Azetidine derivatives useful in treating pain, diabetes and disorders of lipid metabolism

[0001] This application claims the benefit of Provisional Application No. 60/845,077 filed on Sep. 15, 2006.

[0002] Treatment of chronic pain, particularly inflammatory and neuropathic pain, is an area of high unmet medical need. Neuropathic pain is nerve injury resulting in hyperexcitability of neurons involved in pain sensation. T-currents are present in neurons of pain pathways. T-type calcium channel blockers are effective in preclinical models of neuropathic pain.

[0003] Type II diabetes, also known as non-insulin dependent diabetes mellitus, is a progressive disease characterized by impaired glucose metabolism resulting in elevated blood glucose levels. Patients with type II diabetes exhibit impaired pancreatic beta-cell function resulting in failure of the pancreatic beta-cells to secrete an appropriate amount of insulin in response to a hyperglycemic signal, and resistance to the action of insulin at its target tissues (insulin resistance).

[0004] Current treatments of type II diabetes aim to reverse insulin resistance, control intestinal glucose absorption, normalise hepatic glucose production, and improve beta-cell glucose sensing and insulin secretion. The sulfonylurea class of oral antihyperglycemic agents promote insulin secretion from pancreatic beta-islet cells, but have the potential to cause hypoglycemia as their action is independent of glucose levels. Antihyperglycemic agents include: insulin sensitizers that reduce hepatic glucose production by inhibiting gluconeogenesis; α-glucosidase inhibitors that inhibit breakdown of complex carbohydrates thus delaying glucose absorption and dampening postprandial glucose and insulin peaks; and thiazolidinediones that improve the action of insulin and reduce insulin resistance. Over time approximately one-half of type II diabetes patients lose their response to these agents. Because of the shortcomings of current treatments, new treatments for type II diabetes are highly desirable.

[0005] GPR119 is a constitutively active G-protein coupled receptor expressed predominantly in pancreatic beta-islet cells. Activation of GPR119 by an agonist increases insulin release from pancreatic beta-islet cells in a glucose dependent manner. Thus an agonist of GPR119 offers the potential to normalize blood glucose levels in a type II diabetic patient in response to post-prandial blood glucose elevation, but would not be expected to stimulate insulin release in the pre-prandial or fasted state.

[0006] WO 2004/110375 describes combination therapies for the treatment of diabetes comprising the administration of a combination of an anti-obesity agent and an anti-diabetic agent.

[0007] Niemann-Pick C1-like (NPC1L1) has been identified as a critical mediator of cholesterol absorption. It has been determined that the cholesterol absorption inhibitor ezetimibe targets NPC1L1.

[0008] The treatment of disorders of lipid metabolism, diabetes, vascular conditions, demyelination and nonalcoholic fatty liver disease with Spirocyclic Azetidinone Derivatives has been disclosed. Spirocyclic Azetidinone Derivatives that inhibit cholesterol absorption in the small intestine are well known in the art and are described, for example, in U.S. Pat. No. RE 37,721; U.S. Pat. No. 5,631,356; U.S. Pat. No. 5,767,115; U.S. Pat. No. 5,846,966; U.S. Pat. No. 5,698,548; U.S. Pat. No. 5,633,246; U.S. Pat. No. 5,656,624; U.S. Pat. No. 5,624,920; U.S. Pat. No. 5,688,787; U.S. Pat. No. 5,756,470; US Publication No. 2002/0137689; WO 02/066464; WO 95/08522 and WO96/19450. Each of the aforementioned publications is incorporated by reference. The art indicates that these compounds are useful in treating, for example, atherosclerotic coronary disease, either by administrating these compounds alone or with a second compound such as a cholesterol biosynthesis inhibitor.

[0009] WO 2005/000217 describes combination therapies for the treatment of dyslipidemia comprising the administration of a combination of an anti-obesity agent and an anti-dyslipidemic agent. WO 2004/110375 describes combination therapies for the treatment of diabetes comprising the administration of a combination of an anti-obesity agent and an anti-diabetic agent. US 2004/0122033 describes combination therapies for the treatment of obesity comprising the administration of a combination of an appetite suppressant and/or metabolic rate enhancers and/or nutrient absorption inhibitors. US 2004/0229844 describes combination therapies for treating atherosclerosis comprising the administration of a combination of nicotinic acid or another nicotinic acid receptor agonist and a DP receptor antagonist. Also known is a method for treating nonalcoholic fatty liver disease in a mammal by administering an effective amount of therapeutic composition comprising at least one cholesterol lowering agent and/or at least one H₃ receptor antagonist/inverse agonist.

[0010] A welcome contribution to the art would be compounds useful for the treatment of pain, compounds useful for the treatment of diabetes (e.g., type II diabetes), and compounds useful for the treatment of disorders of lipid metabolism. This invention provides such a contribution.

[0011] The present invention claims compounds of formula I (e.g., compounds that are T-calcium channel blockers, agonists of GPR119, or NPC1L1 antagonists):

[0012]
or a pharmaceutically acceptable salt, solvate, hydrate, ester, prodrug or stereoisomer thereof, wherein:

[0013] R¹ is selected from the group consisting of: (1) H, (2) alkyl, (3) substituted alkyl, (4) cycloalkyl, (5) aryl, (6) substituted aryl, (7) arylalkyl, (8) heteroaryl, (9) substituted heteroaryl, (10) heteroarylalkyl, (11) diphenylmethyl, (12) cycloalkylalkyl, (13) alkenyl, (14) —C(O)NQ^B (wherein Q^B is selected from the group consisting of substituted aryl (e.g., substituted phenyl)), and (15) -alkylene-C(O)N(alkyl)₂; and wherein:

• • [0014] the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, and (p) —P(O)(O-alkyl)₂,
  • [0015] the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, (p) —P(O)(O-alkyl)₂, and (q) alkyl; and
  • [0016] the substituted heteroaryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, (p) —P(O)(O-alkyl)₂, and (q) alkyl;

[0017] R² is selected from the group consisting of: (1) H, (2) alkyl, (3) substituted alkyl, (3) cycloalkyl, (4) aryl, (5) substituted aryl, (6) arylalkyl, (7) heteroarylalkyl, (8) heterocycloalkyl, (9) heterocycloalkylalkyl, (10) R⁶-A-, (11) alkyl-O—C(O)—, (12) (alkyl)₂-N-alkylene-C(O)—, (13) (alkyl)₂-N—C(O)-alkylene-C(O)—, (14) CN-alkylene-C(O)—, (15) alkyl-O-alkylene-C(O)—, (16) alkyl-C(O)-alkylene-C(O)—, (17) alkyl-C(O)—NH-alkylene-C(O)—, (18) alkyl-NH—C(O)—, (19) alkyl-O—C(O)-alkylene-C(O)—, (20) alkyl-O—C(O)-cycloalkylene-alkylene-, (21) NH₂—C(O)—NH-alkylene-C(O)—, (22) NH₂—C(O)-alkylene-C(O)—, (23) alkyl-C(O)—NH-alkylene-S-alkylene-C(O)—, (24) alkyl-O—C(O)-alkylene-C(O)—, (25) alkyl-S-alkylene-C(O)—, (26) alkyl-C(O)-cycloalkylene-alkylene-C(O)—, (27) alkyl-S-alkylene-(—NHC(O)alkyl)-C(O)—, (28) alkyl(-C(O)Oalkyl)-NH—C(O)—, (29) alkyl-S-alkylene(—NHC(O)alkyl)-C(O)—, (30) —C(O)NHQ^A wherein Q^A is selected from the group consisting of: (a) cycloalkyl, (b) alkyl substituted with —C(O)—O-alkyl, (c) substituted aryl, (d) alkyl, (e) substituted arylalkyl, (f) substituted heterocycloalkenylbenzo, and (g) heteroaryl, (31) —C(O)NQ^CQ^D wherein Q^c and Q^D are each independently selected from the group consisting of: (a) H, (b) Q^A (wherein Q^A is as previously defined), (c) substituted aryl, and (d) arylalkyl, (32) substituted heteroarylalkyl, and

[0018]
wherein Z^A is selected from the group consisting of: H and alkyl (e.g., C₁ to C₄ alkyl), and Q^F is selected from the group consisting of: —C(O)Oalkyl (e.g., —C(O)O(C₁ to C₄ alkyl)) and —C(O)N(X^A)₂ wherein each X^A is independently selected from the group consisting of: H and alkyl (e.g., C₁ to C₄ alkyl), and wherein examples of the group (33) include, for example, alkyl(—C(O)Oalkyl)-NH—C(O)— (such as, for example,

[0019]
such as, for example,

[0020]
such as, for example,

[0021]
such as, for example,

[0022]
such as, for example,

[0023]
such as, for example,

[0024]
such as, for example,

[0025]
wherein:

• • [0026] the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, and (p) —P(O)(O-alkyl)₂;
  • [0027] the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g. 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, (p) —P(O)(O-alkyl)₂, and (q) alkyl; and
  • [0028] the substituted heteroarylalkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, (p) —P(O)(O-alkyl)₂, and (q) alkyl, and wherein the heteroaryl portion is substituted, or the alkyl portion is substituted, or both the heteroaryl and alkyl portions are substituted; and

[0029] R³ is selected from the group consisting of: (1) H, (2) alkyl, (3) substituted alkyl, (4) cycloalkyl, (5) aryl, (6) substituted aryl, (7) arylalkyl, (8) arylalkenyl, (9) arylalkynyl (10) heteroaryl, (11) substituted heteroaryl, (12) heteroarylalkyl, (13) heteroarylalkenyl, and (14) heteroarylalkynyl; and wherein:

• • [0030] the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, and (p) —P(O)(O-alkyl)₂;
  • [0031] the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, (p) —P(O)(O-alkyl)₂, and (q) alkyl; and
  • [0032] the substituted heteroaryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, (p) —P(O)(O-alkyl)₂, and (q) alkyl; and

[0033] Each occurrence of R⁴ is independently selected from the group consisting of: —CH₂—, —CH(alkyl)- and —C(alkyl)₂ wherein each alkyl for each R⁴ is independently selected, and wherein examples of said alkyl group include, for example, C₁ to C₄ alkyl, and C₁ to C₂ alkyl;

[0034] Each occurrence of R⁵ is independently selected from the group consisting of: —CH₂—, —CH(alkyl)- and —C(alkyl)₂ wherein each alkyl for each R⁵ is independently selected, and wherein examples of said alkyl group include, for example, C₁ to C₄ alkyl, and C₁ to C₂ alkyl; or

[0035] R⁴ and R⁵ are as defined above, and a ring carbon of said R⁴ is bound to a ring carbon of said R⁵ by a —CH₂—CH₂— group (i.e., there is a C₂ bridge joining a R⁴ ring carbon and a R⁵ ring carbon, and those skilled in the art will appreciate that the bridged carbons for R⁴ and R⁵ are each independently selected from the group consisting of: —CH— and —C(alkyl)-);

[0036] u is an integer from 0 to 3;

[0037] v is an integer from 0 to 3, such that the sum of u and v is from 3 to 5;

[0038] R⁶ is selected from the group consisting of: (1) alkyl, (2) substituted alkyl, (3) aryl, (4) substituted aryl, (4) heteroaryl, (5) substituted heteroaryl, (6) cycloalkyl, (7) cycloalkylalkyl, (8) heterocycloalkyl, (9) cycloalkenyl, (10) heterocycloalkenyl, (11) benzofused cycloalkyl, (12) benzofused heterocycloalkyl, and (13) benzofused heterocycloalkenyl; and wherein

• • [0039] the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NO(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, and (p) —P(O)(O-alkyl)₂;
  • [0040] the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, (p) —P(O)(O-alkyl)₂, and (q) alkyl; and
  • [0041] the substituted heteroaryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) —(C═N—O-alkyl)CH₃, (b) —NC(O)NH₂, (c) —NC(O)NH(alkyl), (d) —NC(O)N(alkyl)₂, (e) —SO₂NH₂, (f) —SO₂NH(alkyl), (g) —SO₂N(alkyl)₂, (h) —CF₃, (i) —OH, (j) -halo, (k) —CN, (l) -alkoxy, (m) —C(O)O-alkyl, (n) —S(O)alkyl, (o) —SO₂-alkyl, (p) —P(O)(O-alkyl)₂, and (q) alkyl;

[0042] A is selected from the group consisting of: (1) —C(O)—, (2) —C(O)-alkylene-, (3) —C(O)-alkylene-O—, (4) —C(O)—(CH₂)_0-2—C(O)—, (5) —C(O)—CH₂—NH—C(O)—, (6) —C(O)—CH₂—N(alkyl)-C(O)—, (7) -alkylene-, (8) -alkenylene-, (9) —C(O)-alkenylene-, (10) —O—C(O)-alkylene-C(O)—, (11) —C(O)—NH-cycloalkylene-, (12) —C(O)—NH—, (13) —C(O)—NH-alkylene-, (14) —C(O)-alkylene(—NHC(O)alkyl)-, (15) —C(O)-alkylene-NH—C(O)-alkylene-, (16) —C(O)-alkylene-NH—C(O)—, (17) —C(O)-alkylene-O-alkylene-, (18) —C(O)-alkylene(alkoxy)-, (19) —C(O)-alkylene-S—, (20) —C(O)-alkylene(—N(alkyl)₂)—, and

[0043]

[0044] wherein the compounds defined by an “X” in Tables 3a, 3b, 3c, and 3d, and the compounds defined in Table 4a are excluded from the definition of the compounds of formula I.

[0045] The definitions for the numbers for R² and/or R¹ in Tables 3a, 3b, 3c, 3d, and 4a are given in Tables 1 and 2. Thus, (1) the compounds defined by the formulas assigned to Tables 3a, 3b, 3c, 3d, having the R¹ and R² definitions indicated by an “X” in the box formed by the intersection of the R² column and the R¹ row are not within the scope of the compounds of formula I (boxes without an “X” define compounds that are within the scope of the invention), and (2) the compounds defined in Table 4a are not within the scope of the compounds of formula I. The numbers in the first column in Tables 3a, 3b, 3c, and 3d represent the R² groups defined in Table 2. The numbers in top row of Tables 3a, 3b, 3c, and 3d, as well as the numbers in Table 4a, represent the R¹ groups defined in Table 1.

[0046] In another aspect, this invention relates to compounds of formula I having the structure represented by formula IIA:

[0047]
wherein the compounds defined by the “X” in Tables 3a, 3b, 3c, 3d, and the compounds defined in Table 4a are excluded from the compounds of formula IIA.

[0048] In another aspect, the present invention relates to compounds of formula I.

[0049] In another aspect, the present invention relates to compounds of formula I wherein R¹, R² and R³ are the R¹, R² and R³ moieties on the compounds in any one of Tables 5, 6, 7, 8, and 8A, and Examples 1 to 6.

[0050] In another aspect, the present invention relates to compounds of formula IIA wherein R¹, R² and R³ are the R¹, R² and R³ moieties on the compounds in any one of Tables 5, 6, 7 and 8, and 8A, and Examples 1 to 6.

[0051] In another aspect, the present invention relates to the final compounds of Examples 1 to 6.

[0052] In another aspect, the present invention relates to the compounds in Tables 5, 6, 7, 8, 8A, 9, and 10.

[0053] In another aspect, the present invention relates to a pharmaceutically acceptable salt of the compounds of formula I.

[0054] In another aspect, the present invention relates to a solvate of the compounds of formula I.

[0055] In another aspect, the present invention relates to compounds of formula I in pure and isolated form.

[0056] The compounds of the present invention are T-type calcium channel blockers. The T-calcium channel blocker compounds of formula I are useful in the treatment of pain (such as, for example, such as for example, inflammatory pain, chronic or neuropathic pain).

[0057] Thus, in another aspect, the present invention relates to a method of treating pain (such as for example, inflammatory pain, chronic or neuropathic pain) comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I.

[0058] In another aspect, the present invention relates to a method of treating pain (such as for example, inflammatory pain, chronic pain or neuropathic pain) comprising administering to a patient in need of such treatment an effective amount of a compound of formula I.

[0059] In another aspect, the present invention relates to a method of treating chronic pain comprising administering to a patient in need of such treatment an effective amount at least one (e.g., one) compound of formula I.

[0060] More particularly, in another aspect, the present invention relates to a method of treating inflammatory pain comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula I.

[0061] Also, more particularly, in another aspect, the present invention relates to a method of treating neuropathic pain comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula I.

[0062] In another aspect, the present invention relates to a method of treating pain (such as for example, inflammatory pain, chronic pain or neuropathic pain) comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula I selected from the group consisting of the compounds in Table 5.

[0063] In another aspect, the present invention relates to a method of treating pain (such as for example, inflammatory pain, chronic pain or neuropathic pain) comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula I selected from the group consisting of the compounds in Table 10.

[0064] In another aspect, the present invention relates to a method of treating neuropathic pain comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula I.

[0065] In another aspect, the present invention relates to a method of blocking T-calcium channels comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula I.

[0066] Compounds of formula I are agonists of GPR119. Compounds of formula I that are agonists of GPR119 are useful for the treatment of, for example, diabetes (e.g., type II diabetes).

[0067] Thus, in another aspect, the invention relates to a method of treating a disease mediated by a GPR119 receptor (such as diabetes, such as type II diabetes) comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I.

[0068] In another aspect, the invention relates to a method of treating a disease mediated by a GPR119 receptor (such as diabetes, such as type II diabetes) comprising administering to a patient in need of such treatment an effective amount of a compound of formula I.

[0069] In another aspect, the present invention relates to a method of treating a disease mediated by a GPR119 receptor (such as diabetes, such as type II diabetes) comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I selected from the group consisting of the compounds in Table 6.

[0070] In another aspect, the present invention relates to a method of treating a disease mediated by a GPR119 receptor (such as diabetes, such as type II diabetes) comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I selected from the group consisting of the compounds in Table 9.

[0071] More particularly, the compounds of formula I are useful in treating diabetes.

[0072] In another aspect, the invention relates to the treatment of diabetes comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) GPR119 agonist of formula I to a patient in need of such treatment.

[0073] In another aspect, the invention relates to the method of treating pain comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula I and at least one additional agent for treating pain.

[0074] In another aspect, the invention relates to the method of treating chronic pain comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula I and at least one additional agent for treating chronic pain.

[0075] More particularly, in another aspect, the invention relates to the method of treating inflammatory pain comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula I and at least one additional agent for treating inflammatory pain.

[0076] More particularly, in another aspect, the invention relates to the method of treating neuropathic pain comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula I and at least one additional agent for treating neuropathic pain.

[0077] In particular, in another aspect, the invention relates to the method of treating diabetes comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula I and at least one additional agent for treating diabetes.

[0078] In another aspect the present invention is directed to a method of treating a disorder of lipid metabolism comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula I.

[0079] In another aspect the present invention is directed to a method of inhibiting the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I.

[0080] In another aspect the present invention is directed to a method of inhibiting cholesterol absorption comprising administering to a patient in need of such treatment an effective amount of at least one NPC1L1 antagonist compound of formula I.

[0081] In another aspect the present invention is directed to a method of inhibiting the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one additional agent useful for treating a disorder of lipid metabolism (such as, at least one additional agent useful in lowering cholesterol).

[0082] In another aspect the present invention is directed to a method of inhibiting cholesterol absorption comprising administering to a patient in need of such treatment an effective amount of at least one NPC1L1 antagonist compound of formula I in combination with an effective amount of at least one additional agent useful for treating a disorder of lipid metabolism (such as at least one additional agent useful in lowering cholesterol).

[0083] In another aspect the present invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one inhibitor of HMG-CoA reductase (e.g., statins, such as, for example, simvastatin, atorvastatin calcium, and rosuvastatin calcium).

[0084] In another aspect the present invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one nicotinic acid receptor agonist (e.g., nicotinic acid).

[0085] Another embodiment of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one inhibitor of CETP (e.g., torcetrapib).

[0086] Another embodiment of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one NPC1L1 antagonist (such as, for example, ezetimibe, such as the Zetia® brand of ezetimibe).

[0087] Another embodiment of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one inhibitor of HMG-CoA reductase (e.g., statins, such as, for example, simvastatin, atorvastatin calcium, and rosuvastatin calcium), and in combination with an effective amount of at least one NPC1L1 antagonist (such as, for example, ezetimibe, such as the Zetia® brand of ezetimibe). An example of a medicament already comprising a combination of a HMG-CoA reductase and a NPC1L1 antagonist that can be used in this embodiment is the Vytorin® brand of the combination of ezetimibe and simvastatin.

[0088] Another embodiment of the present invention is directed to a kit comprising in a single package at least one compound of formula I in a pharmaceutical composition, and at least one separate pharmaceutical composition comprising at least one additional therapeutic agent (such as, for example, at least one of the additional agents useful in the treatment of pain, or at least one additional agent useful in the treatment of lipid disorders (such as at least one additional agent useful in lowering cholesterol), or one of the additional agents useful in treating diabetes).

[0089] Current chronic pain therapies provide only partial relief in responsive patients and are either not tolerated or ineffective in others. Chronic pain may arise as a consequence of tissue inflammation, viral infection (HIV, Herpes zoster) direct tissue injury or trauma, as a result of chemotherapy (e.g., taxol, vincristine), lesions of the central nervous system (e.g. stroke, MS) or as a consequence of diabetes. When chronic pain is associated with somatic or visceral tissue injury, symptoms usually include severe sensory disturbances characterized by spontaneous pain (often described as stabbing, burning, electric-shock-like or throbbing), hyperalgesia (exaggerated responsiveness to painful stimuli) and allodynia (perception of non noxious stimuli as painful). Prevalent symptoms in human patients include cold hyperalgesia, tactile allodynia and less commonly, heat hyperalgesia. Symptoms may present in isolation or in combination and there is often appreciable variation in the symptomatology associated with different disease states and typically between patients presenting with the same condition. In cases of somatic or visceral tissue injury/diseases, these distorted sensory perceptions have been linked to inappropriate activity (pathological hyperexcitability) in the peripheral nerves innervating the affected area. Neuronal hyperexcitability may arise as a result of altered ion channel function or activity.

[0090] Chronic pain is a true disease. It is believed to be a result, at least in part, of the plasticity at synapses in nociceptive processing centers, a phenomenon referred to as “central sensitization” which consists of increased excitability of spinal cord dorsal horn neurons. Maintenance of central sensitization is believed to require sustained peripheral neuronal activity (hyperexcitability) in sensory afferent nerves and such activity may be generated as a result of ectopic foci. Large T-type calcium currents can be found in sensory afferent neurons of the dorsal root ganglia (DRG). T-type calcium channels have been implicated as a causal factor in establishing such abnormal hyperexcitability, due to their known ability to function as neuronal pacemakers. Pharmacological and antisense oligonucleotide evidence supports a key role for DRG T-type calcium channels preclinical models of chronic pain.

[0091] T-type calcium channels are voltage-gated channels that can be opened with relatively small depolarizations from the resting potential of excitable cells. There are three distinct genes for T-type calcium currents that encode for Ca_v3.1, Ca_v3.2 and Ca_v3.3. The individual subtypes have unique patterns of distribution and are expressed in peripheral and central portions of pain pathways. T-type calcium channels are found in small and medium sized DRG neurons (Ca_v3.2) and regions of the CNS involved in pain processing including the dorsal horn of the spinal cord an the thalamus (Talley et al, J Neurosci, 1999, 19:1895-1911). T-type calcium currents have been shown to play a role in neuronal burst firing via low-threshold calcium spikes that permit rapid burst of neuronal action potentials (Suzuki and Rogwoski, Proc Natl Acad Sci USA, 1989, 86:7228-7232; White et al., Proc Natl Acad Sci USA, 1989, 86:6802-6806).

[0092] Inhibition of T-type calcium channel function in vivo through either the use of pharmacological blockers or antisense oligonucleotide mediated knockdown strongly implicate T-type channels in normal and pathological pain processing. Mibefradil and/or ethosuximide are selective for T-type calcium channel and have been shown to be effective in a number of preclinical pain models including: acute thermal and mechanical pain, phase I and II of the formalin model, the rat spinal nerve ligation model, capsaicin-induced mechanical hyperalgesia, rat tail flick, paclitaxil- and vincristine-induced chemoneuropathy (Barton et al., Eur J Pharmacol, 2005, 521:79-8; Dogrul et al Pain, 2003, 105:159:168; Flatters and Bennett, Pain, 2004, 109:150-161; Todorovic et al., Brain Res, 2002, 951:336-340).

[0093] Pain relief in response to ethosuximide could be due to either central or peripheral actions. However efficacy in response to mibefradil can be attributed to peripheral effects for two reasons. First systemically administered mibefradil does not enter the brain. In addition intrathecal administration of mibefradil is ineffective (Dogrul et al Pain, 2003, 105:159:168). Further evidence supporting efficacy from block of peripheral T-type channels comes from studies with antisense oligonucleotide directed against on type of T-type channel, Ca_v3.2. Intrathecal injection of hCaV3.2 specific oligonucleotides decreased T-type calcium currents in DRG neurons and produced antinociceptive, anti-hyperalgesic and anti-allodynic effects. In these studies the uptake of oligonucleotide and the antisense mediated knockdown of T-type currents occurred in DRG neurons close to the site of injection but not in spinal cord (Bourinet et al., EMBO J, 2005 24:315-324).

[0094] The compounds of formula I of this invention are T-type calcium channel blockers. Accordingly, the present compounds are useful in the treatment or prevention of conditions that are treatable or preventable by administering T-type calcium channel blockers. Such conditions include the treatment or prevention of neuropathic pain.

[0095] Neuropathic pain as used herein refers to an abnormal state of pain sensation, in which a reduction of pain threshold and the like are continued, due to functional abnormalities accompanying damage or degeneration of a nerve, plexus or perineural soft tissue, which is caused by wound (e.g., lacerations, contusions, nerve avulsion injuries, amputation of a limb), compression (carpal tunnel syndrome, trigeminal neuralgia, tumor activity), infection, cancer, ischemia and the like, or metabolic disorders such as diabetes mellitus and the like, Neuropathic pain includes pain caused by either central or peripheral nerve damage. It also includes the pain caused by either mononeuropathy or polyneuropathy. In some embodiments, the neuropathic pain is induced by diabetes.

[0096] Other examples of neuropathic pain treatable or preventable by the present compounds include, but are not limited to, allodynia (a pain sensation induced by mechanical or thermal stimulus that does not normally provoke pain), hyperalgesia (an excessive response to a stimulus that is normally painful), hyperesthesia (an excessive response to a contact stimulus), diabetic polyneuropathy, entrapment neuropathy, cancer pain, central pain, labor pain, myocardial infarction pain, post-stroke pain, pancreatic pain, colic pain, muscle pain, post-operative pain, post-stroke pain, pain associated with Parkinson's disease, pain associated with intensive care, pain associated with a periodontal disease (including gingivitis and periodontitis), menstrual pain, migraine pain, persistent headaches (e.g., cluster headache or chronic tension headache), persistent pain states (e.g., fibromyalgia or myofascial pain), trigeminal neuralgia, postherpetic neuralgia, bursitis, pain associated with AIDS, pain associated with multiple sclerosis, pain due to spinal trauma and/or degeneration, burn pain, referred pain, enhanced memory of pain and neuronal mechanisms involved in coping with pain. Inflammatory pain may arise as a result of soft tissue injury including that involving the musculature (myositis) and viscera (colitis and inflammatory bowel disease, pancreatitis, cystitis, ileitis, Crohn's disease), nerves (neuritis, radiculopathies, radioculogangionitis), arthritic conditions (e.g. rheumatoid disease and related conditions such as ankylosing spondylitis), joint disease (including osteoarthritis). The compounds of the present invention are particularly useful for treating or preventing allodynia and hyperalgesia.

[0097] Additional agents for treating neuropathic pain include non-opioid analgesics, opioid analgesics, antimigraine agents, Cox-II inhibitors, antiemetics, β-adrenergic blockers, anticonvulsants, antidepressants, other Ca²⁺-channel blockers, sodium channel blockers, anticancer agents, agents for treating or preventing UI, agents for treating hypertension, agents for treating or preventing angina pectoris, agents for treating atrial fibrillation, agents for treating insomnia, agents for treating renal failure, agents for treating Alzheimer's disease, agents for treating or preventing IBD, agents for treating or preventing IBS, agents for treating Parkinson's disease and parkinsonism, agents for treating anxiety, agents for treating epilepsy, agents for treating a stroke, agents for treating psychosis, agents for treating Huntington's chorea, agents for treating ALS, agents for treating vomiting, agents for treating dyskinesia, and agents for treating depression.

[0098] Preferred additional agents for treating neuropathic pain include those selected from the group consisting of: non-opioid analgesics and opioid analgesics.

[0099] Additional agents for treating inflammatory pain include corticosteroids, non-sterodial anti-inflammatory agents, COX-I and COX-II inhibitors, agents useful for treating inflammatory bowel disease and agents useful for treating rheumatoid arthritis.

[0100] Diabetes mellitus, commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia. Premature development of atherosclerosis and increased rate of cardiovascular and peripheral vascular diseases are characteristic features of patients with diabetes. There are two major forms of diabetes: Type I diabetes (also referred to as insulin-dependent diabetes or IDDM) and Type II diabetes (also referred to as noninsulin dependent diabetes or NIDDM). Compounds of formula I are useful in treating Type II diabetes.

[0101] Type I diabetes is the result of an absolute deficiency of insulin, the hormone that regulates glucose utilization. This insulin deficiency is usually characterized by β cell destruction in the pancreas, which usually leads to absolute insulin deficiency.

[0102] Type I diabetes has two forms: Immune-Mediated Diabetes Mellitus, which results from a cellular mediated autoimmune destruction of the β cells of the pancreas; and Idiopathic Diabetes Mellitus, which refers to forms of the disease that have no known etiologies.

[0103] Type II diabetes is a disease characterized by insulin resistance accompanied by relative, rather than absolute, insulin deficiency. Type II diabetes can range from predominant insulin resistance with relative insulin deficiency to predominant insulin deficiency with some insulin resistance. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistant individuals, the body secretes abnormally high amounts of insulin to compensate for this defect. When inadequate amounts of insulin are present to compensate for insulin resistance and adequately control glucose, a state of impaired glucose tolerance develops. Insulin secretion may further decline over time.

[0104] Type II diabetes can be due to a resistance to insulin stimulating regulatory effects on glucose and lipid metabolism in the main insulin-sensitive tissues, such as muscle, liver and adipose tissue. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver. In Type II diabetes, free fatty acid levels are often elevated in obese and some non-obese patients and lipid oxidation is increased.

[0105] In particular, Type II diabetes can be treated by treatment with a GPR119 agonist of formula II, alone or in combination with one or more additional agents for treating diabetes.

[0106] Other therapies for the treatment of type II diabetes that can be used in combination with compounds of formula II of this invention for treating Type II diabetes include sulfonylureas, insulin sensitizers, PPAR agonists, α-glucosidase inhibitors, insulin secretagogues, hepatic glucose output lowering compounds, and insulin.

[0107] In another aspect, the invention relates to compounds of formula I wherein:

• • [0108] (A) R¹ is selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, diphenylmethyl, cycloalkylalkyl and -alkylene-C(O)N(alkyl)₂;
  • [0109] (B) R² is selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, R⁶-A-, alkyl-O—C(O)—, (alkyl)₂-N-alkylene-C(O)—, CN-alkylene-C(O)—, alkyl-O-alkylene-C(O)—, alkyl-C(O)-alkylene-C(O)—, alkyl-NH—C(O)—, alkyl-O—C(O)-alkylene-C(O)—, and

[0110]
wherein Z^A and Q^F are as defined above, and wherein examples of said

[0111]
include for example,

[0112]
such as, for example,

[0113]
such as, for example,

[0114]
such as, for example,

[0115]
such as, for example,

[0116]
such as, for example,

[0117]
such as, for example,

[0118]

• • [0119] (C) R³ is selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkyl-NH—, heteroaryl, substituted heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl;
  • [0120] (D) Each occurrence of R⁴ is independently selected from the group consisting of: —CH₂—, —CH(alkyl)- and —C(alkyl)₂ wherein each alkyl for each R⁴ is independently selected, and wherein examples of said alkyl group include, for example, C₁ to C₄ alkyl, and C₁ to C₂ alkyl;
  • [0121] (E) Each occurrence of R⁵ is independently selected from the group consisting of: —CH₂—, —CH(alkyl)- and —C(alkyl)₂ wherein each alkyl for each R⁵ is independently selected, and wherein examples of said alkyl group include, for example, C₁ to C₄ alkyl, and C₁ to C₂ alkyl; or
  • [0122] (F) R⁴ and R⁵ are as defined above, and a ring carbon of said R⁴ is bound to a ring carbon of said R⁵ by a —CH₂—CH₂— group (i.e., there is a C₂ bridge joining a R⁴ ring carbon and a R⁵ ring carbon, and those skilled in the art will appreciate that the bridged carbons for R⁴ and R⁵ are each independently selected from the group consisting of: —CH— and —C(alkyl)-);
  • [0123] (G) u is an integer from 0 to 3;
  • [0124] (H) v is an integer from 0 to 3, such that the sum of u and v is from 3 to 5;
  • [0125] (I) R⁶ is selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, benzofused cycloalkyl, benzofused heterocycloalkyl, and benzofused heterocycloalkenyl;
  • [0126] (J) A is selected from the group consisting of: —C(O)—, —C(O)-alkylene-, —C(O)-alkylene-O—, —C(O)—CH₂—N(alkyl)-C(O)—, -alkylene-, -alkenylene-, —C(O)-alkenylene-, —C(O)—NH—, —C(O)—NH-alkylene-, and

[0127]

• • [0128] (K) wherein the compounds defined by an “X” in Tables 3a, 3b, 3c, and 3d, and the compounds defined in Table 4a are excluded from the definition of the compounds of formula I.

[0129] In another aspect, this invention relates to compounds of formula I wherein R¹ is selected from the group consisting of the R¹ groups in Table 1, R² is selected from the group consisting of R² groups in Table 2, and wherein the compounds defined by the “X” in Tables 3a, 3b, 3c, 3d and the compounds in Table 4a are excluded from the compounds of formula I.

[0130] In another aspect, this invention relates to compounds of formula I wherein R³ is selected from the group consisting of: (A) phenyl, (B) substituted phenyl (e.g., wherein there are 1 to 3 substituents (e.g., 1 or 2, or 1) independently selected from the group consisting of: halo (e.g., Br, F, and Cl) and —CN, (C) heteroaryl (such as, for example, pyridyl and pyrimidinyl), and (D) substituted heteroaryl (e.g., substituted pyridyl and substituted pyrimindinyl) wherein there are 1 to 3 (e.g., 1 or 2, or 1) substituents independently selected from the group consisting of: halo (e.g., Br, F, and Cl) and —CN.

[0131] In another aspect, this invention relates to compounds of formula I wherein R³ is selected from the group consisting of:

[0132]
wherein X¹ is selected from the group consisting of: halo (e.g., Br, F, and Cl), —CF₃ and —CN.

[0133] In another aspect, this invention relates to compounds of formula IIA wherein R³ is selected from the group consisting of: (A) phenyl, (B) substituted phenyl (e.g., wherein there are 1 to 3 substituents (e.g., 1 or 2, or 1) independently selected from the group consisting of: halo (e.g., Br, F, and Cl) and —CN, (C) heteroaryl (such as, for example, pyridyl and pyrimidinyl), and (D) substituted heteroaryl (e.g., substituted pyridyl and substituted pyrimindinyl) wherein there are 1 to 3 (e.g., 1 or 2, or 1) substituents independently selected from the group consisting of: halo (e.g., Br, F, and Cl) and —CN.

[0134] In another aspect, this invention relates to compounds of formula IIA wherein R³ is selected from the group consisting of:

[0135]
wherein X¹ is selected from the group consisting of: halo (e.g., Br, F, and Cl), —CF₃ and —CN.

[0136] In another aspect, this invention relates to compounds of formula I wherein R³ is selected from the group consisting of:

[0137]

[0138] In another aspect, this invention relates to compounds of formula IIA wherein R³ is selected from the group consisting of:

[0139]

[0140] In another aspect, this invention relates to compounds of formula I wherein R¹ is selected from the group consisting of the R¹ groups in Table 1, R² is selected from the group consisting of R² groups in Table 2, R³ is selected from the group consisting of:

[0141]
and wherein the compounds defined by the “X” in Tables 3a, 3b, 3c, 3d and the compounds in Table 4a are excluded from the compounds of formula I.

[0142] In another aspect, this invention relates to compounds of formula I having the structure represented by formula IIA:

[0143]
wherein R¹ is selected from the group consisting of the R¹ groups in Table 1, R² is selected from the group consisting of R² groups in Table 2, R³ is as defined for formula I, and wherein the compounds defined by the “X” in Tables 3a, 3b, 3c, 3d and the compounds in Table 4a are excluded from the compounds of formula IIA.

[0144] In another aspect, this invention relates to compounds of formula I having the structure represented by formula IIA:

[0145]
wherein R¹ is selected from the group consisting of the R¹ groups in Table 1, R² is selected from the group consisting of R² groups in Table 2, R³ is selected from the group consisting of:

[0146]
and wherein the compounds defined by the “X” in Tables 3a, 3b, 3c, 3d and the compounds in Table 4a are excluded from the compounds of formula IIA.

[0147] In another aspect, the present invention relates to compounds of formula I wherein R¹ is any one of the R¹ moieties on the compounds in any one of Tables 5, 6, 7, 8 and 8A, and Examples 1 to 6.

[0148] In another aspect, the present invention relates to compounds of formula I wherein R² is any one of the R² moieties on the compounds in any one of Tables 5, 6, 7, 8 and 8A, and Examples 1 to 6.

[0149] In another aspect, the present invention relates to compounds of formula I wherein R³ is any one of the R³ moieties on the compounds in any one of Tables 5, 6, 7, 8 and 8A, and Examples 1 to 6.

[0150] In another aspect, the present invention relates to compounds of formula IIA wherein R¹ is any one of the R¹ moieties on the compounds in any one of Tables 5, 6, 7, 8 and 8A, and Examples 1 to 6.

[0151] In another aspect, the present invention relates to compounds of formula IIA wherein R² is any one of the R² moieties on the compounds in any one of Tables 5, 6, 7, 8 and 8A, and Examples 1 to 6.

[0152] In another aspect, the present invention relates to compounds of formula IA wherein R³ is any one of the R³ moieties on the compounds in any one of Tables 5, 6, 7, 8 and 8A, and Examples 1 to 6.

[0153] In another aspect, the present invention relates to the compounds in Table 5.

[0154] In another aspect, the present invention relates to the compounds in Table 6.

[0155] In another aspect, the present invention relates to the compounds in Table 7.

[0156] In another aspect, the present invention relates to the compounds in Table 8.

[0157] In another aspect, the present invention relates to the compounds in Table 8A.

[0158] In another aspect, the present invention relates to the compounds in Table 9.

[0159] In another aspect, the present invention relates to the compounds in Table 10.

[0160] In another aspect, the present invention relates to compounds of formula I in pure form.

[0161] In another aspect, the present invention relates to compounds of formula I in isolated form.

[0162] In another aspect, the present invention relates to compounds of formula IIA in pure form.

[0163] In another aspect, the present invention relates to compounds of formula IIA in isolated form.

[0164] In another aspect, the invention relates to a method of treating pain (such as for example, inflammatory pain, chronic or neuropathic pain) comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula IIA.

[0165] In another aspect, the present invention relates to a method of treating pain (such as for example, inflammatory pain, chronic pain or neuropathic pain) comprising administering to a patient in need of such treatment an effective amount of a compound of formula IIA.

[0166] In another aspect, the present invention relates to a method of treating chronic pain comprising administering to a patient in need of such treatment an effective amount at least one (e.g., one) compound of formula IIA.

[0167] More particularly, in another aspect, the present invention relates to a method of treating inflammatory pain comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula IIA.

[0168] Also, more particularly, in another aspect, the present invention relates to a method of treating neuropathic pain comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula IIA.

[0169] In another aspect, the present invention relates to a method of treating pain (such as for example, inflammatory pain, chronic pain or neuropathic pain) comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula IIA selected from the group consisting of the compounds in Table 5.

[0170] In another aspect, the present invention relates to a method of treating pain (such as for example, inflammatory pain, chronic pain or neuropathic pain) comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula IIA selected from the group consisting of the compounds in Table 10.

[0171] In another aspect, the present invention relates to a method of treating neuropathic pain comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula IIA.

[0172] In another aspect, the present invention relates to a method of blocking T-calcium channels comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) compound of formula IIA.

[0173] Compounds of formula I are agonists of GPR119. Compounds of formula IIA that are agonists of GPR119 are useful for the treatment of, for example, diabetes (e.g., type II diabetes).

[0174] Thus, in another aspect, the invention relates to a method of treating a disease mediated by a GPR119 receptor (such as diabetes, such as type II diabetes) comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula IIA.

[0175] In another aspect, the invention relates to a method of treating a disease mediated by a GPR119 receptor (such as diabetes, such as type II diabetes) comprising administering to a patient in need of such treatment an effective amount of a compound of formula IIA.

[0176] In another aspect, the present invention relates to a method of treating a disease mediated by a GPR119 receptor (such as diabetes, such as type II diabetes) comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula IIA selected from the group consisting of the compounds in Table 6.

[0177] In another aspect, the present invention relates to a method of treating a disease mediated by a GPR119 receptor (such as diabetes, such as type II diabetes) comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula IIA selected from the group consisting of the compounds in Table 9.

[0178] In another aspect, the invention relates to the use of the compounds of formula IIA to treat diabetes (e.g., type II diabetes).

[0179] In another aspect, the invention relates to the treatment of diabetes comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) GPR119 agonist of formula IIA to a patient in need of such treatment.

[0180] In another aspect, the invention relates to the method of treating pain comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula IIA and at least one additional agent for treating pain.

[0181] In another aspect, the invention relates to the method of treating chronic pain comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula IIA and at least one additional agent for treating chronic pain.

[0182] More particularly, in another aspect, the invention relates to the method of treating inflammatory pain comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula IIA and at least one additional agent for treating inflammatory pain.

[0183] More particularly, in another aspect, the invention relates to the method of treating neuropathic pain comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula IIA and at least one additional agent for treating neuropathic pain.

[0184] In particular, in another aspect, the invention relates to the method of treating diabetes comprising administering to a patient in need of such treatment an effective amount of a combination of at least one compound of formula IIA and at least one additional agent for treating diabetes.

[0185] The compounds of formula I (e.g., at least one compound of formula I or IIA) of this invention are NPC1L1 antagonists and are therefore useful for treating disorders of lipid metabolism, in particular for inhibiting absorption of cholesterol.

[0186] The compounds of this invention are useful for treating disorders of lipid metabolism. The compounds of this invention are NPC1L1 antagonists. In one embodiment, the compounds of this invention are therefore useful for treating disorders of lipid metabolism, in particular for inhibiting absorption of cholesterol. It is to be understood that when the compounds of this invention are administered for inhibiting the absorption of cholesterol in a patient, the inhibition may be partial or complete. Accordingly, in one embodiment, the absorption of cholesterol in a patient is partially inhibited. In another embodiment, the absorption of cholesterol in a patient is completely inhibited.

[0187] Methods of treating disorders of lipid metabolism include treating hyperlipidemia, hypercholesterolaemia, hypertriglyceridaemia, sitosterolemia and arteriosclerotic symptoms; inhibiting absorption of cholesterol from the intestine; reducing blood plasma or serum concentrations of LDL cholesterol; reducing the concentrations of cholesterol and cholesterol ester in blood plasma or serum; reducing blood plasma or serum concentrations of C-reactive protein (CRP); reducing blood plasma or serum concentrations of triglycerides; reducing blood plasma or serum concentrations of apolipoprotein B; increasing blood plasma or serum concentrations of high density lipoprotein (HDL) cholesterol; increasing the fecal excretion of cholesterol; treating a clinical condition for which a cholesterol absorption inhibitor is indicated; reducing the incidence of cardiovascular disease-related events; reducing plasma or tissue concentration of at least one non-cholesterol sterol or 5α-stanol; treating or preventing vascular inflammation; preventing, treating or ameliorating symptoms of Alzheimer's Disease; regulating the production or level of at least one amyloid β peptide in the bloodstream and/or brain of a patient; regulating the amount of ApoE isoform 4 in the bloodstream and/or brain; preventing and/or treating obesity; and preventing or decreasing the incidence of xanthomas.

[0188] A method of treating a disorder of lipid metabolism comprises administering a cholesterol absorption inhibitor of formula I (e.g., at least one compound of formula I or IIA).

[0189] Additional agents for treating a disorder of lipid metabolism include inhibitors of cholesterol absorption (e.g., NPC1L1 antagonists, such as, for example, ezetimibe (such as the Zetia® brand of ezetimibe)), inhibitors of cholesterol biosynthesis, including, but not limited to HMG CoA reductase inhibitors (such as statins, such as, for example, simvastatin (such as the Zocor® brand of simvastatin), atorvastatin calcium (such as the Lipitor® brand of atorvastatin calcium), and rosuvastatin calcium (such as the Crestor® brand of rosuvastatin calcium)), inhibitors of cholesterol biosynthesis, cholesterol ester transfer protein (CETP) inhibitors (e.g., torcetrapib), bile acid sequesterants, a nicotinic acid receptor agonist such as nicotinic acid or a derivative thereof (e.g., Niacin (nicotinic acid), and the Niaspan® brand of niacin extended release tablets), peroxisome proliferator-activator receptor (PPAR) alpha agonists or activators, acylcoenzyme A:cholesterol acyltransferase (ACAT) inhibitors; obesity control medications, hypoglycemic agents, antioxidants, antihypertensive agents, ileal bile acid transport (“IBAT”) inhibitors (or apical sodium co-dependent bile acid transport (“ASBT”) inhibitors, probucol or derivatives thereof; low-density lipoprotein (“LDL”) receptor activators, omega 3 fatty acids (“3-PUFA”); natural water soluble fibers; plant sterols, and plant stanols and/or fatty acid esters of plant stanols.

[0190] U.S. Provisional Application 60/752,710, filed Dec. 20, 2005, and U.S. Provisional Application 60/77048, filed Mar. 29, 2006, disclose the use of cholesterol absorption inhibitors.

[0191] Classes of cholesterol lowering agents useful in the present methods for treating disorders of lipid metabolism include the following non-limiting classes of agents: NPC1L1 inhibitors such as ezetimibe; HMG-CoA reductase inhibitors; bile acid sequestrants; PPAR agonists or activators; ileal bile acid transport (“IBAT”) inhibitors (or apical sodium co-dependent bile acid transport (“ASBT”) inhibitors; nicotinic acid (niacin) and/or nicotinic acid receptor agonists; acylCoA:cholesterol O-acyltransferase (“ACAT”) inhibitors; cholesteryl ester transfer protein (“CETP”) inhibitors; probucol or derivatives thereof; low-density lipoprotein (“LDL”) receptor activators; omega 3 fatty acids (“3-PUFA”; natural water soluble fibers; plant sterols, plant stanols and/or fatty acid esters of plant stanols.

[0192] Non-limiting examples of suitable cholesterol biosynthesis inhibitors useful in the present methods include competitive inhibitors of HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, squalene synthase inhibitors, squalene epoxidase inhibitors and mixtures thereof. Non-limiting examples of suitable HMG-CoA reductase inhibitors useful in the present methods include statins such as lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, cerivastatin, CI-981, resuvastatin, rivastatin and pitavastatin, rosuvastatin; HMG-CoA reductase inhibitors, for example L-659,699 ((E,E)-11-[3′R-(hydroxy-methyl) -4′-oxo-2′R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid); squalene synthesis inhibitors, for example squalestatin 1; and squalene epoxidase inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanamine hydrochloride) and other sterol biosynthesis inhibitors such as DMP-565. Preferred HMG-CoA reductase inhibitors include lovastatin, pravastatin and simvastatin. The most preferred HMG-CoA reductase inhibitor is simvastatin.

[0193] Generally, a total daily dosage of cholesterol biosynthesis inhibitor(s) can range from about 0.1 to about 160 mg per day. In one embodiment, the dosage is from about 0.2 to about 80 mg/day, administered in a single dose or in 2-3 divided doses.

[0194] Bile acid sequestrants bind bile acids in the intestine, interrupting the enterohepatic circulation of bile acids and causing an increase in the faecal excretion of steroids.

[0195] Non-limiting examples of suitable bile acid sequestrants useful in the present methods include cholestyramine (a styrene-divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available from Bristol-Myers Squibb), colestipol (a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are available from Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets (poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide) which are available from Sankyo), water soluble derivatives such as 3,3-ioene, N-(cycloalkyl) alkylamines and poliglusam, insoluble quaternized polystyrenes, saponins and mixtures thereof. Suitable inorganic cholesterol sequestrants include bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids.

[0196] The activators or agonists of PPAR act as agonists for the peroxisome proliferator-activated receptors. Three subtypes of PPAR have been identified, and these are designated as peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor gamma (PARRγ) and peroxisome proliferator-activated receptor delta (PPARδ). It should be noted that PPARδ is also referred to in the literature as PPARβ and as NUC1, and each of these names refers to the same receptor.

[0197] PPARα regulates the metabolism of lipids. PPARα is activated by fibrates and a number of medium and long-chain fatty acids, and it is involved in stimulating β-oxidation of fatty acids. The PPARγ receptor subtypes are involved in activating the program of adipocyte differentiation and are not involved in stimulating peroxisome proliferation in the liver. PPARδ has been identified as being useful in increasing high density lipoprotein (HDL) levels in humans. See, e.g., WO 97/28149.

[0198] PPARα activator compounds are useful for, among other things, lowering triglycerides, moderately lowering LDL levels and increasing HDL levels. Useful examples of PPARα activators include fibrates.

[0199] Non-limiting examples of suitable fibric acid derivatives (“fibrates”) useful in the present methods include clofibrate; gemfibrozil; ciprofibrate; bezafibrate; clinofibrate; binifibrate; lifibrol; fenofibrate and mixtures thereof. These compounds can be used in a variety of forms, including but not limited to acid form, salt form, racemates, enantiomers, zwitterions and tautomers.

[0200] Other examples of PPARα activators useful in the present methods include suitable fluorophenyl compounds as disclosed in U.S. Pat. No. 6,028,109 which is incorporated herein by reference; certain substituted phenylpropionic compounds as disclosed in WO 00/75103 which is incorporated herein by reference; and PPARα activator compounds as disclosed in WO 98/43081 which is incorporated herein by reference.

[0201] Non-limiting examples of suitable PPARγ activators useful in the present methods include derivatives of glitazones or thiazolidinediones, such as, troglitazone; rosiglitazone and pioglitazone. Other useful thiazolidinediones include ciglitazone, englitazone, darglitazone and BRL 49653 as disclosed in WO 98/05331 which is incorporated herein by reference; PPARγ activator compounds disclosed in WO 00/76488 which is incorporated herein by reference; and PPARγ activator compounds disclosed in U.S. Pat. No. 5,994,554 which is incorporated herein by reference.

[0202] Other useful PPARγ activator compounds useful in the present methods include certain acetylphenols as disclosed in U.S. Pat. No. 5,859,051 which is incorporated herein by reference; certain quinoline phenyl compounds as disclosed in WO 99/20275 which is incorporated herein by reference; aryl compounds as disclosed by WO 99/38845 which is incorporated herein by reference; certain 1,4-disubstituted phenyl compounds as disclosed in WO 00/63161; certain aryl compounds as disclosed in WO 01/00579 which is incorporated herein by reference; benzoic acid compounds as disclosed in WO 01/12612 & WO 01/12187 which are incorporated herein by reference; and substituted 4-hydroxy-phenylalconic acid compounds as disclosed in WO 97/31907 which is incorporated herein by reference.

[0203] PPARδ compounds are useful for, among other things, lowering triglyceride levels or raising HDL levels. Non-limiting examples of PPARδ activators useful in the present methods include suitable thiazole and oxazole derivatives, such as C.A.S. Registry No. 317318-32-4, as disclosed in WO 01/00603 which is incorporated herein by reference); certain fluoro, chloro or thio phenoxy phenylacetic acids as disclosed in WO 97/28149 which is incorporated herein by reference; suitable non-β-oxidizable fatty acid analogues as disclosed in U.S. Pat. No. 5,093,365 which is incorporated herein by reference; and PPARδ compounds as disclosed in WO 99/04815 which is incorporated herein by reference.

[0204] Moreover, compounds that have multiple functionality for activating various combinations of PPARα, PPARγ and PPARδ are also useful in the present methods. Non-limiting examples include certain substituted aryl compounds as disclosed in U.S. Pat. No. 6,248,781; WO 00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO 00/23451; and WO 00/63153, all of which are incorporated herein by reference, are described as being useful PPARα and/or PPARγ activator compounds. Other non-limiting examples of useful PPARα and/or PPARγ activator compounds include activator compounds as disclosed in WO 97/25042 which is incorporated herein by reference; activator compounds as disclosed in WO 00/63190 which is incorporated herein by reference; activator compounds as disclosed in WO 01/21181 which is incorporated herein by reference; biaryl-oxa(thia)zole compounds as disclosed in WO 01/16120 which is incorporated herein by reference; compounds as disclosed in WO 00/63196 and WO 00/63209 which are incorporated herein by reference; substituted 5-aryl-2,4-thiazolidinediones compounds as disclosed in U.S. Pat. No. 6,008,237 which is incorporated herein by reference; arylthiazolidinedione and aryloxazolidinedione compounds as disclosed in WO 00/78312 and WO 00/78313G which are incorporated herein by reference; GW2331 or (2-(4-[difluorophenyl]-1heptylureido)ethyl]phenoxy)-2-methylbutyric compounds as disclosed in WO 98/05331 which is incorporated herein by reference; aryl compounds as disclosed in U.S. Pat. No. 6,166,049 which is incorporated herein by reference; oxazole compounds as disclosed in WO 01/17994 which is incorporated herein by reference; and dithiolane compounds as disclosed in WO 01/25225 and WO 01/25226 which are incorporated herein by reference.

[0205] Other useful PPAR activator compounds useful in the present methods include substituted benzylthiazolidine-2,4-dione compounds as disclosed in WO 01/14349, WO 01/14350 and WO/01/04351 which are incorporated herein by reference; mercaptocarboxylic compounds as disclosed in WO 00/50392 which is incorporated herein by reference; ascofuranone compounds as disclosed in WO 00/53563 which is incorporated herein by reference; carboxylic compounds as disclosed in WO 99/46232 which is incorporated herein by reference; compounds as disclosed in WO 99/12534 which is incorporated herein by reference; benzene compounds as disclosed in WO 99/15520 which is incorporated herein by reference; o-anisamide compounds as disclosed in WO 01/21578 which is incorporated herein by reference; and PPAR activator compounds as disclosed in WO 01/40192 which is incorporated herein by reference.

[0206] The peroxisome proliferator-activated receptor(s) activator(s) are administered in a therapeutically effective amount to treat the specified condition, for example in a daily dose preferably ranging from about 50 to about 3000 mg per day. In one embodiment, the daily dose is from about 50 to about 2000 mg per day, administered in a single dose or in 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient.

[0207] In an alternative embodiment, the present invention includes the use of one or more IBAT inhibitors or ASBT inhibitors. The IBAT inhibitors can inhibit bile acid transport to reduce LDL cholesterol levels. Non-limiting examples of suitable IBAT inhibitors useful in the present methods include benzothiepines such as therapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxide structure such as are disclosed in PCT Patent Application WO 00/38727 which is incorporated herein by reference.

[0208] Generally, a total daily dosage of IBAT inhibitor(s) can range from about 0.01 to about 1000 mg/day. In one embodiment, the dosage is from about 0.1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses.

[0209] In another alternative embodiment, the methods of the present invention can further comprise nicotinic acid (niacin) and/or nicotinic acid receptor (“NAR”) agonists as lipid lowering agents.

[0210] As used herein, “nicotinic acid receptor agonist” means any compound comprising that will act as an agonist to the nicotinic acid receptor. Compounds include those that have a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, where available. Examples of nicotinic acid receptor agonists useful in the present methods include niceritrol, nicofuranose and acipimox. Nicotinic acid and NAR agonists inhibit hepatic production of VLDL and its metabolite LDL and increases HDL and apo A-1 levels. An example of a suitable nicotinic acid product is NIASPAN® (niacin extended-release tablets) which are available from Kos Pharmaceuticals, Inc. (Cranbury, N.J.).

[0211] Generally, a total daily dosage of nicotinic acid can range from about 500 to about 10,000 mg/day. In one embodiment, the dosage is from about 1000 to about 8000 mg/day. In another embodiment, the dosage is from about 3000 to about 6000 mg/day, administered in a single dose or in divided doses. Generally, the total daily dosage of a NAR agonist can range from about 1 to about 100 mg/day.

[0212] In another alternative embodiment, the methods of the present invention can further comprise one or more ACAT inhibitors as lipid lowering agents. ACAT inhibitors reduce LDL and VLDL levels. ACAT is an enzyme responsible for esterifying excess intracellular cholesterol and may reduce the synthesis of VLDL, which is a product of cholesterol esterification, and overproduction of apo B-100-containing lipoproteins.

[0213] Non-limiting examples of useful ACAT inhibitors useful in the present methods include avasimibe, HL-004, lecimibide and CL-277082 (N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]-methyl]-N-heptylurea). See P. Chang et al., “Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis”, Drugs 2000 July; 60 (1); 55-93, which is incorporated by reference herein.

[0214] Generally, a total daily dosage of ACAT inhibitor(s) can range from about 0.1 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses.

[0215] In another alternative embodiment, the compositions used in the methods of the present invention can further comprise one or more Cholesteryl Ester Transfer Protein (“CETP”) Inhibitors coadministered with or in combination with one of more Spirocyclic Azetidinone Compounds. CETP is responsible for the exchange or transfer of cholesteryl ester carrying HDL and triglycerides in VLDL.

[0216] Non-limiting examples of suitable CETP inhibitors useful in the present methods are disclosed in PCT Patent Application No. WO 00/38721 and U.S. Pat. No. 6,147,090, which are incorporated herein by reference. Pancreatic cholesteryl ester hydrolase (pCEH) inhibitors such as WAY-121898 also can be co-administered with or in combination with the fibric acid derivative(s) and sterol absorption inhibitor(s) discussed above.

[0217] Generally, a total daily dosage of CETP inhibitor(s) can range from about 0.01 to about 1000 mg/day, and preferably about 0.5 to about 20 mg/kg body weight/day, administered in a single dose or in 2 or more divided doses.

[0218] In another alternative embodiment, the methods of the present invention can further comprise probucol or derivatives thereof (such as AGI-1067 and other derivatives disclosed in U.S. Pat. Nos. 6,121,319 and 6,147,250), which can reduce LDL and HDL levels, as cholesterol lowering agents.

[0219] Generally, a total daily dosage of probucol or derivatives thereof can range from about 10 to about 2000 mg/day. In one embodiment, the dosage is from about 500 to about 1500 mg/day, administered in a single dose or in 2-4 divided doses.

[0220] In another alternative embodiment, the methods of the present invention can further comprise one or more low-density lipoprotein (LDL) receptor activators, as lipid lowering agents. Non-limiting examples of suitable LDL-receptor activators useful in the present methods include HOE-402, an imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity. See M. Huettinger et al., “Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway”, Arterioscler Thromb. 1993; 13:1005-12.

[0221] Generally, a total daily dosage of LDL receptor activator(s) can range from about 1 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses.

[0222] In another alternative embodiment, the methods of the present invention can further comprise fish oil, which contains Omega 3 fatty acids (3-PUFA), which can reduce VLDL and triglyceride levels, as a lipid lowering agent. Generally, a total daily dosage of fish oil or Omega 3 fatty acids can range from about 1 to about 30 grams per day, administered in a single dose or in 2-4 divided doses.

[0223] In another alternative embodiment, the methods of the present invention can further comprise natural water-soluble fibers, such as psyllium, guar, oat and pectin, which can reduce cholesterol levels. Generally, a total daily dosage of natural water soluble fibers can range from about 0.1 to about 10 grams per day, administered in a single dose or in 2-4 divided doses.

[0224] In another alternative embodiment, methods of the present invention can further comprise plant sterols, plant stanols and/or fatty acid esters of plant stanols, such as sitostanol ester used in BENECOL® margarine, which can reduce cholesterol levels. Generally, a total daily dosage of plant sterols, plant stanols and/or fatty acid esters of plant stanols can range from about 0.5 to about 20 grams per day, administered in a single dose or in 2-4 divided doses.

[0225] Thus, another aspect of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I.

[0226] Another aspect of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula IIA.

[0227] Another aspect of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one additional agent for treating a disorder of lipid metabolism.

[0228] Another aspect of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula IIA in combination with an effective amount of at least one additional agent for treating a disorder of lipid metabolism.

[0229] Another aspect of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one nicotinic acid receptor agonist (e.g., nicotinic acid).

[0230] Another embodiment of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula IIA in combination with an effective amount of at least one nicotinic acid receptor agonist (e.g., nicotinic acid).

[0231] Another aspect of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one inhibitor of HMG-CoA reductase (e.g., statins, such as, for example, simvastatin, atorvastatin calcium, and rosuvastatin calcium).

[0232] Another embodiment of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula IIA in combination with an effective amount of at least one inhibitor of HMG-CoA reductase (e.g., . statins, such as, for example, simvastatin, atorvastatin calcium, and rosuvastatin calcium).

[0233] Another aspect of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one inhibitor of CETP (e.g., torcetrapib).

[0234] Another aspect of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula IIA in combination with an effective amount of at least one inhibitor of CETP (e.g., torcetrapib).

[0235] Another aspect of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I in combination with an effective amount of at least one NPC1L1 antagonist (such as, for example, ezetimibe, such as the Zetia® brand of ezetimibe).

[0236] Another aspect of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula IIA in combination with an effective amount of at least one NPC1L1 antagonist (such as, for example, ezetimibe, such as the Zetia® brand of ezetimibe).

[0237] Another embodiment of the invention is directed to the inhibition of the absorption of cholesterol comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I (e.g., a compound of formula I or IIA) in combination with an effective amount of at least one inhibitor of HMG-CoA reductase (e.g., statins, such as, for example, simvastatin, atorvastatin calcium, and rosuvastatin calcium), and in combination with an effective amount of at least one NPC1L1 antagonist (such as, for example, ezetimibe, such as the Zetia® brand of ezetimibe). An example of a medicament already comprising a combination of a HMG-CoA reductase and a NPC1L1 antagonist that can be used in this embodiment is the Vytorin® brand of the combination of ezetimibe and simvastatin.

[0238] For compounds of formula I, R⁴ and R⁵ are preferably each —CH₂— and u and v are preferably each 2, i.e., R⁴ and are R⁵ are preferably each —CH₂—CH₂—.

[0239] In another aspect this invention relates to compounds of formula I wherein R¹ is selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, heteroaryl, substituted heteroaryl and -alkylene-C(O)N(alkyl)₂. In another aspect this invention relates to compounds of formula I wherein R¹ is selected from the group consisting of: H, C₁-C₄ alkyl, phenyl, pyrimidyl, pyridyl, halo substituted pyridyl, benzyl substituted by halo, and phenyl substituted with 1 or 2 substituents selected from the group consisting of: phenyl, halo substituted phenyl, F, Cl, Br, CN and —CF₃.

[0240] In another aspect this invention relates to compounds of formula IIA wherein R¹ for formula IIA is selected from the group consisting of: methyl, i-propyl, —CH₂CH(CH₃)₂, CH₂CH₂(CH₃)₂,

[0241]
wherein each X⁴ is independently selected from the group consisting of: Br, Cl, F, CN and —CF₃. An Example of the R¹ moiety:

[0242]

[0243] In another aspect this invention relates to compounds of formula I wherein R² is selected from the group consisting of:

[0244]
wherein Z^A and Q^F are as defined above, and wherein examples of said

[0245]
include for example,

[0246]
such as for example,

[0247]
such as, for example,

[0248]
such as, for example,

[0249]
such as, for example,

[0250]
such as, for example,

[0251]
such as, for example,

[0252]
R⁶-A- wherein A is —C(O)—NH—, —C(O)— or —C(O)-alkylene- and R⁶ is an optionally substituted group selected from aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, benzofused cycloalkyl, benzofused heterocycloalkyl, and benzofused heterocycloalkenyl.

[0253] In another aspect this invention relates to compounds of formula I wherein said aryl groups for R⁶ in R² in formula I are phenyl, and said heteroaryl groups for R⁶ are pyridyl.

[0254] In another aspect this invention relates to compounds of formula I wherein said substituted aryl (e.g., substituted phenyl and substituted naphthyl) groups for R⁶ in R² are substituted with 1 to 3 (e.g., 1 or 2, or 1) substituents independently selected from the group consisting of: alkyl, halo (e.g., F, Cl, and Br), —CF₃, CN, alkoxy, phenoxy and —CO₂alkyl. In another aspect this invention relates to compounds of formula I wherein said substituted aryl R⁶ groups in R² are substituted with 1 to 3 (e.g., 1 or 2, or 1) substituents independently selected from the group consisting of: F, Cl, Br and CN. Examples of substituted phenyls include:

[0255]
wherein each X² is independently selected from the group consisting of: alkyl, halo (e.g., F, Cl, and Br), —CF₃, CN, alkoxy, phenoxy and —CO₂alkyl. In another aspect, each X² is independently selected from the group consisting of: F, Cl, Br and CN. Examples of substituted phenyl R⁶ groups include

[0256]

[0257] In another aspect this invention relates to compounds of formula I wherein said substituted heteroaryl (e.g., substituted pyridyl) groups for R⁶ in R² are substituted with 1 to 3 (e.g., 1 or 2, or 1) substituents independently selected from the group consisting of: alkyl, halo (e.g., F, Cl, and Br), —CF₃, CN, alkoxy, phenoxy and —CO₂alkyl. In another aspect this invention relates to compounds of formula I wherein said substituted heteroaryl groups for R⁶ in R² are substituted with 1 to 3 (e.g., 1 or 2, or 1) substituents independently selected from the group consisting of: F, Cl, Br and CN. Examples of substituted pyridyls include:

[0258]
wherein X³ is independently selected from the group consisting of: alkyl, halo (e.g., F, Cl, and Br), —CF₃, CN, alkoxy, phenoxy and —CO₂alkyl. In another aspect, X³ is independently selected from the group consisting of F, Cl, Br and CN. Examples of substituted heteroaryl R⁶ groups include

[0259]

[0260] In another aspect this invention relates to compounds of formula I wherein said cycloalkyl groups for R⁶ in R² in formula I are selected from the group consisting of: cyclopentyl, cyclohexyl, and cycloheptyl.

[0261] In another aspect this invention relates to compounds of formula I wherein said cycloalkenyl groups for R⁶ in R² in formula I is dihydropyran.

[0262] In another aspect this invention relates to compounds of formula I for use as T-type calcium channel blockers wherein:

• • [0263] R¹ is selected from the group consisting of: H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
  • [0264] R³ is selected from the group consisting of aryl and substituted aryl; and
  • [0265] R² is selected from the group consisting of: H, aryl-NH—C(O)—, alkyl-NH—C(O)—, alkyl-O—C(O)—, alkyl-O—C(O)-alkylene-NH—C(O)—, and

[0266]
wherein Z^A and Q^F are as defined above, and wherein examples of said

[0267]
include for example,

[0268]
such as, for example,

[0269]
such as, for example,

[0270]
such as, for example,

[0271]
such as, for example,

[0272]
such as for example,

[0273]
such as, for example,

[0274]

[0275] In another aspect this invention relates to compounds of formula I wherein said “Aryl” in R¹, R² and R³ is optionally substituted phenyl.

[0276] In another aspect this invention relates to compounds of formula I for use as T-type calcium channel blockers wherein:

• • [0277] R¹ is selected from the group consisting of: H, isopropyl, methyl, phenyl, 4-fluorophenyl, 2-chlorophenyl and cyclopropyl;
  • [0278] R³ is selected from the group consisting of: 4-chlorophenyl, phenyl, 4-bromophenyl, and 4-benzyloxy-phenyl; and
  • [0279] R² is selected from the group consisting of: H, 3,5-di-chloro-phenyl-NH—C(O)—, 3,4-di-fluoro-phenyl-NH—C(O)—, 4-chloro-phenyl-NH—C(O)—, 3,5-di-fluoro-phenyl-NH—C(O)—, 4-fluoro-phenyl-NH—C(O)—, (CH₃)₂—C—CH₂—C(CH₃)₂—NH—C(O)—, phenyl-NH—C(O)—, 2-methyl-phenyl-NH—C(O)—, 4-(CH₃—O—C(O)-)phenyl-NH—C(O)—, 2-cyano-phenyl-NH—C(O)—, 2-chloro-phenyl-NH—C(O)—, 2-fluoro-phenyl-NH—C(O)—, t-Bu-O—C(O)—, 4-isopropyl-phenyl-NH—C(O)—, 2-CF₃-phenyl-NHC(O)—, 2-chloro-6-methyl-phenyl-NHC(O)—, 2,6-di-chloro-phenyl-NHC(O)—, t-Bu-phenyl-NHC(O)—,

[0280]

[0281] In the aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl, cycloalkenyl, benzofused cycloalkyl, benzofused heterocycloalkyl and benzofused cycloalkenyl groups ring system substituents can be present. In another aspect this invention relates to compounds of formula I wherein said ring system substituents are selected from the group consisting of: alkyl, alkoxy, —C(O)alkyl, halo, —C(O)Oalkyl, —CF₃, —OCF₃, optionally substituted phenyl, phenoxy, benzyl, benzyloxy, piperidinyl, piperazinyl, N-methyl-piperazinyl, morpholinyl, —CN, —SO₂alkyl, OH, —NHC(O)alkyl, —N(alkyl)-alkylene-CN, —C(═CH₂)CH₃, —O-alkylene-N(alkyl)₂, —N(alkyl)₂, optionally substituted heteroaryl, and heteroarylalkyl, wherein heteroaryl is selected from the group consisting of pyrrolyl, triazolyl, thienyl, pyridyl, pyrazolyl, and ozazolyl. Optionally, for said heterocycloalkyl group and said benzofused heterocycloalkyl group, a —CH₂— group can be replaced by a —C(—N)— or —C(O)— group. Optionally, for said aryl group and for said heteroaryl group, two adjacent ring carbons can be joined by a —(CH₂)₃—, —(CH₂)₄—, —O—CH₂—O—, —O(CH₂)₂—O—, or —O(CH₂)₃—O— group.

[0282] In another aspect this invention relates to compounds of formula I wherein R¹ for formula I is any one of the R¹ moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8, or 8A.

[0283] In another aspect this invention relates to compounds of formula I wherein R² for formula I is any one of the R² moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A.

[0284] In another aspect this invention relates to compounds of formula I wherein R³ for formula I is any one of the R³ moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A.

[0285] In another aspect this invention relates to compounds of formula I wherein R¹ for formula I is any one of the R¹ moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A, and R² for formula I is any one of the R² moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A, and R³ for formula I is any one of the R³ moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A.

[0286] In another aspect this invention relates to compounds of formula I wherein R¹ for formula IIA is any one of the R¹ moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A.

[0287] In another aspect this invention relates to compounds of formula I wherein R² for formula IIA is any one of the R² moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A.

[0288] In another aspect this invention relates to compounds of formula I wherein R³ for formula IIA is any one of the R³ moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A.

[0289] In another aspect this invention relates to compounds of formula I wherein R¹ for formula IIA is any one of the R¹ moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A, and R² for formula IIA is any one of the R² moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A, and R³ for formula IIA is any one of the R³ moieties in the formulas in any one of Examples 1 to 6, or in any one of the formulas in Tables 5, 6, 7, 8 or 8A.

[0290] In another aspect this invention relates to compounds of formula I (e.g., compounds of formula I or IIA, useful, for example, as T-calcium channel blockers, and useful, for example, for the treatment of pain) wherein:

• • [0291] (A) R¹ is selected from the group consisting of: (1) alkyl (such as, for example, i-propyl, methyl, —(CH₂)₂CH(CH₃)₂), —CH₂CH(CH₃)₂), (2) alkenyl (such as, for example, —CH₂CH═CH₂), (3) cycloalkyl (such as, for example, cyclopropyl), (4) aryl (such as, for example, phenyl), (5) halo substituted phenyl (such as, for example, p-F-phenyl), (6) arylalkyl- (such as, for example, benzyl), and (7) —C(O)NQ^B wherein Q^B is selected from the group consisting of: substituted phenyl (such as, for example, phenyl substituted with halo (such as, for example, o,p-di-F-phenyl))
  • [0292] (B) R² is selected from the group consisting of:
    • [0293] (1) —C(O)NHQ^A wherein Q^A is selected from the group consisting of:
      • [0294] (a) cycloalkyl (such as, for example, adamantyl (a multicyclic cycloalkyl) and cycloheptyl),
      • [0295] (b) alkyl substituted with —C(O)—O-alkyl (such as, for example, —CH(C(O)OCH₃)CH(CH₃)₂, —CH(C(O)OCH₃)CH(CH₃)CH₂CH₃, —CH(C(O)Ot-butyl)CH(CH₃)CH₂CH₃, —CH(C(O)OCH₃)CH(CH₃)₂, and —CH₂C(O)OCH₂CH₃),
      • [0296] (c) substituted aryl, e.g., substituted phenyl, such as, for example, halo substituted phenyl (such as, for example 3,5-di-F-phenyl, 3-F-phenyl, p-Cl-phenyl, m-Cl-phenyl, o-Cl-phenyl, m-Br-phenyl, p-Br-phenyl, m,p-di-F-phenyl, p-F-phenyl, o-F-phenyl, o,p-di-F-phenyl, o,m-di-F-phenyl), m-CN-phenyl, p-CN-phenyl, m-CF₃-phenyl, p-CF₃-phenyl, m-methoxyphenyl, m-CH₃CH₂OC(O)-phenyl, m-methylphenyl, m-CH₃O-phenyl, p-methylphenyl, o-methylphenyl, o-methoxyphenyl, p-methoxyphenyl, and m-F-p-methyl-phenyl),
      • [0297] (d) alkyl (such as, for example, —CH(CH₃)₂CH₂C(CH₃)₃, and t-butyl),
      • [0298] (e) substituted arylalkyl, such as, for example, a halo substituted arylalkyl, such as, for example, a halo substituted benzyl, such as, for example, m-F-benzyl,
      • [0299] (f) substituted heterocycloalkenylbenzo, such as, for example, oxo substituted heterocycloalkenylbenzo, such as, for example,

[0300]

• • • • [0301] (g) heteroaryl, such as, for example, pyridyl, such as, for example, m-pyridyl
    • [0302] (2) H,
    • [0303] (3) substituted benzoheterocycloakyl-C(O)—, such as, for example,
      • [0304] (a) halo substituted benzoheterocycloalkyl-C(O)—, such as, for example,

[0305]

• • • • [0306] (b) alkoxy substituted benzoheterocycloalkyl-C(O)— such as, for example,

[0307]

• • • [0308] (4) —C(O)O-alkyl, such as, for example, —C(O)Ot-butyl,
    • [0309] (5) heterocycloalkyl (such as, for example, morpholinyl), and
    • [0310] (6) —C(O)NQ^CQ^D wherein Q^C and Q^D are each independently selected from the group consisting of: H, Q^A (as defined above), substituted aryl (such as, for example, substituted phenyl, such as, for example, halo substituted phenyl, such as, for example, such as, for example, m,m-di-F-phenyl), and arylalkyl (such as, for example, phenylalkyl- such as, for example, benzyl); and wherein, in one example, Q^C and Q^D are selected as follows: Q^C is substituted aryl (such as, for example, substituted phenyl, such as, for example, halo substituted phenyl, such as, for example, as m,m-di-F-phenyl), and Q^D is arylalkyl (such as phenylalkyl-, such as, for example, benzyl); and
  • [0311] (C) R³ is selected from the group consisting of:
    • [0312] (1) substituted phenyl, such as, for example, (a) halo substituted phenyl, (such as, for example, p-Cl-phenyl, p-Br-phenyl, and p-F-phenyl), (b) phenyl substituted phenyl (i.e., phenyl-phenyl-), (c) phenyl substituted with heteroaryl (such as, for example, pyridyl-phenyl-, such as, for example,

[0313]
(d) cyano substituted phenyl (such as, for example, p-CN-phenyl), and

• • • [0314] (2) heteroaryl (such as, for example, pyridyl such as, for example, m-pyridyl and o-pyridyl).

[0315] In another aspect this invention relates to compounds of formula I (e.g., compounds of formula I or IIA, useful, for example, as T-calcium channel blockers, and useful, for example, for the treatment of pain) wherein:

• • [0316] (A) R¹ is selected from the group consisting of: (1) alkyl (such as, for example, i-propyl, methyl, —(CH₂)₂CH(CH₃)₂), —CH₂CH(CH₃)₂), (2) alkenyl (such as, for example, —CH₂CH═CH₂), (3) cycloalkyl (such as, for example, cyclopropyl), (4) aryl (such as, for example, phenyl), (5) halo substituted phenyl (such as, for example, p-F-phenyl), (6) arylalkyl- (such as, for example, benzyl), and (7) —C(O)NQ^B wherein Q^B is selected from the group consisting of: substituted phenyl (such as, for example, phenyl substituted with halo (such as, for example, o,p-di-F-phenyl))
  • [0317] (B) R² is selected from the group consisting of:
    • [0318] (1) —C(O)NHQ^A wherein Q^A is selected from the group consisting of:
      • [0319] (a) cycloalkyl (such as, for example, adamantyl (a multicyclic cycloalkyl) and cycloheptyl),
      • [0320] (b) alkyl substituted with —C(O)—O-alkyl (such as, for example, —CH(C(O)OCH₃)CH(CH₃)₂, —CH(C(O)OCH₃)CH(CH₃)CH₂CH₃, —CH(C(O)Ot-butyl)CH(CH₃)CH₂CH₃, —CH(C(O)OCH₃)CH(CH₃)₂, and —CH₂C(O)OCH₂CH₃),
      • [0321] (c) substituted aryl, e.g., substituted phenyl, such as, for example, halo substituted phenyl (such as, for example 3,5-di-F-phenyl, 3-F-phenyl, p-Cl-phenyl, m-Cl-phenyl, o-Cl-phenyl, m-Br-phenyl, p-Br-phenyl, m,p-di-F-phenyl, p-F-phenyl, o-F-phenyl, o,p-di-F-phenyl, o,m-di-F-phenyl), m-CN-phenyl, p-CN-phenyl, m-CF₃-phenyl, p-CF₃-phenyl, m-methoxyphenyl, m-CH₃CH₂OC(O)-phenyl, m-methylphenyl, m-CH₃O-phenyl, p-methylphenyl, o-methylphenyl, o-methoxyphenyl, p-methoxyphenyl, and m-F-p-methyl-phenyl),
      • [0322] (d) alkyl (such as, for example, —CH(CH₃)₂CH₂C(CH₃)₃, and t-butyl),
      • [0323] (e) substituted arylalkyl, such as, for example, a halo substituted arylalkyl, such as, for example, a halo substituted benzyl, such as, for example, m-F-benzyl, and
      • [0324] (f) heteroaryl, such as, for example, pyridyl, such as, for example, m-pyridyl
    • [0325] (2) H,
    • [0326] (3) —C(O)O-alkyl, such as, for example, —C(O)Ot-butyl,
    • [0327] (4) heterocycloalkyl (such as, for example, morpholinyl), and
    • [0328] (5) —C(O)NQ^CQ^D wherein Q^C and Q^D are each independently selected from the group consisting of: H, Q^A (as defined above), substituted aryl (such as, for example, substituted phenyl, such as, for example, halo substituted phenyl, such as, for example, such as, for example, m,m-di-F-phenyl), and arylalkyl (such as, for example, phenylalkyl- such as, for example, benzyl); and wherein, in one example, Q^C and Q^D are selected as follows: Q^C is substituted aryl (such as, for example, substituted phenyl, such as, for example, halo substituted phenyl, such as, for example, as m,m-di-F-phenyl), and Q^D is arylalkyl (such as phenylalkyl-, such as, for example, benzyl); and
  • [0329] (C) R³ is selected from the group consisting of:
    • [0330] (1) substituted phenyl, such as, for example, (a) halo substituted phenyl, (such as, for example, p-Cl-phenyl, p-Br-phenyl, and p-F-phenyl), (b) phenyl substituted phenyl (i.e., phenyl-phenyl-), (c) phenyl substituted with heteroaryl (such as, for example, pyridyl-phenyl-, such as, for example,

[0331]
(d) cyano substituted phenyl (such as, for example, p-CN-phenyl), and

• • • [0332] (2) heteroaryl (such as, for example, pyridyl such as, for example, m-pyridyl and o-pyridyl).

[0333] In another aspect this invention relates to compounds of formula I (e.g., compounds of formula I or IIA, useful, for example, as GPR119 agonists, and useful, for example, for the treatment of diabetes (e.g., type II diabetes)):

• • [0334] (A) R¹ is selected from the group consisting of:
    • [0335] (1) alkyl (such as, for example, —CH₂CH(CH₃)₂),
    • [0336] (2) substituted arylalkyl, such as, for example,
      • [0337] (a) halo substituted phenylalkyl-, such as, for example, o,p-di-F-benzyl, o-Cl-benzyl, and o,p-di-F-benzyl,
      • [0338] (b) substituted aryl, such as, for example, (i) alkyl substituted phenyl (such as, for example, p-methylphenyl), (ii) alkoxy substituted phenyl (such as, for example, p-methoxyphenyl, and m-methoxyphenyl), (iii) haloalkyl substituted phenyl (such as, for example, p-CF₃-phenyl), and (iv) halo substituted phenyl (such as, for example, p-F-phenyl),
    • [0339] (3) cycloalkylalkyl (such as, for example, cyclopropyl-CH₂—), and
    • [0340] (4) substituted alkyl (such as, for example, aryl substituted alkyl, such as, for example, phenyl substituted alkyl, such as, for example, —CH(phenyl)₂)
  • [0341] (B) R² is selected from the group consisting of:
    • [0342] (1) —C(O)aryl wherein said aryl is substituted with 1 to 3 substituents independently selected from the group consisting of: alkoxy, alkyl-C(O)—, and —SO₂alkyl; and wherein examples of said substituted —C(O)aryl moiety include, for example, —C(O)(substituted phenyl), and examples of said —C(O)(substituted phenyl) moiety include, for example, (a) —C(O)(alkoxy substituted phenyl), such as, for example, o,m,p-tri-methoxyphenyl-C(O)—, (b) —C(O)(alkyl-C(O)-phenyl), such as, for example, —C(O)-(p-CH₃C(O)phenyl), and (c) —C(O)(SO₂alkyl substituted phenyl)-, such as, for example, —C(O)-(p-SO₂CH₃-phenyl),
    • [0343] (2) —C(O)benzoheterocycloalkyl, such as, for example,

[0344]

• • • [0345] (3) substituted heterocycloalkyl, such as, for example,

[0346]

• • • [0347] (4) substituted arylalkyl, such as, for example, substituted phenyl-alkyl-such as, for example, alkoxy substituted phenyl-alkyl-, such as, for example, p-methoxybenzyl; and
  • [0348] (C) R³ is selected from the group consisting of: H, aryl (such as phenyl), substituted aryl (such as, for example, substituted phenyl, such as, for example, halo substituted phenyl, such as, for example, p-F-phenyl, p-Cl-phenyl, and o,p-di-F-phenyl)

[0349] Tables 1, 2, 3a, 3b, 3c, 3d, and 4a are given below. Table 1 defines the R¹ moieties used in Tables 3a, 3b, 3c, 3d and 4a by assigning a number to the moieties which number is used in Tables 3a, 3b, 3c, 3d and 4a. Table 2 defines the R² moieties used in Tables 3a, 3b, 3c, and 3d by assigning a number to the moieties which number is used in Tables 3a, 3b, 3c, and 3d. With reference to the particular structure assigned to Tables 3a, 3b, 3c, and 3d, the compounds whose R¹ and R² moieties are defined by an “X” in the box formed by the intersection of the R² column and the R¹ row are excluded from the definition of formula I (and formula IIA). If there isn't an “X” in the box, the compounds having such R¹ and R² moieties are within the definition of formula I (and formula IIA). The compounds defined by the structure assigned to Table 4a having the R¹ moieties defined in Table 4a are excluded from the definition of the compounds of formula I (and formula IIA).

[0350] Tables 1, 2, 3a, 3b, 3c, 3d, and 4a are defining compounds of the formula (IIA):

[0351]

[0352] In Table 1 “#” represents number, which is the number assigned to the R¹ moiety, and is the number that is referenced in Tables 3a, 3b, 3c, 3d, and 4a.

[0353] In Table 2 “#” represents number, which is the number assigned to the R² moiety, and is the number that is referenced in Tables 3a, 3b, 3c, and 3d.

[0354] In Tables 1 and 2 “Z” represents the point of attachment to the rest of the molecule (i.e., “Z” represents where R¹ and R² are attached to the rest of the molecule). Thus, for example, for the compounds of formula IIA, when R¹ is Z-CH(CH₃)₂ (i.e., group number 50 in Table 1), the compound of formula IIA is:

[0355]

[0356]

TABLE 1
Definition of the R1 Moieties
R1	#
	2
	3
	7
	8
	9
	10
	11
	13
	14
	15
	17
	19
	20
	21
	22
	23
	25
	26
	27
	28
	29
	30
	31
	32
	33
	34
	35
	36
	37
	38
	39
	40
	41
	42
	43
	44
	45
	46
	47
	48
	49
	50
	51
	52
	93

[0357]

TABLE 2
Definition of the R2 Moieties
R2	#
	1
	2
	3
	4
	5
	6
	7
	8
	9
	10
	11
	12
	13
	14
	15
	16
	17
	18
	19
	20
	21
	22
	23
	24
	25
	26
	27
	28
	29
	30
	31
	32
	33
	34
	35
	36
	37
	38
	39
	40
	41
	42
	43
	44
	45
	46
	47
	48
	49
	50
	51
	52
	53
	54
	55
	56
	57
	58
	59
	60
	61
	62
	63
	64
	65
	66
	67
	68
	69
	70
	71
	72
	73
	74
	75
	76
	77
	78
	79
	80
	81
	82
	83
	84
	85
	86
	87
	88
	133
	134
	135
	136
	137
	138
	139
	140
	141
	142
	143
	144
	145
	146
	147
	148
	149
	150
	151
	152
	153
	154
	155
	156
	157
	158
	159
	160
	161
	162
	163
	164
	165
	166
	167
	168
	169
	170
	171
	172
	173
	174
	175
	176
	177
	178
	179
	180
	181
	182
	183
	184
	185
	186
	187
	188
	189
	190
	191
	192
	193
	194
	195
	196
	197
	198
	199
	200
	201
	202
	203
	204
	205
	206
	207
	208
	209
	210
	211
	212
	213
	214
	215
	216
	217
	218
	219
	220
	221
	222
	223
	224
	225
	226
	227
	228
	229
	230
	231
	232
	233
	234
	235
	236
	237
	238
	239
	240
	241
	242
	243
	244
	245
	246
	247
	248
	249
	250
	251
	252
	253
	254
	255
	256
	257
	258
	259
	260
	261
	262
	263
	264
	265
	266
	267
	268
	269
	270
	271
	272
	273
	274
	275
	276
	277
	278
	279
	280
	281
	282
	283
	284
	285
	286
	287
	288
	289
	290
	291
	292
	293
	294
	295
	296
	297
	298
	299
	300
	301
	302
	303
	304
	305
	306
	307
	308
	309
	310
	311
	312
	313
	314
	315
	316
	317
	318
	319
	320
	321
	322
	323
	324
	325
	326
	327
	328
	329
	330
	331
	332
	333
	334
	335
	336
	337
	338
	339
	340
	341
	342
	343
	344
	345
	346
	347
	348
	349
	350
	351
	352
	353
	354
	355
	356
	357
	358
	359
	360
	361
	362
	363
	364
	365
	366
	367
	368
	369
	370
	371
	372
	373
	374
	375
	376
	377
	378
	379
	380
	381
	382
	383
	384
	385
	386
	387
	388
	389
	390
	391
	392
	393
	394
	395
	396
	397
	398
	399
	400
	401
	402
	403
	404
	405
	406
	407
	408
	409
	410
	411
	412
	413
	414
	415
	416
	417
	418
	419
	420
	421
	422
	423
	424
	425
	426
	427
	428
	429
	430
	431
	432
	433
	434
	435
	436
	437
	438
	468
	469
	470
	471
	472
	473
	474
	475
	476
	531
	532
	533
	534
	535
	536

[0358] Table 3a is directed to compounds of the formula (IIIa):

[0359]
wherein R¹ and R² are as defined in Table 3a.

[0360] An “X” in the box formed by the intersection of the R² and the R¹ row represents an R² and R¹ combination of a compound of formula IIIA that is excluded from the definition of the compounds of formula I (and formula IIA). For example, compounds of formula IIIA wherein R² is moiety 1 (see Table 2 for definition) and R¹ is moiety 2 (see Table 1 for definition) are excluded from the definition of formula I (and formula IIA) (there is an “X” in the box formed by the intersection of the R² column and the R¹ row).

[0361] If there is no “X” in the box, then that compound is within the definition of the compounds of formula I (and formula IIA). For example, compounds of formula IIIA wherein moiety R² is 2 and moiety R¹ is 23 (no “X” in the box formed by the intersection of the R² column and the R¹ row) are within the definition of the compounds of formula I (and formula IIA).

[0362]

	TABLE 3a
	R1
R2	2	3	9	10	11	14	15	23	20
1	X	X	X	X	X	X	X	X	X
2	X	X	X	X	X	X	X		X
3		X	X	X	X	X	X	X	X
4	X	X	X	X	X	X	X	X	X
5	X	X						X	X
6	X	X	X	X	X	X	X	X	X
7	X	X	X	X	X	X	X		X
8	X	X	X	X	X	X	X	X	X
9	X	X	X	X	X	X	X		X
10	X	X	X	X	X	X	X	X	X
11	X	X	X	X	X	X	X	X	X
12	X	X	X	X	X	X	X	X	X
13	X	X	X	X		X	X	X	X
14	X	X	X	X	X	X	X	X	X
15	X	X	X	X	X	X	X	X	X
16	X	X	X	X	X	X	X	X	X
17	X	X	X	X	X	X	X	X	X
18	X	X	X	X	X	X	X	X	X
19	X	X	X	X	X	X	X	X	X
20	X	X	X	X	X	X	X		X
21	X	X	X	X	X	X	X	X	X
22	X	X	X	X	X	X	X	X	X
23	X	X	X	X	X	X	X	X	X
24	X	X	X	X	X	X	X	X	X
25	X	X	X	X	X	X	X	X	X
26	X	X	X	X	X	X	X	X	X
27	X	X		X	X	X	X
28	X	X	X	X	X	X	X	X	X
29	X	X	X	X	X	X	X	X	X
30	X	X	X	X	X	X	X	X	X
31	X	X	X	X		X	X	X	X
32	X	X	X	X	X	X	X	X	X
33	X	X	X	X	X	X	X	X	X
34	X	X	X	X	X	X	X	X	X
35	X		X	X	X	X	X	X	X
36	X	X	X	X	X	X	X	X	X
37	X	X	X	X	X	X	X	X	X
38	X	X	X	X	X	X	X	X	X
39	X	X	X	X	X		X	X	X
40	X	X	X	X	X	X	X	X	X
41	X			X	X		X	X	X
42	X	X	X	X	X	X	X	X	X
43	X	X	X	X	X	X	X	X	X
	R1
R2	22	27	38	39	40	41	42	31	32	34	35	36	37
1	X	X	X	X	X	X	X	X	X	X	X	X	X
2	X	X	X	X	X	X	X	X	X	X	X	X	X
3	X	X	X	X	X	X	X	X	X	X	X	X	X
4	X	X	X	X	X	X	X	X	X	X	X	X	X
5	X	X	X	X	X		X	X		X	X	X	X
6	X	X	X	X	X	X	X	X	X	X	X	X	X
7	X	X	X	X	X	X	X	X	X	X	X	X	X
8	X	X	X	X	X	X	X	X	X	X	X	X	X
9	X		X	X	X	X	X	X	X	X	X	X	X
10	X	X	X	X	X	X	X	X	X	X	X	X	X
11	X	X	X	X	X	X	X	X	X	X	X	X	X
12	X	X	X	X	X	X	X	X	X	X	X	X	X
13	X	X	X	X	X	X	X	X	X	X	X	X	X
14	X	X	X	X	X	X	X	X	X	X	X	X	X
15	X	X	X	X	X	X	X	X	X	X	X	X	X
16	X	X	X	X	X	X	X	X	X	X	X	X	X
17	X	X	X	X	X	X	X	X	X	X	X	X	X
18	X	X	X	X		X	X	X	X	X	X	X	X
19	X	X	X	X	X	X			X		X	X	X
20	X	X	X	X	X	X	X	X	X	X	X	X	X
21	X	X	X	X	X	X	X	X	X	X	X	X	X
22	X	X	X	X	X	X	X	X	X	X	X	X	X
23	X	X	X	X	X	X	X	X	X	X	X	X	X
24	X	X	X	X	X	X	X	X	X	X	X	X	X
25	X	X	X	X	X	X	X	X	X	X	X	X	X
26	X	X	X	X	X	X	X	X	X	X	X	X	X
27
28	X	X	X	X	X	X	X	X	X	X	X	X	X
29	X	X	X	X	X	X	X	X	X	X	X	X	X
30	X		X	X	X	X	X	X	X	X	X	X	X
31	X	X	X	X	X	X	X	X	X	X	X	X	X
32	X	X	X	X	X	X	X	X	X	X		X	X
33	X	X	X	X	X	X	X		X	X	X	X	X
34	X	X	X	X	X	X		X	X	X		X	X
35	X		X	X		X		X				X	X
36	X	X	X	X	X	X	X	X	X	X	X	X	X
37	X	X	X	X	X	X	X	X	X	X	X	X	X
38	X	X	X	X	X	X	X	X	X	X	X	X	X
39	X	X	X	X	X	X	X	X	X	X	X	X	X
40	X	X	X	X			X	X	X	X	X	X	X
41	X	X	X	X	X	X	X	X	X	X	X	X	X
42	X	X	X	X	X		X	X	X	X	X	X	X
43	X	X	X	X	X		X	X	X	X	X	X	X
	R1
R2	30	44	45	47	49	50	51	52	7	8	13
1
2	X
3	X	X	X	X	X	X	X	X
4
5	X	X	X	X	X	X	X	X
6	X								X	X	X
7	X								X	X	X
8	X								X	X	X
9	X								X	X	X
10	X								X	X	X
11	X								X	X	X
12	X								X	X	X
13	X								X	X	X
14	X								X	X	X
15	X								X	X	X
16	X	X	X	X	X	X	X	X	X	X	X
17	X								X	X	X
18	X								X	X	X
19									X	X	X
20	X	X	X	X	X	X	X	X	X	X	X
21	X								X	X	X
22	X	X	X	X	X	X	X	X	X	X	X
23	X								X	X	X
24	X								X	X	X
25	X								X	X	X
26	X								X	X	X
27									X	X	X
28	X								X	X	X
29	X								X	X	X
30	X	X	X	X	X	X	X	X	X	X	X
31	X								X	X	X
32	X								X	X	X
33									X	X	X
34	X								X	X	X
35	X		X	X		X	X	X	X	X	X
36	X								X	X	X
37	X								X	X	X
38	X								X	X	X
39	X								X	X	X
40	X								X	X	X
41	X								X	X	X
42	X								X	X	X
43	X								X	X	X
	R1
R2	2	3	9	10	11	14	15	23	20
44	X	X	X	X	X	X	X		X
45	X	X	X	X	X	X	X	X	X
46					X	X	X	X	X
47	X	X	X	X	X	X	X	X	X
48	X	X	X	X	X	X	X	X	X
49	X	X	X		X	X	X	X	X
50	X	X	X	X	X	X	X	X	X
51	X	X		X	X	X	X
52	X	X	X	X	X	X	X	X	X
53	X	X	X	X	X	X	X	X	X
54	X	X	X	X	X	X	X	X	X
55	X	X	X	X	X	X	X	X	X
56	X	X	X	X	X	X	X	X	X
57	X	X	X	X	X	X	X	X	X
58	X	X	X	X	X	X	X	X	X
59	X	X	X	X	X	X	X	X	X
60	X	X	X	X	X	X	X	X	X
61	X	X	X	X	X	X	X	X	X
62	X	X	X	X	X	X	X	X	X
63	X	X	X	X	X	X	X	X	X
64	X	X	X	X		X	X	X	X
65	X	X	X	X	X	X	X	X	X
66	X	X	X	X	X	X	X	X	X
67	X	X	X	X	X	X	X	X	X
68	X	X	X	X	X	X	X	X	X
69	X	X	X	X	X	X	X	X	X
70	X	X	X	X	X	X	X	X	X
71	X	X	X	X		X	X	X	X
72	X	X	X	X	X	X	X	X	X
73	X	X	X	X	X	X	X	X	X
74	X	X	X	X	X	X	X	X	X
75	X	X	X	X		X	X	X	X
76	X	X	X	X	X	X	X	X	X
77	X	X	X	X		X	X	X	X
78	X	X	X	X	X	X	X
79	X	X	X	X	X	X	X	X	X
80	X	X	X	X	X	X	X	X	X
81	X	X	X			X		X	X
82	X	X	X	X	X	X	X	X	X
83		X		X	X			X	X
84			X	X	X	X		X	X
85			X		X			X	X
86					X				X
87			X		X				X
88					X			X	X
	R1
R2	22	27	38	39	40	41	42	31	32	34	35	36	37
44	X		X	X	X	X	X	X	X	X	X	X	X
45	X	X	X	X	X	X	X	X	X	X	X	X	X
46	X	X		X	X		X	X	X		X
47	X	X		X	X		X	X	X	X	X	X
48	X		X	X	X	X	X	X	X	X	X	X	X
49	X	X	X	X	X		X	X	X	X	X	X	X
50	X	X	X	X	X	X	X	X	X	X	X	X	X
51		X		X	X	X	X	X	X	X	X
52	X	X	X	X	X	X	X	X	X	X	X	X	X
53	X	X	X	X	X	X	X	X	X	X	X	X	X
54	X	X	X	X	X	X	X	X	X	X	X	X	X
55	X	X	X	X	X	X	X	X	X	X	X	X	X
56	X	X
57	X	X	X	X	X		X		X	X	X	X	X
58	X	X		X	X		X	X	X	X	X	X
59	X	X	X	X	X		X	X	X	X	X	X	X
60	X		X	X	X	X	X	X	X	X	X	X	X
61	X	X		X	X		X	X	X	X	X	X
62	X	X	X	X	X	X	X	X	X	X	X	X	X
63	X	X	X	X	X	X	X	X	X	X	X	X	X
64	X	X	X	X	X		X	X	X	X	X	X	X
65	X	X	X	X	X		X		X	X	X	X	X
66	X	X	X	X	X		X	X	X	X	X	X	X
67	X	X	X	X	X		X	X	X	X	X	X	X
68	X	X	X	X	X		X	X	X	X	X	X
69	X	X		X	X		X	X	X	X	X
70	X	X		X	X		X	X	X	X	X	X
71	X	X		X	X		X	X	X	X	X	X
72	X	X	X	X	X		X	X	X	X	X	X
73	X	X	X	X	X		X	X	X	X	X		X
74	X	X	X	X	X		X	X	X	X	X	X
75	X	X	X	X	X		X	X	X	X	X	X	X
76	X	X	X	X	X		X	X	X	X	X	X	X
77	X	X	X	X	X	X	X	X	X	X	X	X
78
79	X	X	X	X	X		X	X	X	X	X	X	X
80	X	X	X	X	X		X	X	X	X	X	X	X
81	X	X	X	X	X	X	X		X	X	X	X	X
82	X	X	X	X	X	X	X			X	X	X	X
83	X		X	X		X		X					X
84	X	X	X	X	X		X		X		X	X	X
85	X	X	X	X		X		X				X	X
86	X	X	X	X		X				X			X
87	X		X	X		X		X					X
88	X	X	X	X		X		X					X
	R1
R2	30	44	45	47	49	50	51	52	7	8	13
44	X	X	X	X	X	X	X	X	X	X	X
45	X								X	X	X
46	X								X	X	X
47	X	X	X	X	X	X	X	X	X	X	X
48	X	X	X	X	X	X	X	X	X	X	X
49	X								X	X	X
50	X								X	X	X
51	X								X	X	X
52	X								X	X	X
53	X								X	X	X
54	X								X	X	X
55	X	X	X	X	X	X	X	X	X	X	X
56									X	X	X
57									X	X	X
58	X								X	X	X
59	X	X	X	X	X	X	X	X	X	X	X
60	X	X	X	X	X		X	X	X	X	X
61	X								X	X	X
62	X								X	X	X
63	X								X	X	X
64	X	X	X	X	X	X	X	X	X	X	X
65	X								X	X	X
66	X								X	X	X
67	X								X	X	X
68	X	X	X	X	X	X	X	X	X	X	X
69	X								X	X	X
70	X								X	X	X
71	X								X	X	X
72	X								X	X	X
73	X								X	X	X
74	X								X	X	X
75	X								X	X	X
76	X								X	X	X
77	X								X	X	X
78									X	X	X
79	X								X	X	X
80	X								X	X	X
81	X								X	X	X
82	X								X	X	X
83		X		X			X	X
84	X	X	X	X	X	X	X	X
85	X	X		X	X	X	X	X	X	X	X
86									X	X	X
87	X								X	X	X
88
	R1
R2	2	3	9	10	11	14	15	20	22
133	X	X	X	X	X	X		X	X
134	X	X	X	X	X	X		X	X
135	X	X	X	X	X	X		X	X
136	X	X	X	X	X	X		X	X
137	X	X	X	X	X	X		X	X
138	X	X	X	X	X	X		X	X
139	X	X	X	X	X				X
140	X	X	X	X	X				X
141	X	X	X	X					X
142	X	X	X	X	X	X		X	X
143	X	X	X	X	X	X		X	X
144	X	X	X	X	X	X		X	X
145	X	X	X		X	X		X	X
146	X	X	X	X	X	X		X	X
147	X	X	X		X				X
148	X	X	X	X	X	X		X	X
149	X	X	X	X	X	X		X	X
150	X	X	X	X	X	X		X	X
151	X	X	X	X	X	X		X	X
152	X	X	X	X	X	X		X	X
153	X	X	X	X		X		X	X
154	X	X	X	X		X		X	X
155	X	X	X	X	X	X		X	X
156	X	X	X	X	X	X		X	X
157	X	X	X	X	X	X		X	X
158	X	X	X	X	X	X		X	X
159	X	X	X	X	X	X		X	X
160	X	X	X	X	X	X		X	X
161	X	X	X	X	X	X		X	X
162	X	X	X	X	X	X		X	X
163	X	X	X	X	X	X		X	X
164	X	X	X	X	X	X		X	X
165	X	X	X	X	X	X		X	X
166	X	X	X	X	X	X		X	X
167	X	X	X	X	X	X		X	X
168	X	X	X	X	X	X		X	X
169	X		X						X
170	X		X						X
171	X		X						X
172	X		X	X	X	X		X	X
173	X		X			X		X	X
174	X		X						X
175	X		X		X	X		X	X
176	X		X	X	X	X		X	X
	R1
R2	44	45	47	49	50	51	52	7	8	13	17	19	21
133			X		X	X		X	X	X			X
134		X	X		X	X	X	X	X	X			X
135		X	X		X	X	X	X	X	X			X
136		X	X		X	X	X	X	X	X			X
137								X	X	X			X
138		X	X		X	X	X	X	X	X			X
139		X	X		X	X	X	X	X	X			X
140		X	X		X	X		X	X	X			X
141		X	X		X	X	X	X	X	X
142								X	X	X			X
143								X	X	X			X
144		X	X		X	X	X	X	X	X			X
145								X	X	X			X
146		X			X	X	X	X	X	X			X
147								X	X	X			X
148								X	X	X			X
149								X	X	X			X
150								X	X	X			X
151								X	X	X			X
152		X	X		X	X	X	X	X	X			X
153									X	X			X
154									X	X			X
155								X	X	X			X
156								X	X	X			X
157		X	X		X	X	X	X	X	X			X
158								X	X	X			X
159								X	X	X			X
160									X	X			X
161								X	X	X			X
162								X	X	X			X
163								X	X	X			X
164								X	X	X			X
165								X	X	X			X
166								X	X	X			X
167		X	X		X	X	X	X	X	X			X
168								X	X	X			X
169									X	X
170									X	X			X
171									X	X
172								X	X	X			X
173									X	X			X
174									X	X
175		X	X		X	X	X	X	X	X			X
176								X	X	X			X
	R1
R2	2	3	9	10	11	14	15	23
180	X		X	X		X	X	X
181	X		X	X	X	X	X	X
182	X		X	X		X		X
183	X		X	X	X	X	X	X
184	X		X	X	X	X	X	X
185	X		X	X		X	X	X
186	X		X			X		X
187	X		X	X	X	X	X	X
188	X		X	X	X	X	X	X
190	X		X		X	X	X	X
191	X		X		X	X	X	X
192	X		X	X	X	X	X	X
193	X		X		X	X	X	X
194	X		X	X	X	X	X	X
195	X		X	X	X	X	X	X
196	X		X	X	X	X	X	X
197	X		X	X	X	X	X	X
199	X		X	X	X	X	X	X
201	X		X	X	X	X		X
203	X		X	X	X	X	X	X
204	X		X	X	X	X	X	X
205	X		X	X	X	X	X	X
206	X		X	X	X	X		X
207	X		X	X	X	X	X	X
208	X		X	X	X	X	X	X
209	X		X	X	X	X		X
210	X		X	X	X	X	X	X
211	X		X	X	X	X	X	X
212	X		X	X	X	X	X	X
213	X		X	X	X	X		X
214	X		X	X	X	X	X	X
215	X		X			X	X	X
216	X		X	X	X	X	X	X
220	X		X	X	X	X	X	X
221	X		X	X	X	X	X	X
222	X		X			X	X	X
228	X		X	X	X	X	X	X
229	X		X	X	X	X	X	X
231	X		X	X	X	X	X	X
232	X		X	X	X	X	X	X
233	X		X	X	X	X	X	X
234	X		X	X	X	X	X	X
235	X		X	X	X	X	X	X
	R1
R2	20	22	27	38	39	40	41	42	31	32	34	35	36	37
180		X			X	X	X	X	X	X	X		X	X
181		X			X	X	X	X	X	X	X		X	X
182		X			X	X	X	X		X	X		X	X
183		X			X	X	X	X	X	X	X		X	X
184		X			X	X	X	X	X	X	X		X	X
185
186					X	X	X	X	X	X	X
187		X			X	X	X	X	X	X	X		X	X
188		X			X	X	X	X	X	X	X		X	X
190		X			X	X	X	X	X	X	X		X	X
191		X			X	X	X	X	X	X	X		X	X
192		X			X	X	X	X	X	X	X		X	X
193		X			X	X	X	X	X	X	X		X	X
194		X			X	X	X	X	X	X	X		X	X
195		X			X	X	X	X	X	X	X		X	X
196		X			X	X	X	X	X	X	X		X	X
197		X			X	X	X	X	X	X	X		X	X
199		X			X	X	X	X	X	X	X		X	X
201		X					X		X	X	X		X	X
203		X			X		X		X	X	X		X	X
204		X			X	X	X	X	X	X	X		X	X
205		X			X	X	X	X	X	X	X		X	X
206		X			X	X	X	X	X	X	X		X	X
207		X			X	X	X	X	X	X	X		X	X
208		X			X	X	X	X	X	X	X		X	X
209		X					X		X	X	X
210		X					X		X	X	X		X	X
211		X			X	X	X	X	X	X	X		X	X
212		X			X	X	X	X	X	X	X
213		X					X		X	X	X			X
214		X			X		X	X	X	X	X		X
215
216		X			X	X	X	X	X	X	X		X
220		X			X	X	X	X	X	X	X		X	X
221		X			X	X	X	X	X	X	X		X	X
222		X			X	X	X	X	X	X	X		X	X
228		X			X	X	X	X	X	X	X		X	X
229
231					X	X	X	X	X	X	X		X	X
232		X			X	X	X	X	X	X	X		X	X
233		X			X	X	X	X	X	X	X		X	X
234		X			X	X	X	X		X	X		X	X
235					X	X	X	X	X	X	X		X	X
	R1
R2	7	8	13	17	19	21	25	33	43	26
180			X		X	X		X	X	X
181	X		X		X	X	X		X	X
182	X		X					X	X	X
183	X		X		X	X	X	X	X	X
184	X		X		X	X		X	X
185			X			X
186								X
187	X		X		X	X	X	X	X	X
188	X		X		X	X	X		X	X
190	X				X		X	X	X	X
191	X		X		X	X	X	X	X	X
192	X		X		X	X	X	X	X
193	X		X		X	X	X	X	X	X
194	X		X		X	X	X	X	X	X
195	X		X		X	X	X	X	X
196	X		X		X	X	X		X
197	X		X		X	X	X	X	X	X
199	X		X		X	X	X	X	X	X
201	X		X		X	X	X	X	X	X
203	X		X		X	X	X	X		X
204	X		X		X	X	X	X	X	X
205	X		X		X	X	X		X	X
206	X		X		X	X	X	X	X	X
207	X		X		X	X	X		X	X
208	X		X		X	X	X	X	X	X
209	X		X		X	X	X	X		X
210	X				X	X	X	X		X
211	X		X		X	X	X	X	X	X
212	X		X		X	X	X	X	X	X
213	X		X		X	X	X	X	X	X
214	X		X		X	X	X	X	X	X
215										X
216	X		X		X	X	X	X	X	X
220	X		X			X	X	X	X	X
221	X		X		X	X	X		X	X
222						X	X	X	X	X
228	X		X		X	X	X	X	X	X
229	X		X		X	X	X			X
231	X		X				X	X		X
232	X		X		X	X	X		X	X
233	X		X		X		X	X	X	X
234	X		X		X	X	X		X	X
235	X		X		X	X	X	X		X
	R1
R2	2	3	9	10	11	14	15	23
237	X		X	X	X	X	X	X
238	X		X	X	X	X	X	X
239	X		X	X	X	X	X	X
240	X		X	X	X	X	X	X
241	X		X	X	X	X	X	X
243	X		X	X	X	X	X	X
244	X		X	X	X	X	X	X
246	X		X	X	X	X	X	X
247	X		X	X	X	X	X	X
249	X		X	X	X	X	X	X
250	X		X	X	X	X	X	X
252	X		X	X	X	X	X	X
253	X		X	X	X	X	X	X
254	X		X	X	X	X	X	X
255	X		X	X	X	X	X	X
256	X		X	X	X	X	X	X
257	X		X	X	X	X	X	X
259	X		X	X	X	X	X	X
261	X		X	X	X	X	X	X
262	X		X	X	X	X	X	X
	R1
R2	20	22	27	38	39	40	41	42	31	32	34	35	36	37
237		X					X		X	X	X		X	X
238		X			X	X	X	X			X		X	X
239					X	X	X	X	X	X	X		X	X
240		X			X	X	X	X		X	X		X	X
241		X			X	X	X	X	X	X	X		X	X
243		X			X	X	X	X	X	X	X		X	X
244		X			X	X	X	X	X	X	X		X	X
246		X			X	X	X		X	X	X		X	X
247		X			X	X	X		X	X	X
249		X			X	X	X	X	X	X	X		X	X
250		X			X	X	X	X	X	X	X		X	X
252		X			X	X	X	X	X	X	X		X	X
253							X		X	X	X
254		X			X	X	X	X	X	X	X		X	X
255		X			X	X	X	X	X	X	X		X	X
256		X			X	X	X	X	X	X	X		X	X
257		X			X	X	X	X	X	X	X		X	X
259		X			X		X		X	X	X		X	X
261		X			X	X	X	X	X	X	X		X	X
262		X			X	X	X	X	X	X	X		X	X
	R1
R2	7	8	13	17	19	21	25	33	43	26	28	29
237	X		X		X	X	X	X	X	X
238	X		X		X	X	X	X	X	X
239	X		X		X	X	X	X		X
240	X		X		X	X	X		X	X
241	X		X		X	X	X	X	X	X
243	X		X		X	X	X		X	X
244	X		X		X	X	X		X	X
246	X		X		X	X	X	X	X	X
247	X		X		X	X	X	X	X	X
249	X		X		X	X	X	X		X
250	X		X		X	X	X	X	X	X
252	X		X		X	X	X	X	X	X
253	X		X		X	X	X	X	X	X
254	X		X		X	X	X	X	X	X
255	X		X		X	X	X	X	X	X
256	X		X		X	X	X	X	X	X
257	X		X		X	X	X	X		X
259	X		X		X	X	X	X	X	X
261	X		X		X	X	X	X	X	X
262	X		X		X	X	X	X		X
	R1
R2	2	3	9	10	11	14	15	23
265
266	X	X	X	X	X	X	X	X
267	X	X	X	X	X	X	X	X
268	X	X	X	X	X	X	X	X
269	X	X	X	X		X	X	X
270	X	X	X	X	X	X	X	X
271	X	X	X	X	X	X		X
272	X	X	X	X	X	X		X
273	X	X	X	X	X	X		X
274			X
275	X	X	X	X	X		X	X
276	X	X	X	X	X	X		X
277	X	X		X	X	X	X	X
278	X	X	X	X	X	X	X	X
279	X	X	X	X	X	X	X	X
280	X	X	X	X	X	X		X
281	X	X	X	X	X	X		X
282	X	X	X	X	X	X	X	X
283	X	X	X	X	X	X		X
284	X	X	X	X	X	X	X	X
285	X	X	X	X	X	X		X
286	X	X	X		X
287	X	X		X	X			X
288	X	X	X	X	X	X		X
289	X	X	X	X	X			X
290	X	X	X	X	X			X
291	X	X	X	X				X
292	X	X	X	X	X	X		X
293	X	X	X	X	X	X		X
294	X	X	X		X			X
295	X	X	X	X	X	X	X	X
296	X	X	X	X	X	X		X
297	X	X	X	X	X	X	X	X
298	X	X	X	X	X		X	X
299	X	X						X
	R1
R2	20	22	27	38	39	40	41	42	31	32	34	35	36	37
265
266				X	X	X	X	X			X	X
267		X		X	X	X	X	X	X	X	X	X	X	X
268		X		X	X	X	X	X	X	X	X	X	X	X
269		X		X	X	X	X	X	X	X	X	X	X	X
270		X		X	X	X	X		X	X	X	X	X	X
271		X		X		X	X		X	X	X	X	X	X
272		X		X	X		X	X	X	X	X		X	X
273		X		X	X	X	X	X	X	X	X	X	X	X
274		X								X
275		X			X	X	X	X	X	X	X	X	X	X
276		X		X	X	X	X	X	X	X	X	X	X	X
277		X			X	X	X	X	X	X	X	X	X
278		X			X	X	X	X	X	X	X	X	X	X
279		X		X	X	X	X	X	X	X	X	X	X	X
280		X			X	X	X	X	X		X	X	X
281		X		X	X	X	X	X	X	X	X	X	X	X
282		X		X	X	X	X	X	X	X	X	X	X	X
283		X		X		X	X	X	X	X	X	X	X	X
284		X		X	X	X	X	X	X	X	X	X	X	X
285		X		X	X		X	X		X		X	X	X
286		X						X		X	X		X	X
287		X		X		X	X	X	X			X	X
288		X		X	X	X	X	X	X	X	X	X	X	X
289		X		X	X	X	X	X	X		X	X	X	X
290		X		X	X	X		X	X	X	X		X
291		X		X	X	X		X	X	X	X	X	X
292		X		X	X	X	X	X	X	X	X	X	X
293		X		X	X	X	X	X	X	X	X	X	X	X
294		X		X	X	X	X		X	X	X	X	X	X
295		X		X	X	X		X	X	X	X	X	X	X
296		X		X	X	X	X	X	X	X	X	X	X
297		X		X	X	X	X	X	X	X	X	X	X	X
298		X		X	X	X	X	X	X	X	X	X	X	X
299		X					X	X		X
	R1
R2	7	8	13	17	19	21	25	33	43	26	28	29	30
265
266		X	X	X		X					X		X
267	X	X	X	X	X	X	X	X			X	X	X
268	X	X	X	X	X	X	X	X			X	X	X
269	X	X	X		X	X		X			X	X	X
270	X	X	X		X	X	X	X			X	X	X
271	X	X	X	X	X	X	X	X					X
272	X	X	X	X	X	X	X	X					X
273		X	X		X	X	X	X			X	X	X
274		X				X							X
275	X	X	X	X	X	X	X	X			X		X
276		X	X		X	X	X	X			X	X	X
277			X		X	X	X	X			X	X
278		X	X		X	X	X	X			X	X	X
279		X	X		X		X	X			X	X	X
280	X	X	X	X	X	X	X	X					X
281	X	X	X		X	X	X	X					X
282	X	X	X	X	X	X	X	X			X	X	X
283	X	X	X	X	X	X		X					X
284	X		X	X	X	X		X			X		X
285	X	X	X	X	X	X							X
286	X	X	X		X	X	X	X					X
287		X		X	X		X
288	X	X	X	X	X		X						X
289	X	X	X	X	X	X	X						X
290	X	X	X	X	X	X	X						X
291	X		X	X	X	X		X					X
292	X	X	X	X	X		X	X					X
293	X	X	X	X	X		X	X					X
294	X	X	X	X	X		X	X					X
295	X	X	X	X	X	X	X	X					X
296	X	X	X	X	X	X	X	X			X
297	X	X	X	X	X	X	X	X			X	X
298	X	X	X	X	X	X	X	X			X		X
299	X	X		X	X		X	X
	R1
R2	2	3	9	10	11	14	15	23
300	X	X	X	X	X	X
301	X	X	X	X	X	X		X
302	X	X	X					X
303					X			X
304	X	X	X	X	X	X	X	X
305	X	X	X
306	X	X		X	X			X
307	X	X	X	X	X
308	X	X	X
309	X			X	X	X		X
310	X	X	X	X	X	X	X	X
311	X	X	X	X	X			X
312	X	X	X					X
313	X				X			X
314		X	X
315
316	X	X	X	X	X	X		X
317	X			X	X	X		X
318	X	X	X	X	X			X
319	X	X		X				X
320	X	X	X	X	X			X
321	X	X	X	X	X	X	X	X
322	X	X	X	X	X	X	X	X
323	X	X	X	X	X	X	X	X
324	X	X	X			X		X
325					X			X
326	X				X			X
327		X	X		X
328
330
331
332
333
334			X	X	X	X
335
336				X		X
337			X		X	X
338			X	X	X	X
	R1
R2	20	22	27	38	39	40	41	42	31	32	34	35	36	37
300		X		X	X	X	X	X	X	X		X	X	X
301		X		X	X	X	X		X	X	X	X	X	X
302										X	X		X
303											X			X
304		X		X	X	X	X	X	X	X	X	X	X	X
305		X				X	X	X	X	X		X	X	X
306		X		X	X	X	X	X	X	X	X	X	X
307		X		X		X	X		X	X		X	X
308		X		X	X	X	X	X	X	X	X	X	X	X
309		X		X	X	X	X	X	X		X	X	X
310		X		X	X	X	X	X	X	X	X	X	X	X
311				X	X	X	X	X	X			X	X
312				X	X	X	X	X	X		X	X	X
313				X	X	X		X			X	X	X
314						X	X	X	X		X	X	X
315
316		X		X	X	X	X	X	X	X	X	X	X	X
317				X	X	X	X		X		X		X
318		X		X			X		X			X	X
319		X		X		X	X		X	X	X	X	X	X
320		X		X	X		X		X	X	X	X	X	X
321		X		X	X	X	X	X	X	X	X	X	X
322		X		X	X	X	X		X	X	X	X	X	X
323		X		X		X	X	X	X	X	X	X	X	X
324							X
325
326		X									X
327										X			X
328		X					X			X
330				X	X	X		X	X	X	X	X	X	X
331		X			X		X		X	X	X		X	X
332					X		X		X	X	X		X	X
333		X			X		X		X	X	X		X	X
334					X	X		X	X		X
335					X	X			X
336						X		X	X
337					X	X		X	X
338					X	X		X	X
	R1
R2	7	8	13	17	19	21	25	33	43	26	28	29	30
300	X	X	X		X	X	X	X					X
301		X	X		X	X	X				X
302		X			X	X		X
303					X
304	X	X	X		X	X	X	X					X
305		X			X	X	X	X					X
306	X	X	X	X	X	X	X						X
307		X			X	X	X
308		X		X	X	X	X	X					X
309	X	X	X	X	X		X					X	X
310	X	X	X	X	X		X	X			X		X
311	X	X			X	X	X						X
312	X				X	X							X
313	X	X			X		X	X					X
314	X					X							X
315	X
316	X	X	X		X		X	X				X	X
317	X	X	X	X	X						X	X	X
318		X		X	X	X	X						X
319	X		X	X	X		X						X
320	X	X	X	X	X		X	X					X
321	X	X	X	X	X	X	X	X			X	X	X
322	X	X	X	X	X	X	X	X			X	X	X
323	X	X	X		X	X	X	X			X		X
324	X		X					X				X
325	X		X
326	X	X	X	X			X						X
327		X	X	X	X	X		X					X
328							X	X					X
330													X
331								X	X
332								X	X
333								X	X
334												X	X
335													X
336													X
337													X
338													X
	R1
R2	2	3	9	10	11	14	15	23
339			X	X	X	X
340			X	X		X
341			X	X	X	X
342			X	X	X	X
343
344				X		X
345			X
346				X	X	X
347			X	X	X	X
348			X	X	X	X
349				X
350				X	X	X
351				X	X	X
352			X	X		X
353
354
355			X	X		X
356			X	X	X	X
357				X
358			X
359			X	X	X	X
360			X	X		X
361				X	X	X
362				X	X	X
363
364			X
365			X	X	X	X
366			X	X
367				X	X	X
368
369			X	X	X
370			X	X	X
371			X	X	X
372			X
373			X	X	X
374			X
375			X	X	X
376			X		X
377			X
	R1
R2	20	22	27	38	39	40	41	42	31	32	34	35	36	37
339					X	X		X	X		X
340					X	X		X	X		X	X
341					X			X	X		X
342					X	X		X	X		X
343						X		X	X			X
344					X	X			X		X	X
345					X	X		X	X		X
346					X	X		X	X		X	X
347					X	X		X	X		X	X
348					X			X	X
349					X	X			X		X	X
350					X	X		X	X		X
351					X	X			X		X
352					X	X		X	X		X	X
353						X
354						X		X
355					X	X		X	X		X	X
356					X	X		X	X		X	X
357								X
358					X	X		X	X
359					X	X		X	X		X	X
360									X
361					X	X		X	X		X
362					X	X			X		X
363					X				X
364
365											X
366											X
367											X
368								X
369					X				X		X	X
370					X				X		X	X
371					X				X		X	X
372					X				X		X	X
373					X				X		X	X
374					X				X		X	X
375					X				X		X	X
376					X							X
377					X				X		X	X
	R1
R2	7	8	13	17	19	21	25	33	43	26	28	29	30
339													X
340												X	X
341													X
342												X	X
343													X
344
345													X
346													X
347													X
348													X
349													X
350													X
351												X	X
352												X	X
353													X
354
355												X	X
356													X
357													X
358													X
359												X	X
360													X
361												X	X
362												X	X
363													X
364
365												X	X
366
367												X	X
368
369
370
371
372
373
374
375
376
377
	R1
R2	2	3	9	10	11	14	15	23
378				X	X
379				X	X
380				X	X
381
382
383
177	X		X		X	X	X	X
178	X		X	X	X	X	X	X
179	X		X	X	X	X	X	X
264
189	X		X	X	X	X	X	X
198	X		X	X	X	X	X	X
200	X		X			X		X
202	X		X	X	X	X		X
217	X		X	X	X	X	X	X
218	X		X	X	X	X	X	X
219	X		X	X	X	X	X	X
223	X		X	X	X	X	X	X
224	X		X	X	X	X	X	X
225	X		X	X	X	X	X	X
226	X		X	X	X	X	X	X
227	X		X	X	X	X	X	X
230	X		X	X	X	X	X	X
242	X		X	X	X	X	X	X
245	X		X	X	X	X	X	X
248	X		X	X	X	X	X	X
251	X		X	X	X	X	X	X
258	X		X	X	X	X	X	X
260	X		X	X	X	X	X	X
329
263
236	X		X	X	X	X	X	X
	R1
R2	20	22	27	38	39	40	41	42	31	32	34	35	36	37
378					X				X		X	X
379					X				X		X	X
380									X			X
381									X			X
382												X
383									X		X	X
177	X	X			X	X	X	X	X	X	X		X	X
178	X	X					X		X	X	X		X	X
179	X	X					X		X	X	X			X
264			X	X	X	X		X	X	X	X	X	X	X
189		X			X	X	X	X	X	X	X		X	X
198		X			X	X	X	X	X	X	X		X	X
200		X			X	X	X	X	X	X	X		X	X
202		X			X	X	X	X	X	X	X		X	X
217		X			X	X	X	X	X	X	X		X	X
218		X			X	X	X	X	X	X	X		X	X
219		X			X	X	X	X	X	X	X		X	X
223		X			X	X	X	X	X	X	X		X	X
224		X			X	X	X	X	X	X	X		X	X
225		X			X	X	X	X	X	X	X		X	X
226		X			X	X	X	X	X	X	X		X	X
227		X			X	X	X	X	X	X	X		X	X
230		X			X	X	X	X	X	X	X		X	X
242		X			X	X	X	X	X	X	X		X	X
245		X			X	X	X	X	X	X	X		X	X
248		X			X	X	X	X	X	X	X		X	X
251		X			X	X	X	X	X	X	X		X	X
258		X			X	X	X	X	X	X	X		X	X
260		X			X	X	X	X	X	X	X		X	X
329				X	X	X	X	X	X	X	X	X	X	X
263			X
236					X	X	X	X	X	X	X		X	X
	R1
R2	30	44	45	47	49	50	51	52
378
379
380
381
382
383
177
178
179
264	X
189		X	X	X			X
198		X	X	X	X	X	X	X
200		X	X	X	X	X	X	X
202		X	X	X	X	X	X	X
217		X	X	X			X
218		X	X	X			X
219		X	X	X			X
223		X	X	X			X
224		X	X	X			X
225		X	X	X	X	X	X	X
226		X	X	X	X	X	X	X
227		X	X	X		X	X	X
230		X	X	X	X	X	X	X
242		X	X	X	X	X	X	X
245		X	X	X	X		X	X
248		X	X	X	X	X	X	X
251		X	X	X	X	X	X	X
258		X	X	X	X	X	X	X
260		X	X	X	X	X	X	X
329	X		X	X	X	X	X	X
263		X	X	X	X	X	X	X
236		X		X			X
	R1
R2	7	8	13	17	19	21	25	33	43	26	28	29
378
379
380
381
382
383
177			X		X		X	X	X
178	X		X		X	X	X	X	X	X
179	X		X		X	X	X	X		X
264
189	X		X		X	X	X	X	X	X
198	X		X		X	X	X	X	X	X
200						X		X
202	X		X		X	X	X		X	X
217	X		X		X		X	X	X	X
218	X		X		X	X	X	X	X	X
219	X		X		X	X			X	X
223	X				X	X	X	X	X	X
224	X		X		X	X	X	X	X	X
225	X		X		X	X	X	X	X	X
226	X		X		X	X	X	X	X	X
227	X				X	X	X	X	X	X
230	X		X		X	X	X	X	X	X
242	X		X		X	X	X	X	X	X
245	X		X		X	X	X	X	X	X
248	X		X		X	X	X	X	X	X
251	X		X		X	X	X	X	X	X
258	X		X		X	X	X	X	X	X
260	X		X		X	X	X	X	X	X
329
263
236			X		X	X	X	X		X
	R1
R2	2	9	10	11	14	15	23	22	39	40	41	42
180	X	X	X		X	X	X	X	X	X	X	X
181	X	X	X	X	X	X	X	X	X	X	X	X
182	X	X	X		X		X	X	X	X	X	X
183	X	X	X	X	X	X	X	X	X	X	X	X
184	X	X	X	X	X	X	X	X	X	X	X	X
185	X	X	X		X	X	X
186	X	X			X		X		X	X	X	X
187	X	X	X	X	X	X	X	X	X	X	X	X
188	X	X	X	X	X	X	X	X	X	X	X	X
190	X	X		X	X	X	X	X	X	X	X	X
191	X	X		X	X	X	X	X	X	X	X	X
192	X	X	X	X	X	X	X	X	X	X	X	X
193	X	X		X	X	X	X	X	X	X	X	X
194	X	X	X	X	X	X	X	X	X	X	X	X
195	X	X	X	X	X	X	X	X	X	X	X	X
196	X	X	X	X	X	X	X	X	X	X	X	X
197	X	X	X	X	X	X	X	X	X	X	X	X
199	X	X	X	X	X	X	X	X	X	X	X	X
201	X	X	X	X	X		X	X			X
203	X	X	X	X	X	X	X	X	X		X
204	X	X	X	X	X	X	X	X	X	X	X	X
205	X	X	X	X	X	X	X	X	X	X	X	X
206	X	X	X	X	X		X	X	X	X	X	X
207	X	X	X	X	X	X	X	X	X	X	X	X
208	X	X	X	X	X	X	X	X	X	X	X	X
209	X	X	X	X	X		X	X			X
210	X	X	X	X	X	X	X	X			X
211	X	X	X	X	X	X	X	X	X	X	X	X
	R1
R2	31	32	34	36	37	7	13	19	21	25	33	43	26
180	X	X	X	X	X		X	X	X		X	X	X
181	X	X	X	X	X	X	X	X	X	X		X	X
182		X	X	X	X	X	X				X	X	X
183	X	X	X	X	X	X	X	X	X	X	X	X	X
184	X	X	X			X	X	X	X		X	X
185							X		X
186	X	X	X								X
187	X	X	X	X	X	X	X	X	X	X	X	X	X
188	X	X	X	X	X	X	X	X	X	X		X	X
190	X	X	X	X	X	X		X		X	X	X	X
191	X	X	X	X	X	X	X	X	X	X	X	X	X
192	X	X	X	X	X	X	X	X	X	X	X	X
193	X	X	X	X	X	X	X	X	X	X	X	X	X
194	X	X	X	X	X	X	X	X	X	X	X	X	X
195	X	X	X	X	X	X	X	X	X	X	X	X
196	X	X	X	X	X	X	X	X	X	X		X
197	X	X	X	X	X	X	X	X	X	X	X	X	X
199	X	X	X	X	X	X	X	X	X	X	X	X	X
201	X	X	X	X	X	X	X	X	X	X	X	X	X
203	X	X	X	X	X	X	X	X	X	X	X		X
204	X	X	X	X	X	X	X	X	X	X	X	X	X
205	X	X	X	X	X	X	X	X	X	X		X	X
206	X	X	X	X	X	X	X	X	X	X	X	X	X
207	X	X	X	X	X	X	X	X	X	X		X	X
208	X	X	X	X	X	X	X	X	X	X	X	X	X
209	X	X	X			X	X	X	X	X	X		X
210	X	X	X	X	X	X		X	X	X	X		X
211	X	X	X	X	X	X	X	X	X	X	X	X	X
	R1
R2	2	9	10	11	14	15	23	22	39	40	41	42
212	X	X	X	X	X	X	X	X	X	X	X	X
213	X	X	X	X	X		X	X			X
214	X	X	X	X	X	X	X	X	X		X	X
215	X	X			X	X	X
216	X	X	X	X	X	X	X	X	X	X	X	X
220	X	X	X	X	X	X	X	X	X	X	X	X
221	X	X	X	X	X	X	X	X	X	X	X	X
222	X	X			X	X	X	X	X	X	X	X
228	X	X	X	X	X	X	X	X	X	X	X	X
229	X	X	X	X	X	X	X
231	X	X	X	X	X	X	X		X	X	X	X
232	X	X	X	X	X	X	X	X	X	X	X	X
233	X	X	X	X	X	X	X	X	X	X	X	X
234	X	X	X	X	X	X	X	X	X	X	X	X
235	X	X	X	X	X	X	X		X	X	X	X
237	X	X	X	X	X	X	X	X			X
238	X	X	X	X	X	X	X	X	X	X	X	X
239	X	X	X	X	X	X	X		X	X	X	X
240	X	X	X	X	X	X	X	X	X	X	X	X
241	X	X	X	X	X	X	X	X	X	X	X	X
243	X	X	X	X	X	X	X	X	X	X	X	X
244	X	X	X	X	X	X	X	X	X	X	X	X
246	X	X	X	X	X	X	X	X	X	X	X
247	X	X	X	X	X	X	X	X	X	X	X
249	X	X	X	X	X	X	X	X	X	X	X	X
250	X	X	X	X	X	X	X	X	X	X	X	X
252	X	X	X	X	X	X	X	X	X	X	X	X
253	X	X	X	X	X	X	X				X
254	X	X	X	X	X	X	X	X	X	X	X	X
255	X	X	X	X	X	X	X	X	X	X	X	X
256	X	X	X	X	X	X	X	X	X	X	X	X
257	X	X	X	X	X	X	X	X	X	X	X	X
259	X	X	X	X	X	X	X	X	X		X
261	X	X	X	X	X	X	X	X	X	X	X	X
262	X	X	X	X	X	X	X	X	X	X	X	X
	R1
R2	31	32	34	36	37	7	13	19	21	25	33	43	26
212	X	X	X			X	X	X	X	X	X	X	X
213	X	X	X		X	X	X	X	X	X	X	X	X
214	X	X	X	X		X	X	X	X	X	X	X	X
215													X
216	X	X	X	X		X	X	X	X	X	X	X	X
220	X	X	X	X	X	X	X		X	X	X	X	X
221	X	X	X	X	X	X	X	X	X	X		X	X
222	X	X	X	X	X				X	X	X	X	X
228	X	X	X	X	X	X	X	X	X	X	X	X	X
229						X	X	X	X	X			X
231	X	X	X	X	X	X	X			X	X		X
232	X	X	X	X	X	X	X	X	X	X		X	X
233	X	X	X	X	X	X	X	X		X	X	X	X
234		X	X	X	X	X	X	X	X	X		X	X
235	X	X	X	X	X	X	X	X	X	X	X		X
237	X	X	X	X	X	X	X	X	X	X	X	X	X
238			X	X	X	X	X	X	X	X	X	X	X
239	X	X	X	X	X	X	X	X	X	X	X		X
240		X	X	X	X	X	X	X	X	X		X	X
241	X	X	X	X	X	X	X	X	X	X	X	X	X
243	X	X	X	X	X	X	X	X	X	X		X	X
244	X	X	X	X	X	X	X	X	X	X		X	X
246	X	X	X	X	X	X	X	X	X	X	X	X	X
247	X	X	X			X	X	X	X	X	X	X	X
249	X	X	X	X	X	X	X	X	X	X	X		X
250	X	X	X	X	X	X	X	X	X	X	X	X	X
252	X	X	X	X	X	X	X	X	X	X	X	X	X
253	X	X	X			X	X	X	X	X	X	X	X
254	X	X	X	X	X	X	X	X	X	X	X	X	X
255	X	X	X	X	X	X	X	X	X	X	X	X	X
256	X	X	X	X	X	X	X	X	X	X	X	X	X
257	X	X	X	X	X	X	X	X	X	X	X		X
259	X	X	X	X	X	X	X	X	X	X	X	X	X
261	X	X	X	X	X	X	X	X	X	X	X	X	X
262	X	X	X	X	X	X	X	X	X	X	X		X
	R1
R2	2	3	9	10	11	14	15	23	22
265
266	X	X	X	X	X	X	X	X
267	X	X	X	X	X	X	X	X	X
268	X	X	X	X	X	X	X	X	X
269	X	X	X	X		X	X	X	X
270	X	X	X	X	X	X	X	X	X
271	X	X	X	X	X	X		X	X
272	X	X	X	X	X	X		X	X
273	X	X	X	X	X	X		X	X
274			X						X
275	X	X	X	X	X		X	X	X
276	X	X	X	X	X	X		X	X
277	X	X		X	X	X	X	X	X
278	X	X	X	X	X	X	X	X	X
279	X	X	X	X	X	X	X	X	X
280	X	X	X	X	X	X		X	X
281	X	X	X	X	X	X		X	X
282	X	X	X	X	X	X	X	X	X
283	X	X	X	X	X	X		X	X
284	X	X	X	X	X	X	X	X	X
285	X	X	X	X	X	X		X	X
286	X	X	X		X				X
287	X	X		X	X			X	X
288	X	X	X	X	X	X		X	X
289	X	X	X	X	X			X	X
290	X	X	X	X	X			X	X
291	X	X	X	X				X	X
292	X	X	X	X	X	X		X	X
293	X	X	X	X	X	X		X	X
294	X	X	X		X			X	X
295	X	X	X	X	X	X	X	X	X
296	X	X	X	X	X	X		X	X
297	X	X	X	X	X	X	X	X	X
298	X	X	X	X	X		X	X	X
299	X	X						X	X
300	X	X	X	X	X	X			X
301	X	X	X	X	X	X		X	X
	R1
R2	38	39	40	41	42	31	32	34	35	36	37	30
265
266	X	X	X	X	X			X	X			X
267	X	X	X	X	X	X	X	X	X	X	X	X
268	X	X	X	X	X	X	X	X	X	X	X	X
269	X	X	X	X	X	X	X	X	X	X	X	X
270	X	X	X	X		X	X	X	X	X	X	X
271	X		X	X		X	X	X	X	X	X	X
272	X	X		X	X	X	X	X		X	X	X
273	X	X	X	X	X	X	X	X	X	X	X	X
274							X					X
275		X	X	X	X	X	X	X	X	X	X	X
276	X	X	X	X	X	X	X	X	X	X	X	X
277		X	X	X	X	X	X	X	X	X
278		X	X	X	X	X	X	X	X	X	X	X
279	X	X	X	X	X	X	X	X	X	X	X	X
280		X	X	X	X	X		X	X	X		X
281	X	X	X	X	X	X	X	X	X	X	X	X
282	X	X	X	X	X	X	X	X	X	X	X	X
283	X		X	X	X	X	X	X	X	X	X	X
284	X	X	X	X	X	X	X	X	X	X	X	X
285	X	X		X	X		X		X	X	X	X
286					X		X	X		X	X	X
287	X		X	X	X	X			X	X
288	X	X	X	X	X	X	X	X	X	X	X	X
289	X	X	X	X	X	X		X	X	X	X	X
290	X	X	X		X	X	X	X		X		X
291	X	X	X		X	X	X	X	X	X		X
292	X	X	X	X	X	X	X	X	X	X		X
293	X	X	X	X	X	X	X	X	X	X	X	X
294	X	X	X	X		X	X	X	X	X	X	X
295	X	X	X		X	X	X	X	X	X	X	X
296	X	X	X	X	X	X	X	X	X	X
297	X	X	X	X	X	X	X	X	X	X	X
298	X	X	X	X	X	X	X	X	X	X	X	X
299				X	X		X
300	X	X	X	X	X	X	X		X	X	X	X
301	X	X	X	X		X	X	X	X	X	X
	R1
R2	7	8	13	17	19	21	25	33	43	28	29
265
266		X	X	X		X				X
267	X	X	X	X	X	X	X	X		X	X
268	X	X	X	X	X	X	X	X		X	X
269	X	X	X		X	X		X		X	X
270	X	X	X		X	X	X	X		X	X
271	X	X	X	X	X	X	X	X
272	X	X	X	X	X	X	X	X
273		X	X		X	X	X	X		X	X
274		X				X
275	X	X	X	X	X	X	X	X		X
276		X	X		X	X	X	X		X	X
277			X		X	X	X	X		X	X
278		X	X		X	X	X	X		X	X
279		X	X		X		X	X		X	X
280	X	X	X	X	X	X	X	X
281	X	X	X		X	X	X	X
282	X	X	X	X	X	X	X	X		X	X
283	X	X	X	X	X	X		X
284	X		X	X	X	X		X		X
285	X	X	X	X	X	X
286	X	X	X		X	X	X	X
287		X		X	X		X
288	X	X	X	X	X		X
289	X	X	X	X	X	X	X
290	X	X	X	X	X	X	X
291	X		X	X	X	X		X
292	X	X	X	X	X		X	X
293	X	X	X	X	X		X	X
294	X	X	X	X	X		X	X
295	X	X	X	X	X	X	X	X
296	X	X	X	X	X	X	X	X		X
297	X	X	X	X	X	X	X	X		X	X
298	X	X	X	X	X	X	X	X		X
299	X	X		X	X		X	X
300	X	X	X		X	X	X	X
301		X	X		X	X	X			X
	R1
R2	2	3	9	10	11	14	15	23	22
302	X	X	X					X
303					X			X
304	X	X	X	X	X	X	X	X	X
305	X	X	X						X
306	X	X		X	X			X	X
307	X	X	X	X	X				X
308	X	X	X						X
309	X			X	X	X		X	X
310	X	X	X	X	X	X	X	X	X
311	X	X	X	X	X			X
312	X	X	X					X
313	X				X			X
314		X	X
315
316	X	X	X	X	X	X		X	X
317	X			X	X	X		X
318	X	X	X	X	X			X	X
319	X	X		X				X	X
320	X	X	X	X	X			X	X
321	X	X	X	X	X	X	X	X	X
322	X	X	X	X	X	X	X	X	X
323	X	X	X	X	X	X	X	X	X
324	X	X	X			X		X
325					X			X
326	X				X			X	X
327		X	X		X
328									X
330
331									X
332
333									X
334			X	X	X	X
	R1
R2	38	39	40	41	42	31	32	34	35	36	37	30
302							X	X		X
303								X			X
304	X	X	X	X	X	X	X	X	X	X	X	X
305			X	X	X	X	X		X	X	X	X
306	X	X	X	X	X	X	X	X	X	X		X
307	X		X	X		X	X		X	X
308	X	X	X	X	X	X	X	X	X	X	X	X
309	X	X	X	X	X	X		X	X	X		X
310	X	X	X	X	X	X	X	X	X	X	X	X
311	X	X	X	X	X	X			X	X		X
312	X	X	X	X	X	X		X	X	X		X
313	X	X	X		X			X	X	X		X
314			X	X	X	X		X	X	X		X
315
316	X	X	X	X	X	X	X	X	X	X	X	X
317	X	X	X	X		X		X		X		X
318	X			X		X			X	X		X
319	X		X	X		X	X	X	X	X	X	X
320	X	X		X		X	X	X	X	X	X	X
321	X	X	X	X	X	X	X	X	X	X		X
322	X	X	X	X		X	X	X	X	X	X	X
323	X		X	X	X	X	X	X	X	X	X	X
324				X
325
326								X				X
327							X			X		X
328				X			X					X
330	X	X	X		X	X	X	X	X	X	X	X
331		X		X		X	X	X		X	X
332		X		X		X	X	X		X	X
333		X		X		X	X	X		X	X
334		X	X		X	X		X				X
	R1
R2	7	8	13	17	19	21	25	33	43	28	29
302		X			X	X		X
303					X
304	X	X	X		X	X	X	X
305		X			X	X	X	X
306	X	X	X	X	X	X	X
307		X			X	X	X
308		X		X	X	X	X	X
309	X	X	X	X	X		X				X
310	X	X	X	X	X		X	X		X
311	X	X			X	X	X
312	X				X	X
313	X	X			X		X	X
314	X					X
315	X
316	X	X	X		X		X	X			X
317	X	X	X	X	X					X	X
318		X		X	X	X	X
319	X		X	X	X		X
320	X	X	X	X	X		X	X
321	X	X	X	X	X	X	X	X		X	X
322	X	X	X	X	X	X	X	X		X	X
323	X	X	X		X	X	X	X		X
324	X		X					X			X
325	X		X
326	X	X	X	X			X
327		X	X	X	X	X		X
328							X	X
330
331								X	X
332								X	X
333								X	X
334											X
	R1
	R2	9	10	11	14	39
	335					X
	336		X		X
	337	X		X	X	X
	338	X	X	X	X	X
	339	X	X	X	X	X
	340	X	X		X	X
	341	X	X	X	X	X
	342	X	X	X	X	X
	343
	344		X		X	X
	345	X				X
	346		X	X	X	X
	347	X	X	X	X	X
	348	X	X	X	X	X
	349		X			X
	350		X	X	X	X
	351		X	X	X	X
	352	X	X		X	X
	353
	354
	355	X	X		X	X
	356	X	X	X	X	X
	357		X
	358	X				X
	R1
	R2	40	42	31	34	35	30	29
	335	X		X			X
	336	X	X	X			X
	337	X	X	X			X
	338	X	X	X			X
	339	X	X	X	X		X
	340	X	X	X	X	X	X	X
	341		X	X	X		X
	342	X	X	X	X		X	X
	343	X	X	X		X	X
	344	X		X	X	X
	345	X	X	X	X		X
	346	X	X	X	X	X	X
	347	X	X	X	X	X	X
	348		X	X			X
	349	X		X	X	X	X
	350	X	X	X	X		X
	351	X		X	X		X	X
	352	X	X	X	X	X	X	X
	353	X					X
	354	X	X
	355	X	X	X	X	X	X	X
	356	X	X	X	X	X	X
	357		X				X
	358	X	X	X			X
	R1
	R2	9	10	11	14	39
	359	X	X	X	X	X
	360	X	X		X
	361		X	X	X	X
	362		X	X	X	X
	363					X
	364	X
	365	X	X	X	X
	366	X	X
	367		X	X	X
	368
	369	X	X	X		X
	370	X	X	X		X
	371	X	X	X		X
	372	X				X
	373	X	X	X		X
	374	X				X
	375	X	X	X		X
	376	X		X		X
	377	X				X
	378		X	X		X
	379		X	X		X
	380		X	X
	381
	382
	383
	R1
	R2	40	42	31	34	35	30	29
	359	X	X	X	X	X	X	X
	360			X			X
	361	X	X	X	X		X	X
	362	X		X	X		X	X
	363			X			X
	364
	365				X		X	X
	366				X
	367				X		X	X
	368		X
	369			X	X	X
	370			X	X	X
	371			X	X	X
	372			X	X	X
	373			X	X	X
	374			X	X	X
	375			X	X	X
	376					X
	377			X	X	X
	378			X	X	X
	379			X	X	X
	380			X		X
	381			X		X
	382					X
	383			X	X	X
	R1
R2	2	9	10	11	14	15	23	20
177	X	X		X	X	X	X	X
178	X	X	X	X	X	X	X	X
179	X	X	X	X	X	X	X	X
264
189	X	X	X	X	X	X	X
198	X	X	X	X	X	X	X
200	X	X			X		X
202	X	X	X	X	X		X
217	X	X	X	X	X	X	X
218	X	X	X	X	X	X	X
219	X	X	X	X	X	X	X
223	X	X	X	X	X	X	X
224	X	X	X	X	X	X	X
225	X	X	X	X	X	X	X
226	X	X	X	X	X	X	X
227	X	X	X	X	X	X	X
230	X	X	X	X	X	X	X
242	X	X	X	X	X	X	X
245	X	X	X	X	X	X	X
248	X	X	X	X	X	X	X
251	X	X	X	X	X	X	X
258	X	X	X	X	X	X	X
260	X	X	X	X	X	X	X
329
263
236	X	X	X	X	X	X	X
	R1
R2	22	27	38	39	40	41	42	31	32	34	35	36	37	30
177	X			X	X	X	X	X	X	X		X	X
178	X					X		X	X	X		X	X
179	X					X		X	X	X			X
264		X	X	X	X		X	X	X	X	X	X	X	X
189	X			X	X	X	X	X	X	X		X	X
198	X			X	X	X	X	X	X	X		X	X
200	X			X	X	X	X	X	X	X		X	X
202	X			X	X	X	X	X	X	X		X	X
217	X			X	X	X	X	X	X	X		X	X
218	X			X	X	X	X	X	X	X		X	X
219	X			X	X	X	X	X	X	X		X	X
223	X			X	X	X	X	X	X	X		X	X
224	X			X	X	X	X	X	X	X		X	X
225	X			X	X	X	X	X	X	X		X	X
226	X			X	X	X	X	X	X	X		X	X
227	X			X	X	X	X	X	X	X		X	X
230	X			X	X	X	X	X	X	X		X	X
242	X			X	X	X	X	X	X	X		X	X
245	X			X	X	X	X	X	X	X		X	X
248	X			X	X	X	X	X	X	X		X	X
251	X			X	X	X	X	X	X	X		X	X
258	X			X	X	X	X	X	X	X		X	X
260	X			X	X	X	X	X	X	X		X	X
329			X	X	X	X	X	X	X	X	X	X	X	X
263		X
236				X	X	X	X	X	X	X		X	X
	R1
	R2	44	45	47	49	50	51	52
	177
	178
	179
	264
	189	X	X	X			X
	198	X	X	X	X	X	X	X
	200	X	X	X	X	X	X	X
	202	X	X	X	X	X	X	X
	217	X	X	X			X
	218	X	X	X			X
	219	X	X	X			X
	223	X	X	X			X
	224	X	X	X			X
	225	X	X	X	X	X	X	X
	226	X	X	X	X	X	X	X
	227	X	X	X		X	X	X
	230	X	X	X	X	X	X	X
	242	X	X	X	X	X	X	X
	245	X	X	X	X		X	X
	248	X	X	X	X	X	X	X
	251	X	X	X	X	X	X	X
	258	X	X	X	X	X	X	X
	260	X	X	X	X	X	X	X
	329		X	X	X	X	X	X
	263	X	X	X	X	X	X	X
	236	X		X			X
	R1
R2	7	13	19	21	25	33	43	26
177		X	X		X	X	X
178	X	X	X	X	X	X	X	X
179	X	X	X	X	X	X		X
264
189	X	X	X	X	X	X	X	X
198	X	X	X	X	X	X	X	X
200				X		X
202	X	X	X	X	X		X	X
217	X	X	X		X	X	X	X
218	X	X	X	X	X	X	X	X
219	X	X	X	X			X	X
223	X		X	X	X	X	X	X
224	X	X	X	X	X	X	X	X
225	X	X	X	X	X	X	X	X
226	X	X	X	X	X	X	X	X
227	X		X	X	X	X	X	X
230	X	X	X	X	X	X	X	X
242	X	X	X	X	X	X	X	X
245	X	X	X	X	X	X	X	X
248	X	X	X	X	X	X	X	X
251	X	X	X	X	X	X	X	X
258	X	X	X	X	X	X	X	X
260	X	X	X	X	X	X	X	X
329
263
236		X	X	X	X	X		X
	R1
R2	22	44	45	47	49	50	51	52
384		X	X	X	X	X	X	X
385		X	X	X	X	X	X	X
386		X	X	X	X	X	X	X
387		X	X	X	X	X	X	X
388		X	X	X	X	X	X	X
389		X	X	X	X	X	X	X
390		X	X	X	X	X	X	X
391		X	X	X	X	X	X	X
392		X	X	X	X	X	X	X
393		X	X	X	X	X	X	X
394		X	X	X	X		X	X
395		X	X	X	X	X	X	X
396		X	X	X	X	X	X	X
397		X	X	X	X	X	X	X
398		X	X	X	X	X	X	X
399		X	X	X	X	X	X	X
400		X	X	X	X	X	X	X
401		X	X	X	X	X	X	X
402		X	X	X	X	X	X	X
403		X	X	X	X	X	X	X
404		X	X	X	X	X	X	X
405		X	X	X	X	X	X	X
406		X	X	X	X	X	X	X
407		X	X	X	X	X	X	X
408		X	X	X	X	X	X	X
409		X	X	X	X	X	X	X
410		X	X	X	X	X	X	X
411		X	X	X	X	X	X	X
412		X	X	X	X	X	X	X
413		X	X	X	X	X	X	X
414		X	X	X	X	X	X	X
415		X	X	X	X	X	X	X
416		X	X	X	X	X	X	X
417		X	X	X	X	X	X	X
418		X		X		X	X	X
419		X	X	X	X	X	X	X
420		X		X	X	X	X	X
421		X	X	X	X	X	X	X
422		X	X	X	X	X	X	X
423		X	X	X	X	X	X	X
424		X	X	X	X	X	X	X
425		X	X	X	X	X	X	X
426		X	X	X	X	X	X	X
427		X	X	X	X	X	X	X
428		X	X	X	X	X	X	X
429		X	X	X	X	X	X	X
430		X	X	X	X	X	X	X
431		X	X	X	X	X	X	X
432		X	X	X	X	X	X	X
434			X	X	X	X	X	X
437			X	X	X	X	X	X
433				X			X	X
435				X			X	X
436				X			X	X
438				X			X	X