:

[0112] [ka]

[0113] In the above formula, p is as defined above, and the substituent R g The total number of regular available valences Not exceeding. In certain embodiments, ring E has the formula:

[0114] [ka]

[0115] In the above formula, ring E is 1 to 2 R g It is substituted with a substituent. Another interesting species is R g Ga-R 1 , -P(=O)(R 3 )2, -OR 2 , -NR 1 R 2 , -C(O )YR 2 , -NR 1 C(O)YR 2 , -NR 1 SO2R 2 , -S(O) r R 2 , -SO2NR 1 R 2 and- NR 1 SO2NR 1 R 2 Another interesting subclass of compounds is a compound of the above type selected from the group consisting of: In species, R g Ga-NHC(O)R 1 , -NHC(O)NR 1 R 2 , -C(O)NHR 1 , -C(O)N R 1 R 2 , -NR 1 R 2 aryl, heteroaryl, substituted alkyl or heterocyclic group; The compound is of the following embodiment. g A non-limiting example of is -(CH2) y C(=O)NR 1 R 2 , -(CH2) y NHC(=O)R 2 , -(CH2) y NR 1 R 2 , -(CH2) y OR 2 , -(CH2) y Heterocycle, -(C H2) y Aryl, -(CH2) y Heteroaryl, -NH-aryl, -NH-heteroaryl -NH heterocycles, -(CH2) m P(=O)(alkyl)2, where y and m are independently is selected from 0, 1, 2, 3 and 4, and alkyl is straight chain (i.e., unbranched or uncyclic) Formula), branched and cyclic alkyl groups, and alkyl, aryl, heteroaryl and heterocyclic groups may be optionally substituted.

[0116] Non-limiting examples of this class of compounds include those in which ring E is represented by general formula VI: Examples of compounds include:

[0117] [ka]

[0118] Non-limiting examples of this class of compounds include those in which the substituted ring E is of the formula: and compounds of the general formula VI,

[0119] [ka]

[0120] [ka]

[0121] In another specific embodiment, ring E is selected from carbon atoms, N, and S, as exemplified by the formula: and 1 to 3 heteroatoms.

[0122] [ka]

[0123] In the above formula, p is as defined above, and the substituent R g The total number of regular available valences Not exceeding. Of particular interest is R g Ga-R 1 , -P(=O)(R 3 )2, -OR 2 , -NR 1 R 2 , -C(O) YR 2 , -NR 1 C(O)YR 2 , -NR 1 SO2R 2 , -S(O) r R 2 , -SO2NR 1 R 2 and- NR1 SO2NR 1 R 2 Another interesting subclass of compounds is a compound of the above type selected from the group consisting of: In species, R g Ga-NHC(O)R 1 , -C(O)NHR 1 , -C(O)NR 1 R 2 , -NHC(O)N HR 1 , -NR 1 R 2 aryl, heteroaryl, substituted alkyl or heterocyclic group; The compound is of the following embodiment. g A non-limiting example of is -(CH2) y C(=O)NR 1 R 2 , -(CH2) y NHC(=O)R 2 , -(CH2) y NR 1 R 2 , -(CH2) y OR 2 , -SO2NR 1 R 2 , -(CH2 ) y SR 2 , -(CH2) y Heterocycle, -(CH2) y Aryl, -(CH2) y Heteroaryl, -N H-aryl, -NH-heteroaryl, -NH heterocycle and -(CH2) m P(=O)(Al alkyl)2, where y and m are independently selected from 0, 1, 2, 3, and 4; alkyl is includes straight-chain (i.e., unbranched or acyclic), branched, and cyclic alkyl groups; and The alkyl, aryl, heteroaryl and heterocyclic groups may be optionally substituted. .

[0124] Non-limiting examples of this class of compounds include those in which ring E is represented by general formula VI: Examples of compounds include:

[0125] [ka]

[0126] A non-limiting example of this type of compound is one in which the substituted ring E is of the formula: Certain compounds of the general formula VI are mentioned.

[0127] [ka]

[0128] Another non-limiting example is a compound of the general formula: Examples of the compound represented by formula VI include:

[0129] [ka]

[0130] In the above formula, p is as defined above, and the substituent R g The total number of regular available valences Not exceeding. A non-limiting example of this type of compound is one in which the substituted ring E is of the formula: Certain compounds of the general formula VI are mentioned.

[0131] [ka]

[0132] In another embodiment, ring E is a 6-membered heteroaryl ring. For example, ring E is represented by the formula: It may be a pyrimidine of the type.

[0133] [ka]

[0134] In the above formula, p is as defined above, and the substituent R g The total number of regular available valences Not exceeding. Of particular interest is R g Ga-R 1 , -P(=O)(R 3 )2, -OR 2 , -NR 1 R 2 , -C(O) YR 2 , -NR 1 C(O)YR 2 , -NR 1 SO2R 2 , -S(O) r R 2 , -SO2NR 1 R 2 and- NR 1 SO2NR 1 R 2 Another interesting subclass of compounds is a compound of the above type selected from the group consisting of: In species, R g Ga-NHC(O)R 1 , -NHC(O)NHR 1 , -C(O)NHR 1 , -C(O)NR 1 R 2 , -NR 1 R 2 , aryl, heteroaryl, substituted alkyl or heterocyclic group. The compound of the present invention is R a A non-limiting example of is -OCH2CH2NR 1 R 2 , -OCH2C(O) NR 1 R 2 , -NR 1 C(O)NR 1 R 2 , -(CH2) y C(=O)NR 1 R 2 , -(CH2) y NHC(= O)R2 , -(CH2) y NR 1 R 2 , -(CH2) y OR 2 , -SO2NR 1 R 2 , -(CH2) y SR 2 , -(CH2) y Heterocycle, -(CH2) y Aryl, -(CH2) y Heteroaryl, -NH-aryl -NH-heteroaryl, -NH-heterocycle and -(CH2) m P(=O)(alkyl)2 where y and m are independently selected from 0, 1, 2, 3, and 4, and alkyl is straight-chain (i.e., It includes alkyl, i.e., unbranched or acyclic), branched, and cyclic alkyl groups, and alkyl, The aryl, heteroaryl and heterocyclic groups may be optionally substituted.

[0135] Non-limiting examples of this class of compounds include those in which ring E is represented by general formula VI: Examples of compounds include:

[0136] [ka]

[0137] Non-limiting examples of this class of compounds include compounds of general formula VI, wherein ring E is The compounds shown are listed below.

[0138] [ka]

[0139] In another embodiment, ring E is selected from 1 to 4 R g Of particular interest are pyridines substituted with . is R g Ga-R1 , -P(=O)(R 3 )2, -OR 2 , -NR 1 R 2 , -NR 1 C(O)R 2 , -NR 1 SO2R 2 In another interesting subclass, R g Ga-NHC(O)R 2 , -NR 1 R 4 , aryl, heteroaryl, substituted alkyl or hetero The compound according to the above embodiment is a compound in which R is a cyclic group. g A non-limiting example of is -(CH2) y C(=O)NR 1 R 2 , -(CH2) y C(=O)aryl, -(CH2) y C(=O)heteroaryl, -(CH2) y C(= O) heterocycle, —(CH2) y NHC(=O)R 2 , -(CH2) y NR 1 R 2 , -(CH2) y OR 2 , -( CH2) y SR 2 , -(CH2) y Heterocycle, -(CH2) y Aryl, -(CH2) y heteroaryl, -NH-aryl, -NH-heteroaryl, -NH heterocycle and -(CH2) m P(=O)( alkyl)2, where y and m are independently selected from 0, 1, 2, 3, and 4; The alkyl groups include straight chain (i.e., unbranched or acyclic), branched, and cyclic alkyl groups, and alkyl, aryl, heteroaryl and heterocyclic groups are optionally substituted. good.

[0140] Non-limiting examples of this class of compounds include those in which ring E is represented by general formula VI: Examples of compounds include:

[0141] [ka]

[0142] Non-limiting examples of this class of compounds include compounds of general formula VI, wherein ring E is The compounds shown are listed below.

[0143] [ka]

[0144] In another embodiment, ring E is selected from 1 to 3 R g This type of compound is a pyrazine substituted with a group. Non-limiting examples of compounds include compounds in which ring E is represented by the following formula:

[0145] [ka]

[0146] Non-limiting examples of this class of compounds include compounds of general formula VI, wherein ring E is The compounds shown are listed below.

[0147] [ka]

[0148] In another embodiment, ring E is selected from 1 to 2 R g Examples include triazines substituted with the following groups: Examples of compounds in which ring E is represented by the following formula are given.

[0149] [ka]

[0150] In the above formula, p is as defined above, and the substituent R g The total number of valences is the maximum available In the case of triazines, p is 0, 1 or 2. In one embodiment, ring E is a 5-, 6-, or 7-membered saturated, partially saturated, or unsaturated ring. Fused aryl, carbocyclic or 5-, 6- or 7-membered heterocycle or heteroaryl ring, and ring E optionally contains 1 to 5 R g The group is substituted.

[0151] In some embodiments, Ring E is a 5,6- or 5,5-bicyclic fused ring system. Examples of the compound include compounds of the general formula VI in which ring E is represented by the following formula:

[0152] [ka]

[0153] [ka]

[0154] The fused ring system shown above can be further divided into R g The group may be substituted. In some other interesting embodiments, Ring E is a 6,6- or 6,5-bicyclic fused ring system. Non-limiting examples of such compounds include compounds of general formula VI, in which ring E is can be.

[0155] [ka]

[0156] [ka]

[0157] The fused ring system shown above can be further divided into R g The group may be substituted. A non-limiting example of this type of compound is one in which the substituted ring E is of the formula: Certain compounds of general formula VI are mentioned.

[0158] [ka]

[0159] In some other interesting embodiments, Ring E is a 5-, 6-, or 7-membered saturated, partially saturated, or is an aryl fused with an unsaturated ring, and ring E is 1 to 5 R g substituted by a group Non-limiting examples of this type of compound include compounds of general formula VI in which ring E is Things include:

[0160] [ka]

[0161] Non-limiting examples of this class of compounds include those in which the substituted ring E is of the formula: and compounds of the general formula VI,

[0162] [ka]

[0163] In some embodiments of compounds of formula VI, ring A is a 6-membered heteroaryl. Examples of this class of compounds are those in the above classes and subclasses where ring A is pyridine, ... The compound is an azine, pyridazine, pyrimidine or triazine.

[0164] In yet another embodiment, ring A is a 5-membered heteroaryl. Examples of this type of compound are listed above. In the above classes and subclasses of compounds, ring A is imidazole, pyrazole, tetrazole, These compounds include oxazoles, thiazoles, isoxazoles, and pyrroles.

[0165] Of particular interest is R a is halogen, -P(=O)(R 3 )2, -R 1 , -OR 2 , -NR 1 R 2 , -NR 1 C(O)R 2 , -NR 1 C(O)NR 2 , -C(O)NR 1 R 2 , -C(O)OR 1 , -SO2 NR 1 R 2 , -SO2R 1 , and -NR 1 SO2R 2 A compound of the above type selected from the group consisting of Another interesting subspecies is R a -P(=O)(alkyl)2, alkyl, alkynyl , halogen, aryl, heteroaryl, heterocycle, -O-alkyl (e.g., OMe, etc.) , -CN, -C(O)NH-alkyl, -C(O)NH-aryl, -C(O)NH-heterocycle , -OH, -NR 1 R 2 , -NHS(O)2-alkyl or -NHS(O)2-aryl; The compound is of the following embodiment. a A non-limiting example of is -(CH2)m P(=O)(Me)2, -(CH2) m P(=O)(Et)2, -F, -Cl, -CF3, -OCF3, -(CH2) y C(=O)NR 1 R 2 , -(CH2) y C(=O)aryl, -SO2NR 1 R 2 , -NHSO2R 1 , lower alkyl, -(C H2) y C(=O)heteroaryl, -(CH2) y C(=O) heterocycle, -(CH2) y NHC(=O) R 2 , -(CH2) y NR 1 R 2 , -(CH2) y OR 2 , -(CH2) y SR 2 , -(CH2) y heterocycles, -(CH2) y Aryl, -(CH2) y Heteroaryl, -NH-aryl, -NH-heteroaryl aryl, or -NH heterocycle, where y and m are independently 0, 1, 2, 3, and 4; The alkyl may be selected from linear (i.e., unbranched or acyclic), branched, and cyclic alkyl. and alkyl, aryl, heteroaryl and heterocyclic groups are optionally It may be substituted.

[0166] The present invention also relates to compounds of the general formula VIa:

[0167] [ka]

[0168] During the ceremony, X1 is NR b1 or CR b and X 3 is NR d1 or CR d and X 4 is NR e1 or CR e and Ring A and ring E are each independently selected from aryl or heteroaryl rings, Aryl rings are N, O and S(O) r 5 or more heteroatoms containing 1 to 4 heteroatoms selected from is a six-membered ring; R a , R b , R d , R e and R g is independently halogen, -CN, -NO2 , -R 1 , -OR 2 , -O-NR 1 R 2 , -NR 1 R 2 , -NR 1 -NR 1 R 2 , -NR 1 -OR 2 , -C(O)YR 2 , -OC(O)YR 2 , -NR 1 C(O)YR 2 , -SC(O)YR 2 , -NR 1 C (=S)YR 2 , -OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 1 )YR 2 , -YC(= N-OR 1 )YR 2 , -YC(=N-NR 1 R 2 )YR 2 , -YP(=O)(YR 3 )(YR3 ), -Si (R 3a )3, -NR 1 SO2R 2 , -S(O) r R 2 , -SO2NR 1 R 2 , and -NR 1 SO2NR 1 R 2 or R a and R g are independently chosen -P(=O)(R 3 )2 moiety or as a ring component -P(=O)(R 3 )-part may be or contain a ring system such as R b1 , R d1 and R e1 does not exist; Or, R d , R d1 , R e and R e1 two adjacent substituents or two adjacent R a The moieties, along with the atoms to which they are attached, are N, O, and S(O). r Selected from 0~ Contains four heteroatoms and suitable substituents for heterocycles (see below) (various examples of which are provided in this document) The saturated, partially saturated or may form a fused 5-, 6-, or 7-membered ring of unsaturated rings; R a and R g At least one of the following is -P(=O)(R 3 ) 2 parts or containing or -P(=O)(R 3 )-moiety or a ring system containing nderi; L is O or NH; r is 0, 1 or 2; s is 1, 2, 3, 4 or 5; p is 1, 2, 3 or 4; Each occurrence of Y is independently a single bond, -O-, -S-, or -NR 1 - and; R 1 and R 2 Each occurrence of represents independently H, alkyl, alkenyl, alkynyl, cyclohexyl, alkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, hetero selected from cyclic groups and heteroaryl groups; R 3 Each occurrence of is independently alkyl, alkenyl, alkynyl, or cycloalkyl. , cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic groups and heterocyclic groups. or two adjacent R 3 The parts come together and hold the phosphorus atom may form a ring system containing R 3a Each occurrence of is independently alkyl, alkenyl, alkynyl, cycloalkynyl, or cycloalkyl. aryl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic groups and selected from heteroaryl; Or, each NR 1 R 2 The moieties are N, O and S(O) r 0 to 2 additional heteroatoms selected from containing 5, 6 or more optionally substituted saturated, partially saturated or unsaturated may be a seven-membered ring; The above alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl, Alkynyl, aryl, heteroaryl, and heterocyclic groups are optionally substituted. Good too.

[0169] In some embodiments, compounds of general formula VIA are further defined as follows: (1)X 1 is N;(2)X 3 is N and X 4 is CR e (3)X 3 is CR d So, X 4 is CR e in Yes; (4) X 1 is CR b (5)X 3 is N and X 4 is CR e or (6) X 3 is CR d in, X 4 is CR e is.

[0170] In some particular embodiments of compounds of general formula VIA, X 3 is CR d and R d is Cl , F, C1-C4 alkyl, trihaloalkyl, cycloalkyl, C2-C4 alkenyl, and and alkynyl. In such embodiments, Cl, F, Me, and cyclopropyl are This is a particularly interesting group.

[0171] In another embodiment of the compound of general formula VIA, X 3 is CR d , X 4 is CR e and R d and R e are N, O and S(O) along with the atoms to which they are attached. r Selected from 0 to 4 saturated, partially saturated or unsaturated, containing heteroatoms and may contain up to four substituents The sum of these forms a fused 5-, 6-, or 7-membered ring.

[0172] Of particular interest are compounds of general formula VIA, which encompasses the individual embodiments described above. Examples include when s is 1, 2, 3, or 4 and the substituent R a Each of these is a halogen, - R 1 , -OR 2 , -NR 1 R 2 and -P(=O)(R 3 )2, where each R 1 and R 2 The groups may further include compounds that may be substituted or unsubstituted. , the compound has at least one R a Substituent is -OR 2 where R 2 is C1 C2 to C6 alkyl, C2 to C6 alkenyl, and C2 to C6 alkynyl. In this case, as exemplified in the compounds shown herein, R a The group is often MeO-, EtO- and iPrO- are selected.

[0173] Compounds generally represented by the general formula VIA, including the individual embodiments described above, are Also, at least one R a The substituent is bonded to ring A directly or via an ether bond. , a 5-, 6-, or 7-membered heterocyclic moiety, or a 5- or 6-membered heteroaryl moiety. This R a Substituents include halogen, -CN, -NO2, -R 1 , -OR 2 , -O -NR 1 R 2 , -NR 1 R 2 , -NR 1 -NR 1 R 2 , -NR 1 -OR 2 , -C(O)YR 2, -OC (O)YR 2 , -NR 1 C(O)YR 2 , -SC(O)YR 2 , -NR 1 C(=S)YR 2 , -OC(= S)YR 2 , -C(=S)YR 2 , -YC(=NR 1 )YR 2 , -YC(=N-OR 1 )YR 2 , -Y C(=N-NR 1 R 2 )YR 2 , -YP(=O)(YR 3 )(YR 3 ), -Si(R 3a )3, -NR 1 SO2 R 2 , -S(O) r R 2 , -SO2NR 1 R 2 , and -NR 1 SO2NR 1 R 2 independently selected from and optionally further substituted with 1 to 3 substituents, where each Y is independently a single bond, -O -, -S- or -NR 1 -It is.

[0174] For example, compounds of formula VIA include heterocycles or heteroaryls selected from the following: Substituent R a Examples include those having the following structure.

[0175] [ka]

[0176] [ka]

[0177] Also encompassing the individual embodiments described above, the compounds generally represented by the general formula VIA are The compound also contains at least one substituent R a -P(=O)(R 3 ) 2 parts or Contains, where R 3 is C1-C4 alkyl. .

[0178] Also encompassing the individual embodiments described above, the compounds generally represented by the general formula VIA are The compound also includes compounds in which L is NH, ring E is aryl, and each R g became independent and became Haloge N, -R 1 , -OR 2 , -S(O) r R 2 and -P(=O)(R 3 )2 is selected from the general formula VIA In some embodiments, ring E is in the ortho position relative to the ring atom bonded to L. At least one such R g In another embodiment, the R g The part is tied in L. In yet another embodiment, the R g The part is tied in L. It is in the para position relative to the ring atom to which it is bonded.

[0179] Also encompassing the individual embodiments described above, the compounds generally represented by general formulas VI and VIA are The compound embodiments also include -P(=O)(R 3 ) groups are -P(=O)(CH3)2 and -P(=O)( CH2CH3)2.

[0180] In another embodiment of the compounds of general formula I, two adjacent R a The group is 1 to 4 R f basis This forms a 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring F substituted with The compounds are represented by the following general formula VII:

[0181] [ka]

[0182] In the above formula, ring A, R a , R f , n, X 1 , X 2 , X 3 and X 4 is as defined in general formula I t is 1, 2, 3 or 4, and ring F is a ring selected from 1 to 4 R f substituted with a group It is an aryl, a carbocycle, a 5-, 6- or 7-membered heteroaryl or a heterocycle.

[0183] One class of compounds of particular interest for use in the present invention has the general formula VII, where X 2 is CR c and X 3 is CR d and X 4 is CR e This type of compound is The compounds are represented by the following general formula VIIA:

[0184] [ka]

[0185] In the above formula, ring A, ring F, R a , R f ,t,n,X 1 , R c , R d and R e In general formula VII As already defined in Another class of compounds of further interest is represented by the general formula VIIA, where ring A is phenyl. This class of compounds is exemplified by compounds of the following general formula VIIB: do.

[0186] [ka]

[0187] In the above formula, rings F and R a , R f ,t,n,X 1 , R c , R d and R e is represented in general formula VII It is as stated. In general formulas VII, VIIA and VIIB, ring A and ring F together form a fused ring system. The fused ring systems available for compounds of formula VII, VIIA and VIIB are: Examples of the ring E include, but are not limited to, those shown for ring E of general formula VI (see below) and those shown below. Examples of fused ring systems include:

[0188] [ka]

[0189] These fused ring systems may optionally contain additional R a or R f It may be substituted with a group. I'm interested in R f -P(=O)(R 3 )2 or the general formula VII containing The compound is represented by formula VIIA or VIIB. 3 )2 including R f Examples of It may include, but is not limited to, -(CH2) m P(=O)(R 3 )2, -(CH2) m -NR1 -P(=O)(R 3 )2, -(C H2) m -OP(=O)(R 3 )2, -(CH2) m -NR 1 -(CH2) m -P(=O)(R 3 )2, -(CH2 ) m -NR 1 C(O)O-(CH2) m -P(=O)(R 3 )2, and -(CH2) m -C(O)NR 1 -(CH2 ) m -P(=O)(R 3 )2 (wherein m is 0, 1, 2, 3 or 4), and as a ring component - P(=O)(R 3 )-moiety.

[0190] Another particularly interesting one is R e -P(=O)(R 3 )2 or a compound of general formula V containing The compound is represented by II, VIIA or VIIB. In one embodiment of all the above classes and subclasses of compounds, ring A is one to five R a portion In certain embodiments of all the above classes and subclasses of compounds, wherein ring A is a 6-membered heteroaryl (e.g., pyridine, pyrazine, pyridazine, pyrimidine or triazine ring). In yet another embodiment of all the above classes and subclasses of compounds, wherein ring A is a 5-membered heteroaryl (e.g., imidazole, pyrazole, tetrazole, oxazole, thiazole, isoxazole or pyrrole ring).

[0191] In another embodiment of all the above classes and subclasses of compounds, R a is a halogen, -P(= O)(R 3 )2, -R 1 , -OR 2 , -NR 1 R 2 , -NR 1 C(O)R 2 , -NR 1 C(O)NR 2 ,- C(O)NR 1 R 2 , -C(O)OR 1 , -SO2NR 1 R 2 , -SO2R 1 , and -NR 1 SO2R 2 Selected from.

[0192] Another subclass of interest is the compound of the embodiment just described, where R a -P(=O)(Al alkyl)2, alkyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, -O -Alkyl (e.g., OMe, etc.), -CN, -C(O)NH-alkyl, -C(O)NH-aryl -C(O)NH-heterocycle, -OH, -NR 1 R 2 , -NHS(O)2-alkyl, or -NHS(O)2-aryl. a A non-limiting example of -(CH2) m P( =O)(Me)2, -(CH2) m P(=O)(Et)2, -F, -Cl, -CF3, -OCF3, -(C H2) y C(=O)NR 1 R 2 , -(CH2) y C(=O)aryl, -SO2NR 1 R 2 , -NHSO2 R 1 , lower alkyl, -(CH2) y C(=O)heteroaryl, -(CH2) yC(=O) heterocycle , -(CH2) y NHC(=O)R 2 , -(CH2) y NR 1 R 2 , -(CH2) y OR 2 , -(CH2) y SR 2 , -(CH2) y Heterocycle, -(CH2) y Aryl, -(CH2) y Heteroaryl, -NH-a and -NH-heteroaryl, -NH-heteroaryl, and -NH-heterocycle, where y and m are independently The numbers are selected from 0, 1, 2, 3 and 4.

[0193] In yet another embodiment of all the above classes and subclasses of compounds, R a is -P(=O)(Al Kill)2, -(CH2) 1-2 P(=O)(alkyl)2, -O-lower alkyl (e.g., OMe, etc.), Lower alkyl (e.g., methyl, ethyl, cyclopropyl, etc.), halogen, -CF3, -O From CF3, -CN, -NH(alkyl), alkenyl and alkynyl (e.g., acetylene) Be chosen.

[0194] R a Specific examples of the phenyl moiety substituted with include, but are not limited to, the following phenyl moieties: minutes are exemplified.

[0195] [ka]

[0196] [ka]

[0197] In any of the above classes and subclasses of compounds, R a is -(CH2) m P(= O)(R 3 )2, -(CH2) m -NR 1 -P(=O)(R 3 )2, -(CH2) m -OP(=O)(R 3 )2,- (CH2) m -NR 1 -(CH2) m -P(=O)(R 3 )2, -(CH2) m -NR 1 C(O)O-(CH2) m - P(=O)(R 3 )2, and -(CH2) m -C(O)NR 1 -(CH2) m -P(=O)(R 3 )2 selected , where m is 0, 1, 2, 3, or 4. Alternatively, R a is one of the parts shown in the following formula minutes.

[0198] [ka]

[0199] For these and other classes and subclasses of the present invention, compounds of interest include: Especially R a One of them is -P(=O)(R 3 )2 or compounds containing it. -P(=O)(R 3 )2 including R a Examples of the group include, but are not limited to, -(CH2) m P(=O)(R 3 ) 2, -(CH2) m -NR 1 -P(=O)(R 3)2, -(CH2) m -OP(=O)(R 3 )2, -(CH2) m -NR 1 -(CH2) m -P(=O)(R 3 )2, -(CH2) m -NR 1 C(O)O-(CH2) m -P(=O) (R 3 )2, and -(CH2) m -C(O)NR 1 -(CH2) m -P(=O)(R 3 )2 (wherein m is 0, 1 , 2, 3 or 4), as well as cyclic structures containing -P(=O) as shown above. Of particular interest at present are compounds of formula Ia or VIa in which ring A is phenyl. , X 1 is N, n is 0, s is 2, p is 1, R e is H, and R d is halogen (e.g., F, Cl) , lower alkyl (e.g., methyl, ethyl, isopropyl, etc.), cyano, nitro, alkoxy methyl (e.g., methoxy) or CF3, and one of the R a -P(=O)(R 3 )2 or This includes the other R a is lower alkyl, halogen, cyano and alkoxy (e.g., methoxy ), and R g is a compound that is -S(O)2 alkyl.

[0200] Another compound of particular interest for use in the present invention is a compound of formula IIIA in which ring A is phenyl. A non-limiting example of this subclass of compounds is a compound having the formula: It is a compound that can be

[0201] [ka]

[0202] Of particular interest for use in the present invention are compounds of general formula IIIA where R a One of them is -P(= O)(R 3 )2 or containing it (e.g., -CH2P(=O)Me2, -P(=O)Me2, -P(=O)Et2, -OP(=O)Me2, -NHP(=O)Me2, -NHCH2P(=O)Et 2, etc.) compounds. Of particular interest at present are compounds in this subclass, such as X 1 is N, n is 0, R e is H, and R f is alkyl, H, aryl, heteroaryl, heterocycle, halogen (e.g., F, Cl), NHR 1 , OR 2 , CF3, SO2-lower alkyl (e.g., SO2-iP r, etc.), SO2NR 1 R 2 and C(O)NR 1 R 2 The compound is selected from the group consisting of:

[0203] Other compounds of interest include, inter alia, those of general formula IIIA in which R f Ga-(CH2) m P( =O) (alkyl)2 (e.g., -CH2P(=O)Me2, -P(=O)Me2, -P(=O)Et2, etc. Of particular interest at present are compounds in this subclass where X 1 but N, n is 0, R a is methoxy, and R e is a compound where

[0204] Other compounds of interest include, inter alia, those of the classes and subclasses of compounds already mentioned. , R dis H, halogen (e.g., chloro, fluoro, bromo), -CF3, optionally substituted optionally lower alkyl groups (e.g., methyl, ethyl, isopropyl, cyclopropyl, etc.); ), -CN, optionally substituted acetylene, -NO2, -O-alkyl, -S-alkyl, -C(=O)alkyl, -NH-alkyl and -C(=O)N(alkyl) Of more interest are compounds selected from R d is halogen or CF3 This type of compound.

[0205] Other compounds of interest include, inter alia, compounds of the general formulae I and IA and the types and classes already mentioned. In the subclass of compounds, R e are halogen, -CN, -NO2, -R 1 , -OR 2 , -ON R 1 R 2 , -C(O)YR 2 , -OC(O)YR 2 , -SC(O)YR 2 , -NR 1 C(=S)YR 2 , -OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 1 )YR 2 , -YC(=N-OR 1 )Y R 2 , -YC(=N-NR 1 R 2 )YR 2 Compounds selected from the following are also of interest: In this type, R e is H, CN, NO2, lower alkyl or halogen where R 1 , R 2 and Y are as defined in general formula I. I'm interested in Re is a compound selected from H, lower alkyl, and halogen.

[0206] Compounds of the invention of particular interest include those having one or more of the following properties: Can be: Molecular weight less than 1000 mass units, preferably less than 750, more preferably less than 600 (The weight of solvated or co-deposited molecular species, and the weight of salts) (excluding the weight of the on-board); or Wild-type or mutant (especially clinically relevant mutant) kinases, especially ALK and Met , Jak2, bRaf, EGFR, Tie-2, FLT3 or other kinases of interest The inhibitory activity of a kinase is expressed as an IC (measured using any scientifically accepted kinase inhibition assay). The IC50 value is preferably 500 nM or better, and the IC50 value is preferably 1 μM or less. Preferably, the IC50 value is 250 nM or better; or The IC50 value of inhibitory activity against a specific kinase is used to determine the IC50 value of inhibitory activity against other kinases of interest. at least 100-fold lower than its IC50 value; or The IC50 values ​​of inhibitory activity against ALK, Met, Jak2, or b-Raf were or 1 μM or better; - Cancer cell lines maintained in vitro or other scientifically accepted cancer cell lines Cytotoxic or cell growth inhibitory effects in animal studies using seed explant models (especially Preferred are Ba / F3 NMP-ALK, Ba / F3 EML4-ALK, Karpas 299 and / or SU-DHL-1 cells. The efficacy of known ALK inhibitors, such as NVP-TAE684 and PF2341066, in inhibiting the proliferation of The efficacy of the agent is at least as high as, and preferably as high as, a known at least twice the potency of an ALK inhibitor, more preferably less than the potency of a known ALK inhibitor (The compounds of the present invention are both 10 times more potent.)

[0207] Also provided is at least one compound of the invention or a salt, hydrate or Compositions containing other solvates and at least one pharmaceutically acceptable excipient or additive Such compositions are intended to inhibit the growth, development and / or metastasis of cancer. In a broader sense, the compounds of the present invention are mediated by one or more kinases that are inhibited by the compounds of the present invention. For the treatment and prevention of diseases or undesirable symptoms (conditions) to individuals in need thereof "Cancer" refers to solid tumors (e.g., prostate cancer, colon cancer, etc.) pancreatic cancer, ovarian cancer, breast cancer, non-small cell lung cancer (NSCLS), glioblastoma, Nerve tumors such as neuroblastoma, esophageal cancer, soft tissue cancers such as rhabdomyosarcoma); undifferentiated large intestine A variety of non-Hodgkin's lymphoma (NHL)-like forms called ALCL lymphomas; various forms of leukemia; and those resistant to treatment with other kinase inhibitors. This includes cancers that are resistant to other treatments, including cancers that are resistant to other treatments.

[0208] The present invention also relates to a method for treating cancer, which method comprises treating a solid tumor or tumors in a recipient. inhibiting, slowing or preventing the growth, development or spread of cancer, including other forms of cancer such as leukemia For reversal, a therapeutically effective amount of a compound of the present invention is administered to a human or animal in need thereof. (As a monotherapy, or in combination with one or more other anticancer drugs, one or more side effects) Such administration includes administration of the compounds disclosed herein in combination with other therapeutic agents, such as steroids, anti-inflammatory drugs, radiation, etc. One or more kinases inhibited by one of the compounds or a pharmaceutically acceptable derivative thereof The "administration" of the compounds of the present invention is a method for treating or preventing diseases mediated by the Compounds of the type described herein or compounds of the present invention may be administered using any suitable formulation or route of administration, such as delivering a prodrug or other pharmaceutically acceptable derivative thereof to the recipient Typically, the compounds are administered at least once a month, often at least once a week, e.g., daily. Oral and intravenous administration is currently of particular interest. Route of administration.

[0209] As used herein, "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable derivative of such a compound. or a salt, ester, or salt of such an ester, or any other addition product or derivative thereof. When administered to a patient, the compounds described herein act pharmacologically as kinase inhibitors. The activity of the enzyme can directly or indirectly provide its metabolic products (MW>300). Pharmaceutically acceptable derivatives therefore include, inter alia, prodrugs. A prodrug is a derivative of a desired compound that contains an additional moiety that is easily removed in vivo. This removal yields the parent molecule, which is the pharmacologically active species, usually the one with the most pharmacological activity. An example of a prodrug is a compound that is cleaved in vivo to release the target compound. Prodrugs of various compounds, as well as esters of the parent compounds, are available. Materials and methods for derivatizing to make prodrugs are known and are not applicable to the present invention. It can be done.

[0210] Particularly preferred derivatives and prodrugs of the parent compound have properties that are easier to administer to mammals than the parent compound. Increase the bioavailability of a compound when administered (e.g., increase absorption into the blood after oral administration) by increasing the size of the target molecule or by delivering it to a target biological site (e.g., the brain or lymphatic system) Preferred prodrugs are derivatives and prodrugs that increase the activity of the parent compound. Derivatives of the compounds of the present invention that have increased water solubility or active transport across the intestinal membrane compared to can be done.

[0211] One important aspect of the present invention is the administration of a therapeutically effective amount of a composition containing a compound of the present invention to a patient receiving a therapeutic and administering to said individual a compound selected from the group consisting of: The method may be performed in combination with one or more other cancer treatments. Surgery, radiation therapy (e.g., gamma ray, neutron beam radiation therapy, electron beam radiation therapy, proton beam radiation therapy) , brachytherapy, and whole-body radioisotope therapy), endocrine therapy, biological response modifiers (e.g., ibuprofen, interferon, interleukins, and, to a lesser extent, tumor necrosis factor (TNF), These include heat therapy, cold therapy, side effect reducers (e.g., antiemetics), and other cancer chemotherapy drugs. The other drug may be administered in the same or different formulation, route of administration, and other manner as used with the compound of the present invention. The compounds may be administered using any suitable dosing regimen.

[0212] Such other drugs include, but are not limited to, one or more of the following: Anticancer alkylating or intercalating agents (e.g., mechlorethamine, chlorambucil, cyclophosphamide, melphalan, and ifosfamide); purine or pyrimidine antagonists (e.g., 6-mercaptobenzothiazolinone); captopurine, 5-fluorouracil, cytarabine, and gemcitabine); spindle poisons (e.g., , vinblastine, vincristine, vinorelbine and paclitaxel); podophyllotoxin anticoagulants (e.g., etoposide, irinotecan, topotecan); antibiotics (e.g., doxorubicin , bleomycin, and mitomycin); nitrosoureas (e.g., carmustine, lomustine inorganic ions (e.g., cisplatin, carboplatin, oxaliplatin, or oxyplatin); Platinum; enzymes (e.g., asparaginase); hormones (e.g., tamoxifen, leuprolide, thiazolidine, flutamide, and megestrol; mTOR inhibitors (e.g., sirolimus (rapamycin) Temsirolimus (CCI779), Everolimus (RAD001), AP2357 3 or other compounds disclosed in U.S. Pat. No. 7,091,213); proteasome inhibitors (e.g., Velcade, other proteasome inhibitors (see, e.g., WO 02 / 096933) or other NF-kB Inhibitors (e.g., including lkK inhibitors): Other kinase inhibitors (e.g., inhibitors of the following kinases): : Src, BRC / Abl, kdr, flt3, Aurora 2, glycogen synthase kinase 3 (GSK-3), EGF-R kinase (e.g., Iressa, Tarceva, etc.), VEGF-R kinase kinase, PDGF-R kinase, etc.); antibodies against receptors or hormones involved in cancer; Soluble receptor or other receptor antagonists (EGFR, ErbB2, VEGFR, PDGFR, and receptors such as IGF-R; and drugs such as Herceptin, Avastin, and Erbitux. For a more comprehensive explanation of the latest cancer treatments, see http: / / www. nci.nih.gov / and a list of FDA-approved oncology drugs can be found at http: / / www.fda. gov / cder / cancer / druglistframe.htm and The Merck Manual, 17th Edition, 1999, the entire contents of which are incorporated herein by reference.

[0213] Examples of other therapeutic agents are described elsewhere herein, among others, Zyloprim, Alemtuzumab, altretamine, amifostine, nastrozole, prostate-specific membrane antigen Original antibodies (MLN-591, MLN591RL, MLN2704, etc.), arsenic trioxide, Bexarotene, bleomycin, busulfan, capecitabine, Gliadel wafer, Celecoxib, chlorambucil, cisplatin-epinephrine gel, cladribine, Posomal cytarabine, liposomal daunorubicin, daunorubicin, daunomycin , dexrazoxane, docetaxel, doxorubicin, Elliot's B solution, epirubicin, Estramustine, etoposide phosphate, etoposide, exemestane, fludarabine, 5 -FU, fulvestrant, gemcitabine, gemtuzumab-ozogamicin, gosserely acetate hydroxyurea, idarubicin, idamycin, ifosfamide, imatinib mesylate, irinotecan (or antibodies such as MLN576 (XR11576) other topoisomerase inhibitors, including letrozole, leucovorin, Levamisole, liposomal daunorubicin, melphalan, L-PAM, mesna, Thotrexate, methoxsalen, mitomycin C, mitoxantrone, and MLN518 are also or MLN608 (or other inhibitors of the flt-3 receptor tyrosine kinase, PDF GR or c kit), itoxantrone, paclitaxel, pegademase, pentostaphylococcus aureus Chin, profimer sodium, rituximab (Rituxan<registered trademark>), talc, Tamoxifen, temozolamide, teniposide, VM-26, topotecan, toremifene, 2C4 (or other antibodies that block HER2-mediated signaling), tretinoin, ATRA , valrubicin, vinorelbine, or pamidronate, zoledronate or other bisphosphonates Examples include phonates.

[0214] The present invention further provides a method for the preparation of compounds of formula I, Ia, II, IIa, III, Indicated by IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa and VIIb The present invention further encompasses the preparation of compounds of the present invention, or any other compounds according to the present invention.

[0215] The present invention also relates to cancer (including primary or metastatic lymphoma and solid tumors, as defined herein). Cancers including those described above that are resistant or have progressed to one or more other treatments a compound of the invention or The compounds of the present invention are useful in the manufacture of anti-cancer drugs. The compounds of the present invention may also be used to treat ALK, jak2, b-raf, met, Tie- 2. One or more kinases such as EGFR, FLT3, FAK, Pim-1, and P13k The present invention may also be useful in the manufacture of a medicament for alleviating or preventing a disease (abnormality) by inhibiting enzymes.

[0216] The present invention further provides a method for treating a rheumatoid arthritis, preferably comprising administering to a patient a therapeutically effective amount of a compound of the present invention (especially any of the compounds described above). at least one compound of the above general formula (including compounds of any class or subclass of compounds, including compounds of any of the above general formulas) Compositions containing the compound in combination with at least one pharmaceutically acceptable carrier, excipient, or diluent are also contemplated. It also includes:

[0217] The compounds of the present invention also inhibit various kinases, including but not limited to ALK, Met, and α-kinases. Characterization of various kinases including ak2, b-raf, Tie-2, EGFR, and FLT3 and to study the role of such kinases in biological and pathological phenomena. For this purpose, novel kinases have been developed to study the intracellular signal transduction pathways mediated by such kinases. For comparative evaluation of enzyme inhibitors and for studies of various cancers in cell lines and animal models It may also be useful as a standard and reagent for

[0218] 3.Definition For the purposes of reading this document, the following information and definitions apply unless otherwise indicated. The term "alkyl" refers to straight-chain (i.e., unbranched or acyclic), branched, cyclic, or polycyclic alkyl groups. is meant to include non-aromatic hydrocarbon groups of the formula, optionally substituted with one or more functional groups Unless otherwise specified, the alkyl group may be 1 to 8, preferably 1 to 6. Contains carbon atoms of C 1-6 Alkyl means C1, C2, C3, C4, C5, and C6 alkyl The term "lower alkyl" means an alkyl having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl. , cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, Pentyl, isopentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, The alkyl may be substituted or unsubstituted. Examples of alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, Trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, phenethyl , substituted phenethyl, and the like.

[0219] The term "alkoxy" means an alkyl group, as defined above, having the designated number of carbon atoms, containing an oxygen bridge. represents a subset of alkyl attached via an -O-alkyl group. For example, "alkoxy" refers to an -O-alkyl group. means a group, wherein the alkyl group contains from 1 to 8 carbon atoms in a straight, branched, or cyclic configuration. Examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, n-propyl, and propyl. Examples include propoxy, i-propoxy, t-butoxy, n-butoxy, and s-pentoxy. can be.

[0220] "Haloalkyl" refers to branched and straight-chain alkyl groups in which one or more carbons are substituted with halogen. Examples of haloalkyl include, but are not limited to, Examples include trifluoromethyl, trichloromethyl, and pentafluoroethyl. do.

[0221] The term "alkenyl" refers to any one of a number of possible alkyl groups at any stable point along a carbon chain or ring. or containing hydrocarbon chains in linear, branched or cyclic form with two or more unsaturated carbon-carbon bonds. Unless otherwise specified, "alkenyl" usually refers to groups having 2 to 8 carbon atoms, often It means a group having 2 to 6 carbon atoms. For example, "alkenyl" means prop-2-enyl, but- 2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, It can mean hex-5-enyl, 2,3-dimethylbut-2-enyl, etc. The phenyl group can be substituted or unsubstituted.

[0222] The term "alkynyl" refers to one or two possible alkyl groups at any stable point along the carbon chain. A hydrocarbon chain, either linear or branched, having one or more unsaturated carbon-carbon triple bonds. Unless otherwise specified, "alkynyl" groups have 2 to 8 carbon atoms, preferably Examples of "alkynyl" include, but are not limited to, protons, arginines, arginines, and the like. 2-butynyl, 2-butynyl, 3-butynyl, pent-2-ynyl, 3-methyl Examples include rupent-4-ynyl, hex-2-ynyl, and hex-5-ynyl. , an alkynyl group can be substituted or unsubstituted.

[0223] Cycloalkyl is a subgroup of alkyl, and is a stable saturated alkyl group with 3 to 13 carbon atoms. It includes any cyclic or polycyclic hydrocarbon group. Examples of such cycloalkyls include: including but not limited to cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, etc., which, like other alkyl groups, The term "cycloalkyl" is used interchangeably with the term "carbocycle" (carbon may be used interchangeably with heterocyclic ring).

[0224] Cycloalkenyl is a subset of alkenyl, which can be any position along the ring. A stable olefin having 3 to 13 carbon atoms, preferably 5 to 8 carbon atoms, containing one or more carbon-carbon double bonds. Examples of such cycloalkenyl groups include any cyclic or polycyclic hydrocarbon group. Examples of cyclohexenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

[0225] Cycloalkynyl is a subset of alkynyl, which can be substituted at any point along the ring. Any stable cyclic or polycyclic compound having 5 to 13 carbon atoms and containing one or more carbon-carbon triple bonds. As with other alkenyl and alkynyl groups, cycloaliphatic hydrocarbon groups are also included. The alkyl and cycloalkenyl may be optionally substituted.

[0226] The term "heteroalkyl" refers to any group independently selected from the group consisting of N, O, S, and P. Branched or unbranched alkyl groups having 1 to 7 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms. Heteroalkyl refers to an alkyl, alkenyl, or alkynyl group. However, tertiary amines, secondary amines, ethers, thioethers, amides, and thioamides are not , carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoryl amides, sulfonamides, and disulfides. Heteroalkyl is optionally More preferably, each ring may be a monocyclic, bicyclic or tricyclic ring, each of which is a 3- to 6-membered ring. The alkyl group may be substituted or unsubstituted. Examples of heteroalkyl include, but are not limited to, However, examples include polyethers such as methoxymethyl and ethoxyethyl.

[0227] As used herein, the terms "heterocycle" (= heterocyclic ring), "heterocyclyl" or "heterocyclic " means that one or more, preferably 1 to 4, ring carbon atoms are substituted with a heteroatom such as N, O, or S. Hetero refers to a non-aromatic ring system having 5 to 14 ring atoms, each of which is substituted by The ring group may be substituted or unsubstituted and may contain 1, 2 or 3 fused or unfused rings. Non-limiting examples of heterocycles include 3-1H-benzimidazoline systems. 2-Oxo-benzimidazol-3-yl, (1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydro Furanyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydro thiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomo morpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolidinyl Diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl, benzopyranyl benzothiazinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl and benzothiazinyl Heterocyclic groups can contain two or more of the ring systems listed above. Also included within the term "heterocycle" or "heterocyclic" group as used are indolinyl, non-aromatic heterocyclic groups such as chromanyl, phenanthridinyl, or tetrahydroquinolinyl; A group in which an atom-containing ring is fused to one or more aromatic or non-aromatic rings, That is, a group in which the bonding position is on a non-aromatic heteroatom-containing ring. "Cyclic" or "heterocyclic" groups, whether saturated or partially unsaturated, are also included. means a ring optionally substituted by:

[0228] The term "aryl" may be used alone or in combination with "aralkyl," "aralkoxy," Used as part of a larger group, such as "aryloxy" or "aryloxyalkyl" However, all of them are phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. "Aryl" refers to an aromatic ring group having 6 to 14 ring atoms, such as aryl. or may contain two or more substituents. The term "aryl" is interchangeable with the term "aryl ring." "Aryl" can also refer to an aromatic ring fused to one or more rings. Fused polycyclic aromatic ring systems are also included. Non-limiting examples of useful aryl ring groups include phenyl, Hydroxyphenyl, halophenyl, alkoxyphenyl, dialkoxyphenyl, triphenyl Alkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl, ant aryl, phenanthro, etc., as well as 1-naphthyl, 2-naphthyl, 1-anthracyl and 2 Also included within the scope of the term "aryl" as used herein are aryl-anthracyls, ... and aryl-anthracyls. The aromatic ring is indanyl, phenanthridinyl or tetrahydronaphthyl. A group fused to one or more non-aromatic rings, in which the base or bonding point is on the aromatic ring. It is something.

[0229] As used herein, the term "heteroaryl" refers to a stable heterocyclic ring having from 5 to 14 ring atoms. and polyheterocyclic aromatic groups. Heteroaryl groups can be substituted or unsubstituted, It may contain one or more rings. Representative examples of heteroaryl ring groups include thienyl, phenyl ... Loryl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxa Five-membered monocyclic groups such as zolyl and thiazolyl; pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl six-membered monocyclic groups such as benzo[b]thienyl, naphtho[2,3-b]thienyl, and triazinyl; thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathione Enyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, iso quinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, Benzothiazole, benzimidazole, tetrahydroquinoline, cinnolinyl, pteryl dinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimine phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, phen and polycyclic heterocyclic groups such as benzoxazinyl (e.g., Katritzky heterocyclic chemistry handbook). (See Handbook of Heterocyclic Chemistry).

[0230] Further examples of heteroaryl ring groups include 2-furanyl, 3-furanyl, N-isopropyl, and 2-isopropyl. Midazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxa 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-isoxazolyl Oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrroly 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4- Thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl , 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, Benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl , acridinyl or benzisoxazolyl.

[0231] Heteroaryl groups further include heteroaromatic rings joined to one or more aromatic or non-aromatic rings. Also included are fused groups in which the base or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinoline, tetrahydroisoquinoline, and pyrido[3,4 -d]pyrimidinyl, imidazo[1,2-a]pyrimidyl, imidazo[1,2-a]pyrazinyl , imidazo[1,2-a]pyridinyl, imidazo[1,2-c]pyrimidyl, pyrazolo[1,5- a][1,3,5]triazinyl, pyrazolo[1,5-c]pyrimidyl, imidazo[1,2-b]pyrimidyl Ridazinyl, imidazo[1,5-a]pyrimidyl, pyrazolo[1,5-b][1,2,4]triazinyl quinolyl, isoquinolyl, quinoxalyl, imidazotriazinyl, pyrrolo[2,3d] Examples of heteroaryl include pyrimidyl, triazolopyrimidyl, and pyridopyrazinyl. The term "heteroaryl" also refers to groups that are optionally substituted. may be used interchangeably with the terms "heteroaryl ring" or "heteroaromatic."

[0232] Aryl groups (aralkyl, aralkoxy, or aryloxyalkyl groups) a heteroaryl group (including heteroaryl moieties) or a heteroaryl group (heteroaralkyl or heteroarylalkyl) The heteroaryl moiety (including heteroaryl moieties such as alkoxy) may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group include: Halogen (F, Cl, Br or I), alkyl, alkenyl, alkynyl, heteroalkynyl Lu, -CN, -R 1 , -OR 2 , -S(O) r R 2 , (where r is an integer of 0, 1 or 2), -S O2NR 1 R 2 , -NR 1 R 2 , -O-NR 1 R 2 , -NR 1 -NR 1 R 2 , -(CO)YR2 , -O( CO)YR 2 , -NR 1 (CO)YR 2 , -S(CO)YR 2 , -NR 1 C(=S)YR 2 , -OC(= S)YR 2 , -C(=S)YR 2 where each Y is independently - O-, -S-, -NR 1 - or a single chemical bond, thus -(CO)YR 2 is -C(= O)R 2 , -C(=O)OR 2 and -C(=O)NR 1 R 2 Additional substituents include: -YC(=NR 1 )YR 2 , -YC(=NOR 1 )YR 2 , -YC(=N-NR 1 R 2 )YR 2 , -C OCOR 2 , -COMCOR 2 (wherein M is an alkyl group having 1 to 6 carbon atoms), YP(=O)(Y R 3 )(YR 3 )(In particular, -P(=O)(R 3 )2), -Si(R 3a )3, -NO2, -NR 1 SO2R 2 , and -NR 1 SO2NR 1 R 2 Further, when Y is -NR 1 in Certain substituents therefore include, inter alia, -NR 1 C(=O)R 2 , -NR 1 C(=O)NR 1 R 2, -NR 1 C(=O)OR 2 , and -NR 1 C(=NH)NR 1 R 2 Examples include:

[0233] R 3 The substituents may be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or R is selected from the group consisting of aryl, cycloalkynyl, aryl, heteroaryl, and heterocyclic groups; 1 and R 2 The substituents, each occurring independently, are hydrogen, alkyl, alkenyl, alkynyl, Cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic groups, R 1 , R 2 , and R 3 The substituents may themselves be substituted. May be unsubstituted. R 1 , R 2 and R 3 Examples of possible substituents on the above include, inter alia, amino, Alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, aryl , heteroalkyl, heteroaryl, carbocyclic group, heterocyclic group, alkylaminocarbonyl , dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyl carbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl Further examples include alkoxy, hydroxyl, alkoxy, and haloalkoxy groups. and protected OH (e.g., acyloxy), phenyl, substituted phenyl, -O-phenyl, -O- (Substituted) phenyl, benzyl, substituted benzyl, -O-phenethyl (e.g., -OCH2CH2C6 H5), -O-(substituted)phenethyl.

[0234] replacement R1 , R 2 , or R 3 Non-limiting examples of groups include haloalkyl and trihaloalkyl. -M-aryl, alkoxyalkyl, halophenyl, -M-heteroaryl, -M-heterocyclic group, - M-aryl, -M-OR 2 , -M-SR 2 , -M-NR 1 R 2 , -M-OC(O)NR 1 R 2 , -MC(=NR 2 )NR 1 R 2 , -MC(=NR 1 ) OR 3 , -MP(=O)(R 3 )2, -Si( R 3a )3, -M-NR 1 C(O)R 2 , -M-NR 1 C(O)OR 2 , -MC(O)R 2 , -MC( =S)R 2 , -MC(=S)NR 1 R 2 , -MC(O)NR 1 R 2 , -MC(O)NR 2 -M- NR 1 R 2 , -M-NR 2 C(NR 1 )NR 1 R 2 , -M-NR 1 C(S)NR 1 R 2 , -MS(O)2 R 1 , -MC(O)R 1 , -M-OC(O)R 1 , -MC(O)SR 2 , -MS(O)2NR 1 R 2 , -C(O)-MC(O)R 2 , -MCO2R2 , -MC(=O)NR 1 R 2 , -MC(=NH) NR 1 R 2 and -M-OC(=NH)NR 1 R 2 (wherein M is an alkyl group having 1 to 6 carbon atoms) Examples include:

[0235] Some of the more specific examples include, but are not limited to, chloromethyl, trichloromethyl, Methyl, trifluoromethyl, methoxyethyl, alkoxyphenyl, halophenyl, - CH2-aryl, -CH2-heterocycle, -CH2C(O)NH2, -C(O)CH2N(CH3)2 , -CH2CH2OH, -CH2OC(O)NH2, -CH2CH2NH2, -CH2CH2CH2N Et2, -CH2OCH3, -C(O)NH2, -CH2CH2-heterocycle, -C(=S)CH3, -C(=S)NH2, -C(=NH)NH2, -C(=NH)OEt, -C(O)NH-cyclopro Pyr, C(O)NHCH2CH2-heterocycle, -C(O)NHCH2CH2OCH3, -C(O)C H2CH2NHCH3, -CH2CH2F, -C(O)CH2-heterocycle, -CH2C(O)NHC H3, -CH2CH2P(=O)(CH3)2, Si(CH3)3, etc.

[0236] The ring system (e.g., cycloalkyl, heterocycle, aryl, or heteroaryl) is specifically defined. If the group is substituted with several substituents which may vary within the ranges given, the total number of substituents will of course be Therefore, for example, n A phenyl ring substituted with 1 to 5 substituents (n is in the range of 1 to 5) has 1 to 5 substituents. whereas in a pyridinyl ring substituted with n substituents, the number of substituents can be 1 to 1. Naturally, the number of substituents that a group in the compound of the present invention may have is 4. The maximum number of can be easily determined.

[0237] Alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, silyl A cycloalkyl, cycloalkenyl, cycloalkynyl group or a non-aromatic heterocyclic group may also be used. Thus, it may contain one or more substituents. Examples of suitable substituents which may be present on such groups include: Examples include, but are not limited to, substituents on carbon atoms of aryl or heteroaryl groups. In addition, the following substituents may be used for saturated carbon atoms: Also included are: =O, =S, =NH, =NNR 2 R 3 , =NNHC(O)R 2 , =NNHCO2 R 2 , or =NNHSO2R 2 where R 2 and R 3 is independently hydrogen, a alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl The alkyl group is a aryl, heteroalkyl, aryl, heteroaryl or heterocyclic group.

[0238] Representative examples of substituents on the aliphatic, heteroaliphatic or heterocyclic groups include amino, alkyl, Amino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl carbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkyl Aminocarbonyloxy, alkoxy, nitro, -CN, carboxy, alkoxycarbonyl Examples include -nyl, alkylcarbonyl, -OH, haloalkoxy or haloalkyl groups.

[0239] For example, examples of substituents on a nitrogen in a heteroaryl or non-aromatic heterocycle include: -R 1 , -NR 1 R 2 , -C(=O)R 2 , -C(=O)OR 2 , -C(=O)SR 2 , -C(=O)N R 1 R 2 , -C(=NR 2 )NR 1 R 2 , -C(=NR 2 ) OR 2 , -C(=NR 1 )R 3 , -COCO R 2 , -COMCOR 2 , -CN, -SO2R 2 , -S(O)R 2 , -P(=O)(YR 3 )(YR 3 ) , -NR 1 SO2R 2 and -NR 1 SO2NR 1 R 2 Here, R 3 Every time it appears independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, selected from cycloalkynyl, aryl, heteroaryl and heterocyclic groups; R 1 and R 2 teeth , each occurrence independently represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocycle is selected from the group.

[0240] The ring system (e.g., cycloalkyl, heterocycle, aryl, or heteroaryl) is specifically defined. If the group is substituted with several substituents which may vary within the ranges specified, the total number of substituents will of course be , the number of valences available under the conditions of the compound is not exceeded. For example, A phenyl ring substituted with a group (where m is in the range of 0 to 5) has 0 to 5 substituents. The number of substituents in a pyridinyl ring substituted with m substituents is, of course, Therefore, the number of substituents that a group in the compound of the present invention may have is in the range of 0 to 4. The maximum number of can be easily determined.

[0241] Some compounds of the present invention may exist in tautomeric forms. and includes all such tautomeric forms of these compounds. Unless otherwise indicated, the structures depicted herein represent all stereochemical forms of the structure, i.e. That is, it includes both the R and S configurations for each asymmetric center. The single stereochemical isomers of the compounds as well as the enantiomeric mixtures and diastereomeric mixtures Mixtures of stereoisomers are within the scope of the present invention, i.e., the present invention does not substantially contain other isomers. Each diastereomer or enantiomer (more than 90% on a molar basis, preferred) is free or more than 95% free of other stereoisomers), as well as mixtures of such isomers. do.

[0242] by resolution of the racemic mixture according to conventional methods, for example by formation of diastereoisomeric salts, or Specific optical isomers can be obtained by treatment with optically active acids or bases. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and and camphorsulfonic acid, which is then crystallized to form a mixture of diastereoisomers. After separation of the optical isomers, the optically active bases are liberated from these salts. The method is a chiral chromatographic technique optimally selected to maximize the separation of the enantiomers. Yet another method involves the use of a photocatalytic column to detect the activated form of the compounds of the invention. Covalent diaste- ranges are obtained by reacting them with optically pure acids or optically pure isocyanates. This is a method for synthesizing diastereoisomeric molecules. The synthesized diastereoisomers are The enantiomers are separated by conventional means such as filtration, distillation, crystallization or sublimation, followed by hydrolysis to give the enantiomers. Thiomerically pure compounds can be liberated.

[0243] The optically active compounds of the present invention can also be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. The compounds of the present invention may also exist in radiolabeled (radioisotope-labeled) form. That is, the compound has an atomic mass or mass number that is different from that normally found in nature. It may contain one or more atoms having a molecular weight of hydrogen, carbon, phosphorus, fluorine and salts. The basic radioactive isotopes are 3 H, 14 C. 32 P, 35 S, 18 F, and 36 Cl mentioned The present invention, which contains such radioisotopes and / or other radioisotopes of other atoms, The clear compounds are also within the scope of the present invention. 3 H) and carbon-14 (i.e., 14 C ) is a particularly preferred radioisotope because of its ease of preparation and detectability.

[0244] The radiolabeled compounds of the present invention can generally be prepared by methods well known to those skilled in the art. Advantageously, such radiolabeled compounds are readily available in place of non-radiolabeled reagents. By carrying out the synthetic procedures disclosed herein, except for using radiolabeling reagents that can be used, It can be manufactured more efficiently.

[0245] 4. Synthesis Overview Those skilled in the art will recognize that R a , R b , R c , R d , R e , R b1 , R c1 , R d1 , R e1 , R f , R g , and ring The compounds of the present invention include compounds containing various options of A, B, C, D, E, and F. This document provides guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis, recovery, and characterization of hydroxybenzoates. Regarding heterocycles and other related compounds, which may be used in combination with the information contained in the examples below, There is a well-established literature on chemical conversion, recovery and purification techniques for these processes.

[0246] The compounds described herein can be synthesized using a variety of synthetic methods, including those illustrated in the reaction schemes below. Those skilled in the art will recognize that protecting groups may be used in these procedures. It is understood that a "protecting group" is a group that protects potentially reactive sites in a multifunctional compound. Temporarily inhibits chemical reactions with (e.g., amines, hydroxyls, thiols, aldehydes, etc.) , a moiety (group) used to allow a reaction to take place selectively at another site In a preferred embodiment, the protecting group is selected to yield a protecting substituent suitable for the intended reaction. the protecting groups react selectively with the hydroxy groups in good yields; the protecting groups are readily available without excessive attack on other functional groups present. selectively removable in good yields by commercially available, preferably non-toxic, reagents; The group preferably gives rise to easily separable derivatives (more preferably to new stereoisomeric centers) and protecting groups are preferably used to avoid complications at other sites in the reaction. It has minimal additional functional groups.

[0247] A wide variety of protecting groups, as well as strategies, reagents and conditions for their placement and removal, are described in this technical paper. See, for example, "Protection in Organic Synthesis" edited by TW Greene and PG Wuts. "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, New York, 1999. Protecting group methodology (protection and deprotection) useful in preparing the compounds described herein is also described. For information on materials, methods, and strategies for protection and other synthetic chemical transformations, see R. Larock, "Total Organic Transformations" Comprehensive Organic Transformations” VCH Publishers (1989); TW Greene and and P.G.M. Wuts, eds., Protecting Groups in Organic Synthesis, 3rd ed., John Wiley & Sons (1999); L. Fieser and M. Fieser "Fieser and Fieser's Reagents for Organic Synthesis" "Reagents for Organic Synthesis" John Wiley & Sons (1994); and L. Paquette (ed.) Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons See ons (1995), the entire contents of which are incorporated herein by reference.

[0248] Also, the desired isotope, e.g., deuterium instead of hydrogen, may be enriched. Reagents can also be selected to produce compounds of the invention that contain such isotopes. containing deuterium in place of hydrogen in one or more positions, or C, N, P, and Compounds containing various isotopes of O and O are also encompassed by the present invention, for example, the metabolism and and / or to study tissue distribution, or metabolic rates or pathways or other aspects of biological function. Can be used to change the surface.

[0249] The compounds of the present invention can be prepared by combining the methods described below with synthetic methods known in the field of organic synthetic chemistry. These can be used in combination or synthesized by modifications thereof that will be understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. It is carried out in a solvent appropriate to the reagents and materials used and suitable for the transformation being carried out. It is a matter of organic synthesis that the functional groups present should be compatible with the proposed transformation (chemical reaction). As will be appreciated by those skilled in the art, in order to obtain the desired compounds of the present invention, Any change in the order of the synthesis steps or selection of one method over another judgment may be necessary.

[0250] The compounds of the present invention can be prepared as outlined in Scheme 1 to Scheme 57a. Certain compounds of the present invention can be synthesized using standard methods known to those skilled in the art. In this case, microwave-assisted synthesis was carried out using conventional techniques under the conditions described in the Examples below. The reaction can be carried out using Biotage Initiator 2.0, which is also used in the examples described below. TM (Biotage AB, Kungsgatan 76, SE-753, 18 Uppsala, Sweden or 1725 Discovery Drive, Charlottesville, Virginia 22911), or CEM Discover TM Systems (CEM Corporation, This can be accomplished using a commercially available microwave reactor, such as the one available from Matthews, North Carolina. can.

[0251] The terms in the following reaction scheme have the following meanings: intermediate: intermediate microwave or mw: microwave (heating); microwave heating: microwave heating Ethanol: ethanol; pyridine: pyridine; toluene or Tol: toluene dioxane; solvent rt or rt: room temperature 2-methoxyethanol Suzuki coupling: Suzuki coupling base; Hunig's base (=DIPEA) heat; reflux hydrogenation overnight: N,N-dimethylaniline Compounds of general formula Ia or VIA where n is 0 and X is N can be prepared by the reaction of 2 as shown in Scheme 1. First, [Ring A]-NH2 is converted to diisopropyl ethyl amine. In the presence of a base such as diphenyl ether (DIPEA), 2,4-dichloro-5-(trifluoromethyl)piperidin is reacted at elevated temperatures. The [Ring A] moiety is introduced into the central pyrimidine moiety by reaction with pyrimidine to form intermediate 1. The [Ring E]-L- moiety can then be attached to intermediate 1, depending on the nature of the linker L. The intermediates [Ring E]-L- and [Ring A] can be introduced using different conditions depending on the reaction. The meanings of the various variables are as defined above, and ring A and ring E are each a predetermined R a Reach BiR g The group is substituted.

[0252] [ka]

[0253] The synthetic approach to intermediate 1 is shown below in Scheme 1A for the case where ring A is phenyl.

[0254] [ka]

[0255] Compounds of general formula VIA where L is O can be prepared using microwave chemistry as shown in Reaction Scheme 2. Intermediate 1 is then reacted with [Ring E]-OH in a solvent such as dimethylformamide (DMF) at elevated temperature. It can be prepared by reacting

[0256] [ka]

[0257] The synthesis of compounds of general formula VIA in which L is O is the same as that in the case where ring A and ring E are both phenyl. An example is shown in Reaction Scheme 2A below.

[0258] [ka]

[0259] Compounds of general formula VIA where L is NH can be prepared using microwave chemistry as shown in Scheme 3. Intermediate 1 is then reacted with [Ring E]-NH2 in a polar solvent such as ethanol at high temperature. In order to promote this substitution reaction, a base (e.g., Diisopropylethylamine, triethylamine, etc.) or an acid may be added.

[0260] [ka]

[0261] The synthesis of some compounds of formula VIA where L is NH is described below, Examples of damantane amines are shown below in Schemes 3A and 3B.

[0262] [ka]

[0263] L is NH(CH2) 1-4 Compounds of general formula VIA, Using microwave chemistry, intermediate 1 is converted to ethanol in the presence of a base such as triethylamine. Using high temperature in a polar solvent such as 1-4 Prepared by reacting with NH2 It can be manufactured.

[0264] [ka]

[0265] L is NH(CH2) 1-4The synthesis of some compounds represented by the general formula VIA is shown below. Reaction Schemes 4A and 4B are shown. In reaction Scheme 4A, ring E is phenyl and L is NHCH2. Scheme 4B shows the synthesis of compounds of formula VIA, where ring E is a 3-1H-indole and L The synthesis of compounds of general formula VIA where is NH(CH2)2 is shown.

[0266] [ka]

[0267] L is S(CH2) y Compounds of general formula VIA, Using chemistry, intermediate 1 is converted to dimethylformamide in the presence of a base such as cesium carbonate. At high temperatures in solvents such as y It can be prepared by reacting with SH. The variable y has the meaning defined above.

[0268] [ka]

[0269] L is S(CH2) y A synthetic approach to compounds of general formula VIA is shown below in Scheme 5A.

[0270] [ka]

[0271] Compounds of general formula VIA where L is a single bond and [ring E] is aryl or heteroaryl are It can be prepared using Suzuki coupling conditions. Reaction Scheme 6 shows this Suzuki coupling reaction. Shows.

[0272] [ka]

[0273] As a non-limiting example, Scheme 6A shows a compound of general formula V where L is a single bond and [Ring E] is phenyl. The synthesis of compound IA is shown.

[0274] [ka]

[0275] Compounds of general formula VIA where L is a single bond and [ring E] is an N-bonded heterocycle are shown in the reaction diagram Microwave chemistry can be used to convert intermediate 1 to a salt such as triethylamine, as shown in Scheme 7. The heterocyclic compound is reacted with the aryl group using high temperature in a polar solvent such as ethanol. It can be prepared by

[0276] [ka]

[0277] As a non-limiting example, Scheme 7A shows a compound in which L is a single bond and [Ring E] is N-phenylpiperazine. 1 shows the synthesis of compounds of general formula VIA,

[0278] [ka]

[0279] An alternative reaction route can be used to synthesize compounds of formula VIA where L is NH. Before introducing the [Ring A]-NH moiety, the [Ring E]-NH moiety is first introduced into the central pyrimidine moiety. Reaction Scheme 8 shows the introduction of dimethylformamide to form intermediate 2. A base (e.g., potassium carbonate or sodium hydride) in a solvent such as an amide or ethanol Reacting 2,4,5-trichloropyrimidine with the [Ring E]-NH2 moiety in the presence of The reaction can be carried out at room temperature (rt) or at higher temperatures. Sometimes a meter (or a gauge) is required.

[0280] [ka]

[0281] Another example of this reaction is shown below in Scheme 9, where 2,4-dichloro-5-(trifluoromethyl)- ... (Fluoromethyl)pyrimidine was reacted with the [Ring E]-NH2 moiety by sodium hydride in dimethylformamide. Intermediate 3 is synthesized by reacting at a lower temperature in the presence of ammonium.

[0282] [ka]

[0283] Intermediate 2 or 3 can then be reacted using general substitution conditions as shown in Scheme 10 below. [Ring A]-(CH2) n It can be reacted with an NH2 moiety.

[0284] [ka]

[0285] As a non-limiting example, Reaction Schemes 10A and 10B show compounds of general formula VIA where L is NH The synthesis of a compound in which ring A and ring E are substituted phenyl is exemplified.

[0286] [ka]

[0287] The synthetic guidelines presented in Schemes 1-10 are applicable to a variety of Rings A and E of the present invention. which allows the preparation of all compounds according to the invention. Reaction Scheme 11 shows the general formulas IA and VIA where n is 0, L is NH, and X 1 is CH The synthesis of the compound

[0288] In Scheme 11, palladium coupling conditions are used to prepare 2-chloro-4-iodo -5-(trifluoromethyl)pyridine is reacted with [Ring E]-NH2 to give pyridine Then, the [Ring E]-NH moiety is introduced onto the central skeleton of the above reaction scheme. The [Ring A]-NH moiety is introduced by a substitution chemistry such as Microwaves and heat can also be used for actuation.

[0289] [ka]

[0290] As a non-limiting example, Scheme 11A shows a compound of general formula VIA where L is NH, X 1 is CH, The synthesis of a compound in which ring A and ring E are substituted phenyl is then shown.

[0291] [ka]

[0292] Reaction Scheme 12 shows the general formula IVA in which X 1 is CH and R d and R e forms a phenyl ring The synthesis of the compound is shown below.

[0293] [ka]

[0294] As a non-limiting example, Reaction Scheme 12A shows a compound of general formula IVA in which X 1 CH, R d and R e The synthesis of a compound in which rings A and E form a phenyl ring is shown below.

[0295] [ka]

[0296] Reaction Scheme 13 shows the general formula IIIA in which X 1 is CH and R b and R c is further phenyl The synthesis of compounds forming phenyl rings substituted with rings is shown.

[0297] [ka]

[0298] As a non-limiting example, Reaction Scheme 13A shows a compound of general formula VA in which X 1 is CH and R b and R c form a phenyl ring, ring A is a substituted phenyl, and R f is a substituted phenyl The synthesis of

[0299] [ka]

[0300] Reaction Scheme 14 shows the general formula IIIA in which X 1 is N and R c and R d forms a pyrrole ring The synthesis of the compound is shown below.

[0301] [ka]

[0302] In the above formula, rings A and R a is as defined in Part 1, and in RX, R is alkyl, heteroaryl, aryl, arylalkyl, heteroarylalkyl, Heterocycle and Substituent R f and X is a halide or other group selected from the list It is a leaving group.

[0303] Another example of the synthesis of compounds of general formula IIIA is shown below in Scheme 15. The substituent R depicted in Scheme 14 is phenyl.

[0304] [ka]

[0305] In the above formula, R' is R f and rings A and R are substituents selected from the list a Part 1 This is as defined above. As a non-limiting example, Reaction Scheme 15A shows a compound of general formula IIIA in which X 1 is N and R c and R d form a pyrrole ring, ring A is a substituted phenyl, and R f Compounds in which the phenyl is also substituted Shows the synthesis of substances.

[0306] [ka]

[0307] As a non-limiting example, Reaction Scheme 16 shows a compound of general formula IIIA in which X 1 is N and R c and R d The synthesis of compounds in which the imidazole ring is substituted with phenyl is shown.

[0308] [ka]

[0309] In the above formula, R' is R f and rings A and R are substituents selected from the list a Part 1 This is as defined above. In the compounds of the present invention, R a , R b , R b1 , R c , R c1 , R d , R d1 , R e , R e1 , R f , or R g If present, one of the 3 )2 or contains it.

[0310] Schemes 17-24 illustrate the synthesis of phosphorus-containing substituents or moieties of current interest. Show. Reaction Scheme 17 shows that ring A is -P(=O)(R 3 )2-substituted pyridine [Ring A]-NH2 The synthesis of the moiety is illustrated.

[0311] [ka]

[0312] In the above formula, R 3 is as defined in Part 1. Using a similar synthetic route, phenyl or -P(=O)(R 3 )2 places Substituents may also be introduced. This synthesis scheme is applicable when L is NH and ring E is aryl or The synthesis of heteroaryl [Ring E]-L moieties is also shown. This scheme is based on the general formulas I-VI. It can be used to synthesize compounds of the invention.

[0313] Another interesting compound is R a The substituent is a phosphorus-containing substituent. is that ring A is -P(=O)(R 3 Synthesis of the intermediate [Ring A]-NH2, a phenyl substituted with 2 show.

[0314] [ka]

[0315] In reaction scheme 19, ring A is -(CH2) m P(=O)(R 3 )2, and m The synthesis of the [Ring A]-NH2 intermediate is shown below.

[0316] [ka]

[0317] Reaction Scheme 20 shows that ring A is R f As -P(=O)(R 3 )2-substituted naphthalenes The synthesis of the bicyclic structure [Ring A]-NH2 moiety is shown. This reaction scheme also applies when ring E is naphthalene, L is NH, and R g -P(=O)(R 3 )2 This scheme may also be used to synthesize the [Ring E]-L moiety, which is shown in general formula VIIA. The compounds can also be used to synthesize the compounds of the present invention.

[0318] [ka]

[0319] Reaction Scheme 21 shows that ring A is -P(=O)(R 3 )2-substituted phenyl [Ring A]-(CH2 ) n The synthesis of the -NH2 intermediate (n is 1) is shown.

[0320] [ka]

[0321] Scheme 21 also shows that L is CHNH and ring E is -P(=O)(R 3 )2-substituted phenyl It can also be used to synthesize the [Ring E]-L moiety, which is a hydroxyl group. In some embodiments, -P(=O)(R 3 ) R containing 2 substituents a , R f or R g But the cyclic structure It can become something.

[0322] Reaction Schemes 22-23 show the reaction of -P(=O)(R 3 The synthesis of interesting cyclic structures containing 2 is presented. Reaction Scheme 22 shows the reaction of -P(=O)(R 3 )2-containing cyclic substituent R a (or R f or R g ) combination Indicates the formation.

[0323] [ka]

[0324] Schemes 22A and 22B illustrate the introduction of this cyclic substituent into either the A or E ring. Reaction Scheme 22A shows that ring A is a methoxy group and -P(=O)(R 3 )2-containing cyclic substituents and This scheme shows the synthesis of the [Ring A]-NH2 moiety, where L is NH and Ring E is a phenyl. is a methoxy group and -P(=O)(R 3 )2-containing cyclic substituent and [Ring E]- is a phenyl substituted with It could also be used for the synthesis of the L moiety.

[0325] [ka]

[0326] Reaction Scheme 23 shows that ring A is a methoxy group and -P(=O)(R 3 ) phenyl substituted with two groups So, two R's 3 The groups, together with the phosphorus atom to which they are attached, form a six-membered saturated ring. The synthesis of the [Ring A]-NH2 intermediate is shown below.

[0327] [ka]

[0328] Scheme 24 shows the synthesis of a piperazine substituent further substituted with -CH2P(=O)(CH3)2. This reaction scheme shows the structure of a phenyl group in which ring A is substituted with a phosphorus-containing piperazine group. This scheme can also be used to synthesize the ring A-NH2 intermediate. a , R b , R c , R d , R e , R f or R g ) is NR 1 R 2 and NR 1 R 2 -CH2P(=O)( Any compound of the general formula in the present invention forming a piperazine ring substituted with CH3)2 It can also be used to synthesize things.

[0329] [ka]

[0330] Compounds of general formula IB or VI can be synthesized in a two-step synthesis as shown in Scheme 1. First, [Ring A]-NH2 is reacted with the hydroxyl group at high temperature in the presence of a base such as diisopropylethylamine. The central pyrimidine is obtained by reaction with substituted or unsubstituted 4,6-dichloropyrimidine. The [Ring A] moiety can then be introduced to form intermediate 1a. The moiety can be introduced into intermediate 1a using different conditions depending on the nature of the linker L. The meanings of the various variables in the intermediates [Ring E]-[L]- and [Ring A] formed have already been defined. As described above, ring A and ring E are each a predetermined R a and R g is substituted with a group.

[0331] [ka]

[0332] The synthetic approach to intermediate 1a is shown below in Scheme 1A for an example where Ring A is phenyl.

[0333] [ka]

[0334] Compounds of formula IB or VII where L is NH can be prepared by the n-bromo- By reacting intermediate 1a with [Ring E]-NH2 under acidic conditions in a solvent such as ethanol, It can be synthesized using microwave chemistry.

[0335] [ka]

[0336] The synthesis method of the compound of general formula VI in which L is NH is shown below with reference to an example in which ring A and ring E are phenyl. This is shown in Reaction Scheme 26A below.

[0337] [ka]

[0338] Compounds of general formula IB or VII in which L is a single bond and [ring E] is an N-bonded heterocycle are As shown in Scheme 27, diisopropyl diethyl ether is reacted with 1,2-dimethyl-2,4 ... Reacting intermediate 1a with a heterocycle using elevated temperature in the presence of a base such as ethylamine It can be synthesized by

[0339] [ka]

[0340] As a non-limiting example, Reaction Scheme 27A shows a reaction c is [L]-[ring E], where L is a single bond. and the synthesis of compounds of general formula VII or IB in which [ring E] is N-phenylpiperazine is shown. vinegar.

[0341] [ka]

[0342] R c is [L]-[ring E], and L is O, the compound of formula IB or VII is In the presence of sodium hydride in a solvent such as dimethylformamide, as shown in Equation 28 4,6-dichloropyrimidine is reacted with an optionally substituted phenol in Then, a base is added to promote the substitution reaction. (e.g., diisopropylethylamine, triethylamine, etc.) or in the presence of an acid, [Ring A]- (CH2) n By reacting -NH2, the [Ring A] moiety is introduced into the central pyrimidine moiety. This can be done.

[0343] [ka]

[0344] The synthesis of some compounds of general formula IB or VII where L is NH is described below. An example where Ring E is phenyl is shown below in Scheme 28A.

[0345] [ka]

[0346] L is NH(CH2) 1-4 Compounds of general formula IB or VII, In addition, high temperatures are used in the presence of a base such as triethylamine in a polar solvent such as ethanol. Intermediate 1a is converted to [Ring E]-(CH2) 1-4 By reacting with NH2, microwave chemistry It can be synthesized using

[0347] [ka]

[0348] L is NH(CH2) 1-4 The synthesis of some compounds of general formula VII is described below. Reaction Scheme 29A is shown in Scheme 29B where Ring E is phenyl and L is NHC. Scheme 29B shows the synthesis of compounds of formula VII where ring E is 3-1H-yne. In the dole, the synthesis of compounds of general formula VII where L is NH(CH2)2 is shown.

[0349] [ka]

[0350] L is S(CH2) y Compounds of general formula IB or VII, Using microwave chemistry, intermediate 1a can be converted to dimethyl ether in the presence of a base such as cesium carbonate. In a solvent such as formamide, at elevated temperatures, [Ring E]-(CH2) y By reacting with SH, The variable y is defined above.

[0351] [ka]

[0352] X 3 is CH and X 2 is N and L is S(CH2) y In general, ring A and ring E are substituted phenyl. A synthetic approach to compounds of Formula VII is shown below in Scheme 30A.

[0353] [ka]

[0354] Compounds of general formula IB or VII, wherein L is a single bond and [ring E] is aryl or heteroaryl The compound can be prepared using Suzuki coupling conditions. Scheme 31 shows this Suzuki coupling. Shows ring reaction.

[0355] [ka]

[0356] As a non-limiting example, Reaction Scheme 31A shows a compound represented by the formula: X 3 CH, X 2 is N, L is a single bond, [ring E] and The synthesis of a compound of general formula VII in which [Ring A] is phenyl is shown below.

[0357] [ka]

[0358] R c is [L]-[ring E] and L is O, compounds of formula IC or VI are represented by the reaction scheme It can be prepared by a two-step synthesis as shown in Figure 32. First, [Ring E]-OH is reacted with substituted or unsubstituted 3,5-dichloropyridazine in the presence of a suitable base. This introduces the [Ring E]-L-moiety into the central pyridazine moiety to form intermediate 2a. Then, a base (e.g., diisopropyl ether) is added to promote the substitution reaction. In the presence of an acid, [ring A]-(CH2) n -NH2 It can be reacted with intermediate 2a.

[0359] [ka]

[0360] As a non-limiting example, Scheme 32A shows a compound in which L is O, X 3 N, X 2 is CH, [ring E] and [ The synthesis of compounds of general formula VII in which ring A is substituted phenyl is shown.

[0361] [ka]

[0362] R c is [L]-[ring E], where L is NH(CH2) y Compounds of general formula IC are represented by the reaction diagram It can be prepared in four steps as shown in Scheme 33. First, In the presence of triethylamine in a solvent, [Ring E]-(CH2) y -NH2 with 4,5-dichloropyridin By reacting with din-3(2H)-one, the central pyridazine moiety is converted to [Ring E]-(CH2) y The -NH2 moiety can be introduced to form intermediate 3a. Intermediate 3a can then be reacted with hydrogen and reacting with phosphorus oxychloride to form intermediate 4a, which then promotes the substitution reaction. A base (e.g., diisopropylethylamine, triethylamine, etc.) added for the purpose of In the presence of an acid, intermediate 4a is converted to [Ring A]-(CH2) n The NH2 moiety can be reacted.

[0363] [ka]

[0364] As a non-limiting example, Scheme 33A shows a compound in which L is NH, X 3 N, X 2 is CH, [ring E] and The synthesis of a compound of general formula VII in which [Ring A] is a substituted phenyl is shown below.

[0365] [ka]

[0366] Similarly, R c is [L]-[ring E], and L is O, the compound of general formula IC or VI is In the presence of potassium carbonate, [Ring E]-OH is converted to 4,5-dichloropyridazin-3(2H)-one. After reaction, the synthesis can be carried out following the same sequence of steps as described in Scheme 33. This modified synthesis is shown in Scheme 34.

[0367] [ka]

[0368] Similarly, R c Compounds of formula IC in which is an N-linked heterocycle are suitable for use as substituted piperidines. Such heterocyclic compounds are reacted with 4,5-dichloropyridazin-3(2H)-one, followed by reaction. This synthesis can be carried out following the same sequence of steps as described in Scheme 9. As shown in Equation 35.

[0369] [ka]

[0370] Reaction Scheme 36 below shows the reaction e and R b is H and R c and R d and imidazoline substituted with phenyl groups 1 shows the synthesis of sol-forming compounds of formula IIIA.

[0371] [ka]

[0372] In the above formula, R is R f and the rings A and R are substituents selected from a and n is defined above That's right. As a non-limiting example, Reaction Scheme 36A shows a reaction c and R d and form an imidazole, and ring A substituted phenyl, R f The synthesis of compounds of general formula IIIA where is a substituted phenyl is shown.

[0373] [ka]

[0374] Compounds of formula I, IB, IIB or IVA where n is 0 can be prepared as shown in Scheme 37. It can be prepared in a convenient two-step synthesis. Under pulling conditions, [Ring A]-Br was converted to 5-chloro-6-substituted-1,2,4-triazine-3-amine. The [Ring A] moiety was introduced into the central triazine moiety by reaction with amine to give intermediate 1 (I -1) can then be formed by adding the [ring E]-L- moiety depending on the nature of the linker L. The intermediate I-1 can be introduced into the intermediate I-1 using different conditions. The meanings of the variables in [ring A] are as already defined, and ring A and ring E are respectively Prescribed R a and R g is substituted with a group.

[0375] [ka]

[0376] The synthesis of intermediate I-1a is shown in Scheme 37A below for an example where ring A is phenyl. vinegar.

[0377] [ka]

[0378] Intermediate I-1a is then reacted with a substituted aniline as shown in Scheme 37B to form a compound in which L is NH, ring A and ring E are phenyl, n is 0, R d to form a compound of the general formula VIA, where Complete.

[0379] [ka]

[0380] Intermediate I-1a can be prepared by reacting a substituted phenol or thiophenol with a substituted phenol or thiophenol as shown in Scheme 37C. by reacting with L is O or S, ring A and ring E are phenyl, n is 0, R d is methyl Compounds of the general formula VIA can also be formed.

[0381] [ka]

[0382] An alternative synthesis of compounds of formula I, IB, IIB or VIA is shown in Scheme 38. In the central triazine moiety, L is first replaced with O, S, or The [Ring E]-LH moiety, which is NH, can be introduced. Reaction Schemes 38 and 39 show the intermediate To form I-2 and I-3, for example, dimethylformamide, methylene chloride or In a suitable solvent such as tetrahydrofuran, a base (e.g., triethylamine, potassium carbonate) , sodium carbonate, sodium hydride, etc.) in the presence of 3,5-dichloro-6-substituted This reaction is carried out at room temperature. The intermediate I-2 or I-3 may then be reacted with the reaction mixture at a temperature of 1000 K or higher. I-3 can be reacted with 1-3 under acidic conditions at elevated temperature in the presence of a suitable solvent, such as tetrahydrofuran. (e.g. camphorsulfonic acid) is reacted with [Ring A]-NH2. This reaction pathway is It is described in patent application WO 2006 / 015985.

[0383] [ka]

[0384] R d When is chloro, 3,5,6-trichloro-1,2,4-triazine is 1,2,4-triazine-3,5(2H, 4H) dione with bromine in the presence of a suitable solvent, such as water, to give a compound of general formula I-4 It can be prepared by forming the intermediate 3,5,6-trichloro-1,2, The synthesis of 4-triazines is shown in Scheme 40. Intermediate I-4a can then be reacted with, for example, N,N -Reaction with POCl3 and PCl5 in the presence of a base such as diethylaniline.

[0385] [ka]

[0386] R d is methyl, 3,5-dichloro-6-methyl-1,2,4-triazine is P It can be prepared according to the method described in CT patent application WO 2005 / 054199. R d When is H, 3,5-dichloro-1,2,4-triazine is Chemistry, 23, 1522-4; 1958, and this method In this example, 1,2,4-triazine-3,5(2H,4H)dione is reacted with POCl3. The synthesis of 1,2,4-dichloro-1,2,4-triazine is shown in Scheme 41.

[0387] [ka]

[0388] The compounds of formula I, IA, IC, IIC or VIB can be prepared as shown in Reaction Scheme 42. It can be prepared by a two-step synthesis: [Ring A]-(CH2) n -NH2 in a suitable solvent, For example, 2,4-dichloro-6-isopropyl amine in the presence of a base such as diisopropyl ethylamine By reacting with substituted 1,3,5-triazine, the central triazine moiety is first converted to [Ring A]. -(CH2) n The -NH- moiety can then be introduced into the [Ring E]-L- moiety. Depending on the nature of L, different conditions can be used to introduce it into intermediate I-6. The meanings of the variables in [Ring E]-[L]- and [Ring A] are as previously defined. Each ring E is a given R a and R g The group is substituted.

[0389] [ka]

[0390] R e When is methyl, 2,4-dichloro-6-methyl-1,3,5-triazine is According to the method described in Organic Medicinal Chemistry Letters 16(21), 5664-5667, 2006 As shown in Scheme 42A, 2,4,6-trichloro-1, 3,5-Triazine is reacted with methylmagnesium bromide to give 2,4-dichloro-6-methyl -1,3,5-triazine is produced.

[0391] [ka]

[0392] As a non-limiting example, R e Intermediate of general formula I-6, wherein is H, n is 0, and ring A is phenyl is shown in Scheme 42B.

[0393] [ka]

[0394] Compounds of formula VIB where L is O can be prepared by di-reaction of intermediate I-6 as shown in Scheme 43. By reacting with [Ring E]-OH at elevated temperature in a solvent such as methylformamide, It can be prepared using microwave chemistry.

[0395] [ka]

[0396] The synthesis of compounds of general formula VIB in which L is O is as follows: This is shown in Reaction Scheme 43A.

[0397] [ka]

[0398] Compounds of formula VIB where L is NH can be prepared by reaction of intermediate I-6 as shown in Scheme 44. By reaction with [Ring E]-NH2 in a polar solvent such as ethanol at elevated temperature, It can be synthesized using microwave chemistry. To facilitate this substitution reaction, a base is required. (eg, diisopropylethylamine, triethylamine, etc.) or an acid may be added. Similar substitution reactions are described in PCT patent application WO 2005 / / 047279.

[0399] [ka]

[0400] The synthesis of some compounds of formula VIB where L is NH is described below. The reactions for benzoyl and adamantane are shown in Schemes 44A and 44B below, respectively.

[0401] [ka]

[0402] L is NH(CH2) 1-4 Compounds of general formula VIB, In a polar solvent such as alcohol, in the presence of a base such as triethylamine, high temperature is used to Intermediate I-6 [Ring E]-(CH2) 1-4 Using microwave chemistry, by reacting with NH2 can be synthesized.

[0403] [ka]

[0404] L is NH(CH2) 1-4 The synthesis of some compounds of general formula VIB is shown below. Reaction Schemes 45A and 45B are shown. Reaction Scheme 45A is R e is Cl, ring E is phenyl, L is NHCH2, and Scheme 45B shows the synthesis of compounds of formula VIB. e is Cl, ring E The synthesis of compounds of general formula VIB where is 3-1H-indole and L is NH(CH2)2 is shown.

[0405] [ka]

[0406] L is S(CH2) y Compounds of general formula VIB, Using wave chemistry, intermediate I-6 is converted to dimethylformamide in the presence of a base such as cesium carbonate. At high temperatures in solvents such as amides, [Ring E]-(CH2) y It can be prepared by reacting with SH. The variable y is defined above.

[0407] [ka]

[0408] L is S(CH2) y A synthetic approach to compounds of general formula VIB is shown below in Scheme 46A.

[0409] [ka]

[0410] Compounds of general formula VIB where L is a single bond and [ring E] is an aryl or heteroaryl are It can be prepared using Suzuki coupling conditions. Reaction Scheme 11 illustrates this Suzuki coupling reaction. The reaction is shown. Replacement of one of the chlorines with an aryl Grignard or arylboronic acid is It is described in patent application WO 01 / 25220 and in Helv. Chim. Acta, 33, 1365 (1950). The substitution of one heteroaryl ring of 1, 417 (1974); and Tetrahedron 31, 1879 (1975). These reactions are Microwave chemistry can be used to accelerate the process. The coupling reaction is also described in Journal of Medicinal Chemistry, 2007, 50(17), 3497. There are.

[0411] [ka]

[0412] R e The Suzuki coupling reaction when is chloro is described in PCT patent application WO 2002 / 22605. is also described. As a non-limiting example, Scheme 47A shows a compound in which L is a single bond and [Ring E] is a substituted phenyl. The preparation of compounds of general formula VIB is shown.

[0413] [ka]

[0414] General formula I, IB or VI, wherein L is a single bond and [ring E] is an aryl or heteroaryl ring. Compound A can be prepared in a similar manner using Suzuki coupling conditions. A similar reaction pathway is described in PCT patent application WO 2005 / 054199 and is shown in the following reaction scheme: Shown in 48.

[0415] [ka]

[0416] Compounds of general formula VIA where L is a single bond and [ring E] is an N-bonded heterocycle are shown in the reaction diagram Using microwave chemistry, intermediate I-6 can be converted to methyl methyl amine with triethylamine as shown in Scheme 49. The heterocyclic compound is reacted with the heterocyclic compound using high temperature in a polar solvent such as ethanol in the presence of a base such as It can be prepared by reacting

[0417] [ka]

[0418] As a non-limiting example, Reaction Scheme 49A shows a compound in which L is a single bond, R e is chloro, [Ring E] is N-fluoro 1 shows the synthesis of compounds of formula VIA, which are phenylpiperazines.

[0419] [ka]

[0420] Reaction Scheme 50 is R c is L-[ring E], L is NH, X 3 N, X 4 is C, and ring C is tri The synthesis of compounds of the general formula IVA, which are azoles, is shown. A similar reaction pathway is described in Bioorganic & M This substitution reaction is also described in Edicinal Chemistry Letters 16(5), 1353-1357, 2006. Microwave chemistry can also be used to accelerate the reaction.

[0421] [ka]

[0422] As a non-limiting example, Reaction Scheme 50A shows a compound in which L is NH, X 3 N, X 4 is C, ring C is tria The synthesis of zoles and compounds of general formula IVA in which ring A and ring E are substituted phenyl is shown.

[0423] [ka]

[0424] An alternative route to compounds of formula IVA where ring C is a triazole is shown in Scheme 51. The compound of formula I-15 is reacted with paraacetic acid in the presence of a base such as cesium carbonate. Sodium and phosphorus ligands (e.g., Xantphos <4,5-bis(diphenylphosphino)-9,9-dimethyl In the presence of xanthene, an aryl halide (e.g., an aryl bromide) or a halogenated This reaction produces intermediate I-15a. Then, intermediate I-15a is reacted with m-CPBA to replace sulfur oxide at the ring A-NH2 moiety. The synthesis of intermediate I-15 is reported in Journal of Heterocyclic Chemistry, 37(6), 1587-1 590, 2000.

[0425] [ka]

[0426] As a non-limiting example, Reaction Scheme 51A shows a reaction c is L-[ring E], L is NH, X 3 N, X 4 is C, ring C is triazole, R f is Me, and ring A and ring E are substituted phenyl. 1 shows the synthesis of a compound of formula IVA.

[0427] [ka]

[0428] Reaction Scheme 52 shows that X 3 N, X 4 of the compound of general formula IVA, wherein is C and ring C is pyrazole As shown in Scheme 52, the starting material, aminopyrazole, is converted to pyrazolo[1, The 5-a][1,3,5]triazine ring system can be synthesized. Diverse aminopyrazoles The synthesis and ring closure conditions are described in US Patent Application Publication US 2008 / 187219 and Bioorganic & Medicinal Chemistry. Ministry Letters 17(15), 4191-4195, 2007.

[0429] [ka]

[0430] As a non-limiting example, Reaction Scheme 52A shows a reaction 3 N, X 4 is C, ring C is pyrazole, ring A and the synthesis of compounds of general formula IVA in which ring E is substituted phenyl.

[0431] [ka]

[0432] Reaction Scheme 53 shows that X 4 N, X 3 C, R c is L-[ring E], L is NH, and [ring C] is Pi The synthesis of compounds of general formula IVA, which are the role of hydroxybenzoates, is shown in PCT patent application WO 2008 / 05 7994.

[0433] [ka]

[0434] As a non-limiting example, Reaction Scheme 53A shows a compound represented by the formula: X 4 N, X 3 C, R c is L-[ring E], L is a compound of the general formula IVA, wherein NH, [ring C] is pyrrole, and rings A and E are substituted phenyl; Shows the synthesis of substances.

[0435] [ka]

[0436] Scheme 54 illustrates the synthesis of compounds of general formula IIIA where ring B is pyrrole. Chloro-N-substituted 1,2,4-triazin-5-amines were treated with substituted alkynes under Sonogashira conditions. to form 3-chloro-5-substituted-pyrrolo[2,3-e][1,2,4]triazine A similar synthetic route using the Sonogashira reaction is reported in Tetrahedron Letters, 48(29), 5069- 5072, 2007.

[0437] [ka]

[0438] In the above formula, rings A and R a , n and s are as defined in Part 1, and R and R' is alkyl, heteroaryl, aryl, arylalkyl, heteroarylalkyl, Heterocycle and Substituent R f Examples of R' are methyl, ethyl, Examples of R include substituted phenyl, substituted benzoyl, methyldialkylamino, and phenyl. pyridine, substituted pyridine, etc.

[0439] As a non-limiting example, Scheme 54A shows a compound in which Ring B is a pyrrole, R' is a methyl group, and R is a substituted The synthesis of compounds of general formula IIIA where ring A is phenyl and ring B is substituted phenyl is shown.

[0440] [ka]

[0441] Another example of the synthesis of compounds of general formula IIIA is shown below in Scheme 55, where the ring B is an imidazole. Intermediate I-19 is reacted with an amine to form intermediate I-19a. The ring closure in the presence of SOCl2 and trimethoxymethane produces intermediate I-19b. This ring closure process is described in Liebigs Annalen de Chemie, 7, 631-40, 1990. The methyl thioether of intermediate I-19b is then reacted as previously described in Scheme 52 with the methyl thioether of intermediate I-19b. Oxidized with m-CPBA to [Ring A]-(CH2) n It can be substituted with an NH2 moiety.

[0442] [ka]

[0443] In the above formula, R is alkyl, heteroaryl, aryl, arylalkyl, heteroaryl Aryl alkyl, heterocycle and substituent R f Examples of R are , methyl, ethyl, methyldialkylamino, phenyl, etc. Examples of R are substituted phenyl rings A and R include aryl, substituted benzyl, and substituted pyridine. a is defined in Part 1 That is exactly what happened.

[0444] As a non-limiting example, Scheme 55A shows a compound in which Ring B is imidazole, Ring A is substituted phenyl, The synthesis of compounds of general formula IIIA where R is substituted phenyl is shown.

[0445] [ka]

[0446] Another example of the synthesis of compounds of general formula IIIA is shown below in Scheme 56, where the ring B is a pyrazole. Intermediate I-20 is reacted with hydrazinecarbothioamide to give the carbonate. Ring closure in the presence of potassium affords intermediate I-20a. of Heterocyclic Chemistry, 21(3), 923-6, 1984. Intermediate I-20 a then [ring A]-(CH2) n React with the NH2 moiety. Similar substitution reactions are reported in Praktische Chemie (Leipzig), 326(6), 994-8, 1984.

[0447] [ka]

[0448] In the above formula, R″ is R f and rings A and R are substituents selected from the list a Part 1 This is as defined above. As a non-limiting example, Scheme 56A shows a compound in which Ring B is a pyrazole, Ring A is a substituted phenyl, and The synthesis of compounds of general formula IIIA where R″ is a methoxy group is shown below.

[0449] [ka]

[0450] Another example of the synthesis of compounds of general formula IIIA is shown below in Scheme 57, where the ring B is phenyl. Bioorganic & Medicinal Chemistry Letters 17(21), 5818, 2007 As described in

[2004] , substituted 2-nitroanilines were subjected to ring closure in the presence of Raney nickel. After replacing 2-nitroaniline with bromide or chloride, Suzuki Introducing an aryl or heteroaryl onto the fused phenyl ring B using a coupling reaction The [Ring A]-NH2 moiety is a Buchwald-Hartwig cross-coupled It can be introduced using a binding reaction.

[0451] [ka]

[0452] As a non-limiting example, Scheme 57A shows a compound of general formula I in which ring B and ring A are substituted phenyl. The synthesis of compound IIA is shown.

[0453] [ka]

[0454] The synthetic procedures described above are illustrated in the examples below, in other information provided herein, and by conventional methods. By combining these compounds with other compounds and materials, one skilled in the art can prepare the full range of compounds disclosed herein. It should be possible.

[0455] 5. Uses, Formulations, and Administration Medicinal Uses; Indications The present invention relates to a method for identifying diseases in which kinases may be involved, symptoms of such diseases, or kinase-related disorders. and possessing biological properties that may be beneficial in treating or ameliorating the effects of other enzyme-mediated physiological events. For example, many of the compounds of the present invention have the ability to inhibit the growth (proliferation) and development of cancer. and / or tyrosine kinases thought to mediate metastasis, particularly ALK and fak It has been shown that many of the compounds of the present invention inhibit the tyrosine kinase activity of α- and c-met. The compound also has potent in vitro activity against cancer cell lines, including, inter alia, Karpas 299 cells. Therefore, such compounds are useful in treating solid tumors as well as lymphomas, and other tumors. These compounds are of interest for the treatment of cancers, including those that are resistant to current therapies.

[0456] Such cancers include, among others, thoracic (breast) cancer, non-small cell lung cancer (NSC), LS), neural tumors such as glioblastoma and neuroblastoma; esophageal cancer, especially rhabdomyosarcoma soft tissue cancers such as non-Hodgkin's lymphoma, also known as anaplastic large cell lymphoma (ALCL) This includes various forms of lymphoma, such as non-Hodgkin lymphoma (NHL), and various forms of leukemia; includes c-met-mediated cancers.

[0457] Anaplastic lymphoma kinase (ALK) is a cell membrane-spanning receptor ALK is a tyrosine kinase that belongs to the insulin receptor subfamily. Receptor tyrosine kinases (RTKs) are a type of lymphoma originally called anaplastic large cell lymphoma (ALCL). ALK was identified due to its involvement in a subtype of human non-Hodgkin's lymphoma. Normally, its distribution is restricted to mammalian cells, and significant levels are only found in the nervous system during embryonic development. , suggesting a possible role for ALK in brain development (Duyster, J. et al., Oncogene, 2001, 20, 5623-5637).

[0458] In addition to its role in normal development, normal full-length ALK expression is observed in tumors including: It has also been detected in cell lines derived from various tumors: neuroblastoma, neuroectodermal tumor (Lamant L et al., Am. J. Pathos., 2000, 156, 1711-1721; Osajima-Hakomori Y. et al., Am. J. Pathol., 2005, 167, 213-222) and glioblastoma (Powers C. et al., J. Biol. Chem. 2002, 277, 14153-14158; Grzelinski M. et al., Int. J. Cancer, 2005, 117, 942-95 1; Mentlein R. et al., J. Neurochem., 2002, 83, 747-753); and breast cancer and melanoma tumor cell lines (Dirk WG et al., Int. J. Cancer, 2002, 100, 49-56).

[0459] As with other RTKs, translocations affect the ALK gene, resulting in the oncogenic fusion kinase For example, undifferentiated large cell type Approximately 60% of lymphomas (ALCL) are caused by the intracellular domains of nucleophosmin (NMP) and ALK. It is associated with a chromosomal mutation that generates a fusion protein consisting of α- and β-lactamase (Armitage, JO et al, Cancer, Principle and Practice of Oncology, 6th edition, 2001, 2256-2316; Kutok, JL & Aster, JC, J. Clin. Oncol., 2002, 20, 3691-3702; Wan, W. et al., Blood, 2006, 107, 1617-1623). This mutant protein, NMP-ALK, acts on downstream effectors. Constitutively active tyrosine kinase domains that cause its oncogenic potential through activation of kinase inhibitors (Falini, B et al., Blood, 1999, 94, 3509-3515; Morris, SW et al. ., Brit. J. Haematol., 2001, 113, 275-295).

[0460] Experimental data suggest that aberrant expression of constitutively active ALK is directly involved in the pathogenesis of ALCL. demonstrated that inhibition of ALK can significantly reduce the growth of ALK-positive lymphoma cells. (Kuefer, MU et al., Blood, 1997, 90, 2901-2910; Bai, RY et al., Exp. Hematol. , 2001, 29, 1082-1090; Slupianek, A. et al., Cancer Res., 2001, 61, 2194-2199; T Urturro, F. et al., Clin. Cancer. Res., 2002, 8, 240-245). Constitutively active chimera A LK is a slow-growing sarcoma that primarily affects children and young adults, called inflammatory myofibroblastic tumor (IL-1). MT) was also demonstrated in approximately 60% of cases (Lawrence, B. et al., Am. J. Pathol., 2000, 157, 377-384). Furthermore, recent reports have shown that in cases of esophageal squamous cell carcinoma (SCC), The occurrence of a mutant ALK fusion, TPM4-ALK, in rhesus monkeys has also been described (Jazzi FR et al. al., World J. Gastroenterol., 2006, 12, 7104-7112; Du X., et al., J. Mol. Med., 2007, 85, 863-875; Aklilu M., Semin. Radiat. Oncol., 2007, 17, 62-69).

[0461] Thus, ALK is involved in tumorigenesis in both non-hematopoietic and hematopoietic malignancies. More recently, it has been shown to be a key regulator of RTK activity in non-small cell lung cancer (NSCLC). In cells, a small inversion within chromosome 2p encodes the microtubule-associated protein-like 4 (EML4) gene. This results in the production of a fusion gene containing a portion of the anaplastic lymphoma kinase (ALK) gene. It was shown that (Soda M. et al., Nature, 2007, 448, 561-567).

[0462] Therefore, ALK inhibitors are promising candidates for use as monotherapy or in the treatment of ALCL, IMT, proliferative disorders, and glaucoma. In combination with current chemotherapy for glioma and other potential solid tumors cited herein. When used in combination with other drugs, it provides a tolerable treatment, or as a monotherapy, It can be used in a maintenance role to prevent relapse in patients who require such treatment. The inventors envision this.

[0463] Pharmaceutical methods: The present invention provides a method for treating an individual suffering from or at risk of suffering from cancer by administering to the individual a therapeutically effective amount of Methods of treatment are provided by administering compounds of the present invention.

[0464] A "therapeutically effective amount" means a dose that reduces or prevents the growth (proliferation) or spread of cancer cells, the size or number of tumors, or detectable disappearance or inhibition of other measures of cancer level, stage, progression, or severity The exact amount required will vary depending on the species, age, and general condition of the individual, as well as the severity of the condition. Depending on the severity of the disease, the type of anti-cancer drug, its administration method, and combination therapy with other therapies, Let's change.

[0465] The compounds or compositions containing the compounds may eliminate or inhibit the growth of tumors or other forms of cancer. Any amount and any route of administration effective for suppression may be administered. The anticancer compound of the present invention is preferably formulated into a unit dosage form for ease of administration and uniformity of dosage. The term "unit dosage form" used here refers to the amount of anti-cancer drug administered to a patient receiving treatment. As is common, the compounds of the present invention are physically separated units. The total daily dosage of the product or composition should be determined by the attending physician using ordinary reliance on sound medical judgment. The specific therapeutically effective dosage level for any individual patient or organism will be determined by the the type of disease being treated; the severity of that disease; the efficacy of the specific compound being used; the patient's age, weight, general health, sex and diet; the route and schedule of administration; the rate of metabolism and / or excretion of the compound; the duration of treatment; may be affected by a variety of factors, including concurrently used medications; and similar factors well known in the medical arts. It will fluctuate accordingly.

[0466] The compositions of the present invention can also be formulated with suitable pharmaceutically acceptable carriers at the desired dosages and then administered. The composition may be administered orally, rectally, parenterally, intracisternally (intracisternally), intrathecally or intravaginally, intraperitoneally, or topically (through the skin patch, powder, ointment, or drops), sublingual, buccal, mouth, or nasal spray , and other routes of administration to humans and other animals.

[0467] The effective systemic dose of the compound is typically 0.01 to 100 mg of compound per kg of patient body weight. 500 mg, preferably 0.1 to 125 mg / kg, and in some cases in the range of 1 to 25 mg / kg The compound is administered in a single dose or multiple doses within the range of 0.1 mg / kg / day. It can be administered to patients in need within the daily dose range of about 50 to 2000 mg per person. Once or multiple times daily, weekly (or other intervals of several days), or on an intermittent dosing schedule For example, the compound may be administered one or more times daily on a weekly basis (e.g., every Monday). The test may be conducted indefinitely or over a set number of weeks (e.g., 4 to 10 weeks). The method involves administering the compound daily for a set number of days (e.g., 2-10 days) and then , then the drug is not administered for a certain number of days (e.g., 1 to 30 days), and this cycle continues indefinitely. Alternatively, the reaction may be repeated a predetermined number of times (e.g., 4 to 10 cycles). The compounds of the invention were administered daily for 5 days, discontinued for 9 days, and then administered daily for an additional 5 days. This cycle can be repeated indefinitely or for a total of 4-9 days. You can repeat this 10 times.

[0468] The amount of compound that is effective to treat or prevent a particular disorder or condition will depend on well-known factors that affect dosage. Additionally, to help identify optimal dosage ranges, the dosage will depend, in part, on the following factors: In vitro or in vivo assays may optionally be employed. A rough guide to effective doses is given in Extrapolation may be made from dose-response curves derived from in vitro or animal model test systems. The exact dosage level should be determined by your physician or other health care provider, which The route of administration, and the age, weight, sex and general health of the individual; the nature, severity and clinical condition of the disease the clinical stage; whether or not combination therapy is used; and the surrounding conditions, including the nature and extent of genetic engineering of the patient's cells. It will vary depending on the factor of knowledge.

[0469] When administered to treat or inhibit a particular disease state or disorder, the effectiveness of the compounds of the present invention is The dosage will depend on the type of compound used, the mode of administration, the type and severity of the condition being treated, and This may vary depending on various physical factors related to the individual being treated. The compound is administered in an amount of about 0.01 mg / kg to 500 mg / kg, preferably 0.1 to 125 mg / kg. kg, and more preferably 1-25 mg / kg daily. The determined daily dose is expected to vary depending on the route of administration. For example, parenteral dosages are often approximately 10 to 20% of oral dosage levels.

[0470] When the compound of the present invention is used as part of a combination regimen, the dosage of each of the combined components are administered for the desired duration of treatment. They may be administered simultaneously in a combined single dosage form or as separate dosage units, or The components used may be administered at different times during the treatment period, or The components may be administered as preparatory treatment for the other component.

[0471] Regarding this compound: The compounds of the present invention may be present in free form for treatment or, where appropriate, For example, it may be present as a pharmaceutically acceptable salt, ester or prodrug. The term "pharmaceutically acceptable salt" as used herein means a salt that, within the scope of sound medical judgment, is not excessively toxic, irritating, or toxic to humans. Suitable for use in contact with the tissues of humans and lower animals without causing irritation, allergic reactions, etc. The term "salts" refers to salts of amines, carboxylic acids, Phosphate esters or salts, as well as pharmaceutically acceptable salts of other classes of compounds, are well known in the art. For example, SM Berge et al., J. Pharmaceutical Science, 66: 1-19 (1977) details pharmaceutically acceptable salts. Salts may be prepared in situ during the isolation and purification of the compounds of the invention, or may be prepared from the free base. or by reacting the free acid form of a compound of the invention with an appropriate acid or base, respectively. It can be prepared separately by

[0472] Examples of pharmaceutically acceptable non-toxic acid addition salts are hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids. Inorganic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or is formed by reaction with an organic acid such as malonic acid, or by the present techniques such as ion exchange. Other methods used in the field include salts of amino groups. Acceptable salts include adipate, alginate, ascorbate, and aspartate. Salt, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate , camphorsulfonate, citrate, cyclopentanepropionate, digluconate Salt, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, Glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, iodide water benzoate, 2-hydroxyethanesulfonate, lactobionate, lactate , laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate Sodium nitrate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate Salt, palmitate, pamoate, pectinate, persulfate, 3-fluorouracil Phenylpropionate, phosphate, picrate, pivalate, propionate, stearate Phosphate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate , undecanoate, valerate, etc.

[0473] Representative alkali or alkaline earth metal salts include sodium, lithium, and potassium. Further pharmaceutically acceptable salts include salts of is, if appropriate, a halogen ion, a hydroxide ion, a carboxylate ion, a sulfate ion, a phosphorus ion, Acid ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions Non-toxic ammonium, quaternary ammonium and amino acids formed with counterions such as Examples of suitable salts include cations.

[0474] Also, as used herein, the term "pharmaceutically acceptable ester" preferably refers to a compound that is hydrolyzable in vivo. Esters containing compounds that decompose easily in the human body and release the parent compound or its salt Suitable ester groups include, for example, esters of pharmaceutically acceptable aliphatic carboxylic acids, In particular those derived from alkanoic, alkenoic, cycloalkanoic and alkanedioic acids wherein each alkyl or alkenyl moiety advantageously has 6 or less carbon atoms. Specific examples of esters include formic acid, acetic acid, propionic acid, butyric acid, acrylic acid, and Esters of ethyl succinic acid are of course also useful as esters of the hydrolyzed compounds of the present invention. It can be formed by reaction with an xyl group or a carboxylic acid group.

[0475] Additionally, as used herein, the term "pharmaceutically acceptable prodrug" refers to a prodrug of a compound of the present invention. A "prodrug" means a drug that acts in vivo, e.g., in the blood. means a compound that is converted by hydrolysis of the formula to yield the parent compound of the formula above. For example, T. Higuchi and V. Stella, Prodrugs as Novel Drug Delivery Systems as Novel Delivery Systems), ACS Symposium Series, Vol. 14 and Edward B. Roche Bioreversible Carriers in Drug Design, edited by American Pharmaceutical Association and Pergamon Press, 1987 (both (hereby incorporated by reference).

[0476] Pharmaceutical Composition: According to the present invention, a compound of the present invention, or a prodrug, pharmaceutically acceptable salt or Other pharmaceutically acceptable esters and one or more pharmaceutically acceptable carriers or excipients These pharmaceutical compositions optionally contain one or more Optionally, the compound of the present invention may further comprise one or more of the above additional therapeutic agents. Therapeutic interventions include two or more other therapeutic interventions (e.g., Gleevec or other kinase inhibitors, interferon bone marrow transplantation, farnesyltransferase inhibitors, bisphosphonates, thalidomide It may be administered to individuals receiving other treatments (e.g., cancer vaccines, hormone therapy, antibodies, radiation, etc.) For example, the compounds of the present invention can be used as one component of a combination therapy, in which case and / or one or more additional therapeutic agents (e.g., anti-cancer agents) may be administered together or separately with the compounds of the present invention. The drug is formulated and administered to the individual.

[0477] The pharmaceutical compositions of the present invention contain a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers and excipients that may be used in the composition include, but are not limited to: Any solvent, diluent, or other vehicle, dispersion, or mixture suitable for the particular formulation desired may also be used. or suspending aid, surfactant, isotonic agent, thickening or emulsifying agent, preservative, solid binder, lubricant Remington's Pharmaceutical Science, 15th Edition, E.W. Martin (Mack Publishing Co., Easton, PA, 1975) is used in formulating pharmaceutical compositions. Various carriers that can be used and known techniques for their preparation are disclosed.

[0478] Some examples of materials that can be used as pharmaceutically acceptable carriers or excipients include: sugars such as, but not limited to, lactose, glucose, and sucrose; cornstarch and potato starch; starches such as cellulose, sodium carboxymethylcellulose, ethylcellulose cellulose and its derivatives such as cellulose acetate; powdered tragacanth; malt; gelatin ; talc; excipients such as cocoa butter and suppository wax; peanut oil, cottonseed oil, safflower oil, Oils such as sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol Cholesterol; esters such as ethyl oleate and ethyl laurate; agar; magnesium hydroxide buffers such as sodium and aluminum hydroxide; alginic acid; pyrogen-free water; Isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer; and other non-toxic and compatible lubricants (such as sodium lauryl sulfate and magnesium stearate). Coloring agents, release agents, coating agents, sweetening agents, flavoring and fragrance agents, preservatives, and antioxidants may also be added to the composition. It can be present inside.

[0479] The compounds of the present invention may be administered by any suitable route, preferably by a pharmaceutical agent adapted for such a route. The compounds of the present invention can be administered in the form of pharmaceutical compositions and in dosages effective for the intended treatment. For example, oral, mucosal, topical, rectal, pulmonary, such as inhalation spray, or intravascular, intravenous, or intraperitoneal Parenteral routes, including intravenous, subcutaneous, intramuscular, intrasternal, and infusion, are acceptable for conventional pharmaceutical use. It may be administered as a dosage unit preparation (formulation) containing the appropriate carrier, adjuvant, and vehicle. do.

[0480] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition may be in the form of a dosage unit containing a specific amount of the active ingredient. Each unit dose is about 1 to 2000 mg, preferably about 1 to 5 00 mg, more usually in the range of about 5 to 200 mg, of the active ingredient. The dosage of the compound of the present invention is within the range of 0.01 to 500 mg of the compound per kg of body weight. Preferably, the dose is 0.1 to 125 mg / kg body weight, and in some cases, 1 to 25 mg / kg body weight. As already mentioned, this daily dose can be administered in one administration or in two doses. , 3, 4 or more times.

[0481] For skin conditions, it is preferred to apply a topical formulation of the compounds of this invention to the affected area two to four times daily. Formulations suitable for topical administration may include those suitable for penetration through the skin. Liquid or semi-liquid preparations (e.g., liniments, lotions, ointments, creams, or pastes) These include drops suitable for administration to the eye, ear or nose. A suitable topical dose of the active ingredient is 0.1 to 150 mg, administered 1 to 4 times daily, preferably 1 or 2 times daily. For topical administration, the active ingredient is 0.001 to 10% of the formulation (formulation). The content may be, for example, 1 to 2% by weight, for example, 10% w / w of the formulation. Although it can be as high as 5% w / w or less, it is preferably 5% w / w or less, and more preferably 0. It is 1 to 1%.

[0482] When formulated as an ointment, the active ingredient is placed in either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may be formulated with, for example, propylene glycol. Butane-1,3-diol, Mannitol, Sorbitol, Glycerol, Polyethylene Contains 30% w / w or more of polyhydric alcohols such as polyethylene glycol and mixtures thereof Topical formulations desirably facilitate absorption or administration of the active ingredient through the skin or other affected area. The composition may contain compounds that enhance skin penetration. Such skin penetration enhancers include dimethicone and methylpropional. These include aryl sulfoxides and related analogues.

[0483] The compounds of the invention may also be administered by a transdermal device. Preferably, the device comprises a reservoir / porous membrane. Transdermal administration may be accomplished using a patch either of the viscous or solid matrix variety. In this case, the active ingredient is delivered from the reservoir or microcapsules through a membrane to the recipe. The active agent is continuously delivered to the patient's skin or mucosa through a permeable adhesive. When an active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is delivered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. .

[0484] The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. It may consist solely of an emulsifier, but it may also consist of at least one emulsifier and a fat or oil, or a fat and an oil. Preferably, a hydrophilic emulsifier is used as a stabilizer. It is also preferred to include both an oil and a fat together with the lipophilic emulsifier used. In addition, the emulsifier with or without the stabilizer constitutes the so-called emulsified wax. The emulsion is formed by mixing the wax with oils and fats to form the oily dispersed phase of the cream formulation. It is also preferred to form an ointment base. As emulsion stabilizers, Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol Cole, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate These include the use of silane alone or in combination with wax or other materials known in the art. do.

[0485] This activation in most oils that may be used in medicated emulsion formulations Since the solubility of the compound is very low, the selection of an appropriate oil or fat for the formulation must be consistent with the desired aesthetic. The objective is to achieve cosmetic properties, i.e., the cream is not greasy and does not stain. It should be possible to wash away any imperfections or scratches and to prevent leaks from tubes or other containers. It is preferable that the consistency be such that it is suitable for avoiding spills. Isoadipate, Isocetyl Stearate, Propylene Glycol Diester of Coco-Oleate ester, isopropyl myristate, decyl oleate, isopropyl palmitate, stearyl such as butyl allyl ester, 2-ethylhexyl palmitate or a mixture of branched chain esters Linear or branched chain monobasic or dibasic alkyl esters may be used. They can be used alone or in combination depending on the properties required.

[0486] Alternatively, white soft paraffin (petrolatum) and / or liquid paraffin or other mineral oils High melting point lipids such as Formulations suitable for topical administration to the eye may comprise the active ingredient in a suitable carrier, particularly a soluble form of glycerol for the active ingredient. The present invention also includes eye drops dissolved or suspended in an aqueous solvent. It may be present in a concentration of 0.5 to 20% w / w, advantageously 0.5 to 10%, in particular about 1.5%. preferable.

[0487] Formulations for parenteral administration are in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions or suspensions may be prepared from sterile powders or granules and then used in the preparation of oral formulations. with one or more of the carriers or diluents described above for use in the compositions, or The compound can be formulated using suitable dispersing or wetting agents and suspending agents. Water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, Peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum and / or It may be dissolved in various buffer solutions.

[0488] Other adjuvants and modes of administration are well known and widely known in the pharmaceutical art. a composition using a suitable carrier such as cyclodextrose, dextrose, or water; Solubilized in strings (e.g., Captisol), cosolvents (e.g., propylene glycol), or micelles It may also be administered by injection as a composition containing an anti-inflammatory agent (e.g., Tween 80).

[0489] The sterile injectable preparation is a sterile injectable solution in a non-toxic parenterally acceptable diluent or solvent. Or it may be a suspension, for example a solution in 1,3-butanediol. Acceptable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be used, including diglycerides. Fatty acids also find use in the preparation of injectables.

[0490] For pulmonary administration, the pharmaceutical composition may be administered in the form of an aerosol or as a dry powder aerosol. It may also be administered by means of an inhaler containing Suppositories for rectal administration of drugs are solid at room temperature but become liquid at rectal temperature. Cocoa butter and polyethylene glycols therefore melt in the rectum to release the drug. The formulation can be prepared by mixing the drug with a suitable non-irritating excipient such as:

[0491] The pharmaceutical compositions may be subjected to conventional pharmaceutical procedures such as sterilization and / or may contain preservatives, stabilizers, etc. They may contain conventional adjuvants such as fillers, wetting agents, emulsifiers, buffers, etc. They may also be formulated with enteric coatings. Such compositions may contain wetting agents, sweeteners, flavoring agents, and may contain adjuvants such as flavorings.

[0492] Combination therapy The compounds of the present invention may be administered as part of a treatment regimen in which they are the only active pharmaceutical ingredient. It can also be used as part of a combination therapy in conjunction with one or more other therapeutic agents. When administered as a component of a combination therapy, the therapeutic agents may be administered simultaneously. administered simultaneously or sequentially at different times (e.g., 72 hours, 48 ​​hours, 24 hours apart from each other) The therapeutic agents can be formulated as separate compositions, or the therapeutic agents can be combined into a single formulation. They may also be formulated together as pharmaceutical compositions and administered simultaneously.

[0493] Thus, administration of the compounds of the present invention may be in combination with radiation therapy or other cytostatic, cytotoxic, or other therapeutic agents. Anti-cancer drugs and other drugs that improve the symptoms of cancer or the side effects of either drug. It may also be used in combination with additional treatments known to those skilled in the art for the prevention or treatment of cancer.

[0494] When formulated as a fixed dose, such combination products may be administered in a manner that allows the compounds of the invention to be tolerated. The compounds of the present invention may also be used in combination with other anti-inflammatory drugs if combination use is inappropriate. The present invention is not limited to the administration order. In addition, the compounds of the present invention may be administered prior to, concurrently with, or after other anticancer or cytotoxic agents. This can be done.

[0495] Currently, the standard treatment for primary tumors is surgical resection, if appropriate, followed by radiation or , typically administered intravenously (IV). Therapeutic regimens include DNA alkylating agents, DNA intercalating agents, CDK inhibitors, or microRNAs. The chemotherapy dose is slightly less than the maximum tolerated dose. Therefore, dose-limiting toxicities typically include nausea, vomiting, diarrhea, alopecia, and neutropenia. Examples include:

[0496] Commercially available, clinically evaluated, and clinically available drugs that may be selected for combination drug chemotherapy cancer treatment There are a large number of anti-tumor drugs available in pre-development. These include several major There are several key categories: antibiotic-type agents, alkylating agents, antimetabolites, hormonal agents, immunological agents, interferon-type agents, and other categories of agents.

[0497] A first class of antineoplastic agents that may be used in combination with the compounds of the present invention are antimetabolites. Suitable antimetabolite antineoplastic agents include: They may be selected from the group consisting of, but not limited to: 5-FU fibrinogen; Acanthofolic acid, aminothiadiazole, brequinar sodium , Carmofur, Ciba-Geigy CGP-30694, Cyclopentyl cytosine, Cytara phosphate Binstearates, Cytarabine conjugates, Lilly DATHF, Merrell Dow DDFC, Deza Guanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, dox Fluridin, Wellcome EHNA, Merck EX-015, Fazarabine, Floxuridine, Phosphorus Fludarabine, 5-fluorouracil, N-(21-furanidyl)fluorouracil, Daiichi Pharmaceutical F O-152, isopropylpyrrolidine, Lilly LY-188011, Lilly LY-264618, methobenzapride MZPES, Norspermidine, NCI NSC-127716, NCI NSC -264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, Pentostatin , piritrexim, plicamycin, Asahi Kasei PL-AC, Takeda TAC788, thioguanine, thiazolinone Flynn, Elbamont TIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT, and and urishitin.

[0498] A second class of antineoplastic agents that may be used in combination with the compounds of the present invention consists of alkylating agent-type antineoplastic agents. Suitable alkylating antineoplastic agents may be selected from the group consisting of, but not limited to: Can be used with: Shionogi 254-S, aldophosphamide analogs, altretamine, anaki Chiron, Behringer Mannheim BBR-2207, Best Love Sil, Budotitanium, Yuenaga CA-102 , carboplatin, carmustine, quinone-139, quinone-153, chlorambucil, cis Platinum, cyclophosphamide, American Cyanamide CL-286558, Sanofi CY-233, Cyplatate, Degussa D384, Sumitomo DACHP (Myr) 2, Diphenylspiromustine, Diplatinum saponin Itostatin, Erba-distamycin derivative, Chugai DWA-2114R, ITI E09, Elmustine , Elbamont FCE-24517, Estramustine Phosphate Sodium, Fotemustine, Sea Urchin Med GM, Quinoin GYKI-17230, Hepsulfam, Ifosfamide, Iproplatin, Lomustine, mafosfamide, mitraktorf, Nippon Kayaku NK-121, NCI NSC-264395, NC I NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Protar PTT- 119, Ranimustine, Semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, Piromustine, Tanabe Pharmaceutical TA-077, Tauromustine, Temozolomide, Teloxylon, Tetra Platin and trimelamol.

[0499] A third class of antineoplastic agents that may be used in combination with the compounds of the present invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antitumor agents may be selected from the group consisting of, but not limited to: Taiho 4181-A, aclarubicin, actinomycin D, actinoplanon, ervamon ADR-456, aeroprisinin derivative, Ajinomoto AN II, Ajinomoto AN3, Nippon Soda Anisomycin Anthracyclines, azinomycin A, viscaverin, Bristol-Myers B L-6859, Bristol-Myers BMY-25067, Bristol-Myers BNY-25551, Bris Toll-Myers BNY-26605, Bristol-Myers BNY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calicheamicin, Clomoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC -79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-Al, Kyowa Hakko DC92-B, ditricarubicin B, Shiono GiDOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epi Rubicin, Erbstatin, Esorubicin, Esperamicin-Al, Esperamicin-Alb, Elbamont FCE21954, Fujisawa FK-973, Fostriesin, Fujisawa FR-900482, Glidobakchi gregatin-A, glinkamycin, herbimycin, idarubicin, illudins, Zusamycin, Kesarirosins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko K T-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamide LL-D49194, Meiji Confectionery ME2303, Menogaril, Mitomycin, Mitoxantrone, SmithKline M-TAG, Ne Oenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, Oxalicyin, oxaunomycin, peplomycin, pyratin, pirarubicin, polos Ramycin, Piridamycin A, Tobishi RA-1, Rapamycin, Rhizoxin, Rodolive Shibanomi, Shiwenmycin, Sumitomo SM5887, Snow Brand SN-706, Snow Brand SN-07, Solangi Syn-A, Sparsomycin, SS Pharmaceutical SS-21021, SS Pharmaceutical SS-7313B, SS Drugs SS-9816B, Stefimycin B, Taiho 4181-2, Tallysomycin, Takeda TAN-868A, Terpe Anticancer, Thorazine, Triclozaline A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fuji Sawa WF-3405, Yoshitomi Y-25024 and Zorubicin.

[0500] A fourth class of anti-tumor agents that may be used in combination with the compounds of the present invention are tubulin-interacting agents, topoisomers. A miscellaneous group of anti-cancer drugs including isomerase II inhibitors, topoisomerase I inhibitors, and hormonal agents Oncology drugs, which may be selected from the group consisting of, but not limited to: : α-carotene, α-difluoromethylarginine, acitretin, Biotech AD-5, Kyorin AHC-52, alstonine, amonafide, amfetinil, amsacrine, angiostat anquinomycin, antineoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A4, antineoplaston A5, antineoplaston A6, antineoplaston A7, antineoplaston A8, antineoplaston A9, antineoplaston A10, antineoplaston A10, antineoplaston A2, antineoplaston A10 ... Oplaston A3, Antineoplaston A5, Antineoplaston AS2-1F, Henkel APD , Aphidicolin Glycine, Asparaginase, Avarol, Baccarin, Batracillin Benfluron, Benzotript, Ipsen-Bofur BIM-23015, Bisantrene , Bristol-Myers BNY-40481, Bester Boron-10, Bromophosphamide, Welcom BW-502, Welcom BW-773, caracemide, carmethisol hydrochloride, Ajinomoto CDAF, Lorsulfa Kinokisalon, Chemex CHX-2053, Chemex CHX-100, Warner Lumber CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert Bart CI-958, Cranfenur, Claviridenone, ICN Compound 1259, ICN Compound 4711, Co Ntrakan, Yakult Honsha CPT-11, Crisnatol, Claderm, Sitcharasin B, Tarabin, Cytocitin, Mels D-609, DABIS maleate, Dacarbazine, Daterliptin , didemnin-B, dihematoporphyrin ether, dihydrolenperone, dinaline, di Stamycin, Toyo Pharma DM-341, Toyo Pharma DM-75, Daiichi Pharmaceutical DN-9693, Docetaxel ru, elipravine, elliptinium acetate, Tsumura EPMTC, epothilones, ergotamine, Toposide, etretinate, fenretinide, Fujisawa FR-57704t, gallium nitrate, Gencada Junin, Chugai GLA-43, Glaxo GR-63178, Grifolan NMF5N, Hexadecylphosphocholine Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, Il Mofosine, Isoglutamine, Isotretinoin, Otsuka JI-36, Ramot K-477, Otsuka K-76 COONa, Kureha Chemical K-AM, MECT KI-8110, American Cyanamide L-623, Leucoregulin , Lonidamine, Lundbeck LU 1121, Lilly LY-186641, NCI (US) MAP, Maricin, Mele Le Dow MDL-27048, Medco MEDR-340, merbaron, merocyanine derivatives, methylaniline Noacridine, Molecular Genetics MGI136, Minactivin, Mitonafide, Mitoquidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl) amino acids , Nisshin Flour Milling N-021, N-acylated dehydroalanines, Nafazatrom, Taisho NCU-190, Noko Dazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NC NSC-95580, Octreotide, Ono ONO-112, Oxanocin, Akzo Org-10172, Paclitaxel Kisel, pancratistatin, pazelliptin, Warner-Lambert PD-111707, Warner Warner Lambert PD-115934, Warner Lambert PD-131141, Pierre Fabre PE-1 001, ICRT peptide D, pyroxantrone, polyhematoporphyrin, polyprenoic acid, Famorph porphyrin, probimane, procarbazine, proglumide, Invitrogen Protease Nexin I, Tobishi RA-700, Razoxane, Sapporo Beer RBS, Restrictin -P, Reteriptin, Retinoic Acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-569 76, SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, Seafarm SP10094, Patol, spirocyclopropane derivatives, spirogermanium, Unimed, S.S. Pharmaceuticals SS-554, Strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071 , Superoxide dismutase, Toyama T-506, Toyama T-680, Taxol, Teijin TEI-03 03, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topotecan, Topostin, Teijin TT82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, Ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, Binestramide, vinorelbine, vintriptol, vinzolidine, withanolide and Yamanouchi YM.

[0501] Alternatively, the compounds may be used in co-treatment with other anti-tumor drugs. Examples include: acemannan, aclarubicin, aldesloy Kin, alemtuzumab, alitretinoin, altretamine, amifostine, aminole buprenorphine, amrubicin, amsacrine, anagrelide, anastrozole, Ansar (A NCER), ancestine, arglavine, arsenic trioxide, BAM 002 (Nobelos), bexarotene , bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix , cladribine, clotrimazole, cytarabine ocphosphate, DA 3030 (Dong-A) , daclizumab, denileukin-difitox, deslorelin, dexrazoxane, Dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine , doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT Diclofenac, interferon α, daunorubicin, doxorubicin, tretinoin Noin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin Epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozol filgrastim, finasteride, fludarabine phosphate, formestane, fote Mustine, gallium nitrate, gemcitabine, gemtuzumab ozogamicin, gimeracil / Oteracil / tegafur combination drug, glycopin, goserelin, heptaplatin, human chorionic villus Gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, imipenem Quimod, interferon alpha, natural interferon alpha, interferon alpha-2, interferon -Interferon α-2a, interferon α-2b, interferon α-NI, interferon α-n3, interferon α-con1, natural interferon α, interferon β, interferon Interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon Interferon gamma-1a, interferon gamma-1b, interleukin-1β, iobenguane, irinotecan Can, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenoglas thim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, Vamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin metoclopramide, mifepristone, myrtle, methadone, methadone, methadone Fosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxa Introne, molgramostim, nafarelin, naloxone + pentazocine, nartoglas Chim, Nedaplatin, Nilutamide, Noscapine, Novel Erythropoiesis-Stimulating Protein, NSC 631570, octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel Cell, pamidronate, pegaspargase, peginterferon α-2b, pentose polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody monoclonal antibody, polyethylene glycol interferon α-2a, porfimer sodium Raloxifene, raltitrexed, rasburicase, rhenium (Re 186) etidronate rituximab, romurtide, samarium (153 Sm) lexidronam , sargramostim, sizofiran, sobuzoxane, sonermin, strontium-8 chloride 9. Suramin, tasonermin, tazolotene, tegafur, temoporfin, temozolomide , teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alpha, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, threonine Sulfane, Tretinoin, Trilostane, Trimetrexate, Triptorelin, Natural Tumor necrosis factor alpha, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate Vaccines, valrubicin, verteporfin, vinorelbine, virurisin, zinostatin stimalamer, or zoledronic acid; avalarix, AE 941 (Eterna ), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (De andreone), cetuximab, decitabine, dexaminoglutethimide, diaziquone (diaziq uone), EL 532 (Elan), EM 800 (Andrecherche), eniluracil, etanidazo ol, fenretindel, filgrastim SDO1 (Amgen), fulvestrant, Rocitabine, gastrin-17 immunogen, HLA-17 gene therapy (Bical), granulocyte-macrophage Colony-stimulating factors, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat , IM 862 (Cytolan), Interleukin-Iproxifen, LDI 200 (Milk House ), Religistim, Lintuzumab, CA 125 MAb (Biomira), Cancer MAb (Nihon Yakuhin Kaihatsu), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM iodine-131 MAb (Techniclone), polymorphic epithelial murine Chin-Itrim 90 MAb (antizoma), marimastat, menogaril, mitsumomab, Motexafin, gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 3 0 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, spa Rufosic Acid, SRL 172 (SR Pharma), SU 5416 (Sugen), SU 6668 (Suzi) TA 077 (Tanabe), tetrathiomolybdate, thaliblastin, thrombopoietin , tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma Melanoma Vaccine (New York University), Melanoma Vaccine (Sloan-Kettering Research melanoma oncolysate vaccine (New York Medical College), viral melanoma Norma cell lysate vaccine (Royal Newcastle Hospital), or Valspodar.

[0502] medical kit In another aspect, the present invention provides a kit for conveniently and effectively carrying out the method of the present invention. Generally, a pharmaceutical pack or kit contains one or more components of the pharmaceutical composition of the present invention. and one or more containers filled with the pharmaceutical composition as part of the methods described herein. and instructions for administration (e.g., label or package insert). Such kits are particularly suited for the delivery of solid oral dosage forms such as tablets or capsules. The kit preferably includes a plurality of unit dosage forms, and the dosage forms are packaged in a manner consistent with their intended use. The dosage form may optionally include a card directing the user to the order in which the dosage form is to be administered. Specify the dates of the treatment schedule, e.g., numbers, letters, or other marks. or calendar pages can be provided as a memory aid. The only items that may be combined with such containers are those that regulate the manufacture, use, or sale of pharmaceuticals. This notice is in the form prescribed by the regulatory authority in charge of the manufacture of medicinal products for human use. , reflecting the authorizations of the use or sale authorities.

[0503] The following representative examples may be applied to the practice of various aspects of the present invention and their equivalents. These examples help illustrate the invention and contain important additional information, examples, and guidance that can be used to It is intended to be illustrative and not to limit the scope of, or otherwise affect the accuracy of, the following: Indeed, various embodiments of the present invention in addition to those shown and described herein may be practiced in various other ways. Modifications and many further embodiments thereof are described in the examples below and in the scientific literature and methods cited herein. This will be apparent to those skilled in the art upon review of this document, including references to the patent literature. To assist in this discussion, the contents of the documents cited in the specification are hereby incorporated by reference. For purposes of the invention, chemical elements are defined as those elements listed in the Handbook of Chemistry and Physics, 75th Edition, Item 1. They are designated according to the paper version of the CAS Periodic Table. In addition, they are based on the principles of organic chemistry and Specific functional groups or moieties and reactivities are described in "Organic Chemistry," Thomas Sorrell, Univ. versity Science Books, Sausalito: 1999 and "Organic Chemistry" Morrison & Boyd ( 3rd Edition), the entire contents of both of which are incorporated herein by reference. [Example]

[0504] Example 1 N-[4-(dimethylphosphoryl)phenyl]-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl) (trimethyl)pyrimidin-2-amine

[0505] [ka]

[0506] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidine-2 -amine 4 in 15 mL of N,N-dimethylacetamide and 3.6 mL of diisopropylethylamine A suspension of 2-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) was added to the clear The mixture was stirred at room temperature for 15 minutes until a solution was obtained. Midine (5.7 g, 2.6 mmol) was added in four portions over 5 min. The reaction mixture was heated at 60 °C for 1 The reaction mixture was stirred for 1 hour. The reaction mixture was cooled to room temperature and filtered to obtain a white solid. This white solid was The white solid was washed three times with 50 mL of water and then three times with 50 mL of ethyl ether. The desired product was obtained (3.8 g, 49% yield). MS / ES+: m / z=350.

[0507] N-[4-(dimethylphosphoryl)phenyl]-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl) (trimethyl)pyrimidin-2-amine : 4-chloro-N-[4-(dimethylphosphoric acid)-2-(2-methyl-2-methyl-1H-pyridinyl)-2H-pyridinyl] in 1.5 mL of ethanol [(2- ... To the solution, 10 μL of triethylamine and 1-methylpiperazine (7.2 mg, 0.072 mmol) were added. The mixture was heated in a microwave at 120°C for 20 minutes. Filtration and purification by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase) yielded The compound was obtained as a white solid (24 mg, 79% yield). MS / ES+: m / z=414.

[0508] Example 2 N 2 -[4-(dimethylphosphoryl)phenyl]-N 4 -(Tricyclo "3.3.1.1 3,7 "Deku-1-Il)-5 -(trifluoromethyl)pyrimidine-2,4-diamine

[0509] [ka]

[0510] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- (trimethyl)pyrimidin-2-amine (prepared as described in Example 1: 27 mg, 0.078 mmol) To this solution, 10 μL of triethylamine and 1-adamantanamine (12 mg, 0.078 mmol) were added. The mixture was heated in a microwave at 120° C. for 20 minutes. The reaction mixture was syringe-filled. The mixture was filtered and purified by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase). The product was obtained as a white solid (3 mg, 8% yield). MS / ES+: m / z=465.

[0511] Example 4 N 2 -[4-(dimethylphosphoryl)phenyl]-N 4 -(morpholin-4-ylmethyl)-5-(trifluoromethyl) (trimethyl)pyrimidine-2,4-diamine

[0512] [ka]

[0513] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- Methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) The solution was added with 50 μL of triethylamine and 4-(2-aminoethyl)morpholine (15 mg, 0.12 mmol). The mixture was heated in a microwave at 120°C for 20 minutes. The mixture was filtered and purified by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase). The product was obtained as a white solid (42 mg, 81% yield). MS / ES+: m / z=430.

[0514] Example 5 4-(2-{[2-{[4-(dimethylphosphoryl)phenyl]amino}-5-(trifluoromethyl)pyrimidinyl 4-( ...

[0515] [ka]

[0516] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- Methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) The solution was added with 50 μL of triethylamine and 23 mg of 4-(2-aminoethyl)benzenesulfonamide. 0.12 mmol) was added. The mixture was heated in a microwave at 120°C for 20 minutes. The solution was filtered through a syringe filter and then purified by preparative HPLC (Waters Sunfire C18 column, ACN / Water) to give the product as a white solid (30 mg, 49% yield). MS / ES+: m / z=514.

[0517] Example 6 N 2 -[4-(dimethylphosphoryl)phenyl]-N 4 -(tetrahydrofuran-2-yl)-5-(trifluoromethyl)- (Oromethyl)pyrimidine-2,4-diamine

[0518] [ka]

[0519] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- Methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) The solution was added with 50 μL of triethylamine and (s)-3-aminotetrahydrofuran hydrochloride (14 mg, 0.12 The mixture was heated in a microwave at 120°C for 20 minutes. The mixture was filtered through a filter and then purified by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase). to give the product as a white solid (27 mg, 59% yield). MS / ES+: m / z=401.

[0520] Example 7 N 2 -[4-(dimethylphosphoryl)phenyl]-N 4 -(hexahydrocyclopenta[c]pyrrole-2( 1H)-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0521] [ka]

[0522] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- A solution of (methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) 50 μL of triethylamine and 3-amino-3-azabicyclo[3.3.0]octane hydrochloride (19 mg, 0.12 mmol) was added. The mixture was heated in a microwave at 120°C for 20 minutes. The solution was filtered through a syringe filter and then purified by preparative HPLC (Waters Sunfire C18 column, ACN / Water) to give the product as a white solid (34 mg, 67% yield). MS / ES+: m / z=440.

[0523] Example 8 N 2-[4-(dimethylphosphoryl)phenyl]-N 4 -(morpholin-4-yl)-5-(trifluoromethyl) (I)pyrimidine-2,4-diamine

[0524] [ka]

[0525] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- Methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) To the solution was added 50 μL of triethylamine and 4-aminomorpholine (12 mg, 0.12 mmol). The mixture was heated in a microwave at 120°C for 20 minutes. Filtration and purification by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase) yielded The compound was obtained as a white solid (6 mg, 12% yield). MS / ES+: m / z=416.

[0526] Example 9 N-[4-(dimethylphosphoryl)phenyl]-4-(4-phenylpiperazin-1yl)-5-(trifluoromethyl)- (Oromethyl)pyrimidin-2-amine

[0527] [ka]

[0528] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- Methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) To the solution, 50 μL of triethylamine and 1-phenylpiperazine (19 mg, 0.12 mmol) were added. The mixture was heated in a microwave at 120°C for 20 minutes. The reaction mixture was then filtered through a syringe. The crude product was filtered and purified by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase). The product was obtained as a white solid (40 mg, 73% yield). MS / ES+: m / z=476.

[0529] Example 10 N 2 -[4-(dimethylphosphoryl)phenyl]-N 4 -[2-(1H-indol-3-yl)ethyl]-5-(trimethylsilyl)- ... (trifluoromethyl)pyrimidine-2,4-diamine

[0530] [ka]

[0531] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- Methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) To the solution, 50 μL of triethylamine and tryptamine (18 mg, 0.12 mmol) were added. The mixture was heated in a microwave at 120° C. for 20 minutes. The reaction mixture was filtered through a syringe filter. The product was purified by preparative HPLC (Waters Sunfire C18 column, ACN / water as the mobile phase) to give a white A colored solid was obtained (44 mg, 81% yield). MS / ES+: m / z=474.

[0532] Example 11 N 2 -[4-(dimethylphosphoryl)phenyl]-N 4-[4-methylpiperazin-1-yl]-5-(trifluoromethyl)- (Oromethyl)pyrimidine-2,4-diamine

[0533] [ka]

[0534] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- Methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) The solution was added with 50 μL of triethylamine and 1-amino-4-methylpiperazine (13 mg, 0.12 mmol). The mixture was heated in a microwave at 120° C. for 20 minutes. The mixture was filtered through a filter and purified by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase). The product was obtained as a white solid (17 mg, 34% yield). MS / ES+: m / z=429.

[0535] Example 12 N 2 -[4-(dimethylphosphoryl)phenyl]-N 4 -[4-tricyclo[3.3.1.1 3.7 ]Deku-1-Ilme 5-(trifluoromethyl)pyrimidine-2,4-diamine

[0536] [ka]

[0537] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- Methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) The solution was added with 50 μL of triethylamine and 1-adamantanemethylamine (19 mg, 0.12 mmol). The mixture was heated in a microwave at 120° C. for 20 minutes. The mixture was filtered through a filter and purified by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase). The product was obtained as a white solid (40 mg, 73% yield). MS / ES+: m / z=479.

[0538] Example 13 N 2 -[4-(dimethylphosphoryl)phenyl]-N 4 -[4-(4-methylpiperazin-1-yl)benzyl] -5-(trifluoromethyl)pyrimidine-2,4-diamine

[0539] [ka]

[0540] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- Methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) The solution was diluted with 50 μL of triethylamine and 4-(4-methylpiperazine)benzylamine (24 mg, 0.12 The mixture was heated in a microwave at 120°C for 20 minutes. The mixture was filtered through a filter and then purified by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase). to give the product as a white solid (21 mg, 73% yield). MS / ES+: m / z=519.

[0541] Example 14 N 4-(3,5-dimethylphenyl)-N 2 -[4-(dimethylphosphoryl)phenyl]-5-(trifluoro Methyl)pyrimidine-2,4-diamine

[0542] [ka]

[0543] 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)- Methyl)pyrimidin-2-amine (prepared as described in Example 1: 40 mg, 0.12 mmol) The solution was added with 10 μL of 2M hydrochloric acid in methanol and 3,5-dimethylaniline (14 mg, 0.12 mmol). The mixture was heated in a microwave at 120°C for 20 minutes. The mixture was filtered and purified by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase). The product was obtained as a white solid (32 mg, 65% yield). MS / ES+: m / z=435.

[0544] Example 15 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -phenylpyrimidine- 2,4-diamine

[0545] [ka]

[0546] 2,5-Dichloro-N-phenylpyrimidin-4-amine : Aniline (205 m g, 2.2 mmol) and 2,4,5-trichloropyrimidine (500 mg, 2.7 mmol) were added to a solution of potassium carbonate. 500 mg of ammonium chloride was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography with 10% ethyl acetate in heptane. The desired product was obtained as an oil (370 mg, 70% yield).

[0547] (3-Methoxy-4-nitrophenyl)(dimethyl)phosphane oxide : 5-chloro- A solution of 2-nitroanisole (0.5 g, 2.67 mmol) was added to dimethylphosphine oxide (0. 229 g, 2.93 mmol), palladium acetate (30 mg, 0.13 mmol), Xantphos (0.092 g, 0.16 mmol) mol), and potassium phosphate (0.623 g, 2.93 mmol) were added. The mixture was purged with argon. The reaction mixture was basified with saturated sodium bicarbonate solution and heated to 120°C for 18 hours. Extraction with ethyl acetate was performed. The organic layer was concentrated and purified by preparative HPLC to give the final product (0. 16 g, 30% yield. MS / ES+: m / z=229.

[0548] 4-(Dimethylphosphoryl)-2-methoxyaniline : (3-methoxy-4-nitro) in 5 mL of EtOH A solution of 10 wt. phenyl)(dimethyl)phosphane oxide (0.1 g, 0.44 mmol) was added to a carbon-supported % palladium (0.2 g) was added. The mixture was purged with argon and heated under 30 psi for 2 hours in water. The resulting mixture was filtered through Celite (filtering material) with HCl ethanol solution. The filtrate was concentrated to give the final product (0.088 g, Yield 86%). MS / ES+: m / z=199.

[0549] 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -phenylpyrimidine- 2,4-diamine : 2,5-Dichloro-N-phenylpyrimidin-4-amine (84 mg, 0. 35 mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg, 0.30 mmol) To the mixture was added 0.36 mL of 2.5 M HCl in ethanol, and the reaction mixture was heated in a sealed tube at 140°C overnight. The reaction mixture was filtered through a syringe filter and purified by preparative HPLC (Waters Sunfire C18 column). The desired product was obtained as a white solid (23 mg, 16% yield). MS / ES+: m / z=403.

[0550] Example 16 N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) [phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0551] [ka]

[0552] 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine 4-aminomethyl-4-amine : 1-amino-2-(isopropyl sulfonyl)propanol in 4 mL of N,N-dimethylformamide To a solution of (methyl)phenylbenzene (350 mg, 1.6 mmol) at 0°C, sodium hydride (100 mg) was added. The reaction mixture was stirred at 0° C. for 20 minutes. Dinol (350 mg, 1.6 mmol) was added in one portion and the reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC. The desired product was obtained as a white solid (10 mg, 2% yield).

[0553] N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) [phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine :2-Methoxyethanol 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl) ) pyrimidin-4-amine (7.5 mg, 0.02 mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline A solution of 2.5M HCl in ethanol was added to a solution of 2.5M HCl in ethanol. 1 mL of the ethanol solution was added. The reaction mixture was heated in a sealed tube at 140°C overnight. The mixture was filtered through a filtration filter and purified by preparative HPLC (Waters Sunfire C18 column, ACN / water mobile phase). Purification gave the desired product as a white solid (0.9 mg, 8% yield). MS / ES+: m / z=543.

[0554] Example 17 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-yl) Sulfonyl)phenyl]pyrimidine-2,4-diamine

[0555] [ka]

[0556] 2,5-Dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine : DM F 1-amino-2-(isopropylsulfonyl)benzene (0.955 g, 4.80 mmol) in 2 mL at 0 °C To the solution of 2, 4, and 5, NaH (60% in oil, 0.349 g, 8.72 mmol) was added in one portion. After stirring for 20 minutes, -trichloropyrimidine was added. The mixture was stirred at 0°C for 30 minutes and then at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution, and the mixture was then diluted with water / ethyl acetate. The yellow suspension was filtered to give the final product (0.3 g, 20% yield). MS / ES+: m / z=346.

[0557] 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-yl) Sulfonyl)phenyl]pyrimidine-2,4-diamine : 2,5-dichloromethane in 1 mL of 2-methoxyethanol Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.050 g, 0. To a solution of 4-(dimethylphosphoryl)-2-methoxyaniline (as described in Example 15), To the mixture was added 0.12 mL of 2.5 M HCl in ethanol. The mixture was heated in a sealed tube at 140° C. for 1 hour. The mixture was basified with saturated sodium bicarbonate solution. The organic layer was purified by preparative HPLC to give the final product (20 ml). g, 24% yield). MS / ES+: m / z=508.

[0558] Example 18 5-Chloro-N 2 -[4-(dimethylphosphoryl)phenyl]-N 4 -[2-(propan-2-ylsulfonyl) Phenyl]pyrimidine-2,4-diamine

[0559] [ka]

[0560] 2,5-Dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]phenyl]propan-2-ylsulfonyl ... [Nyl]pyrimidin-4-amine (prepared as described in Example 17, 50 mg, 0.14 mmol) To the solution, 4-(dimethylphosphoryl)-2-methoxyaniline (prepared as described in Example 15) 0.029 g, 0.14 mmol) and 0.12 mL of 2.5 M HCl in ethanol were added. The mixture was heated in a tube at 140°C for 1 hour. The mixture was made basic with saturated sodium bicarbonate solution and ethyl acetate was added. The organic layer was purified by preparative HPLC to give the final product (0.100 g, 15% yield). MS / ES+: m / z=478.

[0561] Example 19 5-Chloro-N 4 -[4-(dimethylphosphoryl)phenyl]-N 2 -{2-Methoxy-4-[4-(4-methylpiperazinyl) (radin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine

[0562] [ka]

[0563] 2,5-Dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine : DMF 1 mL To a solution of 2,4,5-trichloropyrimidine (0.15 mL, 1.31 mmol) in 4-(dimethylphosphoryl)-2,4,5-trichloropyrimidine (0.15 mL, 1.31 mmol) was added (aryl)aniline (0.221 g, 1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol) were added. The mixture was heated at 110°C for 4 hours, then made basic with saturated sodium bicarbonate solution. The resulting suspension was filtered and washed with ethyl acetate to give the final product (0.15 g, yield 36%). MS / ES+: m / z=316.

[0564] 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine : DMF To a solution of 5-fluoro-2-nitroanisole (0.5 g, 2.92 mmol) in 3 mL of 1-methyl-4-( piperazine (0.536 g, 2.92 mmol) and potassium carbonate (0.808 g, 5.84 mmol) The mixture was heated to 120°C for 18 hours. The mixture was washed with saturated sodium bicarbonate solution. It was made basic and extracted with ethyl acetate. The organic layer was purified by chromatography to give the final product. The product was obtained as a yellow solid (0.95 g, 95% yield). MS / ES+: m / z=334.

[0565] 2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline : Argo 1-[1-(3-methoxy-4-nitrophenyl)piperidine-4- ( A solution of 10% palladium on carbon (0. 060 g) was added. After 4 hours under 30 psi, the hydrogenation was completed. The resulting mixture was The solution was filtered through a filter into a flask containing ethanolic HCl. The filtrate was concentrated. The final product was obtained (0.15 g, 88% yield). MS / ES+: m / z=334.

[0566] 5-Chloro-N 4 -[4-(dimethylphosphoryl)phenyl]-N 2 -{2-Methoxy-4-[4-(4-methylpiperazinyl) (radin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine :2-Methoxyetha The compound 2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidine-4- The amine (0.005 g, 0.16 mmol) was treated with 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperazin-1-yl]piperazin-1-yl]propanol. Lysin-1-yl]aniline (0.71 g, 0.16 mmol) was added, and the mixture was stirred at 110°C for 18 hours. The mixture was made basic with saturated sodium bicarbonate solution and a limited amount of ethyl acetate was added. The aqueous layer was purified by chromatography to give the final product (0.015 g, Yield 20%). MS / ES+: m / z=583.

[0567] Example 20 N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) (phenyl)phenyl)pyrimidine-2,4-diamine

[0568] [ka]

[0569] 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine : Room temperature To a suspension of NaH (60% dispersion in mineral oil, 40 mg, 1.0 mmol) in 2.0 mL of DMF was added solid 1-amino- 2-(Isopropylsulfonyl)benzene (0.20 g, 1.0 mmol) was added in three portions. After stirring at rt for 30 min, a solution of 2,4-dichloropyrimidine (0.15 g, 1.0 mmol) in 1.0 mL of DMF was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was diluted with saturated sodium bicarbonate solution After quenching with ethyl acetate, the solution was extracted with ethyl acetate. The organic layers were combined and washed with saturated sodium chloride. The crude residue was washed with water, dried over sodium sulfate, filtered and concentrated. Purification by gel chromatography (0-30% ethyl acetate:heptane) gave the target compound. Obtained as a white solid (53 mg, 17% yield). MS / ES+: m / z=312.

[0570] N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) (phenyl)phenyl)pyrimidine-2,4-diamine : 0.5 mL of 2-methoxyethanol in a vial 2-Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.017 g, 0.054 mmol) was added to a solution of 4-(dimethylphosphoryl)-2-methoxyaniline (0.010 g, 0. 0.044 mmol) was added as the HCl salt. The vial was sealed and the reaction mixture was heated to 90 °C for 16 h. The reaction was quenched with 1N NaOH solution and the solution was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol: The product was purified with dichloromethane to give the desired compound (15 mg, 72% yield). MS / ES+: m / z=4 75.

[0571] Example 21 N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N 4 -[2-(propan-2-yl) Sulfonyl)phenyl]pyrimidine-2,4-diamine

[0572] [ka]

[0573] 2-Chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine : To a suspension of NaH (60% dispersion in mineral oil, 40 mg, 1.00 mmol) in 2 mL of DMF at room temperature, add solid 1 -amino-2-(isopropylsulfonyl)benzene (0.20 g, 1.0 mmol) was added in three portions. After stirring at room temperature for 30 minutes, 2,4-dichloro-5-methylpyrimidine (0.17 g, 1.0 mmol) was added to DMF. The reaction mixture was stirred at room temperature for 3 hours. After quenching with sodium chloride solution, the solution was extracted with ethyl acetate. The organic layers were combined and saturated The resulting crude product was washed with sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate:heptane) to give The desired compound was obtained as an off-white solid (78 mg, 24% yield). MS / ES+: m / z=326.

[0574] N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N 4 -[2-(propan-2-yl) Sulfonyl)phenyl]pyrimidine-2,4-diamine : 2-Methoxyethanol in a vial 2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine- in 1 mL of A solution of 4-amine (0.035 g, 0.11 mmol) was added to 4-(dimethylphosphoryl)-2-methoxyaniline. To the solution was added 100 ml of ethanol (0.020 g, 0.085 mmol) as the HCl salt. The vial was sealed and the reaction mixture was The mixture was heated to 90° C. for 16 hours, and the reaction was quenched with 1N NaOH solution and the solution was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, and filtered. The crude residue was purified by silica gel chromatography (0-10% methanol The product was purified with 7N ammonia:dichloromethane to give the desired compound (12 mg, 29% yield). / ES+: m / z=489.

[0575] Example 22 5-Chloro-N 2 -[5-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-yl) Sulfonyl)phenyl]pyrimidine-2,4-diamine

[0576] [ka]

[0577] 5-(Dimethylphosphoryl)-2-methoxyaniline : 5-Bromo-2-methoxyaniline in 8 mL of DMF A solution of dimethylphosphine oxide (0.171 g, 2.20 mmol) was added to a solution of dimethylphosphine oxide (0.404 g, 2.00 mmol). mol), palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol), and and potassium phosphate (0.467 g, 2.20 mmol) were added. The resulting mixture was purged with nitrogen. The reaction mixture was heated in a microwave at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography. Purification with (0-20% 7N ammonia in methanol:dichloromethane) gave the desired product. (0.365 g, 85% yield).

[0578] 5-Chloro-N2 -[5-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-yl) Sulfonyl)phenyl]pyrimidine-2,4-diamine : 2,5- in 1.5 mL of 2-methoxyethanol Dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (Example 17 To a solution of 5-(dimethylphosphoryl)-2- Methoxyaniline (0.050 g, 0.21 mmol) was added as its hydrochloride salt. The mixture was placed in a sealed tube. The mixture was heated to 90° C. for 16 hours in a bromine bath. The mixture was made basic with 1N NaOH solution and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, and filtered. The resulting crude residue was purified by preparative HPLC to give the final compound (52 mg, yield Efficiency 48%). MS / ES+: m / z=509.

[0579] Example 23 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-methylphenyl]-N 4 -[2-(propan-2-yl) (sulfonyl)phenyl]pyrimidine-2,4-diamine

[0580] [ka]

[0581] 4-(Dimethylphosphoryl)-2-methylaniline : 4-Bromo-2-methylaniline in 8 mL of DMF To a solution of dimethylphosphine oxide (0.171 g, 2.20 mmol) was added dimethylphosphine oxide (0.372 g, 2.00 mmol). , palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol), and Potassium phosphate (0.467 g, 2.20 mmol) was added. The resulting mixture was purged with nitrogen and heated to 150 The reaction mixture was heated in a microwave oven at ℃ for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography ( Purification with 0-20% 7N ammonia in methanol:dichloromethane gave the desired product ( 0.313 g, 85% yield.

[0582] 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-methylphenyl]-N 4 -[2-(propan-2-yl) (sulfonyl)phenyl]pyrimidine-2,4-diamine : 2,5-dichloromethane in 1.5 mL of 2-methoxyethanol Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (see Example 17) To a solution of 4-(dimethylphosphoryl)-2-methyl-2-methylpropanol (prepared as described in Cetylaniline (0.050 g, 0.23 mmol) was added as its hydrochloride salt. The mixture was heated to 90°C for 16 hours. The mixture was made basic with 1N NaOH solution and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, and The crude residue was purified by preparative HPLC to give the final compound (20 mg, yield 18 %). MS / ES+: m / z=493.

[0583] Example 24 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-ethylphenyl]-N 4 -[2-(propan-2-yl) (sulfonyl)phenyl]pyrimidine-2,4-diamine

[0584] [ka]

[0585] 4-(Dimethylphosphoryl)-2-ethylaniline : 4-Bromo-2-ethylaniline in 8 mL of DMF To a solution of dimethylphosphine oxide (0.171 g, 2.20 mmol) was added dimethylphosphine oxide (0.400 g, 2.00 mmol). , palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol), and Potassium phosphate (0.467 g, 2.20 mmol) was added. The resulting mixture was purged with nitrogen and heated to 150 The reaction mixture was heated in a microwave oven at ℃ for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography ( Purification with 0-20% 7N ammonia in methanol:dichloromethane gave the desired product ( 0.308 g, 78% yield.

[0586] 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-ethylphenyl]-N 4 -[2-(propan-2-yl) (sulfonyl)phenyl]pyrimidine-2,4-diamine : 2,5-dichloromethane in 1.5 mL of 2-methoxyethanol Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (see Example 17) To a solution of 4-(dimethylphosphoryl)-2-ethoxybenzoate (prepared as described, 0.079 g, 0.22 mmol) was added 4-(dimethylphosphoryl)-2-ethoxybenzoate. Cetylaniline (0.050 g, 0.21 mmol) was added as its hydrochloride salt. The mixture was heated to 90°C for 16 hours. The mixture was made basic with 1N NaOH solution and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, and The crude residue was purified by preparative HPLC to give the final compound (43 mg, yield 40 %). MS / ES+: m / z=507.

[0587] Example 25 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N 4 -[2-( Propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

[0588] [ka]

[0589] 4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline : 4-Iodine in 8 mL of DMF A solution of 2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) was added to dimethylphosphite. Benzyl alcohol (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), Xantho s (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol) were added. The resulting mixture was purged with nitrogen and heated in a microwave at 150° C. for 20 minutes. The reaction mixture was concentrated. , silica gel chromatography (0–20% 7N ammonia in methanol:dichloromethane ) and acidified with a methanolic solution of HCl to give the desired product as its hydrochloride salt (0 0.573 g, 98% yield.

[0590] 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N 4 -[2-( Propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine : 2-Methoxyethanol 2,5-Dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4-amine in 1 mL of To a solution of 4-(dimethylaminomethyl)-4-(2-methyl-2-propanol)-4-amine (prepared as described in Example 17, 0.040 g, 0.12 mmol) was added 4-(dimethylaminomethyl)-4-(2-methyl-2-propanol). (phosphoryl)-2-(trifluoromethoxy)aniline (0.035 g, 0.12 mmol) and its hydrochloride. The mixture was heated in a sealed tube at 90°C for 16 hours. The mixture was basified with 1N NaOH solution. The combined organic layers were washed with saturated sodium chloride solution and It was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by preparative HPLC to give The final compound was obtained (5.8 mg, 9% yield). MS / ES+: m / z=563.

[0591] Example 26 5-Chloro-N 2 -[2-chloro-4-(dimethylphosphoryl)phenyl]-N 4 -[2-(propan-2-yl) (sulfonyl)phenyl]pyrimidine-2,4-diamine

[0592] [ka]

[0593] 2-chloro-4-(dimethylphosphoryl)aniline : 2-chloro-4-iodoaniline in 8 mL of DMF To a solution of dimethylphosphine oxide (0.171 g, 2.20 mmol) was added dimethylphosphine oxide (0.507 g, 2.00 mmol). , palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol), and Potassium phosphate (0.467 g, 2.20 mmol) was added. The resulting mixture was purged with nitrogen and heated to 150 The reaction mixture was heated in a microwave oven at ℃ for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography ( Purification with 0-20% 7N ammonia in methanol:dichloromethane gave the desired product ( 0.340 g, 83% yield.

[0594] 5-Chloro-N 2 -[2-chloro-4-(dimethylphosphoryl)phenyl]-N 4 -[2-(propan-2-yl) (sulfonyl)phenyl]pyrimidine-2,4-diamine : 2,5-Dimethylbenzoate in 1 mL of 2-methoxyethanol N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (described in Example 17) To a solution of 2-chloro-4-(dimethylphosphoryl)-2-methyl-2-methylpropanol (prepared as described above, 0.040 g, 0.12 mmol) was added 2-chloro-4-(dimethylphosphoryl)-2-methylpropanol. ) Aniline (0.025 g, 0.12 mmol) and 49 μL of 2.5 M HCl ethanol solution were added. The mixture was heated in a sealed tube at 90°C for 16 hours. The mixture was made basic with 1N NaOH solution and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution and dried over sodium sulfate. The crude residue was purified by preparative HPLC to give the final compound (5. 9 mg, 10% yield. MS / ES+: m / z=513.

[0595] Example 27 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-fluorophenyl]-N 4 -[2-(propan-2-yl) Sulfonyl)phenyl]pyrimidine-2,4-diamine

[0596] [ka]

[0597] 4-(Dimethylphosphoryl)-2-fluoroaniline : 4-Bromo-2-fluoroacetate in 8 mL of DMF A solution of dimethylphosphine oxide (0.171 g, 2.20 mmol) was added to a solution of dimethylphosphine oxide (0.380 g, 2.00 mmol). mol), palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol), and and potassium phosphate (0.467 g, 2.20 mmol) were added. The resulting mixture was purged with nitrogen. The reaction mixture was heated in a microwave at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography. Purification with HCl (0-20% 7N ammonia in methanol:dichloromethane) afforded the desired product. Obtained (73.5 mg, 20% yield).

[0598] 5-Chloro-N 2 -[4-(dimethylphosphoryl)-2-fluorophenyl]-N 4 -[2-(propan-2-yl) Sulfonyl)phenyl]pyrimidine-2,4-diamine : 2,5-dichloromethane in 1 mL of 2-methoxyethanol Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (see Example 17) To a solution of 4-(dimethylphosphoryl)-2-fluoropropanediol (prepared as described, 0.040 g, 0.12 mmol) was added 4-(dimethylphosphoryl)-2-fluoropropanediol. Fluoroaniline (0.023 g, 0.12 mmol) and 49 μL of 2.5 M HCl ethanol solution were added. The mixture was heated in a sealed tube at 90°C for 16 hours. The mixture was made basic with 1N NaOH solution and ethyl acetate was added. The combined organic layers were washed with saturated sodium chloride solution and extracted with sodium sulfate. The crude residue was purified by preparative HPLC to give the final compound. (9.0 mg, 22% yield). MS / ES+: m / z=497.

[0599] Example 28 N 2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) (phenyl)phenyl)pyrimidine-2,4,5-triamine

[0600] [ka]

[0601] N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-nitro-N 4 -[2-(propan-2-yl) Sulfonyl)phenyl]pyrimidine-2,4-diamine (461 mg, 0.89 mmol) suspended in ethanol To the solution was added 184 mg of 10% Pd on carbon, and the reaction mixture was stirred at room temperature overnight. The filtrate was concentrated under reduced pressure to give the crude product, which was then diluted with 10% methanol in DCM. The product was purified by silica gel chromatography using N 2 -[4-(dimethylphosphoryl) -2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4,5- The triamine was obtained as a solid. MS / ES+: m / z=490.

[0602] Example 29 2-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}-9-[2-(propan-2-yl) (sulfonyl)phenyl]-7,9-dihydro-8H-purin-8-one

[0603] [ka]

[0604] N 2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) (phenyl)phenyl]pyrimidine-2,4,5-triamine (prepared as described in Example 28, 40 mg, To a THF solution of N,N'-carbonyldiimidazole (40 mg, 0.25 mmol) was added. The solution was stirred at room temperature overnight. The solution was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over magnesium sulfate. The residue was purified by RP preparative HPLC to give the desired product as an off-white solid. ES+: m / z=516.

[0605] Example 30 N 2 -[2-Methoxy-4-(4-oxido-1,4-azaphosphinan-4-yl)phenyl]-N 4 -[2-(Pro (2-(phenyl-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

[0606] [ka]

[0607] (3-Methoxy-4-nitrophenyl)(dimethyl)phosphane oxide : 5-chloro-2-methyl-2-propanol in 20 mL of DMF A solution of 1.00 g of 2-nitroanisole (5.33 mmol) was added to diethyl phosphite (0.80 9 g, 5.86 mmol), palladium acetate (0.060 g, 0.27 mmol), Xantphos (0.185 g, 0.320 mmol), mol), and potassium phosphate (1.24 g, 5.86 mmol) were added. The resulting mixture was purge with nitrogen. The reaction mixture was concentrated and purified by silica gel chromatography. The crude product was purified by chromatography (0-45% ethyl acetate:heptane) to give the desired product (0.504 g, Yield 33%).

[0608] (3-Methoxy-4-nitrophenyl)phosphonic acid dichloride : (3-Methoxy- A solution of 4-nitrophenyl)(dimethyl)phosphane oxide (4.54 g, 15.7 mmol) was added to the solution of chloride. Thionyl (5.7 mL, 78.5 mmol) was added. The reaction flask was fitted with a reflux condenser and heated to The mixture in the flask was heated to reflux. After refluxing for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude oil was redissolved in CH2Cl2 and heptane was added to precipitate the desired compound. The clear solution was decanted, and the precipitate was collected and dried to give the target compound as a white solid. The compound was obtained (1.39 g, 33% yield).

[0609] Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide : (3-methyl) in 15 mL of THF (4-nitrophenyl) phosphonic acid dichloride (1.39 g, 5.15 mmol) under nitrogen at -78°C To the solution was slowly added vinylmagnesium bromide (10.3 mL, 1.0 M in THF). After that, the reaction mixture was stirred at -78°C for an additional 1 hour. To this cold reaction mixture was added saturated NH4Cl (20 mL). The reaction was quenched by addition, and the mixture was extracted with CH2Cl2. The combined organic layers were washed with 1M NaOH and brine. The organic extract was filtered and concentrated to give the desired compound (0 .982 g, 75%).

[0610] 1-Benzyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide : Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.90 mmol) and and benzylamine (0.23 mL, 2.08 mmol) were dissolved in 50% aqueous THF (6 mL) and heated under nitrogen for 1 The reaction mixture was heated to 0.5° C. After 1 hour, additional benzylamine was added to the reaction mixture. The mixture was refluxed for an additional 2 hours and then cooled to room temperature. The reaction mixture was diluted with saturated aqueous NaHCO3 and CHCl The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The mixture was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel. Purification with HCl (0-5% 7N ammonia in methanol:dichloromethane) afforded the desired product. Obtained (0.449g, yield 66%).

[0611] 4-(1-benzyl-4-oxide-1,4-azaphosphinan-4-yl)-2-methoxyaniline : workman 1-benzyl-4-(3-methoxy-4-nitrophenyl)-1,4 in 0.6 mL of a 4:1 mixture of ethanol and water A solution of -azaphosphinane 4-oxide (0.224 g, 0.622 mmol) was added to iron powder (0.348 g, 6.22 mmol). 0.30 mL of ethanolic HCl (2.5 M) was added to the reaction vessel, which was then sealed and heated to 95°C for 1 hour. The reaction mixture was cooled to room temperature, filtered, and concentrated. The crude residue was evaporated on silica gel. Purification by gel chromatography (0–5% 7N ammonia in methanol:dichloromethane) The desired product was obtained (86.1 mg, 42% yield).

[0612] N 2 -[4-(1-benzyl-4-oxide-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]- 5-Chloro-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine : 2- 2,5-Dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]phenyl] in 1.5 mL of methoxyethanol To a solution of 4-(1-benzyl-4-oxide- 1,4-Azaphosphinan-4-yl)-2-methoxyaniline (43.0 mg, 0.13 mmol) and HCl ethanol A 2.5M alcohol solution (0.10 mL) was added, and the mixture was heated in a sealed vial at 90°C for 16 hours. The reaction mixture was heated at 100°C for an additional 2 hours. The mixture was made basic with 1N NaOH solution and diluted with acetic acid. The combined organic layers were washed with saturated sodium chloride solution and extracted with sodium sulfate. The crude residue was purified by silica gel chromatography ( Purification with 0–12% 7N ammonia in methanol:dichloromethane gave the desired product (43 .0 mg, yield 52%).

[0613] N 2 -[2-Methoxy-4-(4-oxido-1,4-azaphosphinan-4-yl)phenyl]-N 4 -[2-(Pro (2-(phenyl-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine : Add N to the flask 2 -[4-(1-Ben Dimethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-5-chloro-N 4 -[2- (Propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine (40.0 mg, 0.0625mmol ) and 10% Pd-C (40.0 mg). The flask was evacuated and filled with nitrogen. Anhydrous methanol (2 mL) was added and the flask was fitted with a reflux condenser equipped with a nitrogen inlet. Ammonium formate (31.5 mg, 0.500 mmol) was added in one portion at room temperature. The mixture was stirred under reflux for 3 hours. The reaction mixture was filtered through a pad of Celite and the Celite was added 2×5 ml The combined filtrate and washings were evaporated under reduced pressure. Purification by preparative HPLC gave the final compound (13.6 mg, 42% yield). MS / ES+: m / z=516.

[0614] Example 31 N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) [phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0615] [ka]

[0616] 2,4-Dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin hmm To a suspension of NaH (119 mg, 60% in oil, 2.98 mmol) in DMF (5 mL) was added 2,4-dichloro-7 H-Pyrrolo[2,3-d]pyrimidine (400 mg, 2.13 mmol) was added at 0° C. The resulting mixture was stirred for 30 Stir for 1 minute, then add 2-(trimethylsilyl)ethoxymethyl chloride (0.42 mL, 1.1 equiv.) The mixture was then warmed to room temperature and stirred for 1 hour. Water was added to quench the reaction. After extraction with CH2Cl2, the combined organic layers were dried, evaporated, and clarified with silica gel. Purification by chromatography (eluent: 20% EtOAc in heptane) afforded the desired product in 84% yield. % (570 mg).

[0617] 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]phenyl {toxoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine : 1-amino-2-(isopropyl methyl acrylate) in 2 mL of DMF A solution of 1,2-dimethylpropylsulfonylbenzene (199 mg, 1 mmol) was added to a solution of 1,2-dimethylpropylsulfonylbenzene (199 mg, 1 mmol) in 1,2-dimethylpropylsulfonylbenzene (60% in oil, 44 mg, 1.1 mmol) was added in one portion. The reaction mixture was stirred for 20 minutes, and then 2,4-dichloro-7-{[2-( {trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (317 mg, 1 mmol) The reaction mixture was then warmed to room temperature and stirred for an additional 2 hours. Water was added. The reaction was stopped by extraction with EtOAc, followed by silica gel column chromatography ( Treatment with a 20% heptane solution of HCl gave the desired product (202 mg, 42% yield). MS / ES+: m / z=481.

[0618] N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) [2-(trimethylsilyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine -2,4-diamine : 2-chloro-N-[2-(propan-2-ylsulfonyl)fluoride] [phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-a amine (180 mg, 0.374 mmol), 4-(dimethylphosphoryl)-2-methoxyaniline hydrochloride (105 mg , 0.45 mmol), Pd2(dba)3 (34 mg, 0.0374 mmol), Xantphos (26 mg, 0.045 mmol), and t -BuONa (129 mg, 1.346 mmol) was added. The mixture was degassed three times under reduced pressure, and then N2 Anhydrous 1,4-dioxane (2 mL from a securely sealed bottle) was added and the reaction The reaction proceeded under microwave irradiation at 140°C for 20 minutes. Water and EtOAc were added to aid in the extraction. Silica gel chromatography (eluent: 10% MeOH in CH2Cl2) afforded the desired product in high yield. Obtained in 54% (130 mg). MS / ES+: m / z=644.

[0619] N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) [phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine : Compound N in THF (1 mL) 2 - [4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl)fluor Phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-2,4- The diamine solution was diluted with tetrabutylammonium fluoride (TBAF) in THF (1.0 M, 3 mL) and Ethylenediamine (0.1 mL) was added. The resulting solution was heated to 60° C. for 24 hours. HPLC monitoring A conversion of about 40% was observed. Volatile components were removed using a rotary evaporator (rotavap). The residue was purified by preparative HPLC. NMR showed that the target product was contaminated with TBAF. This impurity was removed by washing with water (4 times). The target compound was obtained (14 mg). MS / ES+: m / z=514.

[0620] Example 32 5-Chloro-N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[2-(propane -2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

[0621] [ka]

[0622] 6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine : 6-Bromo- in 4 mL of DMF A solution of 2-methoxypyridin-3-ylamine (0.203 g, 1.00 mmol) was added to dimethylphosphine benzoxanoxide (0.171 g, 1.10 mmol), palladium acetate 11.0 mg, 0.0490 mmol), Xantphos ( To this mixture were added potassium phosphate (0.233 g, 1.10 mmol). The mixture was purged with nitrogen and subjected to microwave heating at 150° C. for 20 minutes. The condensed fraction was analyzed by silica gel chromatography (0–10% 7N ammonia in methanol:dichloromethane). The product was purified by HPLC to give the desired product (77.2 mg, 39% yield).

[0623] 2,5-Dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine : DM F 1-amino-2-(isopropylsulfonyl)benzene (0.955 g, 4.80 mmol) in 2 mL at 0 °C To the solution was added NaH (60% in oil, 0.349 g, 8.72 mmol) in one portion. After stirring for 20 min, 2 4,5-Trichloropyrimidine was added, and the mixture was stirred at 0° C. for 30 minutes, then at room temperature for 2 hours. After quenching the reaction with saturated ammonium chloride solution, the mixture was diluted with water and ethyl acetate. The resulting yellow suspension was filtered to give the final product (0.3 g, 20% yield). MS / ES+: m / z=346.

[0624] 5-Chloro-N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[2-(propane -2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine : in 1 mL of 2-methoxyethanol of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (86. 0 mg, 0.250 mmol) was added to a solution of 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine. To this mixture was added 2.5M HCl in ethanol (0.15 mL). The mixture was heated in a sealed tube at 90°C for 16 hours, basified with 1N NaOH solution, and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, and The crude residue was purified by silica gel chromatography (0-10% methanol The final product was obtained by purifying the crude product with 7N ammonia in methanol:dichloromethane (16.7 mg, 2% yield). 2%). MS / ES+: m / z=510.

[0625] Example 33 5-Chloro-N 2 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 4 -[2-(propane -2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

[0626] [ka]

[0627] 5-(Dimethylphosphoryl)-3-methoxypyrazin-2-amine : 5-Bromo-3-methylpropional in 4 mL of DMF A solution of 2-methyl-3-pyrazin-3-ylamine (0.204 g, 1.00 mmol) was added to dimethylphosphine oxide. oxide (0.171 g, 1.10 mmol), palladium acetate (11.0 mg, 0.0490 mmol), Xantphos (35. 0 mg, 0.0600 mmol), and potassium phosphate (0.233 g, 1.10 mmol) were added to this mixture. The mixture was purged with nitrogen and subjected to microwave heating at 150° C. for 20 minutes. The reaction mixture was concentrated and , silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) The desired product was obtained (126 mg, 63% yield).

[0628] 5-Chloro-N 2 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 4 -[2-(propane -2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine : 2,5-dichloro-N-[2-(propane -2-ylsulfonyl)phenyl]pyrimidin-4-amine (prepared as described in Example 32, 0.12 0 g, 0.348 mmol) and 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (70.0 mg, 0.348 mmol) was added to a mixture of tris(dibenzylideneacetone)dipalladium(0)-chloro Formamide adduct (17.6 mg, 0.017 mmol), Xantphos (23.3 mg, 0.040 mmol), and sesquicarbonate Ammonia (0.228 g, 0.700 mmol) and dioxane (3.5 mL) were added. The mixture was sealed and The mixture was heated to 120° C. After 16 hours, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0–10% 7N ammonia in methanol:dichloromethane The desired product was obtained by purification using HPLC (HPLC). (11.4 mg, 6% yield). MS / ES+: m / z=511.

[0629] Example 34 5-Chloro-N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N4 -phenylpyridine 2,4-diamine-myridin

[0630] [ka]

[0631] This compound was synthesized by the same procedure as in Example 32, using 2,5-dichloro-N-phenylpyrimidin-4-amine. Reacted with 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32) It can be prepared by

[0632] 2,5-Dichloro-N-phenylpyrimidin-4-amine : Aniline (205 m g, 2.2 mmol) and 2,4,5-trichloropyrimidine (500 mg, 2.7 mmol) were added to a solution of potassium carbonate. 500 mg of ammonium chloride was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography with 10% ethyl acetate in hexane. Purification gave the desired product as an oil (370 mg, 70% yield).

[0633] Example 35 N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[2-(propan-2-yl) [5-(trifluoromethyl)pyrimidine-2,4-diamine]

[0634] [ka]

[0635] 4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl) Methyl)pyrimidine15 mL of N,N-dimethylacetamide and 3 mL of diisopropylethylamine 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32) in 0.6 mL A suspension of 2,4-dichloro- ... 4-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) was added in four portions over 5 min. The reaction mixture is stirred at 60°C for 1 hour. The reaction mixture is cooled to room temperature and filtered to obtain a white solid. This white solid is washed three times with 50 mL of water and then three times with 50 mL of ethyl ether. The white solid was dried under reduced pressure and purified by filtration using 4-chloro-2-[6-(dimethylphosphoryl)-2-methoxy- pyridin-3-yl]-5-(trifluoromethyl)pyrimidine.

[0636] N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[2-(propan-2-yl) [5-(trifluoromethyl)pyrimidine-2,4-diamine] : Ethanol 1.5 mL of 4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl)pyridin-3-yl A solution of 1-amino-2-( ... (isopropylsulfonyl)benzene (0.072 mmol) was added. The mixture was heated at 120°C for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by preparative HPLC (Waters Purification using a Sunfire C18 column (mobile phase: ACN / water) yields the desired compound.

[0637] Example 36 N 2 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N4 -[2-(propan-2-yl) [5-(trifluoromethyl)pyrimidine-2,4-diamine]

[0638] [ka]

[0639] 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl) Methyl)pyrimidine 15 mL of N,N-dimethylacetamide and 3 mL of diisopropylethylamine 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared in Example 33, 2.2 mL) in 0.6 mL The suspension of 2,4-dichloro-5-( ... (Trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) was added in four portions over 5 minutes. The reaction mixture is stirred at 60° C. for 1 hour. The reaction mixture is cooled to room temperature and filtered to give a white solid. The white solid was washed with 50 mL of water three times and then with 50 mL of ethyl ether three times. The white solid was dried under reduced pressure to give 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazine]. to obtain [benzo-2-yl]-5-(trifluoromethyl)pyrimidine.

[0640] N 2 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 4 -[2-(propan-2-yl) [5-(trifluoromethyl)pyrimidine-2,4-diamine] : Ethanol 1.5 mL of 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrazin-2-yl A solution of 1-amino-2-( ... (isopropylsulfonyl)benzene (0.072 mmol) was added. The mixture was heated at 120°C for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by preparative HPLC (Waters Purification using a Sunfire C18 column (mobile phase: ACN / water) yields the desired compound.

[0641] Example 37 5-Chloro-N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[4-(dimethyl Phosphoryl)phenyl]pyrimidine-2,4-diamine

[0642] [ka]

[0643] This compound was synthesized in the same manner as in Example 32, using 2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl] prepared by reacting 2,6-dimethoxypyridin-3-amine with 2,6-dimethoxypyridin-4-amine. It can be manufactured.

[0644] 2,5-Dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine : DMF 1 mL To a solution of 2,4,5-trichloropyrimidine (0.15 mL, 1.31 mmol) in 4-(dimethylphosphoryl)-2,4,5-trichloropyrimidine (0.15 mL, 1.31 mmol) was added (aryl)aniline (0.221 g, 1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol) were added. The mixture was heated at 110°C for 4 hours and then made basic with saturated sodium bicarbonate solution. The resulting suspension was filtered and washed with ethyl acetate to give the final product (0.15 g, yield 36 %). MS / ES+: m / z=316.

[0645] Example 38 5-Chloro-N 2 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 4 -{2-methoxy- 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine hmm

[0646] [ka]

[0647] This compound was prepared as in Example 32, by the reaction of 2-methoxy-4-[4-(4-methylpiperazin-1-yl) Piperidin-1-yl]aniline was reacted with 2,4,5-trichloropyrimidine to give 2,5-dichloro -N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin It can be prepared by generating 2,5-dichloro-N-{2-methoxy-4-[4-( 4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine 5-(dimethylphosphoryl)-3-methoxypyrazine-2-amine was prepared according to the procedure described in Example 32. The resulting mixture is reacted with methylpropanol (prepared in Example 33).

[0648] 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine : DMF To a solution of 5-fluoro-2-nitroanisole (0.5 g, 2.92 mmol) in 3 mL of 1-methyl-4-( piperazine (0.536 g, 2.92 mmol) and potassium carbonate (0.808 g, 5.84 mmol) The mixture was heated to 120°C for 18 hours. The mixture was washed with saturated sodium bicarbonate solution. It was made basic and extracted with ethyl acetate. The organic layer was purified by chromatography to give the final product. The product was obtained as a yellow solid (0.95 g, 95% yield). MS / ES+: m / z=334.

[0649] 2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline : Argo 1-[1-(3-methoxy-4-nitrophenyl)piperidine-4- ( A solution of 10% palladium on carbon (0. 060 g) was added. After 4 hours under 30 psi, the hydrogenation was completed. The resulting mixture was The filtrate was filtered through a filter into a flask containing ethanolic HCl. The final product was obtained (0.15 g, 88% yield). MS / ES+: m / z=334.

[0650] Example 39 5-chloro-N-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-4-(4-methylpiperazin-3-yl)- (radin-1-yl)pyrimidin-2-amine

[0651] [ka]

[0652] This compound was prepared by converting 2,4,5-trichloropyrimidine to 1-methylpyrimidine as described in Example 32. piperazine to produce 2,5-dichloro-4-(4-methylpiperazin-1-yl)pyrimidine. It can be prepared by synthesizing 2,5-dichloro-4-(4-methylpiperazin-1-yl)pyrimidinone. The amine was then converted to 6-(dimethylphosphoryl)-2-methoxypyridine as described in Example 32. React with din-3-ylamine (prepared in Example 32).

[0653] Example 40 N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -(morpholin-4-ylmethyl) (ethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0654] [ka]

[0655] This compound was prepared by 4-reaction of 1-(morpholin-4-yl)methanamine as described in Example 35. -chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl It can be prepared by reacting with pyrimidine.

[0656] Example 41 4-(2-{[2-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}-5-(trifluoromethyl) (fluoromethyl)pyrimidin-4-yl]amino}ethyl)benzenesulfonamide

[0657] [ka]

[0658] This compound was synthesized by the synthesis of 4-(2-aminoethyl)benzenesulfonyl as described in Example 35. Imido is 4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl)- It can be prepared by reacting with (methyl)pyrimidine.

[0659] Example 42 2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-4-(4-phenylpiperazine-1 -yl)-5-(trifluoromethyl)pyrimidine

[0660] [ka]

[0661] This compound was prepared by reacting 1-phenylpiperazine with 4-chloro-2-[5- (Dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine It can be prepared by reacting

[0662] Example 43 2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N-[2-(1H-indol-3-yl) [ethyl]-5-(trifluoromethyl)pyrimidin-4-amine

[0663] [ka]

[0664] This compound was prepared by the reaction of tryptamine with 4-chloro-2-[5-(dimethylamino)methyl]-2-(4-chloro-2-[5-(dimethylamino)methyl]-2-(4-methyl ... (trifluoromethyl)pyrimidine and react with (3-methoxypyrazin-2-yl)-5-(trifluoromethyl)pyrimidine. It can be prepared by

[0665] Example 44 N 2 -[4-(dimethylphosphoryl)phenyl]-N 4 -[4-(4-methylpiperazin-1-yl)benzyl] -5-(trifluoromethyl)pyrimidine-2,4-diamine

[0666] [ka]

[0667] This compound was synthesized by the synthesis of 4-(4-methylpiperazine)-benzylamine as described in Example 36. 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)- It can be prepared by reacting with (methyl)pyrimidine.

[0668] Example 45 N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N 4 -[2-(propan-2-yl) (sulfonyl)phenyl]pyrimidine-2,4-diamine

[0669] [ka]

[0670] This compound was prepared as described in Example 32, by the synthesis of 2-chloro-N-[2-(propan-2-ylsulfo 6-(dimethylphosphoryl)-2-methoxypyridine-3- It can be prepared by reacting with methylaminomethylamine (prepared in Example 32).

[0671] 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine : Room temperature A suspension of NaH (60% dispersion in mineral oil, 40 mg, 1.0 mmol) in 2.0 mL of DMF was added to 1-amino-2-(isothiazolinone). Isopropylsulfonylbenzene (0.20 g, 1.0 mmol) was added as a solid in three portions. After stirring at room temperature for 30 minutes, 2,4-dichloropyrimidine (0.15 g, 1.0 mmol) in 1.0 mL of DMF was dissolved in The reaction mixture was stirred at room temperature for 3 hours. After the reaction was stopped, the resulting solution was extracted with ethyl acetate. The crude product was washed with sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate:heptane) to give the desired product. The target compound was obtained as an off-white solid (53 mg, 17% yield). MS / ES+: m / z=312.

[0672] Example 46 N 2 -[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-methyl-N 4 -[2-(propane -2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

[0673] [ka]

[0674] This compound was prepared as described in Example 32 by the synthesis of 2-chloro-5-methyl-N-[2-(propane-2- (Isulfonyl)phenyl]pyrimidin-4-amine with 6-(dimethylphosphoryl)-2-methoxypyrimidin-4-amine It can be prepared by reacting with lysin-3-ylamine (prepared in Example 32).

[0675] 2-Chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine A room temperature suspension of NaH (60% dispersion in mineral oil, 40 mg, 1.00 mmol) in 2 mL of DMF was added to 1-(2-hydroxybenzoyl)-2-(2-methyl-1,2-dihydro ... Amino-2-(isopropylsulfonyl)benzene (0.20 g, 1.0 mmol) was added as a solid in three portions. After stirring at room temperature for 30 minutes, 2,4-dichloro-5-methylpyrimidine (0.17 g, 1.0 m mol) was added as a solution in 1 mL of DMF. The reaction mixture was stirred at room temperature for 3 hours. After quenching the reaction with sodium chloride solution, the resulting solution was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-30% ethyl acetate:heptane). The desired compound was obtained as an off-white solid (78 mg, 24% yield). ES+: m / z=326.

[0676] Example 47 5-Chloro-N 4 -[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl] phenyl]-N 2 -(Thiophen-2-ylmethyl)pyrimidine-2,4-diamine

[0677] [ka]

[0678] This compound was prepared as described in Example 32 using 2-methoxy-4-(4-methyl-4-oxide-1, 4-Azaphosphinan-1-yl)aniline is reacted with 2,4,5-trichloropyrimidine to give 2,5- Dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl] It can be prepared by forming 2,5-dichloro-N-[2-methoxy]pyrimidin-4-amine. 4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine The amine was then reacted with 1-(thiophen-2-yl)methanamine as described in Example 32. To respond.

[0679] 2-Methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline

[0680] [ka]

[0681] 1-Benzyl-4-methyl-1,4-azaphosphinane 4-oxide : Methylphosphonic acid at -78°C A solution of 10.0 g of dichloride (75.2 mmol) in CHCl was added to vinylmagnesium bromide (175 mL, TH A solution of 1.0 M in HCl was added via a dropping funnel over 4 hours. The resulting solution was warmed to 0°C and diluted with a minimum of The reaction was quenched by adding a small amount of saturated NH4Cl. The mixture was filtered through a pad of silica gel. The silica was extracted with 10% 7N ammonia in methanol:dichloromethane. Concentration under reduced pressure gave methyldivinylphosphine oxide as a viscous yellow oil. This was used without purification.

[0682] Methyldivinylphosphine oxide (1.16 g, 10.0 mmol) in 1:1 THF / water (25 mL) A solution of 1.20 mL of methylpropanol and benzylamine (1.20 mL, 11.0 mmol) was heated at reflux for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-10% 7N ammonium hydroxide in methanol). The product was purified with 1-benzyl-4-methyl-[1,4]azaphosphinane- The 4-oxide was obtained as a white solid (1.57 g, 70% yield).

[0683] 4-Methyl-[1,4]azaphosphinane-4-oxide : In a flask, add 1-benzyl-4-methyl-[1 ,4]Azaphosphinane-4-oxide (1.00 g, 4.47 mmol) and 10% Pd / C (100 mg) were added. The flask was evacuated and filled with nitrogen. Anhydrous methanol (18 mL) was added to the flask. The flask was fitted with a reflux condenser equipped with a nitrogen inlet tube. (2.25 g, 35.8 mmol) was added in one portion at room temperature. The resulting mixture was stirred under reflux for 2 hours. The reaction mixture was filtered through a pad of Celite and the Celite was washed with 2 x 5 ml of methanol. The combined filtrate and washings were evaporated under reduced pressure. The crude residue was purified by silica gel chromatography. The product was purified by HPLC (0-10% 7N ammonia in methanol:dichloromethane) to give 4-methyl-[1, 4] Azaphosphinane-4-oxide was obtained as a yellow gel (0.589 g, 99% yield).

[0684] 1-(3-Methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide : 4- Methyl-[1,4]azaphosphinane-4-oxide (133 mg, 1.00 mmol), 5-fluoro-2-nitro A mixture of anisole (340 mg, 2.00 mmol), K2CO3 (345 mg, 2.50 mmol), and DMF (5 mL) The mixture was heated to 50° C. After 2 hours, the reaction mixture was concentrated and purified by silica gel chromatography (0 ~5% 7N ammonia in methanol:dichloromethane) to give 1-(3-methoxy-4-nitrophenyl)- (4-phenyl)-4-methyl-1,4-azaphosphinane 4-oxide was obtained as a bright yellow solid (272 m g, yield 96%).

[0685] 2-Methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline : Pressurization 1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide ( The mixture was charged with 10% Pd / C (50 mg), ethanol (5 mL), and 272 mg of ethanol (0.960 mmol). The vessel was connected to a Parr apparatus, evacuated, and then backfilled with nitrogen. The vessel was again evacuated and filled with hydrogen gas. The reaction mixture was shaken under 50 psi for 4 hours. The filtrate was filtered through Celite into a flask containing ethanolic HCl. Concentration of this product gave 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline. Phosphorus was obtained as a grey solid (211 mg, 87% yield).

[0686] Example 48 5-Chloro-N 4 -[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl] phenyl]-N 2 -[5-(propan-2-yl)-1,3-oxazol-2-yl]pyrimidine-2,4-diamine

[0687] [ka]

[0688] This compound was synthesized as described in Example 32, by the synthesis of 2,5-dichloro-N-[2-methoxy-4-(4-methylphenyl)-2,5-dichloro-N ... (4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine (Example 47 (described in ) with 5-(propan-2-yl)-1,3-oxazol-2-amine. It can be manufactured.

[0689] Example 49 5-Chloro-N 2 -[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-N 4 -[2-methoxy-4-(4-methyl 4-Oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidine-2,4-diamine

[0690] [ka]

[0691] This compound was synthesized as described in Example 32, by the synthesis of 2,5-dichloro-N-[2-methoxy-4-(4-methylphenyl)-2,5-dichloro-N ... (4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine (Example 47 (described in ) with 1-(4-fluorobenzyl)-1H-pyrrol-3-amine can.

[0692] Example 50 2-{[(5-chloro-4-{[2-methoxy-4-(4-methyl-4-oxide-1,4-azaphosphinane-1-yl (phenyl)amino)pyrimidin-2-yl)amino]methyl}-N,N-diethylthiophen-3-sulfonyl Sulfonamide

[0693] [ka]

[0694] This compound was synthesized as described in Example 32, by the synthesis of 2,5-dichloro-N-[2-methoxy-4-(4-methylphenyl)-2,5-dichloro-N ... (4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine (Example 47 (described in ) with 2-(aminomethyl)-N,N-diethylthiophene-3-sulfonamide It can be prepared by:

[0695] Example 51 N 2 -[5-(1,4'-bipiperidin-1'-yl)-1,3,4-thiadiazol-2-yl]-5-chloro-N 4 -[5- (Dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidine-2,4-diamine

[0696] [ka]

[0697] This compound was synthesized by the synthesis of 5-(dimethylphosphoryl)-3-methoxypyridine as described in Example 32. Rhazin-2-amine (described in Example 33) was reacted with 2,4,5-trichloropyrimidine to give 2,5- Dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4-amine It can be prepared by generating 2,5-dichloro-N-[5-(dimethylphosphoryl)-3-meth

[0112] pyrimidin-4-amine was then prepared according to the procedure described in Example 32. , and reacted with 5-(1,4'-bipiperidin-1'-yl)-1,3,4-thiadiazol-2-amine.

[0698] Example 52 5-Chloro-N 4 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 2 -{[5-(4-methyl (Iron piperazin-1-yl)-1,3,4-oxadiazol-2-yl]methyl}pyrimidine-2,4-diamine hmm

[0699] [ka]

[0700] This compound was synthesized as described in Example 32 using 2,5-dichloro-N-[5-(dimethylphosphoryl)- 1-[5-(4-methyl-3-pyrazin-2-yl)]pyrimidin-4-amine (described in Example 51) by reacting with methylpiperazin-1-yl-1,3,4-oxadiazol-2-yl]methanamine It can be prepared by:

[0701] Example 53 5-Chloro-N 4 -[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N 2 - {5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-yl}pyrimidin 2,4-diamine

[0702] [ka]

[0703] This compound was synthesized as described in Example 32 using 4-(dimethylphosphoryl)-2-(propane-2 -ylsulfonyl)aniline is reacted with 2,4,5-trichloropyrimidine to give 2,5-dichloro-N -[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine It can be prepared by generating 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propanol). [propan-2-ylsulfonyl]phenyl]pyrimidin-4-amine was then reacted with the amine as described in Example 32. According to the procedure, 5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazole-2- React with an amine.

[0704] 4-(Dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline

[0705] [ka]

[0706] 4-Bromo-1-nitro-2-(propan-2-ylsulfanyl)benzene : Stirred at 0°C A solution of 4-bromo-2-fluoronitroaniline (2.0 g, 9.1 mmol) in DCM was added with sodium iodide. Isopropoxide (2.0 g, 20 mmol) was added in two portions. The reaction mixture was allowed to warm to room temperature. The reaction mixture was filtered through a syringe filter. The product was purified by preparative HPLC ( Water / acetonitrile) and isolated as a bright yellow solid (0.8 g, 2.9 mmol, 32% yield).

[0707] 4-Bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene : 4- in acetic acid (10 mL) Stirring bromo-1-nitro-2-(propan-2-ylsulfanyl)benzene (0.8 g, 2.9 mmol) To the solution was added hydrogen peroxide (30% aqueous solution, 0.6 mL, 5.8 mmol). The reaction mixture was heated in an oil bath. The reaction mixture was heated to 110° C. for 2 hours. The reaction mixture was treated with saturated aqueous sodium sulfide and saturated aqueous sodium bicarbonate. The resulting mixture was made basic with thorium solution, extracted with ethyl acetate, and the combined organic layers were The organic solvent was removed under reduced pressure and the residue was used in the next step without further purification. was used.

[0708] Dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide : D 4-Bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene (0.44 g, 1.6 mL) in 1 mL of MF To a stirred solution of 1.2 mmol) and dimethylphosphine oxide (0.15 g, 1.9 mmol) was added potassium phosphate. (0.37 g, 1.8 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), Xantphos (55 mg, 0.10 mmol The reaction mixture was heated at 110°C overnight. The reaction mixture was cooled to room temperature and The desired product was isolated by preparative HPLC to give a brown-yellow solid (0.24 g, yield 55%).

[0709] 4-(Dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline : Dimethyl [4-nitrilo [3-(propan-2-ylsulfonyl)phenyl]phosphane oxide (0.24 g, 0.88 mmol) To an ethanol solution of Pd on carbon (10% w / w, 24 mg) was added and stirred under hydrogen overnight. The reaction mixture was filtered and the organic solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 100 mg of the product was obtained (yield 50%).

[0710] Example 54 5-Chloro-N 4 -[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N 2 - {[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}pyrimidine-2,4-diamine

[0711] [ka]

[0712] This compound was synthesized as described in Example 32 using 2,5-dichloro-N-[4-(dimethylphosphoryl)- [2-(2-(phenyl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (described in Example 53) by reacting with 1-[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methanamine It can be prepared more easily.

[0713] Example 55 N 2 -benzyl-5-chloro-N 4 -[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl) Phenyl]pyrimidine-2,4-diamine

[0714] [ka]

[0715] This compound was synthesized as described in Example 32 using 2,5-dichloro-N-[4-(dimethylphosphoryl)- [2-(2-(phenyl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (described in Example 53) can be prepared by reacting with benzylamine.

[0716] Example 56 5-Chloro-N 2 -(5-cyclopropyl-1,3-oxazol-2-yl)-N 4 -{2-methoxy-4-[4-(4- Methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidin Zin-2,4-diamine

[0717] [ka]

[0718] This compound was prepared by the synthesis of 2-methoxy-4-[4-(4-methyl-4-oxide

[0043] 2,4,5-Trichloropyrimidin-1-yl)-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline 2,5-dichloro-N-{2-methoxy-4-[4-(4-methyl-4-oxide-1,4-azabicyclo[4-methyl-4-oxo ... phosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine It can be prepared by 2,5-dichloro-N-{2-methoxy-4-[4-(4-methyl-4-oxide-1,4-a The (1-(2 ... React with 5-cyclopropyl-1,3-oxazol-2-amine according to the procedure described in Example 32. Can.

[0719] 2-Methoxy-4-[4-(4-methyl-4-oxide-1,4-azaphosphinan-1-yl)piperidine-1- Il]aniline

[0720] [ka]

[0721] 4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylic acid tert -butyl Methyldivinylphosphine oxide (140 mg, 1.21 mL) in 1:1 THF / water (3 mL) A solution of 1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) and 1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) was heated at reflux for 16 hours. The resulting reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-10% Purification with 7N ammonia in methanol:dichloromethane gave the desired compound as a white solid. Obtained (178 mg, yield 38%).

[0722] 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphine Naan 4-oxide 4-(4-methyl-4-oxide-1,4-azaphosphinane- in CH2Cl2 (2 mL) To a stirred solution of tert-butyl 1-ylpiperidine-1-carboxylate (178 mg, 0.563 mmol) was added trichloroisopropyl methyl ... Trifluoroacetic acid (0.5 mL) was added. After 20 min, the solution was concentrated and the resulting residue was dissolved in DMF (2 mL). The resulting solution was stirred and redissolved in potassium carbonate (160 mg, 1.16 mmol), followed by 5-Fluoro-2-nitroanisole (158 mg, 0.930 mmol) was added portionwise to the reaction mixture. The mixture was heated to 50° C. After 2 h, the reaction mixture was concentrated and the residue was purified by silica gel chromatography. Purify with (0-10% 7N ammonia in methanol:dichloromethane) to obtain the target compound. Obtained as a yellow solid (176 mg, 86% yield).

[0723] 2-Methoxy-4-[4-(4-methyl-4-oxide-1,4-azaphosphinan-1-yl)piperidine-1- Il]aniline : 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4 -methyl-1,4-azaphosphinane 4-oxide (176 mg, 0.485 mmol), ethanol (5 mL), and 10% Pd / C (50 mg). The vessel was connected to a Parr apparatus, evacuated, and then filled with nitrogen. The vessel was again evacuated and filled with hydrogen gas to a pressure of 50 psi. The mixture was shaken under 50 psi for 4 hours. The reaction mixture was filtered through Celite and the ethanolic HCl solution was The filtrate was concentrated to give the desired compound as a gray solid. The product was obtained (178 mg, 98% yield).

[0724] Example 57 5-Chloro-N 2 -(5-cyclopropyl-1,3-oxazol-2-yl)-N 4 -[4-(1-ethyl-4-oxo Cido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidine-2,4-diamine

[0725] [ka]

[0726] This compound was synthesized as 4-(1-ethyl-4-oxide-1,4-azaphos)- (4-phenyl-2-methoxyaniline) is reacted with 2,4,5-trichloropyrimidine to give 2,5 -dichloro-N-[4-(1-ethyl-4-oxide-1,4-azaphosphinan-4-yl)-2-methoxyphenoxy] It can be prepared by generating 2,5-dichloro-N-[4-(1- Ethyl-4-oxide-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidine-4- The amine was then converted to 5-cyclopropyl-1,3-oxazolidinyl amine according to the procedure described in Example 32. React with benzoyl-2-amine.

[0727] 4-(1-ethyl-4-oxide-1,4-azaphosphinan-4-yl)-2-methoxyaniline

[0728] [ka]

[0729] Diethyl (3-methoxy-4-nitrophenyl)phosphonate : 5-chloro-2-nitrobenzoate in 20 mL of DMF A solution of diethyl phosphite (0.809 g, 5.86 mmol) in 1.00 g of methylanisole (1.00 g, 5.33 mmol) was added to the solution of diethyl phosphite (0.809 g, 5.86 mmol). ol), palladium acetate (0.060 g, 0.27 mmol), Xantphos (0.185 g, 0.320 mmol), and Potassium phosphate (1.24 g, 5.86 mmol) was added. The mixture was purged with nitrogen and heated to 150 °C for 20 min. The reaction mixture was concentrated and purified by silica gel chromatography (0-45 % ethyl acetate:heptane) to give the desired product (0.504 g, 33% yield).

[0730] (3-Methoxy-4-nitrophenyl)phosphonic acid dichloride : (3-Methoxy- A solution of diethyl 4-nitrophenylphosphonate (4.54 g, 15.7 mmol) was added to thionyl chloride ( A reflux condenser was attached to the reaction flask, and the mixture in the flask was The mixture was heated to reflux. After refluxing for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude oil was redissolved in CH2Cl2 and heptane was added to precipitate the desired compound. The precipitate was decanted and collected and dried to give the target compound as a white solid. (1.39 g, 33% yield).

[0731] Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide : (3-methyl) in 15 mL of THF (4-nitrophenyl) phosphonic acid dichloride (1.39 g, 5.15 mmol) under nitrogen at -78°C To the solution was slowly added vinylmagnesium bromide (10.3 mL, 1.0 M in THF). After that, the reaction mixture was stirred at -78°C for an additional 1 hour. To this cold reaction mixture was added saturated NH4Cl (20 mL). The reaction was quenched by addition, and the mixture was extracted with CH2Cl2. The combined organic layers were washed with 1M NaOH and brine. The organic extract was filtered and concentrated to give diethenyl(3-methylpropional). To obtain 2,4-dichloro-4-nitrophenyl)phosphane oxide (0.982 g, 75%).

[0732] 1-Ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide : Ji Ethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol), A solution of ethylamine hydrochloride (0.174 g, 2.12 mmol) and 1N NaOH (2 mL) in 50% aqueous THF (5 mL) was and heated to 105°C under nitrogen. After 1 hour, additional benzylamine was added to the reaction mixture. The reaction mixture was refluxed for an additional 2 hours and then cooled to room temperature. Partitioned between aqueous CO3 and CH2Cl2. The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was evaporated on silica gel. Purification was performed by column chromatography (0–10% 7N ammonia in methanol:dichloromethane). The target compound was obtained (0.267 g, yield 46%).

[0733] 4-(1-ethyl-4-oxide-1,4-azaphosphinan-4-yl)-2-methoxyaniline : Hula 1-Ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphos in 5 mL of ethanol in a A solution of finan 4-oxide (0.267 g, 0.895 mmol) was added to 10% Pd / C (27 mg) and 2.MH A solution of Cl in ethanol (1.43 mL) was added. The flask was fitted with a septum, evacuated, and The flask was refilled with hydrogen, a hydrogen balloon was attached, and the reaction was stirred for 3 hours. The flask was then evacuated and backfilled with nitrogen. The reaction mixture was filtered through Celite and concentrated to give The crude product was obtained as the hydrochloride salt and was used without purification.

[0734] Example 58 5-Chloro-N 2 -(2-cyclopropyl-1,3-oxazol-5-yl)-N 4 -[4-(diethylphosphoryl (phenyl)-2-methoxyphenyl]pyrimidine-2,4-diamine

[0735] [ka]

[0736] This compound was synthesized by the procedure described in Example 32, using 4-(diethylphosphoryl)-2-methoxyaniline. The reaction of 2,4,5-trichloropyrimidine with 2,5-dichloro-N-[4-(diethylphosphino]

[0042] The compound can be prepared by forming [2-methoxyphenyl]pyrimidin-4-amine. 2,5-Dichloro-N-[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidin-4-amine 5-Cyclopropyl-1,3-oxazole-2-amine was then prepared according to the procedure described in Example 32. React with .

[0737] 4-(Dipropylphosphoryl)-2-methoxyaniline

[0738] [ka]

[0739] To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495 mmol) in 2 mL of DMF was added dipro- Pyrphosphine oxide (0.0730 g, 0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), l), Xantphos (17.2 mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol) were added. The mixture was purged with nitrogen and subjected to microwave heating at 150°C for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0–12% 7N ammonia in methanol). The residue was purified with 2.5M HCl in ethanol and the desired fraction was concentrated. The resulting solution was concentrated to give 4-(dipropylphosphoryl)-2-methoxyaniline as a salt. The compound was obtained as the acid salt (0.132 g, 91% yield).

[0740] Example 59 N-[4-(dimethylphosphoryl)phenyl]-6-(4-methylpiperazin-1-yl)pyrimidine-4- amine

[0741] [ka]

[0742] 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine : N,N-dimethyl 4-Amino-dimethylphenyl in 15 mL of formamide and 3.6 mL of diisopropylethylamine A suspension of 2.2 mmol of methyl phosphine oxide was stirred at room temperature until a clear solution was obtained. 4,6-Dichloropyrimidine (2.6 mmol) is added in four portions over 5 minutes. The mixture is stirred at elevated temperature until the desired compound is formed.

[0743] N-[4-(dimethylphosphoryl)phenyl]-6-(4-methylpiperazin-1-yl)pyrimidine-4- amine : 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidinone in 1.5 mL of ethanol A solution of 1-methylpiperazine (0.072 mmol) was added to 10 μL of triethylamine and 1-methylpiperazine (0. The reaction mixture can be heated in a microwave at 120°C. The mixture can then be filtered through a syringe filter and purified by preparative HPLC.

[0744] Example 60 N-[4-(dimethylphosphoryl)phenyl]-N'-(tricyclo[3.3.1.1] 3,7 "Deku-1-Il)pi Rimidine-4,6-diamine

[0745] [ka]

[0746] 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidine-4-amine in 1.5 mL of ethanol To a solution of 10 μL of triethylamine (prepared as described in Example 59, 0.078 mmol), 10 μL of 1 -Adamantanamine (12 mg, 0.078 mmol) was added. This mixture was used to produce the desired compound. The reaction mixture can then be syringe filled and heated at 120°C until 50°C. The product can be filtered through a filter and purified by preparative HPLC.

[0747] Example 61 N-[4-(dimethylphosphoryl)phenyl]-N'-(morpholin-4-ylmethyl)pyrimidine-4,6- Diamine

[0748] [ka]

[0749] 6-Chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine in 2 mL of ethanol To a solution of 4-(2-methyl-2-propanol) (prepared as described in Example 59, 0.12 mmol), 50 μL of triethylamine and 4-(2-methyl-2-propanol) were added. -aminoethyl)morpholine (15 mg, 0.12 mmol) was added to the mixture. The resulting reaction mixture can be heated in a microwave at 120°C until HCl is formed. The product can be filtered through a dip filter and purified by preparative HPLC.

[0750] Example 62 4-{2-[(6-{[4-(dimethylphosphoryl)phenyl]amino}pyrimidin-4-yl)amino]ethyl {phenyl}benzenesulfonamide

[0751] [ka]

[0752] 6-Chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine in 2 mL of ethanol To a solution of 4-(2-methyl-2-propanol) (prepared as described in Example 59, 0.12 mmol), 50 μL of triethylamine and 4-(2-methyl-2-propanol) were added. -aminoethyl)benzenesulfonamide (23 mg, 0.12 mmol) was added to this mixture. The resulting reaction mixture can be heated in a microwave at 120°C until the desired compound is produced. The mixture can be filtered through a syringe filter and purified by preparative HPLC.

[0753] Example 63 N-[4-(dimethylphosphoryl)phenyl]-N'-(tetrahydrofuran-2-yl)pyrimidine-4, 6-diamine

[0754] [ka]

[0755] 6-Chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine in 2 mL of ethanol To a solution of 1,2-dimethyl-2,4-trimethyl-1,4-trimethyl ... 3-aminotetrahydrofuran hydrochloride (14 mg, 0.12 mmol) was added. The resulting reaction mixture can be heated in a microwave at 120° C. until the desired compound is formed. can be filtered through a syringe filter and purified by preparative HPLC.

[0756] Example 64 N-[4-(dimethylphosphoryl)phenyl]-N'-(hexahydrocyclopenta[c]pyrrole-2(1 H)-yl)pyrimidine-4,6-diamine

[0757] [ka]

[0758] 6-Chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine in 2 mL of ethanol To a solution of 3-aminopropane (prepared as described in Example 59, 0.12 mmol) was added 50 μL of triethylamine and 3-aminopropane. Add 19 mg of methylamino-3-azabicyclo[3.3.0]octane hydrochloride (0.12 mmol) to this mixture. The reaction mixture can be microwaved at 120°C until the desired compound is formed. The reaction mixture can be filtered through a syringe filter and purified by preparative HPLC.

[0759] Example 65 N-[4-(dimethylphosphoryl)phenyl]-N'-(morpholin-4-yl)pyrimidine-4,6-diamine hmm

[0760] [ka]

[0761] 6-Chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine in 2 mL of ethanol To a solution of 4-aminobenzoate (prepared as described in Example 59, 0.12 mmol) was added 50 μL of triethylamine and 4-aminobenzoate. Add 12 mg of methylaminomorpholine (0.12 mmol) to the mixture. The resulting reaction mixture can be heated in a microwave oven at 120 °C. The product can be filtered through a filter and purified by preparative HPLC.

[0762] Example 66 N-[4-(dimethylphosphoryl)phenyl]-6-(4-phenylpiperazin-1-yl)pyrimidine-4 -amine

[0763] [ka]

[0764] 6-Chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine in 2 mL of ethanol To a solution of 1-furan (prepared as described in Example 59, 0.12 mmol) was added 50 μL of triethylamine and 1-furan. Add phenylpiperazine (19 mg, 0.12 mmol) and the mixture to obtain the desired compound. The resulting reaction mixture can be heated in a microwave oven at 120°C until the reaction is complete. The product can be filtered through a filter and purified by preparative HPLC.

[0765] Example 67 N-[4-(dimethylphosphoryl)phenyl]-N'-[2-(1H-indol-3-yl)ethyl]pyrimidin 4,6-diamine

[0766] [ka]

[0767] This compound was synthesized in the same manner as in Example 59, using 6-chloro-N-[4-(dimethylphosphoryl)phenyl] It is prepared by reacting pyrimidin-4-amine with tryptamine. Example 68 N-[4-(dimethylphosphoryl)phenyl]-N'-(4-methylpiperazin-1-yl)pyrimidine-4, 6-diamine

[0768] [ka]

[0769] This compound was synthesized in the same manner as in Example 59, using 6-chloro-N-[4-(dimethylphosphoryl)phenyl] Prepared by reacting pyrimidin-4-amine with 1-amino-4-methylpiperazine do.

[0770] Example 69 N-[4-(dimethylphosphoryl)phenyl]-N'-(tricyclo[3.3.1.1] 3,7 "Deku-1-Ilmechi (I)pyrimidine-4,6-diamine

[0771] [ka]

[0772] This compound was synthesized in the same manner as in Example 59, using 6-chloro-N-[4-(dimethylphosphoryl)phenyl] Prepared by reacting pyrimidin-4-amine with 1-adamantanemethylamine do.

[0773] Example 70 N-[4-(dimethylphosphoryl)phenyl]-N'-[4-(4-methylpiperazin-1-yl)benzyl] Pyrimidine-4,6-diamine

[0774] [ka]

[0775] This compound was synthesized in the same manner as in Example 59, using 6-chloro-N-[4-(dimethylphosphoryl)phenyl] By reacting pyrimidin-4-amine with 4-(4-methylpiperazine)benzylamine It is prepared by

[0776] Example 71 N-(3,5-dimethylphenyl)-N'-[4-(dimethylphosphoryl)phenyl]pyrimidine-4,6-di amine

[0777] [ka]

[0778] This compound was synthesized in the same manner as in Example 59, using 6-chloro-N-[4-(dimethylphosphoryl)phenyl] It is prepared by reacting pyrimidin-4-amine with 3,5-dimethylaniline. Example 72 N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-2-methyl-N'-phenylpyrimidine-4 ,6-diamine

[0779] [ka]

[0780] 6-chloro-2-methyl-N-phenylpyrimidin-4-amine : Aniline in 5 mL of ethanol ( A solution of 205 mg of methylpyrimidine (2.2 mmol) and 4,6-dichloro-2-methylpyrimidine (2.7 mmol) was added with calcium carbonate. Add 500 mg of sodium. Stir the reaction mixture at room temperature until the desired compound is formed. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography. can be done.

[0781] (3-Methoxy-4-nitrophenyl)(dimethyl)phosphane oxide : 5-chloro- A solution of 2-nitroanisole (0.5 g, 2.67 mmol) was added to dimethylphosphine oxide (0. 229 g, 2.93 mmol), palladium acetate (30 mg, 0.13 mmol), Xantphos (0.092 g, 0.16 mmol) mol), and potassium phosphate (0.623 g, 2.93 mmol) were added. The mixture was purged with argon. The reaction mixture was basified with saturated sodium bicarbonate solution and heated to 120°C for 18 hours. Extraction with ethyl acetate was performed. The organic layer was concentrated and purified by preparative HPLC to give the final product (0. 16 g, 30% yield. MS / ES+: m / z=229.

[0782] 4-(Dimethylphosphoryl)-2-methoxyaniline : (3-methoxy-4-nitro) in 5 mL of EtOH A solution of 10 wt. phenyl)(dimethyl)phosphane oxide (0.1 g, 0.44 mmol) was added to a carbon-supported % palladium (0.2 g) was added. The mixture was purged with argon and heated under 30 psi for 2 hours in water. The resulting mixture was passed through Celite and poured into a flask containing ethanolic HCl. The mixture was filtered through a sco. The filtrate was concentrated to give the final product (0.088 g, 86% yield). MS / ES+: m / z=199.

[0783] N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-2-methyl-N'-phenylpyrimidine-4 ,6-diamine 6-Chloro-2-methyl-N-phenylpyrimidin-4-amine (0.35 m) in 1 mL of DMF mol) and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg, 0.30 mmol), Add 0.36 mL of 2.5M HCl ethanol solution. The reaction mixture is sealed in a tube to form the target compound. The reaction mixture can be filtered through a syringe filter and then heated to 140°C. It can be purified by preparative HPLC.

[0784] Example 73 N 3 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl) (phenyl)phenyl]pyridazine-3,5-diamine

[0785] [ka]

[0786] 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine : N,N-di 1-Amino-2-(isopropylsulfonyl)benzene (350 mg, 1 mL) in 4 mL of methylformamide To a solution of 0.6 mmol of HCl at 0°C, sodium hydride (100 mg) was added and the reaction mixture was stirred at 0°C for 20 minutes. 3,5-Dichloropyridazine (1.6 mmol) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture is stirred at room temperature until the desired compound is produced. The reaction is quenched and extracted with ethyl acetate. The combined ethyl acetate layers are dried over sodium sulfate and The solvent is removed under reduced pressure and the residue can be purified by preparative HPLC.

[0787] N 3 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl) (phenyl)phenyl]pyridazine-3,5-diamine : 6-chloro-N-[2- in 1 mL of 2-methoxyethanol (propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (0.02 mmol) and 4-(dimethylamino)- (ethylphosphoryl)-2-methoxyaniline (prepared as described in Example 72: 15 mg, 0.7 mmol) Add 1 mL of 2.5M HCl ethanol solution to the solution. The reaction mixture is then cooled in a sealed tube to determine whether the target compound is present. Heat to 140°C until the product is formed. Filter the reaction mixture through a syringe filter and then add to a preparative HCl solution. It can be purified by PLC.

[0788] Example 74 N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-[3-fluoro-5-(trifluoromethyl) [Cyi)phenoxy]pyridazin-3-amine

[0789] [ka]

[0790] 3-chloro-5-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridazine : N,N-dime 3-Fluoro-5-(trifluoromethyl)phenol (1.6 mmol) in 4 mL of ethylformamide To the solution of at 0°C, sodium hydride (100 mg) was added, and the reaction mixture was stirred at 0°C for 20 minutes. 3,5-Dichloropyridazine (1.6 mmol) is added and the reaction mixture is allowed to warm to room temperature. The reaction mixture is stirred at room temperature until the desired compound is formed. The reaction mixture is quenched with water. The combined ethyl acetate layers were dried over sodium sulfate and the solvent was removed. Remove under reduced pressure and the residue can be purified by preparative HPLC.

[0791] N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-[3-fluoro-5-(trifluoromethyl) [Cyi)phenoxy]pyridazin-3-amine : 3-chloro-5-[3- in 1 mL of 2-methoxyethanol Fluoro-5-(trifluoromethyl)phenoxypyridazine (0.02 mmol) and 4-(dimethyl phosphoryl)-2-methoxyaniline (prepared as described in Example 72: 15 mg, 0.7 mmol) To the solution, add 1 mL of 2.5M HCl ethanol solution. The reaction mixture is then sealed in a tube to form the target compound. The reaction mixture was filtered through a syringe filter and then analyzed by preparative HPLC. It can be purified by

[0792] Example 75 N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-2-methyl 4,6-diethyl-N'-[4-(dimethylphosphoryl)phenyl]pyrimidine-4,6-diamine

[0793] [ka]

[0794] 6-chloro-N-[4-(dimethylphosphoryl)phenyl]-2-methylpyrimidin-4-amine : DMF A solution of 4,6-dichloro-2-methylpyrimidine (1.31 mmol) in 1 mL of 4-(dimethylphosphoryl)-2-pyrimidine was added. (aryl)aniline (0.221 g, 1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol) were added. This mixture is heated to 110°C until the desired compound is produced. The resulting suspension is filtered and washed with ethyl acetate. do.

[0795] 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine : DMF To a solution of 5-fluoro-2-nitroanisole (0.5 g, 2.92 mmol) in 3 mL of 1-methyl-4-( piperazine (0.536 g, 2.92 mmol) and potassium carbonate (0.808 g, 5.84 mmol) The mixture was heated to 120°C for 18 hours. The mixture was washed with saturated sodium bicarbonate solution. It was made basic and extracted with ethyl acetate. The organic layer was purified by chromatography to give the final product. The product was obtained as a yellow solid (0.95 g, 95% yield). MS / ES+: m / z=334.

[0796] 2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline : Argo 1-[1-(3-methoxy-4-nitrophenyl)piperidine-4- ( A solution of 10% palladium on carbon (0. 060 g) was added. After 4 hours under 30 psi, the hydrogenation was completed. The resulting mixture was The filtrate was filtered through a filter into a flask containing ethanolic HCl. The final product was obtained (0.15 g, 88% yield). MS / ES+: m / z=334.

[0797] N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-2-methyl 4,6-diamino-N'-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine : 2-Meth The compound 6-chloro-2-methyl-N-[2-(propan-2-ylsulfonyl)fluoride] in 1 mL of hydroxyethanol phenyl]pyrimidin-4-amine (0.16 mmol) was added to 2-methoxy-4-[4-(4-methylpiperazine-1 Add [(1-yl)piperidin-1-yl]aniline (0.71 g, 0.16 mmol). The mixture is stirred at 110°C until the compound is formed. The mixture is then basified with saturated sodium bicarbonate solution. The resulting compound is purified by chromatography. It can be further refined.

[0798] Example 76 N-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N'-[2-(propan-2-yl) (sulfonyl)phenyl]pyrimidine-4,6-diamine

[0799] [ka]

[0800] 6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine : 6-Bromo- in 4 mL of DMF A solution of 2-methoxypyridin-3-ylamine (0.203 g, 1.00 mmol) was added to dimethylphosphine Benzene oxide (0.171 g, 1.10 mmol), palladium acetate 11.0 mg, 0.0490 mmol), Xantphos (35.0 mg, 0.0600 mmol), and potassium phosphate (0.233 g, 1.10 mmol) were added to this mixture. The mixture was purged with nitrogen and subjected to microwave heating at 150° C. for 20 minutes. Condensed and purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) The product was purified by HPLC to give the desired product (77.2 mg, 39% yield).

[0801] 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine : DMF 2 Dissolve 1-amino-2-(isopropylsulfonyl)benzene (0.955 g, 4.80 mmol) in 1 mL of HCl at 0°C. To the solution, NaH (60% in oil, 0.349 g, 8.72 mmol) was added in one portion. After stirring for 20 minutes, the 4,6- Dichloropyrimidine can be added. The mixture is stirred at 0°C for 30 minutes, then at room temperature for 30 minutes. Stir until the compound is formed. After quenching the reaction with saturated ammonium chloride solution, The product is poured into a mixture of water and ethyl acetate, and the resulting compound can be purified by HPLC.

[0802] N-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N'-[2-(propan-2-yl) (sulfonyl)phenyl]pyrimidine-4,6-diamine : 6-chloro in 1 mL of 2-methoxyethanol -N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.250 mmol) The solution was diluted with 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250 mmol) ) and 0.15 mL of 2.5M HCl ethanol solution are added. This mixture is then placed in a sealed tube to produce the target compound. The mixture is made basic with 1N NaOH solution and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, and filtered. The crude residue obtained can be purified by silica gel chromatography. do.

[0803] Example 77 N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N'-[2-(propan-2-yl) (sulfonyl)phenyl]pyrimidine-4,6-diamine

[0804] [ka]

[0805] 5-(Dimethylphosphoryl)-3-methoxypyrazin-2-amine : 5-Bromo-3-methylpropional in 4 mL of DMF A solution of 2-methyl-3-pyrazin-3-ylamine (0.204 g, 1.00 mmol) was added to dimethylphosphine oxide. oxide (0.171 g, 1.10 mmol), palladium acetate (11.0 mg, 0.0490 mmol), Xantphos (35. 0 mg, 0.0600 mmol), and potassium phosphate (0.233 g, 1.10 mmol) were added to this mixture. The mixture was purged with nitrogen and subjected to microwave heating at 150° C. for 20 minutes. The reaction mixture was concentrated and , silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) The desired product was obtained (126 mg, 63% yield).

[0806] 5-Chloro-N 2 -[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N 4 -[2-(propane -2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine : 6-chloro-N-[2-(propane-2- (phenyl)pyrimidin-4-amine (prepared in Example 76, 0.348 mmol) and 5-(diphenylsulfonyl)phenyl)pyrimidin-4-amine In a mixture with methylphosphoryl-3-methoxypyrazin-2-amine (70.0 mg, 0.348 mmol) , tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (17.6 mg, 0.0 17 mmol), Xantphos (23.3 mg, 0.040 mmol), and cesium carbonate (0.228 g, 0.700 mmol). and dioxane (3.5 mL) were added. This mixture was stirred in a sealed tube for 1 minute until the desired compound was produced. The reaction mixture is then cooled to room temperature and concentrated. It can be purified by silica gel chromatography.

[0807] Example 78 N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N'-[2-(propan-2-ylsulfonyl) )phenyl]pyrimidine-4,6-diamine

[0808] [ka]

[0809] N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) (phenyl)phenyl)pyrimidine-2,4-diamine : 6-chloro-N-[2-(propan-2-yl)methyl]propan-2-yl ... To a solution of 4-([(aminomethyl)phenyl]pyrimidin-4-amine (prepared in Example 76, 0.054 mmol) (dimethylphosphoryl)-2-methoxyaniline (prepared in Example 73, 0.044 mmol) as the HCl salt The vial is sealed and the reaction is heated to 90°C until the desired compound is formed. The reaction is quenched with 1N NaOH solution and the solution is extracted with ethyl acetate. The organic layers are combined and saturated Wash with sodium chloride solution, dry over sodium sulfate, filter and concentrate. The product residue can be purified by silica gel chromatography.

[0810] Example 79 N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) (phenyl)phenyl)pyridine-2,4-diamine

[0811] [ka]

[0812] 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine : Toluene A solution of 2-chloro-4-iodo-5-methylpyridine (2.00 mmol) in 8 mL of 1-amino-2-(iodo-5-methylpyridine) was added. (isopropylsulfonyl)benzene (2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), Add Xantphos (69.4 mg, 0.120 mmol) and cesium carbonate (2.20 mmol). The mixture was purged with nitrogen and 2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl] Microwave heating at 100°C can be performed until pyridin-4-amine is formed. The mixture can then be concentrated and purified by silica gel chromatography.

[0813] N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) (phenyl)phenyl)pyridine-2,4-diamine : 2-chloro-N-[2-( To a solution of 4-(dipropan-2-ylsulfonyl)phenyl]pyridin-4-amine (0.12 mmol) (methylphosphoryl)-2-methoxyaniline (prepared as described in Example 72, 0.12 mmol) and Add 49 μL of 2.5M HCl ethanol solution to this mixture. The mixture is then made basic with 1N NaOH solution and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, and filtered. The resulting crude residue can be purified by preparative HPLC to give the final product. It is possible.

[0814] Example 80 N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) [phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

[0815] [ka]

[0816] 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine Zin-4-amine : 2-chloro-4-iodo-5-(trifluoromethyl)pyridine in 8 mL of toluene (2.00 mmol), 1-amino-2-(isopropylsulfonyl)benzene (2.20 mmol), Palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol), and carbonate Cesium (2.20 mmol) was added. The mixture was purged with nitrogen and 2-chloro-5-methyl-N-[ 2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine was obtained. The reaction mixture is then concentrated and purified by silica gel chromatography. It can be refined by filtration.

[0817] N 2 -[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N 4 -[2-(propan-2-yl) Sulfonyl)phenyl]pyridine-2,4-diamine : 2-chloroethanol in 1 mL of 2-methoxyethanol -N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine To a solution of 4-(dimethylphosphoryl)-2-methoxyaniline (described in Example 72) was added 4-(dimethylphosphoryl)-2-methoxyaniline (described in Example 72). Add 0.12 mmol of HCl (prepared as described above) and 49 μL of 2.5 M ethanolic HCl. The mixture is heated to 90°C in a sealed tube until the desired compound is formed. The mixture is then basified with 1N NaOH solution. The combined organic layers were washed with saturated sodium chloride solution and The crude residue can be dried over sodium sulfate, filtered, and concentrated. The final product can be obtained by LC purification.

[0818] Example 81 N 2 -[5-(dimethylphosphoryl)-2-methoxyphenyl]-N 4 -[2-(propan-2-ylsulfonyl) [phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

[0819] [ka]

[0820] This compound was prepared as described in Example 80, by the synthesis of 2-chloro-N-[2-(propan-2-yl)sulfo] [Nyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 5-(dimethylphosphoryl)-2 -methoxyaniline.

[0821] 5-(Dimethylphosphoryl)-2-methoxyaniline : 5-Bromo-2-methoxyaniline in 8 mL of DMF A solution of dimethylphosphine oxide (0.171 g, 2.20 mmol) was added to a solution of dimethylphosphine oxide (0.404 g, 2.00 mmol). mol), palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol), and and potassium phosphate (0.467 g, 2.20 mmol) were added. The mixture was purged with nitrogen and heated to 150°C. The reaction mixture was concentrated and subjected to silica gel chromatography. Purify the product by filtration (0-20% 7N ammonia in methanol:dichloromethane). The product was obtained (0.365 g, 85% yield).

[0822] Example 82 N 2 -[4-(dimethylphosphoryl)-2-methylphenyl]-N 4 -[2-(propan-2-ylsulfonyl) Phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

[0823] [ka]

[0824] This compound was prepared as described in Example 80, by the synthesis of 2-chloro-N-[2-(propan-2-yl)sulfo] [Nyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(dimethylphosphoryl)-2 -methylaniline.

[0825] 4-(Dimethylphosphoryl)-2-methylaniline : 4-Bromo-2-methylaniline in 8 mL of DMF To a solution of dimethylphosphine oxide (0.171 g, 2.20 mmol) was added dimethylphosphine oxide (0.372 g, 2.00 mmol). , palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol) and phosphorus Potassium carbonate (0.467 g, 2.20 mmol) was added. The mixture was purged with nitrogen and heated to 150 °C for 20 min. The reaction mixture was concentrated and purified by silica gel chromatography (0-20 % 7N ammonia in methanol:dichloromethane) to give the desired product (0.313 g, yield 85%).

[0826] Example 83 N 2 -[4-(dimethylphosphoryl)-2-ethylphenyl]-N 4-[2-(propan-2-ylsulfonyl) Phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

[0827] [ka]

[0828] This compound was prepared as described in Example 80, by the synthesis of 2-chloro-N-[2-(propan-2-yl)sulfo] [Nyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(dimethylphosphoryl)-2 -ethylaniline.

[0829] 4-(Dimethylphosphoryl)-2-ethylaniline : 4-Bromo-2-ethylaniline in 8 mL of DMF To a solution of dimethylphosphine oxide (0.171 g, 2.20 mmol) was added dimethylphosphine oxide (0.400 g, 2.00 mmol). , palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol) and phosphorus Potassium carbonate (0.467 g, 2.20 mmol) was added. The mixture was purged with nitrogen and heated to 150 °C for 20 min. The reaction mixture was concentrated and purified by silica gel chromatography (0-20 % 7N ammonia in methanol:dichloromethane) to give the desired product (0.308 g, yield 78%).

[0830] Example 84 N 2 -[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N 4 -[2-(propane-2 -ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

[0831] [ka]

[0832] This compound was prepared as described in Example 80, by the synthesis of 2-chloro-N-[2-(propan-2-yl)sulfo] [Nyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(dimethylphosphoryl)-2 -(trifluoromethoxy)aniline.

[0833] 4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline : 4-Iodine in 8 mL of DMF A solution of 2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) was added to dimethylphosphite. Benzyl alcohol (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), Xantho s (69.4 mg, 0.120 mmol) and potassium phosphate (0.467 g, 2.20 mmol) were added to this mixture. The mixture was purged with nitrogen and heated in a microwave at 150° C. for 20 min. The reaction mixture was concentrated and Purification was performed by gel chromatography (0-20% 7N ammonia in methanol:dichloromethane). The desired product was prepared as its hydrochloride salt (0.573 g) and acidified with a methanolic solution of HCl. , yield 98%).

[0834] Example 85 N 2 -[2-chloro-4-(dimethylphosphoryl)phenyl]-N 4 -[2-(propan-2-ylsulfonyl) Phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

[0835] [ka]

[0836] This compound was prepared as described in Example 80, by the synthesis of 2-chloro-N-[2-(propan-2-yl)sulfo] [Nyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 2-chloro-4-(dimethylphosphite) It can be prepared by reacting with phenylalanine.

[0837] 2-chloro-4-(dimethylphosphoryl)aniline : 2-chloro-4-iodoaniline in 8 mL of DMF To a solution of dimethylphosphine oxide (0.171 g, 2.20 mmol) was added dimethylphosphine oxide (0.507 g, 2.00 mmol). , palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol) and phosphorus Potassium carbonate (0.467 g, 2.20 mmol) was added. The mixture was purged with nitrogen and heated to 150 °C for 20 min. The reaction mixture was concentrated and purified by silica gel chromatography (0-20 % 7N ammonia in methanol:dichloromethane) to give the desired product (0.340 g, yield 83%).

[0838] Example 86 N 2 -[4-(dimethylphosphoryl)-2-fluorophenyl]-N 4 -[2-(propan-2-ylsulfonyl) [phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine

[0839] [ka]

[0840] This compound was prepared as described in Example 80, by the synthesis of 2-chloro-N-[2-(propan-2-yl)sulfo] [Nyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(dimethylphosphoryl)-2 -fluoroaniline.

[0841] 4-(Dimethylphosphoryl)-2-fluoroaniline : 4-Bromo-2-fluoroacetate in 8 mL of DMF A solution of dimethylphosphine oxide (0.171 g, 2.20 mmol) was added to a solution of dimethylphosphine oxide (0.380 g, 2.00 mmol). mol), palladium acetate (22.4 mg, 0.0100 mmol), Xantphos (69.4 mg, 0.120 mmol), and and potassium phosphate (0.467 g, 2.20 mmol) were added. The mixture was purged with nitrogen and The reaction mixture was heated in a microwave oven at 0° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography. (0-20% 7N ammonia in methanol:dichloromethane) to give the desired product. (73.5 mg, 20% yield).

[0842] Example 87 N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N'-{2-methoxy 4,6-di-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine amine

[0843] [ka]

[0844] 4-(Dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline

[0845] [ka]

[0846] 4-Bromo-1-nitro-2-(propan-2-ylsulfanyl)benzene : Stirred at 0°C To a DCM solution of 4-bromo-2-fluoronitrobenzene (2.0 g, 9.1 mmol), 2-propanediol was added. Sodium tetrahydrofuran (2.0 g, 20 mmol) was added in two portions. The reaction mixture was allowed to warm to room temperature. The reaction mixture was filtered through a syringe filter. The product was purified by preparative HP chromatography. It was isolated by LC (water / acetonitrile) as a bright yellow solid (0.8 g, 2.9 mmol, 32% yield). %).

[0847] 4-Bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene : 4- in acetic acid (10 mL) Stirring bromo-1-nitro-2-(propan-2-ylsulfanyl)benzene (0.8 g, 2.9 mmol) To the solution was added hydrogen peroxide (30% aqueous solution, 0.6 mL, 5.8 mmol). The reaction mixture was heated in an oil bath. The reaction mixture was heated to 110° C. for 2 hours. The reaction mixture was treated with saturated aqueous sodium sulfide and saturated aqueous sodium bicarbonate. The resulting mixture was made basic with thorium solution, extracted with ethyl acetate, and the combined organic layers were The organic solvent was removed under reduced pressure and the residue was used in the next step without further purification. was used.

[0848] Dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide : D 4-Bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene (0.44 g, 1.6 mL) in 1 mL of MF To a stirred solution of 1.2 mmol) and dimethylphosphine oxide (0.15 g, 1.9 mmol) was added potassium phosphate. (0.37 g, 1.8 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), Xantphos (55 mg, 0.10 mmol The reaction mixture was heated at 110°C overnight. The reaction mixture was cooled to room temperature and The desired product was isolated by preparative HPLC to give a brown-yellow solid (0.24 g, yield 55%).

[0849] 4-(Dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline : Dimethyl [4-nitrilo [3-(propan-2-ylsulfonyl)phenyl]phosphane oxide (0.24 g, 0.88 mmol) To an ethanol solution of Pd on carbon (10% w / w, 24 mg) was added and stirred under hydrogen overnight. The reaction mixture was filtered and the organic solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 100 mg of the product was obtained (yield 50%).

[0850] 6-chloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyridine 4-aminomethyl-4-amine To a solution of 4,6-dichloropyrimidine (1.31 mmol) in 1 mL of DMF, add 4-(dichloropyrimidine). Methylphosphoryl)-2-(propan-2-ylsulfonyl)aniline (1.31 mmol) and potassium carbonate Add ammonium (0.217 g, 1.57 mmol) and heat the mixture to 110°C until the desired compound is formed. The resulting reaction mixture is made basic with saturated sodium bicarbonate solution. The cloudy liquid is filtered and washed with ethyl acetate.

[0851] N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N'-{2-methoxy 4,6-di-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine amine : Compound 6-chloro-N-[4-(dimethylphosphoryl)-2-( Propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.16 mmol) was treated with 2-methoxyphenyl ds-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (prepared in Example 75, 0 Add 0.71 g (0.16 mmol) of HCl and stir the mixture at 110°C until the desired compound is formed. The mixture was made basic with saturated sodium bicarbonate solution and extracted with a limited amount of ethyl acetate. The resulting compound can be purified by chromatography.

[0852] Example 88 N 3 -[4-(1-ethyl-4-oxide-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine

[0853] [ka]

[0854] 4-(1-ethyl-4-oxide-1,4-azaphosphinan-4-yl)-2-methoxyaniline

[0855] [ka]

[0856] Diethyl (3-methoxy-4-nitrophenyl)phosphonate : 5-chloro-2-nitrobenzoate in 20 mL of DMF A solution of diethyl phosphite (0.809 g, 5.86 mmol) in 1.00 g of methylanisole (1.00 g, 5.33 mmol) was added to the solution of diethyl phosphite (0.809 g, 5.86 mmol). ol), palladium acetate (0.060 g, 0.27 mmol), Xantphos (0.185 g, 0.320 mmol), and Potassium phosphate (1.24 g, 5.86 mmol) was added. The mixture was purged with nitrogen and heated to 150 °C for 20 min. The reaction mixture was concentrated and purified by silica gel chromatography (0-45 % ethyl acetate:heptane) to give the desired product (0.504 g, 33% yield).

[0857] (3-Methoxy-4-nitrophenyl)phosphonic acid dichloride : (3-Methoxy- A solution of diethyl 4-nitrophenylphosphonate (4.54 g, 15.7 mmol) was added to thionyl chloride ( A reflux condenser was attached to the reaction flask, and the mixture in the flask was The mixture was heated to reflux. After refluxing for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude oil was redissolved in CH2Cl2 and heptane was added to precipitate the desired compound. The precipitate was decanted and collected and dried to give the target compound as a white solid. (1.39 g, 33% yield).

[0858] Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide : (3-methyl) in 15 mL of THF (4-nitrophenyl) phosphonic acid dichloride (1.39 g, 5.15 mmol) under nitrogen at -78°C To the solution was slowly added vinylmagnesium bromide (10.3 mL, 1.0 M in THF). After that, the reaction mixture was stirred at -78°C for an additional 1 hour. To this cold reaction mixture was added saturated NH4Cl (20 mL). The reaction was quenched by addition, and the mixture was extracted with CH2Cl2. The combined organic layers were washed with 1M NaOH and brine. The organic extract was filtered and concentrated to give diethenyl(3-methoxyphenyl)-2-methylpropional. (4-nitrophenyl)phosphane oxide (0.982 g, 75%) was obtained.

[0859] 1-Ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide : Ji Ethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol), A solution of ethylamine hydrochloride (0.174 g, 2.12 mmol) and 1N NaOH (2 mL) in 50% aqueous THF (5 mL) was and heated to 105°C under nitrogen. After 1 hour, additional benzylamine was added to the reaction mixture. The reaction mixture was refluxed for an additional 2 hours and then cooled to room temperature. Partitioned between aqueous CO3 and CH2Cl2. The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was evaporated on silica gel. Purification was performed by column chromatography (0–10% 7N ammonia in methanol:dichloromethane). The target compound was obtained (0.267 g, yield 46%).

[0860] 4-(1-ethyl-4-oxide-1,4-azaphosphinan-4-yl)-2-methoxyaniline : Hula 1-Ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphos in 5 mL of ethanol in a A solution of finan 4-oxide (0.267 g, 0.895 mmol) was added to 10% Pd / C (27 mg) and 2.MH A solution of Cl in ethanol (1.43 mL) was added. The flask was fitted with a septum, evacuated, and The flask was refilled with hydrogen, a hydrogen balloon was attached, and the reaction was stirred for 3 hours. The flask was then evacuated and backfilled with nitrogen. The reaction mixture was filtered through Celite and concentrated to give The crude product was obtained as the hydrochloride salt and was used without purification.

[0861] N 3 -[4-(1-ethyl-4-oxide-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N 5 -[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine : 2-Methoxyetha 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-4-amine in 1 mL of alcohol amine (prepared in Example 73, 0.02 mmol) and 4-(1-ethyl-4-oxide-1,4-azaphosphinane) To a solution of (4-yl)-2-methoxyaniline (0.7 mmol), 1 mL of 2.5 M HCl in ethanol was added. The reaction mixture is heated in a sealed tube at 140°C until the desired compound is formed. After filtration through a syringe filter, the product can b...

Claims

1. A method for producing the following compound: 【Chemistry 1】 A compound of the formula: 【Chemistry 2】 A compound of the formula: 【Transformation 3】 reacting the compound.

2. The compound of the following formula: 【Chemistry 4】 A compound of the formula: 【Transformation 5】 and a compound of the formula: 【Transformation 6】 The method according to claim 1, comprising the step of preparing the compound by reacting the compound.

3. The compound of the following formula: 【Transformation 7】 A compound of the formula: 【Transformation 8】 and a compound of the formula: 【Chemistry 9】 The method according to claim 2, comprising the step of preparing the compound by reacting the compound.

4. A compound of the formula: 【Chemistry 10】 。

5. A compound of the formula: 【Chemistry 11】 。

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